Diagnostic Hipo-Statural

Official Journal of
ESPE European Society for Paediatric Endocrinology

SLEP
Sociedade Latino-Americana de
Endocrinologia Peditrica
HORMONE
RESEARCH
From Developmental Endocrinology to Clinical Research
Asia Pacific Pediatric Endocrine Society
Founded 1970 as Hormones by M. Marois

Continued by J. Girard (19761995); M.B. Ranke (19962003)
Editor-in-Chief
Editorial Board
P. Czernichow, Paris
I.J.P. Arnhold, So Paulo

W.F. Blum, Bad Homburg
J.-P. Bourguignon, Lige
F. Cassorla, Santiago
J.-P. Chanoine, Vancouver
M. Dattani, London
H. Delemarre-van de Waal,
Amsterdam
M. Donaldson, Glasgow
D.B. Dunger, Cambridge
L. Dunkel, Kuopio
U. Feldt-Rasmussen,
Copenhagen
M.G. Forest, Lyon
K. Fujieda, Asahikawa
Associate Editors
J.-C. Carel, Paris
P.E. Clayton, Manchester
W.S. Cutfield, Auckland
O. Hiort, Lbeck
P.E. Mullis, Bern
M.A. Rivarola, Buenos Aires
P. Saenger, Bronx, N.Y.
M.O. Savage, London
O. Sder, Stockholm
G. Van Vliet, Montreal
J.J. Heinrich, Buenos Aires

A.C. Hokken-Koelega,
Rotterdam
A. Hbner, Dresden
L. Ibaez, Barcelona
K.Y. Loke, Singapore
C.J. Migeon, Baltimore, Md.
J.P. Monson, London
M. Phillip, Petah Tiqwa
M. Polak, Paris
M.B. Ranke, Tbingen
R.G. Rosenfeld, Palo Alto, Calif.
S.M. Shalet, Manchester
T. Tanaka, Tokyo
R.J. Voutilainen, Kuopio
ESPE Council 20062007

President
R. Voutilainen, Kuopio
President-Elect
Atilla Bykgebiz, Istanbul
Secretary General
F. Chiarelli, Chieti
Chairman of Finance Committee
O. Sder, Stockholm
Chairman of Clinical Practice

Committee
S. Cianfarani, Rome
Chairman of Education and
Training Committee
S. Drop, Rotterdam
Chairman of Programme
Organising Committee
Z. Hochberg, Haifa
Chairman of Corporate Liaison
Board
C.J.H. Kelnar, Edinburgh
Member
J. Lger, Paris
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ISBN 9783805583343
ESPE
Classi f icat ion
of
Pae diat ric E ndoc rine
Diagnoses
Edited by
Jan M. Wit
Michael B. Ranke
Christopher J.H. Kelnar
With contributions by
Hans Akerblom
Albert Aynsley-Green
Giampiero Baroncelli
Jean-Pierre Bourguignon
Henriette A. Delemarre-Van de Waal
Malcolm Donaldson
Herwig Frisch
Annette Grters-Kieslich
Lars Hagens
Eberhard Heinze
Ieuan A. Hughes
Daniel Iliev
Brygida Koehler
Klaus Kruse
Agne Larsson
Jrn Mller
Stefan Riedl
Martin Ritzn
Tomas E. Romer
Werner Rosendahl
Giuseppe Saggese
Niels Skakkebaek
Yara Smit
Gyula Soltsz
J. M.W. was supported by a grant of the Sabbatical Leave Programme of the

European Society for Paediatric Endocrinology, supported by Eli Lilly & Co.
CO NTE NTS
Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
User Guide. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX
1
SHORT STATURE
1A
1B
1C
Precocious Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Single Variations of Normal Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Contrasexual Pubertal Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Delayed Puberty . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Menstrual Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
14
15
15
16
16
DISORDERS OF SEX DE VELOPMENT DSD

4A
4B
4C
4D
Primary Growth Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Secondary Growth Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Idiopathic (Normal Variant Tall Stature) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
DISORDERS OF PUBERT Y
3A
3B
3C
3D
3E
1
2
5
TALL STATURE
2A
2B
2C
Primary Growth Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Secondary Growth Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Idiopathic Short Stature. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sex Chromosome Disorders of Sex Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

46,XY Disorders of Sex Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
46,XX Disorders of Sex Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Unclassified Forms of Abnormal Sexual Development/Anatomical Disruptions. .
21
22
23
24
OVERWEIGHT AND OBESIT Y

5A
5B
5C
5D
5E
5F
Simple Obesity, Common Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Genetic Causes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endocrine Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Central Nervous System Causes (Central Obesity) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Obesity Accompanying Immobility, Mental Disturbances,
Social and Cultural Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Iatrogenic Obesity due to Medication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ESPE Classification of Paediatric Endocrine Diagnoses
27
27
28
28
28
29
IV
PITUITARY, HYPOTHAL AMUS, CENTR AL NERVOUS SYSTEM CNS

Section 1: Functional Classification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6A Deficiencies of Anterior Pituitary Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6B Overproduction of Anterior Pituitary Hormones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6C Central Diabetes Insipidus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
6D Hypothalamic Dysfunction, Not Classified Elsewhere. . . . . . . . . . . . . . . . . . . . . . . . . . .
31
31
33
33
33
Section 2: Aetiological Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

6E Congenital Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
6F Acquired Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
7
THYROID DISORDERS
7A
7B
7C
7D
7E
Primary Adrenal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Secondary Adrenal Insufficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Adrenal Excess. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Adrenal Medulla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
55
56
56
57
TESTICUL AR DISORDERS/DISORDERS OF MALE GENITALS

9A
9B
9C
9D
9E
9F
9G
9H
9Y
9Z
10
44
45
46
46
47
ADRENAL DISORDERS
8A
8B
8C
8D
Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hyperthyroidism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Goitre . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thyroid Tumours. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Thyroid Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hypergonadotrophic Hypogonadism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cryptorchidism/Maldescended Testes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acquired Testicular Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Tumours of Testes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Penis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Scrotal Disorders. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Epididymis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of Testicular Blood Vessels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Specified Disorders of the Male Genitalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Other Disorders of the Male Genitalia, Unspecified . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
63
64
64
65
65
66
66
66
66
66
OVARIES, FEMALE REPRODUC TIVE TR AC T AND BREASTS

10A
10B
10C
10D
Ovary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Uterus and Cervix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Vagina and External Female Genitalia . . . . . . . . . . . . . . . . . . . . . . . . .
Disorders of the Breast . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
68
69
70
71
11
DISORDERS OF GLUCOSE AND TRIGLYCERIDE ME TABOLISM

11A Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
11B Hypoglycaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
11C Primary Disturbances of Lipoprotein Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
12
DISORDERS OF BONE METABOLISM, INCLUDING C ALCIUM/

PHOSPHATE ME TABOLISM
12A
12B
12C
12D
12E
13
Transient Hypocalcaemia (Neonatal). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Permanent Hypocalcaemia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Rickets . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Hypercalcaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
87
87
89
90
90
DISORDERS OF WATER BAL ANCE

13A Disorders Characterized by Polydipsia and Polyuria . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
13B Disorders Characterized by Hypernatraemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
13C Disorders Characterized by Hyponatraemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
14
SYNDROMES WITH ENDOCRINE FEATURES

14A Chromosomal Abnormalities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
14B Congenital Dysmorphic Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
14C Non-Dysmorphic Syndromes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
VI
FO R EWO R D
The ESPE Classification of Paediatric Endocrine Diagnoses
One of the cornerstones of medical practice is getting the diagnosis correct. After a diagnosis is made, clinicians usually like to store the information about the diagnoses of
individual patients in their les and registries. This can then improve patient care, because it makes information about the natural history and treatment responses available
of patients that had been seen in the past. It can also be helpful for scientic research, for
example in collecting data on patient groups.
Until now, no list of paediatric endocrine diagnoses has been available. Current diagnostic classications for the whole eld of medicine lack the detail that is requested by the
subspecialist. In some countries, a specic diagnostic classication for paediatrics is available, but even that lacks the necessary detail. This was the main reason which prompted
us to produce the ESPE Classication of Paediatric Endocrine Diagnoses that forms the
body of this publication.
We believe that a classication of diagnoses is an important tool in achieving optimal
communication between paediatric endocrinologists, as it enables physicians around
the world to speak the same language. In designing a formal coding system, the following requirements should be considered: (1) it should allow classication of all patients in
question; (2) there should be room for accommodating new aetiologies and pathogenetic aspects; (3) the diagnoses listed should be well dened, making misclassications
virtually impossible; (4) the classications should follow one general principle (e.g. nosology, aetiology, pathogenesis or symptomatology); (5) it should be easy to use, and (6) it
should optimally serve the purpose for which it was designed. As each diagnosis can be
classied according to dierent aspects, for example function or anatomy, our choices
are to some extent subjective. However, we have tried to follow the logic of the paediatric endocrine clinician as much as possible, so that it would be as easy as possible to nd
the diagnosis in the structure of each chapter. We have extensively made use of the lists
of causes of disorders as presented in various (paediatric) endocrine textbooks.
This list of preconditions makes it obvious that no system for the classication of diseases
can be perfect. The authors have attempted to develop a system of diagnoses in paediatric endocrinology that serves both scientic and practical requirements. In addition to
establishing a coding system, a glossary of the most important disorders has been appended, in the form of endnotes, for the purpose of clarication and unequivocal description. Nevertheless, in areas where we are still ignorant about aetiology, any classication
will be, to an extent, arbitrary (for example idiopathic short/tall stature, familial, normal
variant). The reader should, therefore, keep in mind that in some situations a classication which is still necessarily descriptive can, if used uncritically, obscure rather than il-
VII
luminate understanding. In addition, when thinking about biological systems, there is

no law of nature which says boundaries have to be clear cut [1]. Keeping in mind, therefore, the fact that our understanding of endocrinological diseases is developing rapidly,
we have left room for additions and modications in this classication system. We have
added the codes for the ICD-10 classication, so that the ESPE Classication can be relatively easily incorporated into a hospital registry. In addition, where applicable, OMIM
codes are given for further and updated information about the various syndromes that
have endocrine elements.
The editors thank all the collaborators for their valuable contributions and hope that this
classication will serve the paediatric endocrine community well.
March 2007
Reference
1
Dawkins R: Gaps in the Mind; in: A Devils Chaplain Selected Essays. London, Weidenfeld & Nicolson, 2003.
VIII
USE R GU I D E
In the preparation of this classication we have used several strategies and rules. In the
following paragraphs these are explained for the purpose of easy use.
1
The diagnostic classication is built as a tree structure, with generally up to 5 levels (rarely
going up to 6 levels). We have chosen a system of LETTERS-numbers-letters-numbers-letters(-numbers), which is easier to use than a system only consisting of numbers. The rst
number used is 1, except for the box with Disorders classied elsewhere, which gets a 0.
The rst letter is a, also for boxes with Disorders classied elsewhere.
Each diagnosis has a main site (indicated as [primary]) and can have one or more secondary sites (indicated as [secondary]). Additional information, including the footnotes,
ICD-10 codes, and OMIM codes, is only given at the primary site of classication. If the disorder is also coded in other chapters, or other segments of the same chapter, this is mentioned at the beginning of the pertinent section, under the heading: Disorders classied
elsewhere (coded as 0 or a). The diagnoses that are classied elsewhere are indicated in
italics.
Where applicable, it is indicated which diagnosis is not included in the pertinent section.
This is written as: Excluded:, followed by the diagnoses that are excluded.
Where applicable, the lists of diagnoses under a certain group end with a section called
other specied disorders (labelled as 8, 88, or y) and a section called other disorders,
unspecied (labelled as 9, 99, or z). These serve to code conditions that cannot be found
in the current classication.
With respect to spelling, we have followed the British English spelling. We have used no
s to add to the names of the discoverers of the syndromes (e.g. Turner syndrome instead
of Turners syndrome), but the s has been used for the names of Diseases (e.g. Addisons
disease).
Suggestions for coding are printed in italics.
Explanatory texts are given in the form of footnotes, and have been limited to 3 short
sections: synonyms; phenotype, including concise information about symptoms, signs,
laboratory investigations, radiology, and other further investigations, and comments. In
some instances a reference is added.
Hormonal ndings are indicated in an abbreviated form. First, hormones are abbreviated
in their usual fashion (see list of abbreviations). Second, increased is indicated as +, decreased as , and normal as N, printed immediately behind the abbreviated hormone
(e.g. T (+) means increased testosterone concentration).
If a child has a disorder that expresses itself in dierent endocrine systems, we advise to
classify the condition according to various systems. This also applies to the codes given
to Classied elsewhere. So, the short, obese, hypogonadic and diabetic child with Prader-Willi-Labhart syndrome may be coded 14B.25 (primary), 1A.1a (short), 5B.2a (obesity), 6A.3d (hypogonadotrophic hypogonadism) and 11A.3h.10 (diabetes mellitus).
IX
ESPE Code
Diagnosis
S H O R T STATU R E 1
1A
PR I M ARY G R OW T H FAI LU R E
1A.1
Clinically defined syndromes

Syndromes classified elsewhere:
45,X/46,XY disorder of sex development (4A.1)
45,X and variants with female phenotype ((Ulrich)-Turner
syndrome) (14A.5)
Phenotypic male with X/XY mosaicism (14A.4)
18q deletion syndrome (14A.1)
Aarskog-Scott syndrome (14B.1)
Bloom syndrome (14B.6)
Cornelia de Lange syndrome (14B.9)
DiGeorge syndrome (velocardiofacial syndrome) (14B.10)
Down syndrome (14A.2)
Kabuki makeup syndrome (14C.4f)
Noonan syndrome (14B.24)
Prader-Willi-Labhart syndrome (14B.25)
Von Recklinghausens disease (neurofibromatosis type 1) (14B.27)
Rubinstein-Taybi syndrome (14B.29)
Silver-Russell syndrome (14B.31)
Williams-Beuren syndrome (14B.37)
Other specified syndromes, e.g. Three M slender-boned
dwarfism, Seckel syndrome, Mulibrey nanism
Other syndromes associated with short stature, unspecified
1A.1a
1A.1y
1A.1z
1A.2
1A.2a
1A.2y
1A.2z
1A.3
1A.3a
1A.3a.1
1A.3a.2
OMIM
ICD-10
Small for gestational age (SGA) with failure of catch-up

growth2
Disorders classified elsewhere:
IGF-I deficiency (1B.4e)
IGF resistance (1B.4f)
Due to known cause (specify), e.g. prenatal infection, drugs,
smoking, alcohol
Idiopathic
P05.1
Skeletal dysplasias (constitutional disorders of bone)3

Achondroplasia group (group 1)4
Achondroplasia
Hypochondroplasia
Q77, Q78
Short Stature
P00.24
#100800
#146000
ESPE Code
Diagnosis
1A.3a.8
Other specified disorders included in this group (thanatophoric

dysplasia, SADDAN)
Type II collagenopathies (COL2A1 defects) (group 8)
Spondyloepiphyseal dysplasia congenita
Other specified disorders in this group
Mesomelic dysplasias (group 16)
Dyschondrosteosis (Leri-Weill and other defects in the SHOX
gene, e.g. in children without dysmorphic features)
[primary: 14B.19]
Langer type (homozygous dyschondrosteosis)
Other specified disorders included in this group
Dysostosis multiplex group (group 22)
Mucopolysaccharidosis (type IH, IS, IIVII)
Mucolipidosis (type II and III)
1A.3b
1A.3b.1
1A.3b.8
1A.3c
1A.3c.1
1A.3c.2
1A.3c.8
1A.3d
1A.3d.1
1A.3d.2
OMIM
ICD-10
#183900
#127300
#249700
E76
#252500
E77.0
#252600
1A.3z

Dysplasias with decreased bone density (group 24)
Osteogenesis imperfecta IVI [primary: 12D.1b]
Dysplasias with defective mineralisation (group 25)
Hypophosphatasia
Hypophosphataemic rickets [primary 12C.2]
Disorders included in other groups (27, 915, 1721, 23, 2633)
Other skeletal dysplasia, unspecified
1B
S E CO N DARY G R OW T H FAI LU R E
1B.1
Insufficient nutrient intake (malnutrition)
E4046
1B.2
Disorders in organ systems

Cardiac disorders
Pulmonary disorders, e.g. cystic fibrosis
Q2028
J4099
1A.3d.8
1A.3e
1A.3e.1
1A.3e.8
1A.3f
1A.3f.1
1A.3f.2
1A.3f.8
1A.3y
1B.2a
1B.2b
#241500
#307800
(E84)
1B.2c
1B.2d
1B.2e
Liver disorders
Intestinal disorders, e.g. Crohns disease, malabsorption
syndromes, short bowel syndrome
Renal disorders, e.g. Fanconi syndrome, renal acidosis
K7077
K5052
K9093
N1019
N2529
1B.2f
1B.2g
Chronic anaemia
Multiorgan disorders
D5064
ESPE Code
Diagnosis
OMIM
1B.2h
Muscular and neurological disorders, e.g. Duchenne muscular

dystrophy, congenital myotonia
Connective tissue diseases, e.g. juvenile arthritis
Other specified organ or systemic disorders
G7173
1B.2i
1B.2y
1B.3
1B.3a
1B.3a.0
1B.3a.1
1B.3a.2
1B.3a.2a
1B.3a.2b
1B.3a.2c
1B.3a.2d
1B.3a.2e
1B.3a.2f
1B.3a.2g
1B.3a.2y
1B.3a.3
1B.3a.4
1B.3a.8
1B.3a.9
1B.3a.9a
1B.3a.9b
Growth hormone deficiency (secondary IGF deficiency)5

In case of multiple pituitary deficiencies, classify the various
deficiencies separately:
ACTH deficiency (6A.1)
TSH deficiency (6A.2)
Gonadotropin deficiency (6A.3)
Prolactin deficiency (6A.4)
Vasopressin deficiency (diabetes insipidus) (13A.1)
Congenital growth hormone deficiency
Associated with complex syndromes: Fanconi renotubular
syndrome (14B.13)
Rieger syndrome (14B.28)
Kabuki make-up syndrome (14C.4f)
Associated with other complex syndromes:
ectodactyly-ectodermal dysplasia clefting syndrome
Known genetic defects
HESX1
LHX3
LHX4
PROP1
POU1F1
GHRHR
GH
Other specified genetic defects
Associated with cerebral or facial malformations, e.g. septooptic dysplasia [primary 6E.1a], empty sella syndrome, solitary
central maxillary incisor syndrome, mid-line palateal cleft,
arachnoid cyst, congenital hydrocephalus, hypoplastic anterior
pituitary + missing stalk + ectopic posterior pituitary (HME)
Excluded:
Known genetic defects (1B.3a.2)
Associated with prenatal infection, e.g. rubella
Associated with other specified disorders
Idiopathic
Classical idiopathic growth hormone deficiency6
Neurosecretory dysfunction7
Short Stature
ICD-10
M08
E23.0
E23.0
E23.0
E23.0
*601802
*600577
*602146
*601538
+173110
*139191
+139250
Q04.4
Q37.9
O35.0
P35.0
E23.0
E23.0
ESPE Code
Diagnosis
1B.3b
Acquired growth hormone deficiency

Craniopharyngioma
Other pituitary tumours, e.g. germinoma, hamartoma
Cranial tumours distant from the pituitary/hypothalamic area,
e.g. astrocytoma, ependymoma, glioma, medulloblastoma,
nasopharyngeal tumour
1B.3b.1
1B.3b.2
1B.3b.3
OMIM
ICD-10
E23.0
D44.4
M9064/3
C71
M9400/3
M9391/3
M9380/3
M9470/3
IB.3b.4
IB.3b.5
IB.3b.6
IB.3b.7
IB.3b.8
IB.3b.9
1B.4
1B.4a
1B.4b
1B.4c
1B.4d
1B.4e
1B.4f
1B.4z
1B.5
1B.5a
1B.5b
1B.5y
1B.6
1B.6a
1B.6b
1B.6c
Tumours outside the cranium, e.g. leukaemia, lymphoma

Head trauma
Central nervous system infection
Granulomatous diseases, e.g. histiocytosis
Vascular anomaly
Other causes, unspecified
Other disorders of the growth hormone-IGF axis
(primary IGF-I deficiency and resistance)
Bio-inactive growth hormone (Kowarski syndrome)8
Abnormalities of the growth hormone receptor
(growth hormone insensitivity syndrome, Laron syndrome)
Abnormalities of GH signal transduction, e.g. STAT5B defect
ALS (acid-labile subunit) deficiency
IGF-I deficiency
IGF resistance (IGF1R defects, postreceptor defects)
Other disorders, unspecified
Other endocrine disorders
Cushing syndrome (8C.1)
Hypothyroidism (7A)
Leprechaunism (11A.3b.2)
Poorly controlled diabetes mellitus, Mauriac syndrome (14C.2)
Short adult stature caused by accelerated bone maturation,
e.g. precocious puberty (3A), hyperthyroidism (7B), congenital
adrenal hyperplasia (8A.1), exogenous estrogens or androgens
(3A.2d)
Other specified disorders
Metabolic disorders
Disorders of calcium and phosphorus metabolism (1A.3 and 12)
Disorders of carbohydrate metabolism
Disorders of lipid metabolism
C9196
S06
G0108
D76
Q28
E23.0
#262650
E34.3
#262500
E34.3
#245590
E34.3
+601489
E34.3
#608747
E34.3
#270450
E34.3
E34.3
E74
E75
ESPE Code
Diagnosis
1B.6d
Disorders of protein metabolism

Other specified metabolic disorders
Other metabolic disorders, unspecified
E7072
Psychosocial
Psychosocial (emotional) deprivation9
Anorexia nervosa
Depression
Other specified psychosocial causes
E34.3
1B.6y
1B.6z
1B.7
1B.7a
1B.7b
1B.7c
1B.7y
OMIM
ICD-10
E7683
E88
T74
F50
F32.9
E34.3
1B.8y
Iatrogenic
Systemic glucocorticoid therapy [primary 8C.1c]
Local glucocorticoid therapy (inhalation, intestinal, other)
Other medication
Treatment of childhood malignancy
Total body irradiation
Chemotherapy
Other specified iatrogenic causes
1C
I D I O P AT H I C S H O R T S T AT U R E 10
E34.3
1C.1
Familial (idiopathic) short stature11

With normal pubertal onset
With delayed pubertal onset
Onset of puberty not yet known12
Onset of puberty unknown
E34.3
Non-familial (idiopathic) short stature13

With normal pubertal onset
With delayed pubertal onset (constitutional delay in growth and
puberty, or constitutional delay in growth and adolescence)
Onset of puberty not yet known14
Onset of puberty unknown
E34.3
1B.8
1B.8a
1B.8b
1B.8c
1B.8d
1B.8d.1
1B.8d.2
1C.1a
1C.1b
1C.1c
1C.1d
1C.2
1C.2a
1C.2b
1C.2c
1C.2d
Short Stature
T38.0
T49.0
T3650
T66
T45.1
T78.9
Short stature
Comments: Short stature is dened as a height below 2.0 SDS (2.3rd percentile) for a given age, sex
and population. It is the result of impaired bone growth in the foregoing period, which is expressed
in terms of a reduced length/height velocity in at least some period of life (including the intrauterine
period). In some conditions growth velocity is only diminished early in life (e.g. in children born SGA
with failure of catch-up growth), in other conditions growth velocity is continuously low (e.g. in children with complete growth hormone deciency). The terms growth delay and growth retardation
are also frequently used with the same intention as short stature. In this diagnostic classication an
abnormally low height velocity is also classied under the general heading of Short stature.
The causes of short stature are varied and dier with respect to aetiology and pathogenesis. To our
present knowledge, disorders of the hormonal system account only for a minority of children with
short stature. Since growth disorders are the key symptom of many hormonal abnormalities and
since children with growth disorders are commonly presented to the paediatric endocrinologist,
disorders presenting with short/tall stature are part of this classication system.
2 Small for gestational age (SGA) with failure of catch-up growth
Phenotype: Short stature and birth length and/or weight below 2 SDS (or below the 2.3rd centile)
for gestational age for the reference population.
Comments: There is some discussion about the use of the terms intrauterine growth retardation
(IUGR) and small for gestational age (SGA). There appears now some consensus that the term IUGR
implies impaired fetal growth and should be considered a prenatal diagnosis. SGA describes birth
length and/or weight in relation to gestational age and is a post-partum diagnosis. The majority of
babies born SGA (approximately 85%) catch up in height (within 23 years) and will not be short in
childhood or in adulthood, although their mean height is somewhat lower than expected for target
height. The 15% of babies who do not catch-up (height < 2 SDS after 2 or 3 years) are termed SGA
with failure to catch-up, or shortly SGA. Those who failed to catch-up by 2 years are at high risk of
remaining short in later life. Thus, the term SGA is purely descriptive, and is a working diagnosis for
children born small and continuing to be short. In most cases there is no known aetiology and/or
pathogenesis.
3 Skeletal dysplasias (constitutional disorders of bone)
Comments: Skeletal dysplasias exist in a great variety and are commonly associated with short
stature. Traditionally, the diagnosis was established based on the clinical appearance during development and conventional X-ray ndings. More recently, the classication of skeletal dysplasias
has been based upon the expanding understanding of the pathophysiology of bone development
and the discovery of the underlying molecular genetic defects. This has resulted in an International
nomenclature and classication of osteochondrodysplasias (1997) published by the International
Working Group on Constitutional Diseases of Bone [Am J Med Genet 1998;79:376382] and a more
recent update [Hall CM: International nosology and classication of constitutional disorders of bone
(2001). Am J Med Genet 2002;113:6577]. In this classication 33 groups are presented, each including various clinical entities.
For the ESPE Classication of Paediatric Endocrine Diagnoses just 6 groups out of the 33 are mentioned specically. For a more detailed classication we refer to the most recent paper on International Nosology and Classication.
4 Achondroplasia, hypochondroplasia
Phenotype: Achondroplasia and hypochondroplasia are disorders characterised by disproportionate short stature with rhizomelic limb shortening. They are commonly caused by mutations in the
tyrosine kinase domain of the broblast growth factor receptor 3 (FGFR3) gene. However, in the
absence of these mutations the diagnosis may still be conrmed by typical radiological ndings.
5 Growth hormone deciency (GHD)
Synonym (if combined with other deciencies): Hypothalamo-hypopituitarism, multiple congenital

pituitary hormone deciency.
Phenotype: Growth retardation, retarded bone age, hypoglycaemia, truncal obesity, symptoms of
neonatal hypoglycaemia and those of associated anomalies, e.g. midline defects, micropenis.
Comments: An impaired secretion of GH in children is causally associated with impaired growth,
changes of the anthropometrical characteristics (e.g. normal proportions, relatively large head) and
the composition of the body (e.g. sarcopenia, excess of body fat) as well as functional abnormalities (e.g. hypoglycaemia). Classications based on functional investigations of GH secretion and
action have allowed some degree of understanding of the role of the various components of the
GH-IGF-I axis. Functional investigations include measurements of GH by means of various assays
(immunoassays, bioassays), determination of GH levels after various exogenous stimuli, the analysis
of spontaneously secreted GH, measurements of GH dependent factors (IGF-I, IGFBP-3; ALS), and
the biochemical response to exogenous GH (e.g. IGF generation). In addition to the diculty of conducting such functional tests, the limitations of standardisation and the lack of normative data has
hindered a concise interpretation of the obtained data and their interplay until today. New imaging
tools (CT, MRT) allow the description of qualitative and quantitative anatomical anomalies of the
pituitary region. A higher resolution and functional imaging is likely to lead to a further dimension
in describing more subtle abnormalities. Discoveries by means of molecular genetics allow the description of abnormalities in the development of the pituitary and its ability to produce and secrete
GH and other trophic hormones. Classications systems of GHD may also consider whether GHD is
congenital and follows a certain pattern of inheritance or whether it is acquired.
6
Classical Idiopathic GHD

Comments: Idiopathic GHD (i.e. no aetiology is established) is still the most common form of GHD.
It appears trivial, but nevertheless important to note that every reasonable eort should be made
to exclude diagnoses other than GHD beforehand. The key diagnostic tools to establish the diagnosis are blood GH measurements collected under spontaneous conditions or after physiological or
pharmacological stimuli (e.g. arginine). In order to avoid falsely positive results these tests should be
conducted under strict standardisation and under the least stressful conditions for the child. Since it
is assumed that test results are prone to be falsely low, at least two independent tests are required to
conrm the diagnosis. A cut-o level of 20 mU/l (equivalent to 10, 7.7 or 6.7 g/l, depending on the
standard used; 1 mg = 2, 2.6 or 3 IU) for GH in serum or plasma is generally accepted as a guideline.
This cut-o may, however, vary according to the applied GH assay, the test procedures used and the
normative references available. It is obvious that all available methods should be applied to increase
the likelihood of the diagnosis of GHD. Normal stature, a normal height velocity and a normal bone
age are probably not completely excluding the diagnosis of idiopathic GHD, but make its presence
quite unlikely. Likewise normal/high-normal IGF-I (IGFBP-3, ALS) levels are also not supportive of the
diagnosis. An MRI of the pituitary area is an essential part of the diagnostic process of GHD. A small
Short Stature
anterior pituitary or a pituitary abnormality are not an a priori proof of a disturbed GH secretion, but
are likely to provide evidence that the biochemically established diagnosis of GHD is correct. With
greater renement in our diagnostic arsenal less cases with GHD will be classied idiopathic.
7 Neurosecretory dysfunction (NSD)
Comments: The term NSD describes a specic situation, in which GH levels observed during stimulation tests are normal, but spontaneously secreted GH is low. This situation was rst described in
children who had been treated with radiotherapy to the cranium as part of treatment for a malignancy. In this situation NSD can be seen as a special form of organic GHD. However, this situation
was also found to exist in children without such a history. Critics have emphasised that there is
a great day-to-day variation in spontaneous GH secretion, and that spontaneous GH secretion is
sometimes very low in normally growing children.
8 Bioinactive GH (Kowarski syndrome)
Comments: Bioinactive GH can be suspected in children clinically resembling classical GH, with low
circulating IGF-I levels but with normal GH secretion based on immunoassay measurements. Treatment with GH leads to an increase in IGF-I levels and a growth response to GH. It can be assumed
that one reason for bioinactive GH is a congenital structural abnormality of GH, which impairs/abolishes interaction with the GH receptor and subsequent signal transduction. Sophisticated methods
(e.g. RRA, bioassay, gene analyses) are required to prove such an entity. Up to 2006, only a few welldocumented cases have been published.
9
Psychosocial deprivation
Synonym: Emotional deprivation.
Phenotype: Behavioural abnormalities, such as apathy, watchfulness, autoerotic activity, delayed
developmental behaviour. Poor growth at home, catch-up growth in hospital or foster home. Reversible GH deciency has been described.
10
Idiopathic short stature (ISS)

Comments: The denition of ISS (previously also called normal variant short stature, or non-GH-decient short stature) is based on the exclusion of other likely causes of short stature, as well as the
following minimal criteria:
normal size at birth (> 2 SDS) for gestational age
normal body proportions
no evidence of chronic organic disease
no psychiatric disorder or severe emotional disturbance
normal food intake
no evidence of endocrine deficiency.
The tempo of growth throughout the growth process may either be slow or normal.
Reference: Ranke MB: Horm Res 1996;45:6466.
11
Familial (idiopathic) short stature (FSS)

Phenotype: Height for chronological age is below the 2.3rd centile (< 2 SDS) for given age, sex and
population, and height is within the normal range for parental height. The parent-specic lower
limit of height (SDS) can be calculated in various ways.
References: Preece MA: Horm Res 1996;45:5658; Ranke MB: Horm Res 1996;45:6466; Hermanussen M, Cole J: Horm Res 2003;59:180183; Wit JM: Horm Res 2007;67(suppl 1):5057.
12 Familial short stature, onset of puberty not yet known
Comments: A short prepubertal child who is not short for target height with an age below the
upper limit of the normal age at pubertal onset is classied here. In some cases, a positive family
history for pubertal delay and a delayed bone age suggest the syndrome of constitutional delay in
growth and adolescence, although in typical cases height in childhood is lower than expected for
target height. As soon as the onset of puberty (G2 or B2) is known, the patient can be classied as
1C.1a or 1C.1b.
13
Non-familial (idiopathic) short stature (NFSS)

Phenotype: Height for chronological age is below the 2.3rd centile (< 2 SDS) for given age, sex and
population and height is below the normal range for parental height.
Comments: Non-familial short stature (NFSS) is a purely descriptive term. The majority of children
with NFSS have a condition usually labelled as constitutional delay in growth and adolescence
(CDGA) or small/delay. In CDGA short stature is combined with a retardation of the tempo of growth.
When signs of puberty are delayed beyond the normal age range, CDGA can be diagnosed. Before
pubertal age, a delay in bone maturity may be suggestive for CDGA, but strictly speaking CDGA can
only be diagnosed if puberty is indeed delayed. In these cases the diagnosis NFSS with pubertal
onset not yet known is more appropriate.
14
Non-familial idiopathic short stature, onset of puberty not yet known

A short prepubertal child who is short for parental height with an age below the upper limit of the
normal age at pubertal onset is classied here. In some cases, a positive family history for pubertal
delay and a delayed bone age suggest the syndrome of constitutional delay in growth and adolescence. As soon as the onset of puberty (G2 or B2) is known, the patient can be classied as 1C.2a or
1C.2b.
Short Stature
ESPE Code Diagnosis
TALL STATU R E
2A
PR I MARY G ROW TH D ISO R D E R S1
2A.1
Clinically defined (dysmorphic) syndromes with sex

chromosome abnormality including aneuploidy
47,XXY (Klinefelter syndrome) [primary 14A.3]
47,XYY syndrome [primary 14A.6]
Fragile X syndrome [primary 14B.14; secondary 2A.3a]
47,XXX syndrome2
Other specified X and Y chromosome aneuploidy syndromes3
2A.1a
2A.1b
2A.1y
OMIM
ICD10
Q97.0
Q97.1
Q97.8
Q98.8
2A.1z
Other syndromes, unspecified
2A.2
Dysmorphic syndromes due to metabolic/connective

tissue abnormality
Marfan syndrome (14B.20)
Marfan-like syndrome, not genetically confirmed
Homocystinuria4
Total lipodystrophy
(Berardinelli (generalised) lipodystrophy syndrome)
[primary 11A.3b.5]
Other specified syndromes
Q97.9
Q98.9
2A.2a
2A.2b
2A.2c
2A.2d
2A.2y
2A.2z
2A.3
2A.3a
2A.3y
2A.3z
Other dysmorphic syndromes with symmetrical overgrowth

Bannayan-Riley-Ruvalcaba syndrome (14B.4)
Elejalde syndrome (14B.12)
Fragile X syndrome (14B.14)
Marshall-Smith syndrome (14B.21)
Nevo syndrome (14B.23)
Simpson-Golabi-Behmel syndrome (14B.32)
Sotos syndrome (14B.34)
Weaver syndrome (14B.36)
#154700
Q87.4
#154705
E72.1
#236250
E72.1
#236250
E88.1
Q87.3
10
ESPE Code Diagnosis
2A.4z
Dysmorphic syndromes with partial/asymmetrical

overgrowth
Beckwith-Wiedemann syndrome (14B.5)
Klippel-Trenaunay-Weber syndrome (14B.17)
Proteus syndrome (14B.26)
2B
SECONDARY GROW TH DISORDERS5
2B.1
2B.1c
Growth hormone overproduction

GH-producing adenoma (solitary) [primary] [secondary 6B.0]6
GH-producing adenoma, as part of McCune-Albright syndrome
or MEN1 syndrome
GHRH excess7
2B.2
Hyperinsulinism
2B.2a
Primary
Transient hyperinsulinism (11B.1a)
Congenital hyperinsulinism (11B.1b)
Secondary
simple obesity (5A)
Obesity with acanthosis nigricans 8 hyperlipidaemia and
sexual precocity
2A.4
2A.4a
2A.4y
2B.1a
2B.1b
OMIM
ICD10
Q87.3
E22.0
#102200
#174800
Q78.1
+131100
E22.0
E15.0,
E16.1
2B.2a.1
2B.2a.9
2B.2b
2B.2b.1
2B.2b.2
2B.2b.9
2B.3
Familial (isolated) glucocorticoid deficiency (ACTH

insensitivity, hereditary unresponsiveness to ACTH)
[primary 8A.2d]
2B.4
Hyperthyroidism8
2B.5
Conditions leading to tall stature in childhood, and normal

or short stature in adulthood
Tall Stature
L83
E16.1
#202200
E05
11
ESPE Code Diagnosis
2B.5a
2B.5y
2B.6y
2C
I D I O P AT H I C ( N O R M A L V A R I A N T T A L L S T AT U R E ) 9
2C.1
Genetic (familial, or constitutional) tall stature10
2C.2
Non-familial idiopathic tall stature
2B.6a
2B.6b
2B.6c
ICD10
+107910
E34.9
+133430
E34.9
Diagnoses classified elsewhere:

Precocious puberty (3A)
Exogenous estrogens or androgens (3A.2d)
Hyperthyroidism (7B)
Congenital adrenal hyperplasia (8A.1)
Other specified conditions
Conditions leading to normal height in childhood, and tall
stature in adulthood
Disorder classified elsewhere:
Gonadotrophin deficiency (long limbs and hypogonadism) (6A.3)
Aromatase deficiency
Estrogen receptor dysfunction
2B.6
OMIM
E34.4
Primary growth disorders

Causes of tall stature and causes of short stature are subclassified into three groups: primary, secondary and idiopathic. Some clinicians prefer the term dysmorphic syndromes with overgrowth
instead of primary growth disorders.
2 47,XXX syndrome (Triple X syndrome)
Phenotype: Tall stature. Increased risk of variable degree of behavioural difficulties and learning
disability. Delayed menarche, and premature ovarian failure in some patients. Increased incidence
of other congenital anomalies. Ovarian function usually normal but primary ovarian impairment
seen in some individuals.
Comments: Increased risk of sex chromosome anomaly in child of 47,XXX female, therefore prenatal genetic counselling important. 48,XXXX females are tall with learning disability, radioulnar synostosis, and often incomplete puberty.
3
Other X and Y chromosome aneuploidy syndromes (48,XXXY, 48,XXYY, 49,XXXXY,

49,XXXYY)
Phenotype: Phenotype similar to Klinefelter syndrome but with more marked cognitive impairment, more severe hypogonadism, and additional features (e.g. radioulnar synostosis in 48,XXXY
and 49,XXXYY). Often associated with hypergonadotrophic hypogonadism.
12
4 Homocystinuria
Phenotype: Tall stature with marfanoid habitus and osteoporosis. Learning disability common. Medial degeneration of aorta with frequent arterial and venous thromboses. Myopia and downward
subluxation of lens. Homocystine and methionine accumulation interfere in collagen formation
resulting in lens and skeletal changes, and platelet thrombosis causing vascular occlusion.
5
Secondary growth disorders

Comments: Some clinicians may favour the term tall stature caused by hormone diseases.
6 Growth hormone overproduction, growth hormone producing adenoma (pituitary
gigantism)
Phenotype: Inappropriately tall stature for parental heights. Enhanced height velocity. May have
headache, visual symptoms (e.g. field defect, optic nerve pallor). Elevated GH levels with failure to
suppress below 5 mU/l following oral glucose load. Abnormal overnight GH profile with loss of normal pulsatility, and failure to return to baseline. Enhanced prolactin response to TRH. May show LH,
FSH, ACTH and TSH deficiency if there is a mass effect from the adenoma.
Comments: Can be associated with McCune-Albright syndrome or MEN type 1.
7
GHRH excess (GHRH-producing tumour)

Phenotype: Tall stature/gigantism. Suprasellar/hypothalamic tumour; secondary enlargement of
pituitary. No suprasellar/hypothalamic lesion detectable in some cases. GHRH levels raised.
Hyperthyroidism
Comment: Juvenile hyperthyroidism can lead to tall adult stature, but in most cases adult height is
within the normal range.
9 Idiopathic tall stature
Comments: The term idiopathic tall stature is used for consistency with the classification of short
stature. Some clinicians may favour other terms (e.g. normal variant tall stature), and subclassify
children in this category in various ways, e.g. normal genetic tall stature, constitutional advance in
growth and adolescence. We prefer the term idiopathic as, even if a condition is familial, its cause
is unknown.
10
Genetic tall stature (familial tall stature, constitutional tall stature)

Phenotype: Height SDS > +2.0 and height SDS within target range (for definitions, see under familial short stature). Usually there is no significant bone age advancement.
Comments: Tall child of tall parents, destined to be a tall adult. Height prediction helpful from 10
years in girls and 11 years in boys. NB: Very tall stature in one parent may reflect a dominant disorder
(e.g. Marfan syndrome).
Tall Stature
13
ESPE Code Diagnosis
OMIM
ICD 10
D I SO R D E R S O F PU B E R T Y
3A
P R E C O C I O U S P U B E R T Y1
E30.1
3A.1
Central precocious puberty2

Due to disorder classified elsewhere:
Congenital CNS malformations (6E.1)
Acquired CNS disorders (6F), e.g. cerebral tumours, hydrocephalus,
post infection, post trauma, post cranial irradiation,
neurofibromatosis3
Secondary to peripheral precocity
Hypothalamic hamartoma4
Other specified non-CNS disorders
Idiopathic5 (including associated with migration from developing
countries)
E22.8
3A.2
Peripheral precocious puberty6
E30.1 (R)
3A.2a

Virilising and feminising adrenal tumours (8C.2)
Leydig cell tumour of the testis (9D.2a)
Germ cell tumour of the ovary (10E.4a)
Granulosa tumour of the ovary (10E.4b.1)
Aromatase deficiency in females (4C.2a)
Gonadotrophin secreting tumours7
CNS tumours, e.g. germ cell tumours
Other tumours, e.g. choriocarcinoma, hepatoblastoma, or germ
cell tumours in the mediastinum
Autonomous gonadal function
McCune-Albright Syndrome (14B.22)
Autonomous ovarian follicular cyst
Familial testotoxicosis8
Aromatase deficiency in males9
Exogenous sex steroids
3A.1a
3A.1b
3A.1c
3A.1y
3A.1z
E22.8
E22.8
E22.8
E22.8
E25 (=)
3A.2b
3A.2b.1
3A.2b.2
3A.2c
3A.2c.0
3A.2c.1
3A.2c.2
3A.2c.3
3A.2d
E25.0
E30.1
E30.1
E30.1
#174800
Q78.1
E28.0
E29.0
+107910
drug code
Y42
3A.2e
3A.2f
Primary hypothyroidism10
Tumours producing androgen or estrogen steroids, not
originating from the testis or ovary
E03.9
E25.9
14
ESPE Code Diagnosis
OMIM
ICD 10
3B
S I N G L E V A R I AT I O N S O F N O R M A L P U B E R T Y
3B.1
Premature adrenarche11
E27.0
3B.2
E30.8
3B.2b
Premature thelarche
In infancy (infantile mammoplasia)12
Beyond infancy (thelarche variant)13
3B.3
Premature isolated menarche
E30.1
3B.4
Hypertrichosis
L68.1
3B.2a
L68.9
Q84.2
3C
C O N T R A S E X U A L P U B E R TA L D E V E L O P M E N T
3C.1
Feminisation (males): gynaecomastia

Due to disorders classified elsewhere:
Primary hypogonadal conditions (hypergonadotrophic
hypogonadism) (9A)
Partial androgen insensitivity (4B.2d)
Feminising adrenal tumours (8C.2)
Physiological gynaecomastia
Gynaecomastia of the newborn male
Adolescent gynaecomastia14
Iatrogenic
Neoplasms
Increased conversion of androgen to oestrogen imbalance
oestrogens/androgens (e.g. XXY)
Increased substrate for peripheral aromatase
Increase in extraglandular aromatase
Idiopathic
3C.1a
3C.1b
3C.1b.1
3C.1b.2
3C.1c
3C.1d
3C.1e
3C.1e.1
3C.1e.2
3C.1e.9
3C.2
3C.2a
Virilisation/hirsutism (females)15
Excluded:
Virilised infant/ambiguous genitalia (4C)
Hypertrichosis (3B.4)
Due to disorders classified elsewhere:
Virilising adrenal tumours (8C.2)
Polycystic Ovary Syndrome (10B)
Germ cell tumour of the ovary (10E.4a)
Disorders of Puberty
N62
N62
E25.0
N62
E25, L68.0
15
ESPE Code Diagnosis
3C.2z
Iatrogenic
Other specified disorder
Idiopathic
3D
D E L AY E D P U B E R T Y
3D.0
Due to disorder classified elsewhere

Hypogonadotrophic hypogonadism (6A.4)
Hypergonadotrophic hypogonadism:
In females (10A)
In males (9A)
Hyperprolactinaemia (6B.5)
Steinert syndrome (myotonic dystrophy) (14B.35)
3C.2c
3C.2y
3D.1a
Constitutional delay in (growth and) puberty16

Excluded:
Prepubertal (idiopathic) short stature associated with delayed
pubertal onset (1C.2b)
With positive family history
With negative family history
Parental puberty onset unknown
3E
MENSTRUAL DISORDERS
3E.1
Amenorrhoea
Primary amenorrhoea
Excluded:
Disorders of sex development (4)
Anatomical defect female genitalia (10FG)
Hypergonadotrophic hypogonadism (10A)
Chronic anovulation with oestrogen present
Polycystic ovary syndrome (10B)
Adrenal disorders, e.g. Cushing (8C.1)
Adult-onset congenital adrenal hyperplasia (8A.1c.3)
Thyroid disease: hypothyroidism (7A), hyperthyroidism (7B)
Ovarian tumour (10E.4)
Hypogonadotrophic hypogonadism (6A.4)
Hyperprolactinaemia (6B.5)
3D.1
3D.1a
3D.1b
3E.1a
3E.1a.0
OMIM
ICD 10
E30.0
E23
E23.0
E30.0
N91.2
N91.0
E28.8
16
ESPE Code Diagnosis
3E.1a.8
3E.1a.9
3E.1b
3E.1b.0
3E.1b.8
3E.1b.9
3E.2
3E.2a
3E.2b
Due to other, known causes not classified elsewhere:

E.g. growth-retarding diseases such as anorexia nervosa
Idiopathic
Secondary amenorrhoea
See 3E.1a.0
Due to other, known causes not classified elsewhere:
E.g. growth-retarding diseases such as anorexia nervosa
Idiopathic
Oligomenorrhoea
Primary
Secondary
OMIM
ICD 10
N91.1
N91.5
N91.3
N91.4
3E.3b
Abnormal uterine bleeding (excessive, frequent, irregular

menses)
Dysfunctional uterine bleeding17
Due to structural pelvic pathology, pregnancy or systemic disease
3E.4
Dysmenorrhoea
N94.6
3E.5
Premenstrual syndrome
N94.3
3E.8
Other, specified menstrual disorder
N94.8
3E.3
3E.3a
N92
N93.9
Precocious puberty
Phenotype: Female: Breast development before the age of 8 years. Male: Genital development before the age of 9 years. Both sexes: Acceleration of growth, advancement of bone age.
Comments: Data from the United States suggest that sexual precocity should be defined by the
onset of secondary sexual development before 6 years in black girls and before 7 years in white girls
[Midyett et al., 2003]. This may be associated with the high prevalence of overweight. In Europe the
traditional age limits have been maintained by most clinicians.
Reference: Midyett LK, et al: J Pediatr 2003;111:4751.
Central precocious puberty (CPP)

Synonyms: True precocious puberty, gonadotrophin-dependent precocious puberty.
Phenotype: Pubertal levels of LH, FSH, and E2 or T; pubertal response to GnRH test.
Comments: Pubertal development in CPP is often not only early, but also more rapidly progressive
than observed in normally timed pubertal development. In most girls (90%) with CPP intensive
diagnostic investigation will reveal no underlying causes and therefore is called idiopathic. GnRH
analogs are eectively suppressing gonadotropin secretion, but do not postpone central development of the GnRH pulse generator. In most boys with CPP a CNS disorder can be detected.
17
Acquired CNS disorders

Comments: Various intracranial processes, including increased intraventricular pressure, can induce maturation of the GnRH pulse generator. The mechanisms are unknown. TGF- may play a
role (hamartomas). Infections of the central system at a young age may be associated with CPP in
later life. Cranial irradiation may induce hypothalamic-pituitary deciencies, but also CPP and early
puberty.
4 Hamartoma
Comments: Presumably as a result of pressure on the hypothalamic area, a cerebral tumour may
initiate maturation of the GnRH pulse generator. Glial-derived transforming growth factor (TGF-)
may contribute to the neuro-endocrine mechanisms. Hamartoma may contain GnRH neurons functioning as an ectopic source of GnRH.
5
Idiopathic central precocious puberty

Phenotype: In girls with start of breast development just before the CPP age limit, one should consider borderline early puberty. In girls with start of breast development, isolated or associated with
some other pubertal signs without evidence of CPP, thelarche variant is considered (see 3B.2b). In
boys, idiopathic CPP is rare (10%).
Comments: Children adopted from developing countries and moved to a more affluent
environment have an increased incidence of early and precocious puberty.
Reference: Parent AS, et al: Endocr Rev 2003;24:668693.
6 Peripheral precocious puberty (PPP)
Synonyms: Pseudoprecocious puberty, gonadotrophin-independent precocious puberty

Phenotype: Female: breast development before the age of 8 years. Male: Genital development
and/or virilisation before the age of 9 years. Both sexes: Acceleration of growth, advancement of
bone age. Pubertal levels of sex steroids, low gonadotrophin levels.
Comments: In PPP, development of the sex characteristics is the result of gonadotrophin independent steroid production. In boys, the major cause is late onset 21 hydroxylase deciency; in case of
a familial form PPP may be the result of an activating mutation of the LH receptor (3A.2c.2). In girls,
PPP is often the result of autonomous ovarian cysts; the underlying cause may be ovary stimulating
antibodies and activating mutations of the FSH receptor.
7
HCG-producing tumours
Comments: These tumours are classified by some under the heading of gonadotrophin-dependent
precocious puberty [e.g. Brook CGD, et al (eds): Clinical Pediatric Endocrinology, ed 5, 2005]. If gonadotrophin-dependent precocious puberty is defined as being caused by premature maturation
of an otherwise normal hypothalamic-pituitary system, HCG-producing tumours have a more logical place in the group of gonadotrophin-independent precocious puberty.
8 Familial testotoxicosis
Synonym: Leydic cell hyperplasia.

Phenotype: Development of sex characteristics as a result of premature maturation of the testis
but hardly any testis growth. FSH (), LH (), T (+) caused by constitutive activation of LH receptor.
Comment: Pubertal signs such as virilisation and an increased height velocity start at the age of
14 years.
18
09 Aromatase deficiency
Phenotype: Tall stature due to failure of epiphyseal closure at puberty. Elevated androgen levels
causing virilisation but not skeletal maturation in girls. Cliteromegaly, with polycystic ovaries in
pubertal females. Normal puberty in males with tall stature, eunuchoid habitus and osteoporosis
in adulthood. T (+), DHT (+), adione (+), LH (+), FSH (+), E1 (), E2 ().
10
Primary hypothyroidism
Comments: In some patients with primary hypothyroidism FSH are increased. Furthermore, TSH
has weak agonist properties at the FSH receptor.
11
Premature adrenarche
Synonym: The term premature pubarche is often used for this condition. However, strictly speaking premature pubarche means early onset of pubic hair, independent of the cause. Premature
adrenarche is the most frequent subgroup, diagnosed if other causes of premature pubarche (e.g.
late-onset congenital adrenal hyperplasia) are excluded.
Phenotype: Premature pubarche (pubic hair before the age of 8 years) and premature axillary hair,
and sweating before the age of 8 years; none or slight acceleration of growth and of bone age. No
other sex characteristics. There may be an increased prevalence of functional ovarian hyperandrogenism in mid-teenage years. Pubertal or adult levels of DHEA (S).
12
Premature thelarche in infancy

Phenotype: Premature breast development without other signs of puberty; no or slight acceleration of growth and of bone age; mostly in infancy (60% between 6 months and 2 years). Onset
is rare after 4 years. Most regress 6 months to 6 years after diagnosis. Incomplete suppression of
GnRH axis, FSH (+), LH (N), E2 (N).
Comment: The GnRH test in a girl with premature thelarche will elicit a high response of FSH and
low response of LH in contrast to girls with CPP with exaggerated responses of especially LH and
FSH.
13
Premature thelarche beyond infancy

Synonym: Thelarche variant.
Phenotype: A slowly progressive variant of precocious puberty in girls, characterised by the
start of breast development between the age of 7 and 8 years. The progression is slow. Breast
development is often associated with mild or partial signs such as slight growth acceleration
and/or mild advancement of bone age. This state will gradually transform into a normal pubertal
development at an appropiate age.
14
Adolescent gynaecomastia
Phenotype: Breast development in pubertal boys. E2, T, LH and FSH in early to mid-pubertal range.
By increasing T levels, the gynaecomastia usually disappears.
Comment: Galactorrhoea is extremely rare in adolescents with gynaecomastia.
15
Hirsutism
Phenotype: Excessive growth of terminal hair on the face and body of a woman in a typical male
pattern distribution. Assessment of the amount, distribution, and severity of hirsutism is by the
method of Ferriman-Gallwey.
19
Comment: Causes include: (1) excess androgen production by the ovary and/or the adrenal; (2) rise
in the level of biologically active free androgen, and/or (3) increased sensitivity of the hair follicle
to androgens.
Reference: Ferriman D, Gallwey JD: J Clin Endocrinol Metab 1961;21:14401447.
16
Constitutional delay in (growth and) puberty

Synonyms: Constitutional delayed puberty, familial delay of growth and adolescence, constitutional delay of growth and adolescence.
Phenotype: First signs of puberty after the age of 13 in girls and 14 in boys.
Comment: More common in boys than in girls.
17
Dysfunctional uterine bleeding

Comments: Although usually anovulatory, may also be ovulatory. To be classied as dysfunctional
uterine bleeding it must not be associated with structural pelvic pathology, pregnancy or systemic
disease.
20
ESPE Code Diagnosis
4A
OMIM
ICD 10
D I SO R D E R S O F S E X
DEVE LO PM E NT (DSD) 1
SEX CHROMOSOME DISORDERS OF SEX
DEVELOPMENT
Excluded: Disorders of gonadal differentiation that do not result
in sex reversal/virilised female infant/undervirilised male such as:
Klinefelter syndrome (14A.3)
Turner syndrome (14A.5)
46 XX gonadal agenesis/dysgenesis (10A.1b/c).
For later onset virilisation see contrasexual pubertal development
(3C)
4A.0
Disorders of gonadal differentiation classified elsewhere

Code 4A.0 is only to be used with a corresponding primary code
(in parentheses) if the individual is undervirilised and/or has
ambiguous genitalia; if genitalia are normal then use primary code
alone or together with code for hypergonadotrophic hypogonadism
(9A.0) as indicated
45,X (Turner syndrome and variants) (14A.5)
47,XXY (Klinefelter syndrome and variants) (14A.3)
46 XX gonadal agenesis/dysgenesis (10A.1b/c)
4A.1
45,X/46,XY (mixed gonadal dysgenesis, ovotesticular DSD)2

Only includes individuals with 45X/46XY (or similar forms of sex
chromosome mosaicism, e.g. 45,X/46,XY/47,XYY) and asymmetric
gonads such as dysgenetic testes on one side and streak on other, or
ovotestis on one side with streak on other; individuals with bilateral
dysgenetic testes or dysgenetic testes in association with normal
male or female genitalia are not classified here but classified under
4A.0
Q97.8
4A.2
46,XX/46,XY (chimeric, ovotesticular DSD)3
Q99.0
4A.8
Other, specified forms of sex chromosome DSD causing

abnormal genitalia
Q99.8
Disorders of Sex Development (DSD)
(female
phenotype)
or Q98.8
(male
phenotype)
21
ESPE Code Diagnosis

4B
OMIM
ICD 10
+306100
Q97.3
4 6 , X Y D I S O R D E R S O F S E X D E V E L O P M E N T4
Excluded: Hypospadias (9E.1) or cryptorchidism (9B) without clear
underlying endocrine etiology, and Leydig cell hypoplasia if not
leading to a DSD (9A.1b)
4B.0
Undervirilised male classified elsewhere

Note: this is a supplementary code to be used together with the
primary code from respective chapters
4B.1
Disorders of gonadal (testicular) development

Complete gonadal dysgenesis (Swyer syndrome)5
WT1; WAGR, Frasier syndrome and Denys-Drash syndrome
4B.1a
4B.1a.1
*607102
#136680
#194080
4B.1a.2
4B.1a.3
4B.1a.4
4B.1a.5
4B.1a.6
4B.1a.7
4B.1a.8
4B.1a.9
4B.1a.10
4B.1a.88
4B.1a.99
4B.1b
4B.1c
4B.1d
4B.2
4B.2a
4B.2b
4B.2b.1
4B.2b.2
SF1
SRY
SOX-9 (campomelic dysplasia)
DHH
ATRX
ARX
DMRT1
DAX1
WNT4
Other specified causes
Partial gonadal dysgenesis
Gonadal regression
Ovotesticular DSD (includes 46,XY true hermaphroditism)
Disorders in androgen synthesis or action
Enzyme defects affecting synthesis of both corticosteroids and
testosterone are primarily classified under congenital adrenal
hyperplasia (8A.1):
Lipoid CAH (cholesterol side chain cleavage deficiency, P450scc)
(8A.1a)
3beta-Hydroxysteroid dehydrogenase deficiency (8A.1b)
17alpha-Hydroxylase and 17/20 lyase deficiency (P450c17) (8A.1f)
P450 oxidoreductase deficiency (8A.1g)
Smith-Lemli-Opitz syndrome (14B.33)
Androgen biosynthesis defect
17-Hydroxysteroid dehydrogenase III deficiency6
5-Reductase deficiency7
+184757
*480000
*608160
*605423
*300032
*300382
*602424
#300018
*603490
Q99.1
Q99.1
#235600
Q99.1
E29.1
#264300
E34.5
*184753
E34.5
22
ESPE Code Diagnosis

4B.2c
4B.2d
4B.2d.1
4B.2d.1a
4B.2d.1b
4B.2d.2
4B.2d.2a
4B.2d.2b
4B.3
4B.3a
4B.3b
OMIM
ICD 10
LH receptor defects, e.g. Leydig cell hypoplasia, aplasia8

+152790
Defect in androgen action (androgen insensitivity syndromes)9
#300068
Complete androgen insensitivity syndrome (CAIS)
CAIS with demonstrated mutation of the androgen receptor
gene
CAIS without demonstrated mutation of the androgen receptor
gene
Partial androgen insensitivity syndrome (PAIS)
PAIS with demonstrated mutation of the androgen receptor
gene
PAIS without demonstrated mutation of the androgen receptor
gene
E29.1
Disorders of AMH and AMH receptor (persistent Mllerian

duct syndrome) Synonym: Hernia uteri inguinale, female
genital ducts in otherwise normal male
Defect in the gene for MIS10
Defect in the gene for MIS (type II) receptor11
#261550
Q56.1
*600957
Q56.1
*600956
Q56.1
E34.5
4B.4
Iatrogenic impairment of masculinisation of foetus

(specify agent)
Q56.1
4B.8
Due to other, known causes not classified elsewhere

E.g. severe hypospadias, cloacal extrophy
E29.8
4B.9
Idiopathic
E29.9
4C
4 6 , X X D I S O R D E R S O F S E X D E V E L O P M E N T 12
Excluded: Gonadal dysgenesis (10E.1)
4C.0
Virilised female classified elsewhere

4C.1
Disorders of gonadal (ovarian) development

Ovotesticular DSD (previously called 46,XX true
hermaphroiditism)
Testicular DSD13
SRY+14
dup SOX915
4C.1a
4C.1b
4C.1b.1
4C.1b.2
Q99.1
278850
Q99.1
*480000
*608160
23
ESPE Code Diagnosis
OMIM
ICD 10
#201750
E25.8
4C.2c.5
Androgen excess
Virilisation due to androgen production by the foetus and/or
placenta
3beta-Hydroxysteroid dehydrogenase deficiency (8A.1b)
21-Hydroxylase deficiency (P450c21) (8A.1c)
11beta-Hydroxylase deficiency (8A.1d)
Glucocorticoid receptor defect (8A.1h)
Foetoplacental (P450-aromatase deficiency16, P450
oxidoreductase deficiency)
Maternal
Iatrogenic (specify agent)
Virilising ovarian tumour
Virilising luteoma of pregnancy
Virilising adrenal tumour
Congenital virilising adrenal hyperplasia in mother
4C.8
Due to other, known causes not classified elsewhere
E25.0
4C.9
Idiopathic virilisation of the foetus
E25.0
4D
UNCLASSIFIED FORMS OF ABNORMAL SEXUAL

D E V E L O P M E N T/ A N AT O M I C A L D I S R U P T I O N S
4D.1
Ambiguous genitalia with multiple congenital anomalies

In the 46,XY individual
In the 46,XX individual
4C.2
4C.2a
4C.2b
4C.2c
4C.2c.1
4C.2c.2
4C.2c.3
4C.2c.4
4D.1a
4D.1b
E25.0
D39.1
D27
D35.0
E25.0
Q56.4
General commentary
The LWPES/ESPE Consensus Group proposed the term Disorders of sex development (DSD), as dened by congenital conditions in which development of chromosomal, gonadal, or anatomical sex
is atypical.
Synonyms: Previously used terms: intersex disorders, genital abnormalities [Hughes IA, et al: Arch
Dis Child 2006;91:554].
Mixed gonadal dysgenesis (MGD)

Phenotype: Variable degree of impaired masculinisation, from almost female (in case of complete
female phenotype classify as Turner syndrome (14A.5)) to normal male genitalia (14A.4). Hypospadias, cryptorchidism may be present. At puberty FSH and LH are usually elevated and testosterone decreased. Secondary to sex chromosomal mosaicism in a male, the gonads have become dysgenetic
in combinations ovary/testis, or testis/streak. Sometimes a tumour is found instead of a gonad.
24
Comments: The term MGD can be used when the above chromosomal mosaicism (or, in rare cases,
45,X/46,XY/47,XYY) is found, even if gonadal dysgenesis has not been proven anatomically.
3
Ovotesticular DSD
Synonym: This condition was previously called true hermaphrodite.
Phenotype: Baby born with ambiguous genitalia. Hypospadias, undescended testes/clitoromegaly, labial fusion. Both testicular and ovarian tissues identied in the gonads. T variable, FSH (+/N),
LH (+/N).
46,XY DSD
Synonyms: Was previously called male pseudohermaphrodite, or undervirilisation of an XY male,
or undermasculinisation of an XY male.
Phenotype: Incomplete maculinisation, hypospadias, cryptorchidism, bid scrotum.
Comments: The diagnosis incomplete masculinisation is really a symptom that may be caused by
several dierent diseases. There is no sharp line between 46,XY DSD and hypospadias. Generally,
the former term is used when at any time there has been uncertainty about the sex of rearing.
46,XY complete gonadal dysgenesis

Synonym: Previously called XY sex reversal.
Phenotype: Absence of female puberty. Streak gonads, prepubertal female phenotype. No breast
development, primary amenorrhoea. From puberty FSH (+), LH (+), E2 ().
17-Hydroxysteroid dehydrogenase III deciency

Synonym: 17-ketosteroid reductase deciency (17-KSR deciency).
Phenotype: Female or ambiguous external genitalia, hypospadias, defective virilisation in XY individual. Partial androgenisation at puberty. Defective intrauterine virilisation of male genitalia. Adione (+), T (), DHT (), E1 (+), E2 (), possibly revealed after hCG stimulation. Adione to T ratio (+).
5alpha-Reductase deciency
Phenotype: Ambiguous genitalia or micropenis in XY individuals. Partial androgenisation at puberty. Defective intrauterine virilisation of male external genitalia. T (+), DHT (), possibly revealed
after hCG stimulation. T to DHT ratio (+).
Leydig cell hypoplasia

Synonym: LH receptor deciency.
Phenotype: Ambiguous genitalia. Defective development of Wolan structures and male external
genitalia. LH (+), T ().
Defect in androgen action (androgen insensitivity syndromes)

Synonyms: Reifenstein syndrome; complete or partial AIS (CAIS or PAIS).
Phenotype: External genitalia varying between female, ambiguous, micropenis or normal male.
Hypospadia, cryptorchidism, defective virilisation at puberty; testes small to normal sized in
adulthood. Histology shows quantitative and qualitative defect of spermatogenesis. Adulthood:
FSH (N/+), LH (N/+), T (N/+).
25
10
Defect in the gene for MIS

Phenotype: Persistent Mllerian duct syndrome. Normal male phenotype.
11
Defect in the gene for MIS (type II) receptor

Phenotype: Persistent Mllerian duct syndrome.
12
46,XX DSD
Synonym: Was previously called female pseudohermaphrodite, or overvirilisation of an XX female,
or masculinisation of an XX female.
13
46,XX testicular DSD

Synonym: Was previously called XX male or XX sex reversal.
14
SRY+
Phenotype: External genitalia male or ambiguous. Testis or ovotestis. No Mllerian structures.
Comment: Translocation of SRY.
15
dup SOX9
Phenotype: External genitalia male or ambiguous.
16 P450-aromatase deciency
Phenotype: In XX individuals ambiguous genitalia. Maternal androgenisation during pregnancy,

absent breast development at puberty, except in partial cases.
26
ESPE Code Diagnosis
OVE RWE I G HT AN D O B E S IT Y
5A
S I M P L E O B E S I T Y, C O M M O N O B E S I T Y 1
5A.1
5A.1b
Apparently prevailing environmental factors

Diet/activity balance
Emotional environment
5A.2
Apparently prevailing genetic factors
5B
GENETIC CAUSES
5B.1
Monogenic obesity syndromes

Congenital leptin deficiency2
Leptin receptor deficiency3
Pro-opiomelanocortin (POMC) deficiency4
Prohormone convertase 1 deficiency (if gonadotrophin deficiency
is present, also code as 6A.3b.4)
MC4R deficiency5
Other specified monogenetic syndromes
5A.1a
5B.1a
5B.1b
5B.1c
5B.1d
5B.1e
5B.1y
5B.2
5B.2a
5B.2y
5B.2z
5B.3
5B.3a
5B.3y
5B.3z
Genetic defects associated with obesity

Albrights hereditary osteodystrophy
(pseudohypoparathyroidism) (14B.2)
Alstrm syndrome (14B.3)
Carpenter syndrome (14B.7)
Cohen syndrome (14B.8)
Laurence-Moon-Biedl syndrome (14B.18)
Prader-Willi-Labhart syndrome (14B.25)
Chromosomal disorders associated with obesity
Down syndrome (14A.2)
Klinefelter syndrome (14A.3)
Overweight and Obesity
OMIM
ICD10
E66
E66.0
*601665
E66.8
E66.8
*164160
*601007
#609734
#600955
*155541
*601665
E66.8
E66.9
E66.8
E66.9
27
ESPE Code Diagnosis

5C
ENDOCRINE DISORDERS
5C.0
Disorders classified elsewhere

Hypothyroidism (7A)
Growth hormone deficiency (1B.3)
Insulinoma (11B.1b.7)
Diabetes mellitus inappropriately managed (e.g. insulin omission)
(11A), including Mauriac syndrome (14C.2)
Polycystic ovary syndrome (10A.2a)
5C.8
5D
CENTR AL NERVOUS SYSTEM CAUSES

(CENTR AL OBESIT Y)
5D.0

Cranio-cerebral trauma (6F.4b)
Post-neurosurgical lesions (6F.4a)
Intercranial space occupying lesions (6F.1)
Meningitis/encephalitis (6F.3)
Infiltration (6F.2)
OMIM
ICD10
E66.8
T90
G97.9
D33
G09
G99
5D.8
5E
O B E S I T Y A C C O M P A N Y I N G I M M O B I L I T Y,
M E N TA L D I S T U R B A N C E S , S O C I A L A N D
C U LT U R A L P R E S S U R E
5E.1
Muscular dystrophy6
#310200
G71.0
5E.2
Spina bifida with myelomeningocele7
and other
#182940
Q05
5E.3
Immobilisation after trauma and/or orthopaedic surgery, etc. 8
T88
5E.4
Mental retardation9
F7079
5E.5
Psychological/psychiatric disturbances (bulimia)10
F50.2
5E.8
E66.8
5E.9
E66.9
E66.8
28
ESPE Code Diagnosis

5F
I AT R O G E N I C O B E S I T Y D U E T O M E D I C AT I O N
5F.1
Corticosteroids11
5F.2
Sodium valproate12
5F.3
Insulin13
5F.4
Phenothiazine tricyclate14
5F.5
Cyproheptadine15
5F.8
Other medication, specified
OMIM
ICD10
E66.1
Obesity
Synonyms: Severe overweight, fatness.
Phenotype: Obesity is an excessive storage of body fat, relative to lean body mass. As a criterion
various parameters such as a body mass index or weight-for-height and dierent cut-o limits (e.g.
>P95) are used. A disadvantage of using percentiles of current growth studies is that cut-o levels are
changing along with the world-wide trend toward obesity. Therefore, a time- and place-independent cut-o limit has been proposed for obesity, dened as the SDS level that ends at a BMI of 30 at 18
years of age. A similar line is drawn for overweight, ending at a BMI of 25 at 18 years of age [Cole TJ, et
al: BMJ 2000;320:1240]. Obese children are frequently taller than their age- and sex-matched peers.
Bone age is usually advanced and puberty may occur earlier. Alterations in endocrine functions
are thought to be consequences of the obese state: leptin (+), insulin (+), insulin resistance, glucagon (), growth hormone (), cortisol (N), cortisol secretion rate (N/), DHEAS (+), epinephrine and
norepinephrine (N/+), IGF-I (N/+), PRL (basal (+), after stimulation ()).
Congenital leptin deficiency

Phenotype: Severe early-onset obesity, hyperphagia, metabolic, neuroendocrine and immune dysfunction. Benecial eects of treatment with recombinant leptin. Increased mortality especially in
early childhood.
Comment: Mutations in leptin gene.
Leptin receptor deficiency

Phenotype: Morbid obesity, hyperphagia, hypogonadotrophic hypogonadism, disturbed immune
function. TSH (), GH (). Clinical features less severe than in patients with congenital leptin deciency.
Comments: Mutations in leptin receptor gene. Prevalence 3% in early onset severe obesity.
Pro-opiomelanocortin (POMC) deciency

Phenotype: Congenital deciency of POMC results in a syndrome of severe obesity, hypoadrenalism
and altered skin and hair pigmentation. Leptin (+), cortisol ().
Overweight and Obesity
29
Comments: Mutations of POMC gene on chromosome 2p22. Heterozygote condition and POMC
polymorphisms show association with obesity.
5
Melanocortin 4 receptor (MC4R) mutations

Phenotype: Most relevant monogenic cause for extreme obesity. Frequently binge eating.
Comments: Mutations in MC4R gene. The severity of functional alterations of the mutated MC4R
correlates with the onset and severity of obesity.
Muscular dystrophy
Phenenotype: Duchenne muscular dystrophy is often associated with obesity due to reduction in
physical activity. Therapeutic trials with corticoids may aggravate the situation.
Myelomeningocele
Phenotype: Risk of developing obesity by hypoactivity, subnormal tness and reduced dynamic
activities, especially in non-ambulant individuals.
Immobilisation after trauma or surgery

Phenotype: Lack of physical activity and energy expenditure may promote weight gain. Indication
for early physiotherapeutic intervention.
Mental retardation
Phenotype: Obesity may be due to hypothalamic dysfunction or lack of understanding adequate
food ingestion. Mental retardation may aggravate the situation in syndromes where obesity is already a component of the disease (e.g. Prader-Willi syndrome).
10
Psychiatric disturbances, bulimia

Phenotype: Psychiatric disorder with loss of control over eating while consuming large amounts of
food. Mostly in young women. Multidisciplinary therapeutic approach including psychotherapy.
11
Corticosteroids
Phenotype: In fat cells, corticosteroids increase lipolytic enzymes, resulting in hyperlipidaemia, hypercholesterolaemia and redistribution of fat with truncal obesity and moon facies.
12
Sodium valproate
Phenotype: Valproate treatment is associated with obesity, increased fasting insulin levels, hypertriglyceridaemia and hyperandrogenism. May interfere with insulin metabolism in the liver.
13
Insulin
Phenotype: Chronic hyperinsulinaemia is associated with obesity by increased ingestion of carbohydrates to prevent hypoglycaemia.
14 Phenothiazine tricyclate
Phenotype: Used in psychiatric diseases. Broad spectrum of side eects including weight gain.
15
Cyproheptadine
Phenotype: Increases appetite through its antiserotoninergic eect on 5-HT2 receptors in the brain.
Leptin (+).
30
ESPE Code Diagnosis
PITU ITARY, HYPOTHAL AMUS ,

CE NTR AL N E RVOUS SYSTE M
(CNS)
SECTION 1
FUNCTIONAL CLASSIFICATION 1
6A
D E F I C I E N C I E S O F A N T E R I O R P I T U I TA R Y
HORMONES
6A.0

Growth hormone deficiency (1b.3)
6A.1
ACTH deficiency
Congenital isolated ACTH deficiency2
Congenital ACTH deficiency in combination with other pituitary
deficiencies3
Acquired hypothalamic-pituitary ACTH deficiency, e.g. by longterm glucocorticoid therapy4
6A.1a
6A.1b
6A.1c
6A.2
6A.2a
6A.2a.1
TSH deficiency
Congenital isolated TSH deficiency5
Known genetic defect (TSH-beta, TRHR, TRH, other)6
OMIM
ICD10
E23.0
#201400
E03.9
E23.0
#275100
E23.0
+188545
+275120
6A.2a.2
6A.2b
6A.2b.1
6A.2b.2
6A.2c
6A.3
6A.3a
6A.3a.1
Unknown origin
Congenital TSH deficiency in combination with other pituitary
deficiencies7
Secondary (pituitary) hypothyroidism8
Tertiary (hypothalamic) hypothyroidism9
Acquired hypothalamic-pituitary hypothyroidism10
E23.0
Gonadotrophin deficiency (hypogonadotrophic

hypogonadism)
X-linked inheritance
Isolated hypogonadotrophic hypogonadism and anosmia
(X-linked form of Kallmann syndrome) (KAL1 mutation);
[primary] [secondary 14B.16]11
E23.0
Pituitary, Hypothalamus, Central Nervous System (CNS)
E23.0
E23.0
E23.0
E23.0
E23.0
+308700
E23.0
31
ESPE Code Diagnosis

6A.3a.2
Isolated hypogonadotrophic hypogonadism and adrenal

hypoplasia congenita (DAX1 mutation) (also classified as
8A.2a.1)12
6A.3b
Autosomal inheritance: autosomal forms of Kallmann syndrome

Inactivating mutation of FGFR1 (KAL2)13
Inactivating mutation of PROKR2 (KAL3)14
Inactivating mutation of PROK2 (KAL4)
Inactivating mutation of GnRHR15
GPR54 mutation16
KISS mutation17
Prohormone convertase 1 mutation18
Leptin 1 or leptin receptor mutation19
6A.3b.1
6A.3b.2
6A.3b.3
6A.3b.4
6A.3b.5
6A.3b.6
6A.3b.7
6A.3b.8
OMIM
ICD10
E23.0
E23.0
#147950
244200
610628
*138850
E23.0
*604161
E23.0
*603286
E23.0
600955
E23.0
*164160
E23.0
*601007
6A.3b.9
6A.3b.10
6A.3b.11
6A.3b.88
6A.3c
6A.3c.1
LHR mutation (fertile eunuch syndrome)

Isolated LH deficiency20
Isolated FSH deficiency21
Other specified gene mutations, including NELF, etc.
Hypogonadotrophic hypogonadism in combination with other
pituitary deficiencies22
Known genetic defect, e.g. PROP1, LHX3, HESX123
#228300
+152780
E23.0
#229070
E23.0
*608137
E23.0
E23.0
*601538
E23.0
*600577
*601802
6A.3c.2
6A.3d
6A.3z
6A.4
6A.4a
6A.4b
6A.4b.1
6A.4b.2
6A.4b.8
6A.4b.9
Unknown genetic defect

Hypogonadotrophic hypogonadism in combination with
dysmorphic syndromes, e.g. Prader-Willi-Labhart syndrome
[primary 14B.25], Rieger syndrome [primary 14B.28]
Hypogonadotrophic hypogonadism, isolated, unspecified
Prolactin deficiency
Isolated prolactin deficiency24
Prolactin deficiency in combination with other pituitary
deficiencies
POU1F1 mutation25
PROP1 mutation26
Other specified gene mutations
Unknown origin
E23.0
E23.0
E23.0
264110
E23.0
E23.0
+173110
E23.0
*601538
E23.0
E23.0
E23.0
32
ESPE Code Diagnosis
6B
O V E R P R O D U C T I O N O F A N T E R I O R P I T U I TA R Y
HORMONES
6B.0

ACTH-producing adenoma (Cushings disease) (8C.1)
Growth hormone-producing adenoma (synonyms: acromegaly,
pituitary gigantism) (2B.1)
6B.1
TSH-producing adenoma27
6B.2
Gonadotrophin-producing adenoma28
6B.3
Prolactin overproduction
Prolactinoma29
Hyperprolactinaemia of other cause (e.g. pituitary stalk lesion,
primary hypothyroidism)30
6A.3a
6A.3b
6C
CENTRAL DIABETES INSIPIDUS

[primary 13A.1]
6D
HY P OTHAL A M I C DYS FU N C TI O N , N OT
CLASSIFIED ELSEWHERE
6D.0

Obesity (5D)
6D.8
Other specified functional changes
6D.9
Other functional changes, unspecified
SECTION 2
AETIOLOGICAL CLASSIFICATION 1
6E
C O N G E N I TA L D I S O R D E R S
6E.1
Congenital CNS malformations

Septo-optic dysplasia [primary]31
[secondary 14B.30]
Other midline defects, e.g. cleft palate, central maxillary incisor
syndrome, EEC syndrome (ectodactyly-ectodermal dysplasiaclefting syndrome)32
6E.1a
6E.1b
OMIM
ICD10
E05.9
M8271/0
E22.1
E23.3
Q04
#182230
Q04.4
Q04.8
33
ESPE Code Diagnosis

6E.1c
6E.1d
6E.1z
Ectopic neurohypophysis, absent infundibulum and hypoplastic

adenohypophysis33
Hamartoma34
Other congenital CNS malformations, unspecified
6E.2z
Congenital hypothalamic-pituitary disorders associated

with syndromes
Prader-Willi(-Labhart) syndrome (14B.25)
Rieger syndrome (14B.28)
Chromosomal disorders35
Chromosomal instability syndromes36
Empty sella syndrome37
6F
ACQUIRED DISORDERS
6F.1
Neoplasms
Tumours of the pituitary/hypothalamic region
Craniopharyngioma38
Nonfunctional pituitary adenomas39
Other benign structures40
Isolated glioma41
Glioma as part of neurofibromatosis I (von Recklinghausens
disease, 14B.27)
Germinoma, dysgerminoma42
Leukaemia, lymphoma43
Other neoplasms, specified
Tumours outside the pituitary/hypothalamic region
Pinealoma44
Isolated glioma45
Glioma as part of neurofibromatosis I (von Recklinghausens
disease, 14B.27)
Germinoma, dysgerminoma
Medulloblastoma46
Leukaemia, lymphoma
Other specified neoplasms
6E.2
6E.2a
6E.2b
6E.2c
6E.2d
6E.2y
6F.1a
6F.1a.1
6F.1a.2
6F.1a.3
6F.1a.4
6F.1a.5
6F.1a.6
6F.1a.7
6F.1a.8
6F.1b
6F.1b.1
6F.1b.2
6F.1b.3
6F.1b.4
6F.1b.5
6F.1b.6
6F.1b.8
6F.2
6F.2a
Inflammatory/infiltrative
Langerhans cell histiocytosis47
OMIM
ICD10
Q04.8
241800
Q85.9
Q04.9
C71.9
604856
D76.0
D76.3
34
ESPE Code Diagnosis

6F.2b
Systemic lupus erythematodes48
6F.2c
Neurosarcoidosis49
Lymphocytic neurohypophysitis50
Haemochromatosis51
OMIM
ICD10
#601744
#152700
6F.2d
6F.2e
6F.3
6F.3a
6F.3b
6F.3c
6F.3d
6F.4
6F.4a
6F.4b
6F.4c
6F.5
6F.5a
6F.5b
Infectious
Meningitis52
Encephalitis
Abscess of pituitary53
Congenital infection54
Traumatic injury
CNS surgery55
Head trauma56
Hypoxic injury57
Iatrogenic
Irradiation58
Drugs, e.g. chemotherapy59
6F.6c
Secondary to psychiatric disorders

Anorexia nervosa60
Emotional deprivation61
Other (specified)
6F.7
Idiopathic
6F.6
6F.6a
6F.6b
#181000
#602390
G00
G04, G05
G06.0
G09
G97
S06
G97.8
T66
E23.1
F50.0
Classication
Comments: Diagnoses are classied according to function and aetiology. In many cases, therefore,
two codes will be used for a patient with a CNS disorder.
Congenital isolated ACTH deciency

Phenotype: Rare inherited disorder which may cause hypoglycaemia, Addisonian crisis and death
in neonates. In pregnant women isolated low oestriol levels may indicate the disease in the foetus.
ACTH (), cortisol ().
Comment: Autosomal-recessive inherited mutations in the TBX19 gene encoding a transcription
factor important for dierentiation of pituitary corticotroph cells is found in approximately 50%.
Congenital ACTH deciency in combination with other pituitary deciencies

Phenotype: Congenital panhypopituitarism, mostly caused by hypoplasia or aplasia of the pituitary
gland due to vascular damage. Neonatal symptoms of Addisonian crisis (hypoglycaemia, hypona-
35
traemia), hypothyroidism, growth retardation may occur in association with other brain malformations. ACTH (), cortisol (), TSH (), T4 (), GH ().
Comments: Mutations in transcription factors responsible for pituitary development. In PROP1 mutations evolving ACTH (and cortisol) deciency due to progressive pituitary degeneration.
4
Acquired hypothalamic-pituitary ACTH deciency

Phenotype: Fatigue, weakness, hypopigmentation, nally Addisonian crisis.
Comments: Can occur in chronic infectious diseases (HIV). Side eect of oral, topical or inhaled longterm glucocorticoid therapy (negative feedback on ACTH). ACTH (), cortisol ().
Isolated TSH deciency

Phenotype: Relatively mild symptoms of hypothyroidism due to basal function of thyroid gland.
Thyroid gland normal or hypoplastic. T4 and T3 (), basal TSH (), TRH-stimulated TSH (), Prl (+/N).
Comments: Can be caused by hypophysitis, empty sella or Langerhans cell histiocytosis, or by mutations of TSH or TRHR.
Known genetic defect (TSH-beta, TRHR)

Phenotype: Congenital secondary hypothyroidism may not be detected in neonatal screening in
many countries, because TSH levels are not increased. T4 and T3 (), basal TSH (), TRH-stimulated
TSH (), Prl (N or ).
Comment: Dierent mutations in the coding region of the TSH-beta subunit gene and TRHR.
TSH deciency in combination with other pituitary deciencies

Synonym: Hypopituitarism, combined pituitary hormone deciency (CPHD).
Phenotype: Hypoplastic or normal thyroid, symptoms of CH usually mild. Thyroid hormones (),
TSH (), Tg (), GH (), Prl () or gonadotrophins ().
Secondary (pituitary) hypothyroidism

Phenotype: Due to pituitary TSH deciency. TSH (), T4 (). Symptoms of hypothyroidism. Variable
phenotype depending on other pituitary hormones aected.
Comments: Mutations in POU1F1 or PROP1 and TRH receptor gene are coded elsewhere. Malformation syndromes (septo-optic dysplasia, midline defects) and mass lesions may aect pituitary
TSH secretion.
Tertiary (hypothalamic) hypothyroidism

Phenotype: Hypothyroidism due to hypothalamic TRH deciency. Mostly other hypothalamic hormones are aected as well. TSH (N/), T4 (), prolonged TSH rise after TRH injection.
10
Acquired hypothalamic-pituitary hypothyroidism

Phenotype: Consequence of pituitary surgery or lymphocytic adenohypophysitis. May occur in very
low birth weight infants or critically ill children (non-thyroidal illness syndrome).
11
Isolated hypogonadotrophic hypogonadism and anosmia (Kallman syndrome)

Phenotype: Clinically and genetically heterogeneous disorder with a wide spectrum of reproductive function and anosmia. Absence or severely delayed or slowly progressive or abortive puberty.
36
Histologically immature gonads. LH (), FSH (), T (), inhibin-B (). Hypoplasia of the bulbus olfactorius in MRI. In severe forms hypoplastic genitalia.
Comments: Lack of GnRH neurones. X-linked mutations in KAL-1 gene (encodes anosmin-1, a protein
involved in olfactory and neuronal migration). Autosomal-dominant loss of function mutations in
FGFR-1 gene. Anosmia occurs in all KAL-1 mutations but only a small percentage of FGFR-1 mutations.
12
Isolated hypogonadotrophic hypogonadism and adrenal hypoplasia congenita

(DAX1 mutation)
Phenotype: X-linked congenital adrenal insuciency in neonatal period, lack of pubertal development, abnormalities in spermatogenesis. Variable clinical presentation. In female carriers delayed
puberty. Hypoplastic adrenals; inadequate testis development, decreased spermatogonia. LH (),
FSH (), T (), especially at the time of puberty. Glucocorticoid and mineralocorticoid deciency.
Comments: Deletion or mutation of the NROB1 (DAX1) gene, encoding DAX1, an orphan nuclear receptor. DAX1 expression has been shown in regions of the hypothalamic/pituitary/adrenal/gonadal
axis.
13
KAL2 (FGFR1 defect)

Comment: Together with KAL mutations, FGR1 mutations are responsible for 20% of cases with Kallmann syndrome.
14
KAL3 and KAL4

Comments: PROKR and PROK2 defects may be responsible for 10% of cases with Kallmann syndrome.
15
Inactivating mutation of GnRHR

Phenotype: Lack of pubertal development; wide spectrum of phenotypes. Patients are normosmic.
LH (), FSH (), T ().
Comment: Autosomal recessive.
16
GPR54 mutation
Phenotype: Lack of pubertal development and fertility. LH (), FSH (), sex steroids ().
Comments: GPR54 is a G protein-coupled receptor gene, expressed by GnRH neurons. Autosomal
recessive. Patients respond to GnRH or Gn treatment.
17
KISS mutation
Phenotype: Lack of pubertal development, infertility.
Comment: Kisspeptins stimulate gonadotrophins by stimulating GnRH after activation of GPR54.
18
Prohormone convertase 1 mutation

Phenotype: Lack of pubertal development. LH (), FSH (), sex steroids ().
Comment: Defects in prohormone processing.
37
19
Leptin 1 mutation
Phenotype: Morbid obesity and hypogonadism. LH (), FSH (), sex steroids ().
Comments: Sympathetic system dysfunction, thyroid dysfunction, type 2 DM and immune dysfunction may occur. Increased mortality in obese subjects.
20
Isolated LH deciency
Synonym: Fertile eunuch.
Phenotype: Decreased virilisation and fertility. LH (), T ().
21
Isolated FSH deciency

Phenotype: Decreased fertility. Decreased number of germ cells. FSH ().
22
Hypogonadotrophic hypogonadism in combination with other pituitary deciencies

Synonym: Combined pituitary hormone deciency (CPHD).
23
Known genetic defect, e.g. PROP1, LHX3, HESX1

Phenotype: Mutations in pituitary transcription factors result in combined pituitary hormone deciency. In LHX3 mutation combination with rigid cervical spine. LH (), FSH (), sex steroids ();
depending on the defect combination with other pituitary hormone decits. PROP1: mutations in
the PROP gene are associated with a highly variable phenotype. ACTH deciency can occur late.
HESX1: inactivating mutations in this gene were found in few patients with septo-optic dysplasia.
LHX3: mutations in the LHX3 gene which encodes LIM transcription factors responsible for pituitary
and nervous system development.
24
Isolated prolactin deciency

Phenotype: Pituitary Prl is synthesised by lactotrophs and mammosomatotrophs which release also
GH. Prl is also synthesised in the decidua of the pregnant uterus. In adults, Prl is primarily involved
with reproductive functions. In children no symptoms of isolated Prl deciency. Prl ().
Comments: Predominant negative hypothalamic control by dopamine. The main releasing factor
is TRH.
25
POU1F1 mutation
Phenotype: Symptoms related to congenital hypothyroidism and GH deciency. Prl deciency itself
has no clinical sequelae in children. GH (). Basal and TRH-stimulated TSH (). Prl (). Variable phenotype.
Comments: AD or AR. POU1F1 is expressed in lactotrophs, somatotrophs and thyrotrophs in which
it is involved in the transcription of the GH, Prl and TSHbeta genes.
26
PROP1 mutation
Phenotype: Short stature due to complete GH deciency, congenital hypothyroidism, hypogonadism. Evolving ACTH deciency in older patients (hyponatraemia, hypoglycaemia). Deciency of anterior pituitary hormones. Progressive shrinking of the pituitary gland. Occasional pituitary enlargement imposing as adenoma, which can resolve spontaneously.
Comments: PROP1 mutations were found in approximately 1/3 of patients with familial combined
pituitary hormone deciency; rare in sporadic cases.
38
27
TSH-producing adenoma
Phenotype: TSH- (and Prl-) producing micro- and macroadenomas cause symptoms of hyperthyroidism (and hyperprolactinaemia). TSH (+), T4 (+), Prl (+).
Comments: In most cases other pituitary hormones are involved as well. Carcinomas very rare.
28
Gonadotrophin-producing adenoma
Phenotype: Functioning adenomas exhibit mainly FSH hypersecretion and ovarian overstimulation.
FSH (+), E2 (+). Clinical symptoms of mass lesion (optic chiasm compression, deciency of other pituitary hormones) may occur. LH-secreting adenoma may cause precocious puberty. LH (+), T (+).
Comments: The majority of clinically nonfunctioning pituitary macroadenomas are of gonadotroph
origin, LH and FSH are rarely increased.
29
Prolactinoma
Phenotype: Prolactinomas may present with delayed puberty. Mostly girls aected: menstrual disorders and galactorrhoea. In large adenomas symptoms of intracranial mass lesion. Prl (+), pulsatile
secretion, variable response to TRH stimulation.
Comments: 40% of acromegalic patients have hyperprolactinaemia. The extent of Prl elevation may
discriminate between nonfunctioning macroadenoma and macroprolactinoma.
30
Hyperprolactinaemia of other cause

Phenotype: Pituitary stalk compression by a tumour may lead to hyperprolactinaemia by decreasing Prl inhibition by dopamine. In primary hypothyroidism the serum level of TRH, which is the primary Prl-releasing factor, is increased.
31
Septo-optic dysplasia (De Morsier syndrome)

Phenotype: Growth retardation, visual impairment, nystagmus; hypothalamic dysfunction and pituitary failure may occur. Neonatal hypoglycaemia and seizures. Developmental anomalies of the
midline structures of the brain like hypoplasia of optic nerves, agenesis of septum pellucidum and
agenesis of corpus callosum. Variable pituitary hormone deciencies. Very variable phenotype.
Comment: HESX1 mutations were found only in few cases.
32
Other midline defects: cleft palate, central maxillary incisor syndrome, EEC syndrome
(ectodactyly-ectodermal dysplasia-clefting syndrome)
Phenotype: Developmental anomalies of the midline may aect the pituitary to a variable extent,
mostly GH deciency.
Comments: Common development of palate/Rathke pouch/pituitary. The central incisor syndrome
may be associated with holoprosencephaly and various other congenital anomalies.
33
Ectopic neurohypophysis, absent infundibulum and hypoplastic adenohypophysis

Phenotype: Short stature due to GH deciency and other symptoms due to TSH, ACTH and gonadotrophin deciency, mostly panhypopituitarism. MRI shows hypoplastic adenohypophysis and small
sella, hypoplastic or absent infundibulum and ectopic neurohypophysis at the median eminence.
Basal and stimulated GH (), TSH (), Gn (), ACTH ().
Comments: This condition is likely to be the end result of perinatal disruption of the hypophyseal
portal system. The ectopic neurohypophysis functions normally.
39
34
Hamartoma
Phenotype: Precocious puberty of central type, psychomotor delay, seizures. Benign tumours composed of neurons, astrocytes and oligodendroncytes; appears attached to the tuber cinereum or the
oor of the 3rd ventricle. The tumour may express GnRH.
35
Chromosomal disorders
Phenotype: Turner syndrome, 18p deletion syndrome, XXXXY syndrome. Brain malformations and
pituitary hormone deciencies (mainly GH deciency) were found in a variable degree.
36
Chromosomal instability syndromes

Phenotype: Fanconi syndrome, Bloom syndrome, Nijmegen breakage syndrome. GH deciency has
been described. GH treatment in these cases may cause increased susceptibility to malignancies.
37
Empty sella syndrome

Phenotype: In most cases asymptomatic; rarely clinical manifestation with headache, rhinorrhoea,
impaired visual eld and benign intracranial hypertension. Rarely with pituitary deciencies. GH (),
TSH (), LH (), FSH (), Prl (+).
Comments: Disorder of the anlage of the diaphragm of the sella. Enlarged pituitary fossa by herniated arachnoid content. In unselected autopsies up to 20%.
38
Craniopharyngioma
Phenotype: Symptoms depend on the relationship to the pituitary, hypothalamus or optic chiasma.
Hypopituitarism by compression of the adenohypophysis. Compression of the hypophyseal stalk
causes hyperprolactinaemia. Visual eld disturbance, intracranial pressure, headache, vomiting,
papilloedema, somnolence. After surgery virtually all patients show hypopituitarism. Derives from
remnant of Rathke pouch, supra- or intrasellar, calcications.
Comment: Approximately 10% of childhood tumours.
39
Nonfunctional pituitary adenomas

Phenotype: A mass lesion impinging on the pituitary or hypothalamus may cause local neurological
eects on the optic tract, the cavernous sinus, temporal and frontal lobe and may cause symptoms
of increased intracranial pressure. Involvement of the hypothalamus (temperature dysregulation,
appetite and thirst disorders, etc.) and pituitary (hormone deciencies).
40
Other benign structures

Phenotype: May cause the same phenotype as in non-functional pituitary adenomas (6F.1a.2).
41
Isolated glioma
Phenotype: Brain tumours originating from neuroglia. Symptoms depend on impingement on local
structures (chiasmatic/hypothalamic area), hydrocephalus. Variable pituitary hormone decits.
42
Germinoma, dysgerminoma
Phenotype: Germinomas arise near the base of the hypothalamus and aect vasopressin axons
thereby causing neurohormonal diabetes insipidus. Can be very small (pituitary stalk thickening)
and undetectable for several years following the onset of polyuria. hCG (+), hCG in CSF, diabetes
insipidus. Dysgerminoma may produce gonadotrophins and give rise to precocious puberty.
40
43
Leukaemia, lymphoma
Phenotype: Most frequent causes of CNS-aecting malignant diseases. May aect hypothalamicpituitary axis by leukaemic inltration (leukaemic meningitis) or as a consequence of treatment.
Comments: Normal growth may be maintained despite biochemical GH deciency due to hypothalamic hyperphagia in children with hypothalamic disorder.
44
Pinealoma
Phenotype: Pineal parenchymal tumours (pineocytoma, pineoblastoma) or pure pineal germinomas (occur mainly in boys). Symptoms of mass lesion, obstructive hypertension. Melatonin has no
diagnostic signicance.
45
Isolated glioma
Phenotype: Tumours outside the hypothalamo-pituitary region may cause symptoms of mass lesion and obstructive hypertension and thereby aect pituitary hormone secretion.
46
Medulloblastoma
Phenotype: Embryonal tumour of the cerebellum, metastases into the CSF. Most common malignant brain tumour in children. Aection of the hypothalamus-pituitary axis as consequence of treatment (surgery, high dose irradiation, chemotherapy).
Comment: Mutations of genes encoding proteins involved in embryonic growth factors or mutations of growth factor receptors are frequently found.
47
Langerhans cell histiocytosis (LCH)

Phenotype: Can occur as an isolated lesion, as multifocal or as widespread systemic disease. Focal
proliferation/accumulation of Langerhans cells. Class I, II and III histiocytosis based on histopathologic ndings. Single or multiple lesions of the bone, skin involvement, exophthalmos, pulmonary inltrates, pituitary involvement or hypothalamic dysfunction. Diabetes insipidus in approximately 25%,
variable deciencies of the anterior pituitary. LCH has an extremely variable clinical presentation.
48
Systemic lupus erythematodes (SLE)

Phenotype: SLE is a multisystem autoimmune disorder which can present with neurological complications. Brain lesions on MRI. The pituitary-thyroid and pituitary-gonadal axis may be aected in
newly diagnosed, untreated patients.
Comments: Genetic predisposition, female preference.
49
Neurosarcoidosis
Phenotype: Inltrative granulomatous disease which may involve hypothalamic-pituitary area. Central diabetes insipidus, hypogonadism, GH deciency, hyperprolactinaemia. Thickening of the pituitary stalk. Dicult dierentiation from lymphocytic hypophysitis (biopsy).
50
Lymphocytic neurohypophysitis
Phenotype: Recent pregnancy or other autoimmune disease in 50% of cases, occasionally after pituitary surgery. Diuse destruction of pituitary and infundibulum. Aection of anterior and posterior pituitary hormone axis. Central diabetes insipidus, LH (), FSH (), T/E2 (), TSH (), T4 (),
ACTH (), cortisol (), GH ().
41
51
Haemochromatosis
Phenotype: May lead to pituitary inltration, deposits in pituitary cells. Idiopathic or secondary
(thalassaemia or sickle cell disease). Correlation with serum ferritin levels; MRI shows decreased signal intensity. Mainly gonadotrophic axis aected, delayed puberty. LH (), FSH (), T or E2 ().
52
Meningitis
Phenotype: Viral or bacterial meningoencephalitis can be associated with anterior and posterior
pituitary insuciency which may resolve after cure of the disease. Central diabetes insipidus is frequently seen in congenital meningitis of various aetiology.
53
Abscess of pituitary
Phenotype: Intrasellar infection presenting with headache, visual changes, fever, meningismus and
endocrine abnormalities. Imaging demonstrates pituitary mass. Correct diagnosis mostly only after
(surgical) treatment. Generally pituitary dysfunction does not recover after treatment.
54
Congenital infection
Phenotype: Prenatal rubella infection in the rst trimester causes dysmorphic stigmata (microphthalmos, microcephaly), cardiac anomalies, dystrophia, GH deciency has been described. Hypothyroidism was described in congenital immunodeciency syndromes. Neurohormonal diabetes
insipidus was found in congenital cytomegalovirus infection. GH deciency was found in Schwachmann-Diamond syndrome (pancreatic insuciency, recurrent infections, metaphyseal anomalies).
55
CNS surgery
Phenotype: Tumours in the sella or hypothalamus region are mostly associated with hypothalamic-pituitary hormone decits; after surgery decits will usually get worse, rarely recovery. Usually
multiple pituitary hormone decits. Brain surgery outside the hypothalamo-pituitary region may affect hormone production and secretion by pressure, blood circulatory disturbance or haemorrhage.
Trans-sphenoidal surgery frequently followed by SIADH (hyponatraemia, elevated vasopressin).
56
Head trauma (traumatic brain injury, TBI)

Phenotype: Up to 2550% of patients have been reported to develop anterior pituitary deciency,
in particular GH deciency. Can evolve over years. Systematic screening of pituitary function in all
patients after head trauma and TBI appears warranted.
57
Hypoxic injury
Phenotype: Hypoxic brain injury, especially in the neonate, can produce irreversible tissue damage.
Predominantly diabetes insipidus as a sign of severe brain damage. Anterior pituitary hormone decits may develop with some delay.
58
Irradiation
Phenotype: Cranial irradiation for prophylaxis or treatment of leukaemic meningitis or for treatment of various brain tumours. Radiotherapy has a dose-dependent eect on hypothalamic-pituitary hormone secretion, GH secreting cells being most sensitive. Hormone decits occur years after
treatment.
Comment: May also aect cartilage plates and bone growth.
42
59
Drugs, e.g. chemotherapy, alcohol

Phenotype: Chemotherapy aects growth mainly by a catabolic condition and by direct eects on
bone, possible eects on hypothalamus. Foetal alcohol syndrome results from maternal alcohol use
during pregnancy (facial abnormalities, impairment in neurodevelopment and growth). Cases with
GH deciency have been reported.
60
Anorexia nervosa
Phenotype: Amenorrhoea, weight loss, behavioural changes (fear of gaining weight, disturbance of
self-evaluation of body shape, hyperactivity, sleep disturbance). Endocrine abnormalities represent
an adaptation to starvation. LH (), FSH (), E2 (), T4 (), TSH (N), Prl (N), basal GH (+), IGF1 (). Generally in young women under age 25. Female:male ratio 9:1.
61
Emotional deprivation (psychosocial dwarsm, deprivational dwarsm)

Phenotype: Short stature, abnormal behaviour patterns (perverted or voracious appetite, enuresis,
encopresis, insomnia), occurs in children with a disturbed social environment. GH (), IGF1 (), occasional TSH and ACTH deciency. Reversible if placed in a favourable psychosocial environment.
43
ESPE Code Diagnosis
THYRO I D D I SO R D E R S
7A
HYPOTHYROIDISM1
7A.1
Congenital (primary) hypothyroidism (permanent)2

Included: Late-onset hypothyroidism due to thyroid dysgenesis
or dyshormonogenesis
Secondary and tertiary hypothyroidism (6A.2)
Thyroid hormone resistance (7E.3)
Developmental defects/thyroid dysgenesis3
Athyrosis/agenesis4
Hypoplasia/hypogenesis5
Ectopy6
Inherited defects of thyroid hormone biosynthesis/thyroid
dyshormonogenesis7
Iodine transport defect8
Organification defects due to an abnormality in the TPO enzyme
or in the H2O2 generating system (includes Pendred syndrome)9
7A.1a
7A.1b
7A.1b.1
7A.1b.2
7A.1b.3
7A.1c
7A.1c.1
7A.1c.2
OMIM
ICD10
E03.1
#218700
E03.1
#218700
E03.1
#218700
Q89.2
E07.1
#274400
#274500
#274600
#607200
7A.1c.3
7A.1c.4
7A.1d
Defective thyroglobulin synthesis or transport10

Abnormal iodotyrosine deiodinase (dehalogenase) activity11
TSH-receptor defects/TSH unresponsiveness12
+188450
%274800
#218700
E07.9
#275200
7A.1y
7A.1z

7A.2b.1
Transient congenital hypothyroidism

Iodine deficiency13
Drug induced
Maternal anti-thyroid drug therapy14
7A.2b.2
Iodine excess due to iodinated contrast media
7A.2b.3
Iodine excess from other sources15
7A.2b.8
Other specified goitrogen
7A.2b.9
Other goitrogen, unspecified
7A.2c
Maternal thyroid autoantibodies16
7A.2
7A.2a
7A.2b
E00
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
E03.2
P72.2
44
ESPE Code Diagnosis

7A.2d
7A.2y
7A.2z
Thyroid dysfunction in prematurity (including transient

hypothyroxinaemia, transient primary hypothyroidism, transient
hyperthyrotropinaemia, low T3 syndrome)
Idiopathic
7A.3z
Acquired primary hypothyroidism

Non-autoimmune thyroiditis (7E.4)
Autoimmune thyroiditis/Hashimotos thyroiditis with decreased
thyroid function17
Iodine deficiency18
Iatrogenic19
Post-irradiation
Post-operative
Iodine excess20
Drug-induced, including environmental conditions
(goitrogens)21
Systemic diseases22
Idiopathic
7B
H Y P E R T H Y R O I D I S M 23
7B.1
Congenital hyperthyroidism (neonatal thyrotoxicosis)24

Isolated pituitary resistance to thyroid hormone (7E.3b)
Maternal autoimmune thyroid disease25 (neonatal Graves
disease) (usually transient)
Activating TSH-receptor mutation26
G-protein mutations27
As part of McCune Albright [primary 14B.22]
Other
7A.3
7A.3a
7A.3b
7A.3c
7A.3d
7A.3d.1
7A.3d.2
7A.3e
7A.3f
7A.3g
7A.3y
7B.1a
7B.1b
7B.1c
7B.1d
7B.1d.1
7B.1d.2
7B.2
7B.2a
7B.2b
7B.2c
OMIM
Acquired primary hyperthyroidism

Thyroid adenoma (7D.1)
Hyperfunctioning carcinoma (7D.2)
Steinert syndrome (14B.35)
Graves disease, hashitoxicosis (Hashimotos toxicosis)28
Exogenous
Thyroid Disorders
ICD10
P72.2
P72.2
P72.2
%140300
E06.3
E01
E89.0
E03.2
E03.2
E03.8
E03.8
E03.9
P72.1
#609152
E05.8
E05.8
#174800
E05.8
E05.8
%140300
E05.0
45
ESPE Code Diagnosis
OMIM
7B.2z
Excessive intake of thyroid hormones29

Iodine induced (Jod-Basedow)
Other specified disorder, e.g. choriocarcinoma, hydatidiform
mole
Idiopathic
7C
GOITRE
7C.0

Supplementary code only
If hypothyroid use code from 7A
If hyperthyroid use code from 7B
7C.1
Euthyroid goitre
Dyshormonogenetic
Iodine transport defect30
#274400
Organification defects due to an abnormality in the TPO enzyme #274500
or in the H2O2 generating system (includes Pendred syndrome)31 #274600
7B.2c.1
7B.2c.2
7B.2y
7C.1a
7C.1b
7C.1b.1
7C.1b.2
ICD10
E05.4
E05.4
E05.9
E05.9
E04
E07.1
#607200
7C.1b.3
7C.1b.4
7C.1c
Defective thyroglobulin synthesis or transport32

Abnormal iodotyrosine deiodinase (dehalogenase) activity33
TSH-receptor defects/TSH unresponsiveness
+188450
%274800
#218700
E07.9
#275200
7C.1z
Iodine deficiency34
Autoimmune/Hashimotos thyroiditis with normal thyroid
function35
Drug-induced/goitrogen exposure
Nodular goitre due to cysts or haemorrhage36
Idiopathic (juvenile goitre, adolescent goitre, simple goitre)37
7D
THYROID TUMOURS
7D.1
Adenomas38
7D.2
Carcinomas
Papillary39
Follicular40
7C.1d
7C.1e
7C.1f
7C.1g
7C.1y
7D.2a
7D.2b
E01, E02
%140300
E06.3
E04.8
E04.8
E04.9
D34
C73, D44
#188550
46
ESPE Code Diagnosis
OMIM
ICD10
7D.2c.2
Medullary (C cell carcinoma)41

Sporadic
Part of MEN 2A [primary 14C.5b]
#171400
D44.8
7D.2c.3
MEN 2B [primary 14C.5c]
#162300
7D.2c.4
Other familial forms (RET, NTRK1)

Undifferentiated/anaplastic
Other specified carcinoma
Other carcinoma, unspecified
#155240
7D.2c
7D.2c.1
M8360/1
D44.8
M8360/1
7D.2d
7D.2y
7D.2z
7D.8
7D.9
Other specified tumour

E.g. lymphoma, sarcoma
D44
Other tumour, unspecified
D44.0, C73
C73
D34
7E
OTHER THYROID DISORDERS
7E.1
Sick-euthyroid syndrome
Excluded: Thyroid dysfunction in prematurity (7A.2d)
7E.2
Disorders of thyroid hormone transport42

TBG deficiency
TBG excess
Transthyretin (TTR) variants
Familial dysalbuminaemic hyperthyroidism
7E.2a
7E.2b
7E.2c
7E.2d
7E.3
7E.3a
7E.3b
7E.3c
Thyroid hormone resistance syndromes43

Generalised thyroid hormone resistance (GTHR)
Pituitary resistance to thyroid hormone (PitRTH)
Peripheral resistance to thyroid hormone (PRTH)
7E.4c
Non-autoimmune thyroiditis
Non-autoimmune thyroiditis due to viral or bacterial agents
Acute suppurative thyroiditis44
Subacute thyroiditis
7E.5
Other thyroid disorders, unspecified
7E.4
7E.4a
7E.4b
Thyroid Disorders
E07.8
E07.8
+314200
+176300
+176300
E07.9
#188570
#145650
#188570
E06.0
E06.0
E06.1
47
Hypothyroidism
Phenotype: Decreased activity, dry skin and hair, excessive weight gain secondary to uid retention,
growth failure, retarded bone age. TSH (+ in primary; /N in secondary/tertiary hypothyroidism),
FT4 (), FT3 ().
Congenital (primary) hypothyroidism (CH)

Phenotype: Delayed skeletal maturation, enlarged fontanels, constipation, enlarged tongue, lethargy, developmental delay. Thyroid gland either absent, hypoplastic, ectopic, normally-sized or enlarged. In all forms of primary hypothyroidism: low thyroid hormones, elevated TSH.
Comments: Heterogenous pathogenesis. 80% due to developmental defects. Neonatal screening
enables early diagnosis and treatment.
Developmental defects/thyroid dysgenesis

Phenotype: Dierent forms: athyrosis, ectopy, hypoplasia. Diagnosis by thyroid imaging (ultrasound, scintigraphy).
Athyrosis/agenesis
Phenotype: Most pronounced form of hypothyroidism. Remnants of brotic tissue might be detectable.
Hypoplasia/hypogenesis
Phenotype: Similar as in athyrosis. Remnants of normal tissue can be visualised, but of smaller size
than normal.
Ectopy
Phenotype: Hypothyroidism usually milder than in athyrosis. Normal tissue can be visualised in an
abnormal location.
Inherited defects of thyroid hormone biosynthesis/thyroid dyshormonogenesis

Phenotype: Symptoms and signs of hypothyroidism. Goitre is rare in the neonate, but frequent in
older children.
Iodine transport defect

Phenotype: Inability of the thyroid to maintain a concentration dierence of readily exchangeable
iodine between the plasma and the thyroid gland. The defect is also found in the salivary gland
and gastric mucosa. It is presumed to arise either because of a decient supply of energy for the
transport system or because of abnormality of a carrier or receptor substance. Failure to concentrate
radioiodide by the salivary gland (saliva/plasma (123) I ratio was 1.6, in contrast to the normal ratio
of more than 20) and the clinical and biologic response to potassium iodide treatment.
Comment: The defect in iodide transport is produced by mutations in the sodium-iodide symporter
gene (SLC5A5).
Organication defect
Phenotype: Normal or enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also
rapid discharge after perchlorate administration (perchlorate discharge test).
48
Comment: Defect of iodine organication (thyroidperoxidase and H2O2 generation defects have
been identied).
10
Defective thyroglobulin synthesis or transport

Phenotype: Normal or enlarged gland in ultrasound, rapid uptake of radioactive iodine, normal discharge after perchlorate administration (perchlorate discharge test). Tg (/N/+) (immunoreactivity
might be normal).
Comment: Defect of the thyroglobulin molecule, which results in an ineective thyroid hormone
production.
11
Abnormal iodotyrosine deiodinase (dehalogenase) activity

Phenotype: Normal or enlarged gland in ultrasound, symptoms of CH usually milder than in athyrosis. MIT and DIT elevated in serum and urine.
Comment: Defect of the deiodinase which leads to failure of deiodination of iodotyrosine and loss
of iodine in the form of MIT and DIT in the urine, frequent development of goitre.
12
TSH-receptor defects/TSH unresponsiveness

Phenotype: Normal or hypoplastic thyroid, symptoms of CH usually varying from severe to mild.
Tg (N/).
Comment: Defect of the TSH receptor may be associated with euthyroid hyperthyrotropinaemia or
hypothyroidism.
13
Iodine deciency
Synonym: Endemic cretinism.
Phenotype: Enlarged, normal or hypoplastic thyroids, symptoms of CH varying from severe to mild.
Tg (+), urinary iodine excretion ().
Comments: Congenital hypothyroidism due to iodine deciency is common in developing countries. It is preventable by iodine prophylaxis. In some industrialised countries with lesser degrees
of iodine deciency, the incidence of congenital hypothyroidism and hyperthyrotropinaemia is increased as well.
14
Maternal anti-thyroid drug therapy

Phenotype: Normal or enlarged thyroid, mild symptoms of CH.
Comments: Transplacental passage of anti-thyroid drugs may result in the inhibition of the foetal
thyroid function. Condition is transient and disappears with elimination of the anti-thyroid drug
from the infants circulation.
15
Iodine excess
Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, however, long-term sequelae are possible. Tg (+), extremely elevated urinary iodine excretion.
Comments: Administration of large amounts of iodide, e.g. disinfectants or contrast media to the
mother or infant leads to transient suppression of thyroid function (Wol-Chaiko eect). Transient
hypothyroidism due to iodine excess is frequent in newborns and premature infants in intensive
care.
Thyroid Disorders
49
16
Maternal thyroid autoantibodies

Phenotype: Normal or hypoplastic thyroid, symptoms of CH varying from severe to mild. Anti-thyroid antibodies detectable.
Comments: Transplacental passage of thyroid autoantibodies (thyroid peroxidase (TPO), TSH receptor, cytotoxic) may disturb thyroid function and development of the foetal thyroid gland. Usually
transient condition, in some cases with cytotoxic and thyroid blocking IgG it is permanent.
17
Autoimmune thyroiditis/Hashimotos thyroiditis with decreased thyroid function

Phenotype: Thyroid enlarged or normally sized, abnormal echo pattern in ultrasound investigation,
mild to severe symptoms of hypothyroidism, short stature. Histology: inammatory signs, lymphocytic inltration.
Comments: Hypothyroidism due to an inammation and destruction of thyroid caused by anti-thyroid autoantibodies or viral/bacterial agents. Incidence variable, more frequent in iodine replete
areas.
18
Iodine deciency
Phenotype: Enlarged or normal thyroids, symptoms of CH usually mild, short stature is the most
prominent feature in infants and children. Tg (+), low urinary iodine excretion.
Comment: Hypothyroidism due to iodine deciency caused by inadequate nutritional supply or
substances which inhibit iodine uptake, e.g. soy, cassava.
19
Iatrogenic
Phenotype: Absent or diminished thyroid tissue, symptoms of hypothyroidism.
Comment: Hypothyroidism following the surgical or radiotherapy treatment of hyperthyroidism,
cancer or nodular goitre.
20
Iodine excess
Phenotype: Enlarged or normal thyroid, symptoms of CH usually mild. Tg (+), extremely elevated
urinary iodine excretion.
Comment: Administration of large amounts of iodide, e.g. disinfectants or contrast media, infrequently leads to transient suppression of thyroid function in an older child (Wol-Chaiko eect).
21
Drug-induced
Phenotype: Thyroid enlarged or normally sized, mild to severe symptoms of hypothyroidism, short
stature.
Comment: Hypothyroidism due to administration of drugs which block thyroid function (perchlorate, carbimazole, methimazole) or iodine uptake (perchlorate, amiodarone) or cause autoimmune
inammation (interferon).
22
Systemic diseases
Phenotype: Hypothyroidism, storage of iron, cystin, etc., in the thyroid, usually small glands.
Comment: Hypothyroidism as a symptom of systemic disease (e.g. cystinosis, -thalassemia), usually caused by storage of non-thyroidal material or inammation in the thyroid.
50
23
Hyperthyroidism (thyrotoxicosis)
Phenotype: Rapid growth associated with restlessness, tremor, heat intolerance, diarrhea, polydipsia and poor concentration. T4 (+), FT4 (+), T3 (+), TSH (). TSH suppressed despite TRH stimulation.
24
Congenital hyperthyroidism (neonatal thyrotoxicosis)

Phenotype: Manifestations of hyperthyroidism before birth, and in neonatal period.
25
Neonatal thyrotoxicosis due to maternal autoimmune thyroid disease

Synonym: Neonatal Graves disease.
Phenotype: In utero tachycardia can occur. From birth (or a few days later): thyroid enlarged or normally sized, abnormal echo pattern in ultrasound investigation, mild to severe symptoms of hyperthyroidism, failure to thrive, tachycardia, exophthalmos, restlessness. T4 (+), T3 (+), TSH (), measurable
stimulating auto-antibodies. Mother has circulating thyroid-stimulating immunoglobulins (TSI).
Comments: Hyperthyroidism due to the transplacental passage of thyroid autoantibodies which
stimulate the thyroid gland, usually TSH receptor antibodies (TRAb) (TSI). Pregnant women with
a history of thyroid disease should be screened for TSI in early pregnancy. In case of positive TSI,
foetal heart rate has to be checked regularly. Increased familial occurrence. More frequent in iodinereplete areas.
26
Activating TSH-receptor mutation

Phenotype: Thyroid normally sized, rarely enlarged at birth, normal echo pattern in ultrasound investigation, severe symptoms of hyperthyroidism, failure to thrive, tachycardia, relatively resistant
to anti-thyroid drug treatment. T4 (+), T3 (+), TSH (), no measurable auto-antibodies.
Comment: Hyperthyroidism due to constitutively activating mutations of the TSH receptor.
27
G-protein mutations
Phenotype: Thyroid normally sized, rarely enlarged, normal echo pattern in ultrasound investigation, severe symptoms of hyperthyroidism, failure to thrive, tachycardia, relatively resistant to antithyroid drug treatment. T4 (+), T3 (+), TSH (), no measurable auto-antibodies.
Comment: Hyperthyroidism due to constitutively activating mutations of the G-protein signalling
pathway, sometimes combined with dysfunction of other endocrine cells, e.g. precocious pseudopuberty, hypo- or hyperparathyroidism (McCune-Albright).
28
Graves disease
Synonym: Hashitoxicosis.
Phenotype: Thyroid enlarged, abnormal echo pattern in ultrasound investigation, mild to severe
symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure, exophthalmos, most severe symptoms evident in thyroid storm. T4 (+), T3 (+), TSH (), measurable
stimulating auto-antibodies (anti-TSH receptor (TRab) and anti-TPO, and anti-thyroglobulin (Tg) autoantibodies).
Comment: Increased familial occurrence.
29
Excessive intake of thyroid hormones

Phenotype: Thyroid not enlarged, severe symptoms of hyperthyroidism, tachycardia, weight loss,
nervousness, increased blood pressure, nausea. T4 (+), T3 (+), TSH ().
Thyroid Disorders
51
Comments: Hyperthyroidism due to large doses of exogenous thyroid hormones. Doses of mg to g

of L-thyroxine are needed to produce symptoms, while T3 is more toxic with symptoms already in
g amounts.
30
Iodine transport defect

Phenotype: Goitre, enlarged gland in ultrasound, but not visualised in scintigraphy. Tissue can be
visualized by decreased iodine content of saliva. T4 (N), TSH (N/+).
Comment: Defect of iodine transport into the thyroid and salivary glands.
31
Organication defect
Phenotype: Goitre, enlarged gland in ultrasound, rapid uptake of radioactive iodine, but also rapid
discharge after perchlorate administration (perchlorate discharge test). T4 (N/), T3 (N), TSH (N/+).
Comment: Defect of iodine organication (thyroid peroxidase and H2O2 generation defects have
been identied).
32
Defective thyroglobulin synthesis or transport

Phenotype: Goitre, enlarged gland in ultrasound, rapid uptake of radioactive iodine, normal discharge after perchlorate administration (perchlorate discharge test). T4 (N), TSH (N), Tg (/N/+) (immunoreactivity might be normal).
Comment: Defect of the thyroglobulin molecule, which results in an ineective thyroid hormone
production.
33
Abnormal iodotyrosine deiodinase (dehalogenase) activity

Phenotype: Goitre, enlarged gland in ultrasound. T4 (N), TSH (N), MIT and DIT elevated in serum and
urine.
Comments: Defect of the deiodinase which leads to failure of deiodination of iodotyrosine and loss
of iodine in the form of MIT and DIT in the urine, frequent development of goitre.
34
Iodine deciency
Phenotype: Enlarged thyroid. Increased radioactive iodine uptake. There can be a cold nodule. T4
(N), TSH (N), Tg (+), urinary iodine excretion ().
Comments: Congenital cases: goitre due to iodine deciency caused by inadequate nutritional supply or substances which inhibit iodine uptake, e.g. soy, cassava. Acquired cases: goitre development
due to iodine deciency is common in many developing countries but also in some industrialised
countries with lesser degrees of iodine deciency. Possible inuence of IGF-1, the incidence of juvenile goitre ranges from 0 to 60% in correlation to iodine supply. Can be associated with nodular
goitre.
35
Autoimmune/Hashimotos thyroiditis with normal thyroid function

Phenotype: Thyroid enlarged, abnormal echo pattern in ultrasound investigation. Auto-antibodies
(anti-TPO, anti-Tg, rarely anti-TSH receptor) present. T4 (N) and TSH (N) found in euthyroid cases.
Comments: In euthyroid cases the compensatory power of the thyroid is sucient for normal thyroid hormone production, albeit with an increased gland volume. Increased familial occurrence.
52
36
Nodular goitre due to cysts or haemorrhage

Phenotype: Goitre, cystic appearance in ultrasound, cold nodule in scintigraphy. T4 (N), TSH (N), no
antibodies.
Comments: Nodular goitre, nodules represent cysts or haemorrhages. More prevalent in iodine decient areas.
37
Idiopathic (juvenile goitre, adolescent goitre, simple goitre)

Phenotype: Thyroid enlarged. In nodular goitre single or multiple nodules in ultrasound, usually
representing cold, very rarely warm or hot nodules in scintigraphy. T4 (N), TSH (N).
Comment: Goitre due to multiple nodule formation, probably due to somatic mutations in genes
for thyroid specic proteins.
38
Adenomas
Phenotype: Thyroid not enlarged, thyroid nodule demonstrable in ultrasound. In cases with hyperthyroidism a hot nodule is found in scintigraphy, and there are mild to severe symptoms of hyperthyroidism, tachycardia, weight loss, nervousness, increased blood pressure. Thyroid function can
also be normal. Histology: single or multiple nodules without inammatory signs or lymphocytic
inltration.
Comment: Hyperthyroidism due to a hyperfunctioning thyroid nodule carrying a somatic mutation
of the TSH receptor gene or G-proteins causing constitutive activation of the thyroid cells.
39
Papillary carcinoma
Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as
warm nodules in scintigraphy, frequently early lymph node metastases, bilateral occurrence, favourable prognosis. T4 (N), TSH (N).
Comments: Most common thyroid tumour in children, relatively dierentiated due to rearrangements of ret-proto-oncogenes. More frequent after neck irradiation.
40
Follicular carcinoma
Phenotype: Single or multiple nodules in ultrasound, usually representing as cold, very rarely as
warm nodules in scintigraphy, infrequently lymph node metastases, bilateral occurrence, vascular
invasion common. T4 (N), TSH (N).
Comment: Rare, hard to distinguish from follicular adenoma. More frequent after neck irradiation.
41
Medullary (C cell carcinoma)

Phenotype: Single or multiple nodules in ultrasound, usually representing as cold nodules in scintigraphy, early metastasis in lungs and lymph nodes. T4 (N), TSH (N). Elevated calcitonin (after pentagastrin).
Comments: In 75% sporadic. Rare tumour caused by ret-proto-oncogene mutations, frequently
found in MEN IIa and b, which is hard to distinguish from follicular adenoma. In families with MEN
or MTC, children should be screened for mutations of the MEN genes. Calcitonin frequently only
increased after pentagastrin stimulation.
Thyroid Disorders
53
42
Disorders of thyroid hormone transport

Phenotype: Normal thyroid, euthyroidism. T4 (), FT4 (N), TSH (N).
Comment: Usually euthyroid conditions with low measurements of total thyroid hormones but normal free thyroid hormones due to defects of thyroid hormone binding proteins (TBG, albumin).
43
Thyroid hormone resistance syndromes

Phenotype: Ranging from overt hypothyroidism with deafness and mental retardation to mild
hypothyroidism combined with hyperthyroid symptoms, e.g. tachycardia. Normal thyroid. T4 (+),
TSH (+).
Comment: Hypothyroidism due to defects of the nuclear T3 receptor with a variable clinical picture
ranging from overt hypothyroidism to a mixed clinical picture of hypothyroidism and hyperthyroidism due to dierent regulation of T3 receptors in dierent tissues.
44
Acute suppurative thyroiditis

Phenotype: Goitre, pain, fever, dysphagia (acute) or weakness, malaise, tenderness of the thyroid
(sub-acute), elevated ESR and CRP. T4 (N//+), TSH (N/+/), no antibodies.
54
ESPE Code Diagnosis
AD R E NAL D ISO R D E R S
8A
PRIMARY ADRENAL INSUFFICIENCY
8A.1
Congenital adrenal hyperplasia (CAH)

Cholesterol side-chain cleavage deficiency (lipoid CAH)
(P450scc)1
3beta-Hydroxysteroid dehydrogenase deficiency2
8A.1a
8A.1b
OMIM
ICD10
#201710
E25
E25.0
+201810
E25.0
*109715
8A.1c
8A.1c.1
8A.1c.2
8A.1c.3
8A.1d
8A.1e
8A.1e.1
8A.1e.2
8A.1e.3
8A.1f
8A.1g
8A.1h
8A.1z
21-Hydroxylase deficiency (P450c21)3

Salt-wasting 21-OHD4
Simple virlising 21-OHD5
Non-classical 21-OHD6
11beta-Hydroxylase deficiency7
P450c11AS deficiency
Corticosterone methyl oxidase deficiency type I8
Corticosterone methyl oxidase deficiency type II9
Glucocorticoid suppressible hypertension10
17alpha-Hydroxylase/17/20 lyase deficiency11
P450 oxidoreductase deficiency (may be part of Antley Bixler
congenital malformation syndrome)12
Glucocorticoid receptor defect13
8A.2z
Other causes of adrenal insufficiency

Congenital adrenal hypoplasia
DAX-1 (NROB1) mutation14 (also classified as 6A.3a.2 if combined
with hypogonadotrophic hypogonadism)
Idiopathic
Adrenoleukodystrophy (Schilders disease) and
adrenomyeloneuropathy15
Primary xanthomatosis (Wolmans disease)16
Familial glucocorticoid deficiency (ACTH insensitivity, hereditary
unresponsiveness to ACTH)17
Triple A (Allgrove) syndrome18
Pseudohypoaldosteronism, type 119
8A.3
Autoimmune adrenalitis (Addisons disease)20
8A.2
8A.2a
8A.2a.1
8A.2a.2
8A.2b
8A.2c
8A.2d
8A.2e
8A.2f
Adrenal Disorders
+201910
E25.0
#202010
E25.0
*124080
E25.0
E25.0
E25.0
#103900
E25.0
#202110
#201750
E25.0
E25.0
+138040
E25.0
E25.9
#300200
Q89.1
#202370
E71.3
+278000
Q89.1
#202200
Q89.1
#231550
Q89.1
#264350
Q89.1
Q89.1
E27.1
55
ESPE Code Diagnosis
8A.3a
8A.3b
8A.4
8A.4a
8A.4b
8A.4c
8A.4d
8A.4y
Infections
Tuberculosis21
Fungal infections22
Bacterial sepsis23
AIDS24
Other specified infections
8A.5z
8A.9
Idiopathic
8B
SECONDARY ADRENAL INSUFFICIENCY
8A.5a
8A.5y
ICD10

Part of autoimmune polyglandular syndromes:
Type 1 classified as 14C.4a
Type 2 classified as 14C.4b
Other types (see 14C.4c, d and e)
Part of Steinert syndrome (14B.35)
Isolated
Haemorrhage
Associated with meningococcal infection
(Waterhouse-Friedrichsen syndrome)25
Other specified causes26
Idiopathic
8A.5
OMIM
E27.8
A18.7, E35.1
E27.4
E27.4
E27.4
A39.1,
E35.1
E27.4
E27.4
E27.4
Classified elsewhere: 6A.1
8C
ADRENAL EXCESS
8C.1
Glucocorticoid excess (Cushing syndrome)27 [primary]

[secondary 14C.1]
Caused by ACTH excess
Cushings disease (ACTH-producing pituitary adenoma)28
CRF excess29
Ectopic ACTH syndrome30
Increased peripheral glucocorticoid production
ACTH-independent macronodular adrenal hyperplasia
Multinodular adrenal hyperplasia, isolated or as part of the
Carney complex31
Adrenal adenoma32
8C.1a
8C.1a.1
8C.1a.2
8C.1a.3
8C.1b
8C.1b.1
8C.1b.2
8C.1b.3
E24
E24.0
219090
E24.0
E24.3
E24.3
E24.8
#219080
E24.8
#160980
E24.8
E24.8
56
ESPE Code Diagnosis
8C.1c.z
Adrenal carcinoma33
Glucocorticoids from other sources
Iatrogenic Cushing syndrome34
Other
8C.2
Virilising and feminising adrenal tumours35
8C.3
8C.3b
Mineralocorticoid excess
Conn syndrome36
Substances with mineralocorticoid action (liquorice)37
8D
DISORDERS OF THE ADRENAL MEDULLA
8D.1
Adrenal medulla defect

Haemorrhage
Infection
Tumour
Idiopathic
8C.1b.4
8C.1c
8C.1c.1
8C.3a
8D.1a
8D.1b
8D.1c
8D.1z
8D.2
8D.2a
8D.2b
Primary tumour in adrenal medulla

Phaeochromocytoma38
Neuroblastoma39
OMIM
ICD10
E24.8
E24.8
E24.2
E24.2
E26.0
E26.0
E26.0
A39.1, E35.1
E35.1
E35.1
E35.1
M8700/0
M9500/3
Cholesterol side-chain cleavage deciency (congenital lipoid adrenal hyperplasia; P450scc)

Phenotype: Deciency of all gonadal and adrenal steroid hormones including progesterone, which
is required to maintain normal pregnancy. Rare cases survive untreated for several years. Life-threatening adrenal insuciency and sex reversal in 46,XY individuals.
Comments: Disruption of the P450 side-chain cleavage enzyme. Autosomal-recessive mutations of
the CYP11A1 gene. Heterozygous carriers are healthy and fertile.
3beta-Hydroxysteroid dehydrogenase deciency

Phenotype: Various degrees of salt wasting, premature pubarche and hirsutism in girls and incomplete masculinisation in boys, growth acceleration, advanced bone age. Heterogenous clinical presentation. 17alpha-OHP (), DHEAS (+), 17alpha-hydroxypregnenolone (+).
Comments: Mutations in the type II 3beta-HSD gene. Wide spectrum of mutations associated with
dierent phenotypic manifestations.
21-Hydroxylase deciency (P450c21) (21-OHD)

Comment: Most common cause of congenital adrenal hyperplasia.
Adrenal Disorders
57
Salt-wasting 21-OHD
Phenotype: Most severe form of CAH with total deciency of enzymes of cortisol and aldosterone
biosynthesis. In female newborns masculinised external genitalia (ambiguous genitalia with clitoral
enlargement and urogenital sinus). Life-threatening salt wasting crises, Na (), K (+), cortisol (),
ACTH (+), 17OHP (+), androstenedione (+). Accelerated growth and advanced bone age, peripheral
precocious puberty, early epiphyseal closure and reduced nal height.
Comments: CYP21 gene deletion/conversion that totally ablates enzyme activity. Approximately
30% of CAH cases. Autosomal-recessive inheritance.
Simple virilising 21-OHD

Phenotype: Milder form of CAH without salt wasting crisis, adequate aldosterone synthesis.
Comment: Mutations in the CYP21 gene with 12% of normal enzyme activity, mainly I172N mutations.
Non-classical 21-OHD (late onset CAH)

Phenotype: Symptoms of hirsutism and early pubertal onset, advanced bone age.
Comment: Mildest form of CAH with 20 to 60% of enzyme activity, e.g. V281L and P30L mutations.
In compound heterozygous forms of CAH the milder defect predicts the phenotype.
11beta-Hydroxylase deciency (P450c11)

Phenotype: Androgen excess and hypertension. In females ambiguous genitalia, virilisation, clitoromegaly. Accelerated growth, advanced bone age. Mineralocorticoid excess, sodium retention,
volume expansion. Cortisol (), ACTH (+), deoxycortisol (+), deoxycorticosterone (+), PRA (), aldosterone (), androgens (+).
Comments: Second most common form of CAH. Mutations in CYP11B1 gene. Autosomal recessive.
Corticosterone methyl oxidase deciency type I

Phenotype: Caused by disorders of P450c11AS, the isoenzyme of P450c11, that is exclusively
expressed in the zona glomerulosa. Aldosterone (), 18-OH corticosterone (), corticosterone (+),
ACTH (+), cortisol (N).
Comment: Autosomal-recessive inheritance.
Corticosterone methyl oxidase deciency type II (aldosterone synthase deciency)

Phenotype: Congenital hypoaldosteronism, life-threatening salt loss, failure to thrive. Na (), K (+),
aldosterone (), renin (+), cortisol (N).
Comment: Mutations in the CYP11B2 gene encoding aldosterone synthase (P450c11Aldo), under
control of the renin-angiotensin system. Autosomal-recessive inheritance.
10
Glucocorticoid suppressible hypertension (glucocorticoid remediable aldosteronism, GRA)

Phenotype: Hypertension of variable degree, familial hyperaldosteronism type I. Aldosterone (+),
ACTH (+). Only partial suppression of ACTH by glucocorticoids required for correction of hypertension.
Comment: ACTH-regulated hybrid CYP11B1/CYP11B2 gene.
58
11 17alpha-Hydroxylase/17/20 lyase deciency (P450c17)
Phenotype: Hypertension, undervirilised genitalia in males, lack of pubertal development, salt retention. Cortisol (), ACTH (+), deoxycorticosterone (+), T (), estrogens (), renin (), K (), alkalosis.
Comment: Mutations in CYP17 gene, autosomal recessive.
12
P450 oxidoreductase deciency (may be part of Antley Bixler syndrome)

Phenotype: Skeletal defects like craniosynostosis and radiohumeral synostosis, ambiguous genitalia. In addition, cytochrome P450 enzymes aected and abnormalities in steroidogenesis (17alphahydroxylase, 17,20-lyase, 21-hydroxylase). Cortisol (), 17OHP (+), adrenal androgens ().
Comments: Mutations of POR gene encoding NADPH: cytochrome P450 oxidoreductase (CYPOR) in
patients with Antley Bixler syndrome. Mutations in FGFR2 gene in some patients described.
13
Glucocorticoid receptor defect

Phenotype: Hirsutism, fatigue, menstrual disorders, obesity, hypokalaemic hypertension. Cortisol
(+), adrenal androgens (+), ACTH (+).
Comments: Mutations in the glucocorticoid receptor gene.
14
DAX-1 mutation (familial hypogonadotrophic hypogonadism and adrenal hypoplasia

congenita)
Phenotype: X-linked congenital adrenal hypoplasia and lack of pubertal development, abnormalities in spermatogenesis. Variable clinical presentation; in female carriers delayed puberty. LH (),
FSH (), T (), glucocorticoid and mineralocorticoid deciency.
Comments: Deletion or mutation of the NROB1 (DAX1) gene, encoding DAX1, an orphan nuclear
receptor. DAX1 expression has been shown in regions of the hypothalamo/pituitary/adrenal/gonadal axis.
15 Adrenoleukodystrophy and adrenomyeloneuropathy (X-ALD)
Phenotype: Inherited neurometabolic disease associated with demyelination of the central nervous
system, adrenal insuciency, and accumulation of very long chain fatty acids in plasma and tissues.
Clinically heterogeneous disorder ranging from severe childhood cerebral form to asymptomatic
persons. Adrenomyeloneuropathy and adrenoleukodystrophy are dierent presentations of the
same single gene disorder. Frequently associated with adrenal insuciency (Addisons disease)
which may remain the only clinical expression of ALD.
Comment: Mutations in the ABCD1 gene encoding the adrenoleukodystrophy protein.
16
Primary xanthomatosis (Wolmans disease)

Phenotype: Rapidly fatal lysosomal storage disease caused by complete absence of lysosomal acid
lipase activity. Failure to thrive, anaemia, hepatomegaly, enlarged and calcied adrenal glands and
decreased cortisol secretion develop during the rst months of life. Successful cure by umbilical
cord stem cell transplantation has been reported.
Comments: Autosomal-recessive inheritance. Gene encoding lysosomal acid lipase deciency
mapped to chromosome 10q23.2-q23.3.
Adrenal Disorders
59
17 Familial glucocorticoid resistance
Phenotype: Partial end-organ resistance to glucocorticoids; variable phenotype from asymptomatic to severe hyperandrogenism (sex reversal in females), fatigue and/or mineralocorticoid excess,
hypertension. Cortisol (+), ACTH (+), mineralocorticoids (+), androgens (+).
Comment: Mutations in the glucocorticoid receptor-alpha (hGRalpha) which impair normal glucocorticoid signal transduction, familial and sporadic cases.
18 Triple A (Allgrove) syndrome
Phenotype: Rare autosomal-recessive disorder characterised by ACTH-resistant adrenal failure,

achalasia, alacrimia and a progressive neurological syndrome. Genotype/phenotype analysis shows
high variability in occurrence, age of onset and severity of clinical symptoms even in patients with
the same mutations.
Comment: Mutations in the AAA gene which encodes the ALADIN protein.
19 Pseudohypoaldosteronism type 1
Phenotype: Severe salt loss by a defect in one of the subunits of the epithelial sodium channel
(autosomal recessive). An autosomal-dominant form is caused by a defect in the mineralocorticoid
receptor gene NR3C2.
20Autoimmune adrenalitis (Addisons disease)
Phenotype: Weakness, fatigue, weight loss, hyperpigmentation of the skin and/or mucosae, anorexia, vomiting, hypotension, hypoglycaemia. Glucocorticoid and mineralocorticoid deciency.
ACTH (+), PRA (+). May be associated with other autoimmune diseases (Hashimotos thyroiditis, coeliac disease, etc., autoimmune polyglandular diesease, Schmidt syndrome).
Comment: Adrenal autoantibodies may be transferred transplacentally from an aected mother to
the baby.
21
Tuberculosis
Phenotype: Impairment of adrenal function may occur in active tuberculosis. Also primary adrenal
tuberculosis.
Comment: Rifampicin treatment has an eect on adrenal steroid metabolism.
22
Fungal infections
Phenotype: Histoplasmosis or coccidiomycosis may cause Addisons disease.
23
Bacterial sepsis
Phenotype: Adrenal crisis may occur during an acute meningococcal, pneumococcal, streptococcal
or Haemophilus infection. Waterhouse-Friderichsen syndrome in meningococcal sepsis with meningitis: massive adrenal haemorrhage with very poor prognosis.
24 AIDS
Phenotype: High incidence of adrenal insuciency in critically ill HIV patients.
60
25 Associated with meningococcal infection (Waterhouse- Friderichsen syndrome)
Phenotype: Acute adrenal insuciency occurring with meningococcaemia. High fever, circulatory
collapse, skin haemorrhage, subcapsular adrenal haemorrage. Very high mortality.
26 Haemorrhage other specied causes
Phenotype: Adrenal haemorrhage of the newborn may occur after prolonged labour and traumatic
delivery. Acute shock, hypoglycaemia, hyponatraemia, hyperkalaemia, acidosis.
27 Glucocorticoid excess (Cushing syndrome)
Phenotype: Truncal obesity and moon facies, acne, hypertension, striae, loss of muscle mass, decreased growth velocity, emotional instability. Cortisol (+), androgens (+), estrogens (N/+), aldosterone (+), ACTH (+/N/). Elevated blood glucose, hyperlipidaemia, insulin-resistant diabetes.
Comment: Symptoms of hypercortisolism are similar whatever its cause.
28 Cushings disease (ACTH-producing pituitary adenoma)
Phenotype: See 8C.1. ACTH (+), cortisol (+), adrenal androgens (+), urinary 17-hydroxycorticosteroid (+), urinary free cortisol (+). ACTH and cortisol response to CRH stimulation and suppression
to dexamethasone indicates pituitary-dependent disease. MRI of the brain, eventually with sinus
petrosus sampling for exact localisation of the tumour. May occur as a rare manifestation of MEN1.
29 CRF excess
Phenotype: See 8C.1. ACTH (+), cortisol (+). Ectopic tumors secreting CRH (e.g. phaeochromocytoma, ganglioneuroblastoma). Most CRH-producing tumours also secrete ACTH.
30 Ectopic ACTH syndrome (EAS)
Phenotype: See 8C.1. Ectopic, nonpituitary ACTH secretion. ACTH (+), cortisol (+). Dynamic tests not
very reliable. Bilateral inferior sinus petrosus sampling shows absent central gradient. Imaging discovers 2/3 of cases. Bronchial carcinoid, neuroendocrine tumors, gastrinomas, etc. In 20% no source
of EAS detectable.
31 Multinodular adrenal hyperplasia, isolated or as part of the Carney complex.
Phenotype: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia.
Carney complex is a familial multiple endocrine neoplasia syndrome characterised by spotty skin
pigmentation, myxomas, endocrine overactivity and schwannomas. Cortisol (+), ACTH (), impaired
response to CRH stimulation and dexamethasone suppression.
Comments: Carney complex inherits autosomal dominant. Mutations in the PRKAR1A gene coding
for protein kinase A. Somatic mutations in adrenal neoplasms.
32 Adrenal adenoma
Phenotype: See 8C.1. Autonomous production of cortisol by an adrenal adenoma. Cortisol (+), adrenal androgens (+), ACTH (). No response of ACTH and cortisol to CRH stimulation and dexamethasone suppression.
Comment: Adrenal masses may be detected incidentally by imaging procedures (incidentaloma),
approximately 10% produce glucocorticoids.
Adrenal Disorders
61
33 Adrenal carcinoma
Phenotype: See 8C.1. Hormonally active tumours. Cortisol (+), ACTH ().
34 Iatrogenic Cushing syndrome
Phenotype: See 8C.1. Oral, parenteral, inhaled, topical or intra-articular administration of glucocorticoids causes Cushing syndrome in a dose-dependent manner. Adrenal suppression, osteoporosis,
growth retardation. Cortisol (+ or ), ACTH ().
35 Virilising and feminising adrenal tumours
Phenotype: Virilising tumours: peripheral precocious puberty, virilisation, accelerated growth. T (+),
cortisol (N/+). LH, FSH (N), but no response to LHRH stimulation. Diagnostic imaging. Adenoma or
carcinoma. Feminising tumours: peripheral precocious puberty, gynaecomastia in boys. E2 (+), unresponsiveness of LH and FSH to GnRH stimulation.
36 Conn syndrome (primary hyperaldosteronism)
Phenotype: Hypertension, pollakisuria, muscular weakness, tetany. Na (+), K (N/), metabolic alkalosis. Aldosterone (+), renin (). Primary aldosteronism is caused by bilateral hyperplasia in 2/3 cases
and by aldosterone-producing adenoma in 1/3. Imaging and adrenal vein sampling to distinguish
unilateral and bilateral adrenal aldosterone production.
Comment: Subtype of glucocorticoid-suppressible aldosteronism. Elevated aldosterone synthase
which increases 18-hydroxycortisol in plasma. See 8A.1e.3.
37
Substances with mineralocorticoid action (liquorice)

Phenotype: Hypertension, hypokalaemia, aldosterone (), renin (). Liquorice contains glycyrrhizic
acid, which inhibits 11-hydroxysteroid dehydrogenase activity.
38 Phaeochromocytoma
Phenotype: Hypertension, sweating, headache, palpitations, weight loss, polyuria, pallor/ushing.

Epinephrine (+), norepinephrine (+) in plasma and urine. Imaging procedures for exact localisation,
90% from adrenomedullary tissue, <10% malignant. Frequently familial.
39 Neuroblastoma
Phenotype: Hypertension and ushing are found rarely. Symptoms and signs depend largely on size
and localisation of the tumour and whether it has metastasised (lymph nodes, liver, skin, bone, bone
marrow). Excretion of catecholamines (+), dopamine (+), vanillylmandelic acid (+). Localisation by
imaging procedures. High rate of spontaneous regression. Mainly in children <5 years.
Comments: Several chromosomal loci show loss of heterozygosity, indicative of a tumour suppressor
gene. Gain of the long arm of chromosome 17q is the most frequent chromosomal abnormality.
62
ESPE Code Diagnosis
OMIM
ICD10
TESTI CU L AR D ISO R D E R S/
D I SO R D E R S O F M ALE G E N ITAL S
Excluded: Testicular hyperfunction/testotoxicosis (3A.2c.2)
Congenital defects with malformation of external genitalia
resulting in sexual ambiguity (4B.1, 4B.2)
9A
HYPERGONADOTROPHIC HYPOGONADISM
(primary testicular failure)
E29
Possible secondary codes:

3C.1 (feminisation/gynaecomastia)
3D.0 (delayed puberty)
9A.0

Cryptorchidism (9B)
Klinefelter syndrome and its variants (14A.3)
Laurence-Moon-Bardet-Biedl syndrome
[primary 14B.18] [secondary 5b.2a]
Noonan syndrome (14B.24)
Steinert myotonic dystrophy syndrome (14B.35)
9A.1
Congenital disorders of the testes not leading to a disorder

of sex development
Excluded: 46,XY disorders of sex development (4B)
45,X/46,XY mixed gonadal dysgenesis with normal male genitalia
(14A.4)
46XY gonadal dysgenesis
Isolated elevation of FSH1 (Sertoli-cell-only syndrome/FSH
receptor defect, spermatogenic arrest)2
Androgen receptor defect without malformation of external
genitalia3
Anorchia (vanished testes, testicular regression syndrome)4
Other specified congenital testicular disorders leading to
abnormal postnatal sex development
Other congenital testicular disorders, unspecified, leading to
abnormal postnatal sex development
9A.1a
9A.1b
9A.1c
9A.1d
9A.1e
9A.1y
9A.1z
9A.2
E29.8
E29.8
#400042
E29.8
#300068
E34.5
273250
Q55.0
E29.8
E29.9
Acquired forms of testicular failure
Testicular Disorders/Disorders of Male Genitals
63
ESPE Code Diagnosis
9A.2z

Autoimmune (part of autoimmune polyglandular syndrome type 1,
14C.4a)
(Post-)infection5
Spontaneous torsion
Traumatic
Iatrogenic6
After scrotal or inguineal surgery
After irradiation
After chemotherapy
9B
CRYPTORCHIDISM/MALDESCENDED TESTES7
9A.2a
9A.2b
9A.2c
9A.2d
9A.2e
9A.2e.1
9A.2e.2
9A.2e.3
9A.2y
OMIM
ICD10
E29.1,
E89.5
E29.8
E29.8
E29.8
E29.1
E89.5
E89.5
E89.5
E29.1
E29.1
#219050
Q53
Note: If secondary to an endocrine disorder then use code 9B as

supplementary code
Unilateral
Suprascrotal
Inguinal
Abdominal
Ectopic
Q53.1
Q53.2
9B.2e
Bilateral
Suprascrotal
Inguinal
Abdominal
Ectopic
Combination of various locations
9B.3
Retractile testes
Q55.2
9B.4
Acquired cryptorchidism
(testis has definitely been in scrotum on previous examinations,
but later found to be suprascrotal or inguineal, needing treatment)
Q53.9
9C
ACQUIRED TESTICUL AR DISORDERS
9C.1
Orchitis
If associated with testicular failure then also give code 9A.2b
9B.1
9B.1a
9B.1b
9B.1c
9B.1d
9B.2
9B.2a
9B.2b
9B.2c
9B.2d
N45
64
ESPE Code Diagnosis

9C.2
Testicular torsion8
If associated with testicular failure also give code 9A.2c
9C.8
Other, specified disorders of testes

(e.g. trauma, iatrogenic)
If associated with testicular failure also give appropriate codes
9A.2d or 9A.2e
OMIM
ICD10
75
N44
S30.8
S39.9
9D
TUMOURS OF TESTES
Benign:
D29.2
Malignant:
C62
9D.1
Germ cell origin

Seminomas
Non-seminomas
Carcinoma in situ
Yolk-sac tumours (embryonal cell tumours)
Teratoma
Choriocarcinoma
M906M909
Non-Germ Cell Origin

Leydig cell tumour
Sertoli Cell tumour
Primitive gonadal structures
M859M867
9D.1a
9D.1b
9D.1b.1
9D.1b.2
9D.1b.3
9D.1b.4
9D.2
9D.2a
9D.2b
9D.2c
9D.3
9D.3a
9D.3z
Mixed tumours
Gonadoblastomas
Other mixed testicular tumours
9D.8
Other, specified tumours of testes (e.g. leukaemia,

rhabdomyosarcoma)
9E
DISORDERS OF PENIS
M9073/1
C62.9
C62.9
Note: If due to underlying endocrinological disorder then use code

9E only as secondary code
9E.1
9E.1a
9E.1b
9E.1c
Hypospadias9
Glandular hypospadias
Penile hypospadias
Penoscrotal hypospadias
Q54
Q54.0
Q54.1
Q54.2
65
ESPE Code Diagnosis
OMIM
ICD10
9E.1z
Other
Q54.8
9E.2
Epispadias
Q64.0
9E.3
Cloacal malformation with penile abnormality
Q43.7
9E.4
Microphallus (micropenis)10
Q55.6
9F
S C R O TA L D I S O R D E R S
9F.1
Bifid scrotum
Q55.2
9F.2
Shawl scrotum
(if part of Aarskog-Scott syndrome, use 14B.1 as [primary], and 9F.2
as [secondary])
N50.9
9G
D I SO R D E R S O F TH E E PI D I DYM I S
9G.1
Epididymitis
N45
9G.2
Spermatocele
Q55.4
9G.3
Discontinuity of efferent ducts or vas deferens
Q55.4
9H
DISORDERS OF TESTICULAR BLOOD VESSELS
9H.1
Varicocele
9H.9
9Y
OTHER SPECIFIED DISORDERS OF THE MALE

G E N I TA L I A
Q55.8
9Z
O T H E R D I S O R D E R S O F T H E M A L E G E N I TA L I A ,
UNSPECIFIED
Q55.9
I86.2
66
1 Isolated elevation of FSH (Sertoli-cell-only syndrome (SCO)/FSH receptor defect)
Synonym: Del Castillo syndrome.

Phenotype: Infertility, small testes in adulthood. Histology: Small seminiferous tubules without
germ cells. Adulthood: FSH (+), inhibin B ().
2
Spermatogenic arrest
Phenotype: Infertility, small to normal sized testes in adulthood. Histology: Seminiferous tubules of
reduced diameter; arrest of spermatogenesis at spermatogonial, spermatocytic or spermatid level;
no secondary spermatids. Adulthood: FSH (+).
3 Androgen receptor defect without malformation of external genitalia
Phenotype: Normal or small penis. Infertility, small to normal sized testes in adulthood. Histology:
Quantitative and qualitative defect of spermatogenesis. Adulthood: FSH (N, +, ), LH (N, +), T (N, +).
4
Anorchia, vanished testes, testicular regression syndrome

Synonym: XY gonadal agenesis syndrome, testicular atrophy/aplasia. The term vanishing testes is
also used, but this should be reserved for the rare cases when (small) testis had been present at
birth, but later vanished without known cause, suggesting a continuing process.
Phenotype: Normal penis, empty scrotum, absence of puberty. FSH (+), LH (+), T ().
5 (Post-)infectious secondary testicular failure
Phenotype: Reduced fertility. Atrophy of seminiferous tubules; Leydig cells intact. Adulthood:
FSH (+).
6
Iatrogenic, e.g. post-irradiation, post-chemotherapy testicular failure

Phenotype: Defective pubertal development, infertility. Leydig cell failure may or may not occur,
depending on the severity of damage. Histology: Sertoli-cell-only, atrophy of seminiferous tubules,
atrophy of interstitial tissue including Leydig cells. Adulthood: FSH (+), LH (N, +), T (N,).
Cryptorchidism/maldescended testes
Synonym: Retentio testis, undescended testes, cryptorchism.
Phenotype: Unilateral or bilateral empty scrotum.
Comment: Retractile testes are classied under the general heading of cryptorchidism, although
some may consider this as a variant of normal.
Testicular torsion
Phenotype: Painful swelling of the testis. Occlusion of blood supply to the testis.
Comment: Bilateral intrauterine torsion results in anorchia; postnatal torsion results in primary testicular failure.
Hypospadias
Phenotype: Glandular, penile or penoscrotal hypospadias.
Comment: Occurs in higher frequency in hypogonadotrophic hypogonadism.
10 Microphallus (micropenis)
Phenotype: Small but otherwise normally shaped penis, measuring less than 2 SDS (25 mm at
birth) in stretched length from the pubic bone to the tip of the glans penis. For review of anthropometric measurements, see Hughes et al. [Arch Dis Child 2006;91:554563].
67
ESPE Code Diagnosis
OMIM
ICD10
10
OVAR I ES , FE MALE
R E PRODUC TIVE TR AC T AN D
B R E A STS
10A
OVARY
E28.3
10A.1
Primary ovarian failure

(hypergonadotrophic hypogonadism)
Possible supplementary codes:
3E.1a.0 primary amenorrhoea
3E.1b.0 secondary amenorrhoea
Steroidogenic block:
CAH (8A.1)
Aromatase deficiency (4C.2b)
Autoimmune polyglandular syndrome (14C.4a)
Gonadal agenesis
Gonadal dysgenesis
Pure 46,XX gonadal dysgenesis (complete or incomplete)1
Gonadal dysgenesis with other specified chromosomal/genetic
abnormality (e.g. trisomy 13, trisomy 18, trisomy 21, Denys Drash
syndrome in XX individual)
Mixed gonadal dysgenesis2
Other, specified gonadal dysgenesis, e.g. 47,XXX, etc.
E28.3
10A.1a
10A.1b
10A.1c
10A.1c.1
10A.1c.2
10A.1c.3
10A.1c.8
600171
Q99.1
Q99.1
Q99.1
Q99.8
Q97.0
Q97.1
Q97.2
Q97.8
10A.1c.9
Gonadal dysgenesis, unspecified
Q98.9
10A.1d
E89.4
10A.1z
Post-ablative ovarian failure, e.g. post-irradiation, post-surgical,

post-chemotherapy3
Resistant ovary syndrome (Savage syndrome, mutation of FSH
receptor gene)4
Due to other specified disorder,
e.g. infection/oophoritis, autoimmune SLE5
Idiopathic/unspecified
10A.2
Ovarian androgen excess
10A.1e
10A.1y
E28.3
*136435
E28.3
E28.3
E28.3
E28.1
68
ESPE Code Diagnosis

10A.2a
10A.2b
10A.3
10A.3a
10A.3b
10A.3c
10A.3d
Polycystic ovary syndrome6

Other causes
OMIM
ICD10
#184700
E28.2
E28.2
Ovarian cysts and tumours

Ovarian follicular cyst
Note: if associated with precocious pseudopuberty: 3A.2c.1
Corpus luteum cyst
Cysts, unspecified
Germ cell tumours7
N83.0
N83.1
N83.2
Benign:
D27
Malignant:
C56
10A.3e
Non-germ cell tumours
Benign:
D27
Malignant:
C56
10A.3e.2
Granulosa tumour8
Other specified tumours
10B
DISORDERS OF THE UTERUS AND CERVIX
10A.3e.1
Functional disorders are classified in 3E, menstrual disorders

10B.1
10B.1a
10B.1b
10B.1c
10B.1d
10B.1y
Congenital malformations
Agenesis and aplasia of the uterus (Mllerian agenesis/MayerRokitansky-Kuster-Hauser syndrome, Mllerian-renal-cervical
spine (MURCS) syndrome)9
Congenital absence of the cervix (isolated)
Endometrial hypoplasia/aplasia
Incomplete Mllerian fusion [includes: double uterus (uterus
didelphy), half uterus (uterus unicornis), partial duplication
(uterus bicornis, Fryns syndrome), partial or complete uterine
septum (uterus septus and subseptus)]
Other specified congenital malformations of uterus and cervix
Q51
#277000
Q51.0
Q51.5
Q51.8
192050
Q51.2
Q51.4
Q51.8
Q51.6
Q51.7
Q51.1
10B.1z
Other congenital malformations of uterus and cervix, unspecified
Q51.9
10B.2
Acquired disorders of the uterus and cervix

Uterine synechiae/Asherman syndrome
Cervical stenosis
N85.6
10B.2a
10B.2b
Ovaries, Female Reproductive Tract and Breasts
N88.2
69
ESPE Code Diagnosis
10B.2z
Other specified acquired malformations of uterus and cervix

Acquired malformations of uterus and cervix, unspecified
10B.3
Tumours of uterus and cervix
10B.2y
OMIM
ICD10
Benign:
D25, D26
Malignant:
10B.8
Other specified disorder of uterus and cervix, e.g. polyps
10B.9
Disorder of uterus and cervix, unspecified
10C
D I S O R D E R S O F T H E VAG I N A AN D E X T E R N AL
F E M A L E G E N I TA L I A
C53, C54
N84.0
N84.1
Possible secondary codes:

3E.1a.0 primary amenorrhoea
3E.1b.0 secondary amenorrhoea
10C.1
10C.1a
10C.1b
10C.1c
10C.1d
10C.1e
10C.1y
10C.1z
10C.2
10C.2a
Congenital malformations
Vaginal agenesis (isolated)
Imperforate hymen (can be part of McKusick-Kaufman
syndrome)
Transverse vaginal septum
Labial fusion/agglutination
Congenital malformation of the clitoris
Excluded: Clitoromegaly due to endocrine causes/virilisation
(4C.2)
Other specified congenital malformations of the female external
genitalia and vagina
Congenital malformations of female external genitalia and
vagina, unspecified
Acquired disorders of the vagina and external female
genitalia
Adhaesions (vaginal, labial, vulval)
Q52
Q52.0
#236700
Q52.3
Q52.8
Q52.5
Q52.6
Q52.8
Q52.9
N89.5
N90.8
10C.2b
10C.2c
10C.2z
Acquired disorders of the clitoris

Excluded: Clitoromegaly due to endocrine causes (3C.2)
Trauma
N90.8
S30.2
S30.2
70
ESPE Code Diagnosis

10C.3
OMIM
Tumours of the vagina and external female genitalia
ICD10
Benign:
D28.0
D28.1
D28.7
D28.9
Malignant:
C51, C52
10C.8
Other, specified, disorders of the vagina and external female

genitalia
E.g. polyps
10C.9
Disorders of the vagina and external female genitalia,

unspecified
10D
DISORDERS OF THE BREAST
10D.1
Galactorrhoea (not associated with childbirth)

Excluded: Galactorrhoea in the male (3C.1)
10D.2
Disorders of size
Hypoplasia/aplasia/hypomastia/micromastia
Macromastia
10D.2a
10D.2b
10D.3b
Disorders in numbers
Polythelia, polymastia
Absence of breast and nipple (athelia)
10D.4
Tumours of breasts
10D.3
10D.3a
N84.2
N84.9
N64.3
Q83.8
N62
%163700
Q83.1
113700
Q83.0
Benign:
D24
Malignant:
C50
10D.8
Other specified disorders of the breast
N60, N61
N63
N64.8
Q83.2
Q83.3
Q83.8
10D.9
Other disorder of the breast, unspecified
N64.9
Q83.9
Ovaries, Female Reproductive Tract and Breasts
71
Pure XX gonadal dysgenesis

Phenotype: Presenting as primary amenorrhoea, no dysmorphic features. FSH (+), LH (+), E2 ().
Normal female external genitalia, insucient breast development, streak gonads. Karyotype 46,XX.
Mixed gonadal dysgenesis

Phenotype: Somatic features of Turner syndrome, short stature; genitalia female, ambiguous or
male. Gonads may be asymmetrical with streak ovaries or dysgenetic testes, also external genital
development may be asymmetrical. Dysgenetic testes bear the risk of gonadoblastoma. LH (+),
FSH (+), E/T ().
Comment: Karyotype commonly 45,X/46,XY.
Post-ablative ovarian failure, post-irradiation, post-surgery, post-chemotherapy

Phenotype: Prepubertal or pubertal gonadal injury may result in hypergonadotrophic hypogonadism. Ovarian surgery (cysts, malignancy). Chemotherapy (nitrogen mustard compounds), especially
sensitive during pubertal period. Pelvic irradiation (leukaemia). LH (+), FSH (+), E ().
Resistant Ovary Syndrome (Mutation of FSH receptor)

Phenotype: Premature ovarian failure occurs in 0.1% before the age of 30 years. Mutations have
been identied in genes like inhibin alpha, FSH receptor and LH/choriogonadotrophin receptor. In
addition, various transcription factors that regulate oocyte gene expression may be aected. Amenorrhoea, LH (+), FSH (+), E ().
Due to other specied disorders, e.g. infection/oophoritis, autoimmune

Phenotype: Disturbance of pubertal development depending on the time of onset. Mumps can
cause oophoritis. Autoimmune oophoritis, usually at puberty, may be associated with autoimmune
polyglandular syndrome. Autoimmune steroidal cell autoantibodies may be detected. Galactosaemia may be associated with ovarian failure (increased concentration of galactose-1-phosphate).
Polycystic ovary syndrome (PCO)

Synonym: Stein-Loewenthal syndrome.
Phenotype: Menstrual irregularity, amenorrhoea, anovulatory cycles, hirsutism, obesity, decreased
fertility. Enlarged ovaries with multiple cysts, hyperthecosis. LH (+), FSH (N), LH:FSH ratio >3, T (+),
adrenal androgens (+), Prl (+), insulin resistance.
Comments: Not observed in prepubertal girls. No clear-cut diagnostic criteria during puberty.
Germ cell tumours

Phenotype: Very malignant endodermal (yolk sac) tumours, occur in the upper vagina and cervix,
cause bleeding.
Granulosa cell tumour

Phenotype: Rapidly progressing virilisation, dysmenorrhoea. 4 androgens (++), T (+), DHEA (N to +).
Agenesis and aplasia of the uterus (Mllerian agenesis/Mayer-Rokitansky-Kster-Hauser

syndrome, Mllerian-renal-cervical spine syndrome (MURCS))
Phenotype: Hypoplasia of the external genitalia, agenesis of Mllerian structures, absence of vagina
and hypoplasia of the uterus. Normal ovarian function. In MURCS association with renal and spinal
abnormalities. Normal female karyotype.
72
ESPE Code
Diagnosis
OMIM
ICD10
11
D ISO R D E R S O F G LUCOSE
AN D TR I G LYCE R I D E
M E TABO LISM
11A
DIABETES ME LLITUS1
11A.1
+222100
E10
11A.1a
11A.1b
Type 1 diabetes [I]2

Immune mediated [I.A]
Idiopathic [I.B]
11A.2
Type 2 diabetes [II]3
#125853
E11
11A.3
Other specific types [III]

Genetic defects of -cell function [III.A]4
HNF-1 defect (MODY3) [III.A1]
Glucokinase defect (MODY2) [III.A2]
HNF-4 (MODY1) [III.A3]
Insulin promoter factor-1 (MODY 4) [III.A4]
Hepatocyte nuclear factor-1beta (MODY 5) [III.A5]
NeuroD1 (MODY 6) [III.A6]
Mitochondrial diabetes [III.A7]5
Other (specified), e.g. Kir6.2 activating mutations [III.A8]
Genetic defects in insulin action [III.B]
Type IA insulin resistance [III.B1]6
Leprechaunism [III.B2]
Rabson-Mendenhall syndrome [III.B3]
Lipoatrophic diabetes [III.B4]
Other (specified) [III.B5], e.g.
Seip-Berardinelli syndrome7
Familial partial lipodystrophy (Dunnigan syndrome)
Type B insulin resistance syndrome
Diseases of the exocrine pancreas [III.C]
Pancreatitis [III.C1]
Trauma/pancreatectomy [III.C2]
Neoplasia [III.C3]
Cystic fibrosis [III.C4]8
Haemochromatosis (haemosiderosis) [III.C5]
Fibrocalculous pancreatopathy [III.C6]
Other specified disorders [III.C7]
11A.3a
11A.3a.1
11A.3a.2
11A.3a.3
11A.3a.4
11A.3a.5
11A.3a.6
11A.3a.7
11A.3a.8
11A.3b
11A.3b.1
11A.3b.2
11A.3b.3
11A.3b.4
11A.3b.5
11A.3c
11A.3c.1
11A.3c.2
11A.3c.3
11A.3c.4
11A.3c.5
11A.3c.6
11A.3c.7
Disorders of Glucose and Triglyceride Metabolism
#606391
#600496
#125851
#125850
#606392
*142410
#600394
#500002
*147670
#246200
#262190
#269700
#269700
#151660
*147670
#219700
+235200
#608189
73
ESPE Code
Diagnosis
11A.3c.9
Other disorders, unspecified [III.C7]

Endocrinopathies [III.D]
[secondary codes]. Primary codes are indicated in brackets
Acromegaly [III.D1] (2B.1)
Cushing syndrome [III.D2] (8C.1)
Glucagonoma [III.D3] (can be part of MEN1) (14C.5a)
Phaeochromocytoma [III.D4] (8D.2a)
Hyperthyroidism [III.D5] (7B)
Somatostatinoma [III.D6] (can be part of MEN1) (14C.5a)
Aldosteronoma [III.D7] (8C.3)
Other specified disorders [III.D8]
Other disorders, unspecified [III.D8]
Drug- or chemical-induced [III.E]
Vacor [III.E1]
Pentamidine [III.E2]
Nicotinic acid [III.E3]
Glucocorticoids [III.E4]9
Thyroid hormone [III.E5]
Diazoxide [III.E6]
-Adrenergic agonists [III.E7]
Thiazides [III.E8]
Dilantin [III.E9]
-Interferon [III.E10]
Other [III.E11]
Infections [III.F]
Congenital rubella [III.F1]
Cytomegalovirus [III.F2]
Other [III.F3]
Uncommon forms of immune-mediated diabetes [III.G]
Stiff-person syndrome (stiff man syndrome) [III.G1]
Anti-insulin receptor antibodies [III.G2]10
Other [III.G3]
Other genetic syndromes sometimes associated with diabetes
[III.H] [secondary]. Primary codes are indicated in brackets
Down syndrome [III.H1] (14A.2)
Klinefelter syndrome [III.H2] (14A.3)
Turner syndrome [III.H3] (14A.5)
Wolfram syndrome [III.H4] (DIDMOAD) (14B.38)
11A.3d
11A.3d.1
11A.3d.2
11A.3d.3
11A.3d.4
11A.3d.5
11A.3d.6
11A.3d.7
11A.3d.8
11A.3d.9
11A.3e
11A.3e.1
11A.3e.2
11A.3e.3
11A.3e.4
11A.3e.5
11A.3e.6
11A.3e.7
11A.3e.8
11A.3e.9
11A.3e.10
11A.3e.11
11A.3f
11A.3f.1
11A.3f.2
11A.3f.3
11A.3g
11A.3g.1
11A.3g.2
11A.3g.3
11A.3h
11A.3h.1
11A.3h.2
11A.3h.3
11A.3h.4
OMIM
ICD10
#102200
+131100
#171300
#275000
+131100
184850
#190685
#222300
#598500
11A.3h.5
11A.3h.6
Friedreich ataxia [III.H5]

Huntington chorea [III.H6]
#229300
+143100
74
ESPE Code
Diagnosis
OMIM
11A.3h.7
Laurence-Moon-Bardet-Biedl syndrome [III.H7] (14B.18)
245800
11A.3h.8
11A.3h.11
Myotonic dystrophy, Steinert syndrome [III.H8] (14B.35)

Porphyria [III.H9]
Prader-Willi(-Labhart) syndrome [III.H10] (14B.25)
Other [III.H11], e.g. Alstrm syndrome (14B.3)
11A.4
Gestational diabetes mellitus (GDM) [IV]
11A.5
Malnutrition related or tropical diabetes [V]
11A.6
Pathological glucose tolerance11
11A.7
Diabetic complications
11A.7a
11A.7d
Diabetic ketoacidosis
Diabetic nephropathy
Diabetic retinopathy
Diabetic neuropathy
11B
H Y P O G LY C A E M I A
11B.1
Hyperinsulinism
Excluded: Hyperinsulinism or impaired glucose tolerance
secondary to other conditions, e.g. simple obesity (5A), PCOS
(10A.2a)
Transient hyperinsulinism
Infant of diabetic mother12
Perinatal asphyxia
Rhesus disease
Intrauterine growth retardation
Beckwith-Wiedemann syndrome [primary 14B.5]
Idiopathic
Congenital (permanent) hyperinsulinism13
SUR1 mutations
KIR6.2 mutations
Glucokinase mutations
glutamate dehydrogenase mutations
Defects in the metabolism of fatty acids (SCHAD)
(3alpha-hydroxyacyl-CoA dehydrogenase)
Carbohydrate-deficient glycoprotein syndrome (CDG)
ICD10
#209900
11A.3h.9
11A.3h.10
11A.7b
11A.7c
11B.1a
11B.1a.1
11B.1a.2
11B.1a.3
11B.1a.4
11B.1a.5
11B.1a.9
11B.1b
11B.1b.1
11B.1b.2
11B.1b.3
11B.1b.4
11B.1b.5
11B.1b.6
#160900
#176000
#176270
#201800
E10.1
E10.2
E10.3
E10.4
P70.4
P70.1
P70.4
P70.4
P70.4
#130650
Q87.3
P70.9
E16.1
#256450
#256450
#256450
*138130
*601609
#212065
75
ESPE Code
Diagnosis
11B.1b.7
Insulinomas14
Other specified causes
11B.1b.8
11B.1b.9
11B.2
11B.2a
11B.2b
11B.3
11B.3a
11B.3b
11B.3c
11B.3d
11B.3e
11B.3f
11B.3g
11B.3z
11B.4
11B.4a
11B.4b
OMIM
M8151/0
E16.1
E16.1
Hormonal deficiency
Growth hormone deficiency (1B.3)
Cortisol deficiency: primary (adrenal defect) (8A)
Secondary (ACTH deficiency) (8B and 6A.1)
Noradrenaline (epinephrine) deficiency (8D.1)
Glucagon deficiency15
Defects in hepatic glycogen release/storage (glycogen
storage diseases)
Glucose-6-phosphatase deficiency16
Glucose-6-phosphatase translocase deficiency17
Amylo 1-6 glucosidase deficiency18
Branching enzyme deficiency19
Liver phosphorylase deficiency20
Phosphorylase kinase deficiency21
Hepatic glycogen synthase deficiency22
Other defects, unspecified
Defects in gluconeogenesis
Hereditary fructose intolerance, fructose-1,6-bisphosphatase
deficiency23
Phosphoenolpyruvate carboxykinase (PEPCK) deficiency24
ICD10
E16.1
E74.0
+232200
+232400
+232400
#232500
+306000
+306000
#240600
E74.1
+229600
+261680
+261650
11B.4c
11B.4z
11B.5
11B.5a
11B.5b
11B.5c
11B.5d
11B.5e
11B.5f
11B.5g
Pyruvate carboxylase deficiency25

Defects of fatty acid oxidation and carnitine metabolism
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency26
Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency27
Short-chain acyl-CoA dehydrogenase (SCAD) deficiency
Long-/short-chain-L-3-hydroxy-acyl CoA (L/SCAD, LCHAD)
deficiency (trifunctional protein deficiency)28
Carnitine deficiency29
Carnitine palmitoyltransferase type I deficiency30
Carnitine palmitoyltransferase type II deficiency31
#266150
E16.2
#201475
#201450
#201470
#609015
#212140
#255120
#255110
#608836
#600649
76
ESPE Code
Diagnosis
OMIM
11B.5h
Carnitine-acylcarnitine translocase deficiency32

+212138
11B.5z
11B.6
11B.6a
11B.6b
11B.6c
11B.6z
11B.7
11B.7a
Defects in ketone body synthesis/utilisation

HMG CoA-synthase deficiency/HMG CoA-lyase deficiency
Succinyl-CoA: 3-oxoacid CoA-transferase (SCOT) deficiency
Hepatic glycogen synthase deficiency
Other metabolic conditions
Organic acidaemias (propionic/methylmalonic)
ICD10
E16.2
#605911
#245050
*138571
E71.1
#606054
#251000
11B.7b
11B.7c
11B.7d
11B.7e
11B.7f
Galactosaemia33
Maple syrup disease34
3-Hydroxy 3-methylglutaryl-CoA lyase deficiency35
3-Methylcrotonyl-CoA carboxylase deficiency36
Tyrosinaemia
#230400
#248600
+246450
#210200
+276700
+276600
#276710
11B.7g
11B.7h
11B.7z
11B.8
11B.8a
11B.8b
11B.8z
11B.9
11B.9a
11B.9b
11B.9c
11B.9d
11B.9e
11B.9f
11B.9y
11B.9z
11C
Glutaric aciduria type 237

Mitochondrial respiratory chain complex deficiencies
#231680
#256000
Drug induced
E.g. sulphonylureas, insulin, beta-blockers, salicylates, alcohol
Ethanol toxicity38
Salicylate toxicity39
Toxicity from other sources, unspecified
E16.0
Miscellaneous causes
Idiopathic ketotic hypoglycaemia (diagnosis of exclusion)40
Infections (e.g. septicaemia, malaria)
Congenital heart disease
Fulminant hepatic failure 41
Reye syndrome42
Jamaican vomiting sickness 43
E16.1
PRIMARY DISTURBANCES OF LIPOPROTEIN

M E T A B O L I S M 44
77
ESPE Code
Diagnosis
11C.1
Genetic hyperlipoproteinaemias
Familial hypercholesterolaemia (type IIa
hyperlipoproteinaemia)45
Heterozygous familial hypercholesterolaemia
Homyzygous familial hypercholesterolaemia
Familial defective apolipoprotein B-10046
Polygenic hypercholesterolaemia47
Familial combined hypercholesterolaemia (hyperlipidaemia)
(type IIa)48
Familial hypertriglyceridaemia49
11C.1a
11C.1a.1
11C.1a.2
11C.1b
11C.1c
11C.1d
11C.1e
11C.2
11C.2a
11C.2b
11C.2b.1
11C.2b.2
11C.2b.3
11C.2c
11C.2d
11C.2d.1
11C.2d.2
11C.2d.3
11C.2e
11C.3
11C.3a
11C.3b
11C.3c
11C.3d
11C.3e
11C.4
11C.4a
11C.4b
11C.4c
11C.4d
11C.4e
11C.4y
11C.4z
Disorders of apolipoproteins
Apolipoprotein A disorders: familial APOA-I deficiency and
structural APOA-I mutations50
Apolipoprotein B disorders
Abetalipoproteinaemia51
Familial hypobetalipoproteinaemia52
Chylomicron retention disease53
Apolipoprotein C disorders (apolipoprotein C-II deficiency)
(type Ib)54
Apolipoprotein E disorders
Familial dysbetalipoproteinaemia (type III
hyperlipoproteinaemia)55
Type V hyperlipoproteinaemia (HLP)56
Other apolipoprotein E disorders
Lp(a) disorders57
Other disorders of lipoprotein metabolism
Tangier disease58
Lipoprotein lipase deficiency (type Ia)59
Hepatic lipase deficiency
Familial lecithin-cholesterol acyltransferase deficiency60
Cholesterol ester transfer protein deficiency
Other disorders of lipid and cholesterol metabolism
Smith-Lemli-Opitz syndrome (14B.33)
Cerebrotendinous xanthomatosis61
Phytosterolaemia (beta-sitosterolaemia)62
Cholesterol ester storage disease and Wolman disease
Niemann-Pick C disease
OMIM
ICD10
#143890
E78.0
#144010
E78.8
E78.2
#144250
E78.0
#145750
E78.1
*107680
E78.8
+107730
E78.8
#200100
E78.6
%605019
E78.6
#246700
E78.3
#207750
E78.3
+107741
E78.1
+107741
E78.2
#144650
E78.3
+107741
E78.8
+152200
E78.8
#205400
E78.6
246650
E78.3
246650
E78.3
#245900
E78.6
#607322
E78.8
#213700
E75.5
#210250
E78.8
+278000
E75.5
#257220
E75.2
E78.8
E78.9
78
Diabetes mellitus
Comments: For this classication the most recent updated Etiologic classication of diabetes mellitus is used [American Diabetes Association: Diagnosis and classication of diabetes mellitus. Diabetes Care 2007;30(suppl 1);S4247].
Type 1 diabetes
Synonyms: Insulin-dependent diabetes mellitus (IDDM), juvenile insulin-dependent diabetes.
Phenotype: Polyuria, polydipsia, nocturia, polyphagia, weight loss, or symptoms of frank diabetic
ketoacidosis: air hunger, Kussmaul breathing, acetone on the breath, vomiting, dehydration, abdominal pain, obtundation of consciousness or coma. Loss of insulin secretion, acquired deciencies
of the secretion of some counterregulatory hormones (glucagon, adrenalin). Auto-antibodies: islet
cells (ICA), insulin (IAA), glutamate-decarboxylase (GAD II), etc.
Comment: Caused by beta-cell destruction, usually leading to absolute insulin deciency.
Type 2 diabetes
Synonyms: Type II diabetes, non-insulin-dependent diabetes mellitus (NIDDM).
Phenotype: Non-characteristic. May be suspected in obese patients, family history positive, glycosuria, no ketonuria. Many aected children are asymptomatic, some have signs of hyperglycaemia
(polyuria, polydipsia) without ketosis; the majority are overweight. Insulin insuciency and insulin
resistance (may range from predominantly insulin resistance with relative insulin deciency to predominantly secretory defect with insulin resistance). Auto-antibodies (ICA, IAA, GAD II, etc.) usually
negative.
Comments: Probably multifactorial, familial aggregation is common. Uncommon in children, most
patients are adolescents. Strongly associated with obesity of the population.
Genetic defects of -cell function

Synonyms: Maturity-onset diabetes of the young (MODY), non-insulin-dependent diabetes of
youth (NIDDY).
Phenotype: Non-characteristic, strong family history with mild diabetes at a young age; usually glycosuria, no ketonuria, no insulin resistance. Many aected children are asymptomatic or have mild
symptoms, they are usually adolescents of normal weight or slightly obese. Transcription factor
MODY caused by mutations in the genes encoding hepatocyte nuclear factor (HNF)-1a (chromosome 12q, MODY 3), HNF-1b (MODY 5), HNF-4a (chromosome 20q, MODY 1) and insulin promoter
factor (IPF)-1 (MODY 4) usually results in a progressive beta-cell defect and progressive hyperglycaemia (525 mmol/l) with a very high and early incidence of diabetic complications. In GCK diabetes there is only mild (5.514 mmol/l) hyperglycaemia.
Comment: Questionable in patients without NIDDM family history.
Mitochondrial diabetes
Synonym: Maternally transmitted diabetes with deafness.
Phenotype: Similar to type I or type II diabetes, deafness. Impaired insulin secretion.
Comment: Maternally transmitted trait.
79
Type A insulin resistance

Phenotype: Type A syndrome: Extreme insulin resistance, acanthosis nigricans, hyperandrogenism
without obesity or lipoatrophy. Leprechaunism: In addition to type A symptoms intrauterine and
neonatal growth retardation with fasting hypoglycaemia. Lipatrophic diabetes (generalised lipodystrophy): Overall absence of fat, insulin resistance, acanthosis nigricans with or without hyperlipidaemia and sexual precocity. Typically diagnosed in young thin females before the fourth decade
and sometimes by adolescence; accelerated childhood growth; acral hypertrophy; recurrent muscle
cramps; skin: papillomatosis, epidermal hyperkeratosis and hyperpigmentation commonly of neck,
axillae, antecubital fossae and over knuckles; virilisation with hirsutism (especially at/after puberty);
obesity; menstrual abnormalities or primary or secondary amenorrhoea. Severe insulin resistance
with marked glucose intolerance leading to type 2 diabetes mellitus; SHBG (), T (+), adrenal androgens (+); hyperlipidaemia which may be life-threatening.
Berardinelli syndrome
Synonyms: Congenital generalised lipodystrophy (CGL), total lipodystrophy, Lawrence-Seip syndrome, Berardinelli-Seip syndrome.
Phenotype: Lack of adipose tissue, hypertrophy of muscle. Tall stature, large hands and feet. Phallic/
clitoral hypertrophy. Elevated basal metabolic rate. Hypertrophic cardiomyopathy. Hepatomegaly
leading to cirrhosis. Acanthosis nigricans, insulin resistance, polycystic ovaries. Corneal opacities.
Hyperinsulinism with insulin resistance and hyperlipidaemia.
Cystic brosis
Phenotype: Typical symptoms of diabetes, ketoacidosis is rare. Chronic pancreatic inammation.
Insulin insuciency or deciency.
Secondary diabetes mellitus due to glucocorticoid therapy

Synonym: Steroid diabetes.
Phenotype: Symptoms of diabetes. Insulin resistance and hypoinsulinaemia (in some cases).
10
Anti-insulin receptor antibodies

Synonym: Type B syndrome.
Phenotype: Severe insulin resistance, acanthosis nigricans, frequently other autoimmune diseases:
alopecia, vitiligo, Raynaud disease, lupus erythematosus, Sjgren syndrome, ataxia telangiectasia,
arthritis, antinuclear (anti-DNA) antibodies, elevated erythrocyte sedimentation rate. Severe hyperinsulinism (10- to 100-fold of normal).
11
Pathological glucose tolerance

Synonym: Impaired glucose tolerance (IGT).
Phenotype: Patients are clinically asymptomatic. Insulin resistance and probably hypoinsulinaemia.
Comments: Rare in children, not uncommon in obese adolescents. Persons with IGT appear to be at
higher risk than the general population for the development of type 2 diabetes.
12
Infant of diabetic mother

Phenotype: Large for date infant with hypoglycaemic tendency due to hyperinsulinism. Respiratory
distress syndrome, polycythaemia, jaundice, hypocalcaemia and hypomagnesaemia occur more
80
commonly than in normal infants. Increased incidence of prematurity, and congenital malformations (58%), specically sacral agenesis.
Comment: Features of IDM can be minimised if good metabolic control of diabetes mellitus can be
achieved during pregnancy.
13
Congenital hyperinsulinism
Synonyms: Nesidioblastosis, hyperinsulinaemia of infancy, neonatal hyperinsulinism.
Phenotype: Persistent hypoglycaemia usually beginning in the neonatal period, associated with
elevated/inappropriate insulin levels.
Comments: Medical therapy involves oral diazoxide and chlorothiazide (acting on KATP channel),
nifedipine (acting on calcium channel). Subcutaneous somatostatin and glucagon infusions are
helpful in acute management and can be given long term. 95% pancreatectomy is required for diffuse hyperinsulinism resistant to medical treatment, partial pancreatectomy for focal hyperinsulinism. Surgery should only be performed in designated specialist centres.
14
Insulinomas
Phenotype: Fasting hypoglycaemia, obesity.
15
Glucagon deciency
Phenotype: Symptoms of recurrent neonatal hypoglycaemia.
16
Glucose-6-phosphatase deciency
Synonyms: Glycogenosis type Ia, von Gierkes disease, glycogen storage disease type 1a (GSD Ia).
Phenotype: Hepatomegaly, hypoglycaemia and lactic acidaemia; long-term: growth failure, osteoporosis, anaemia, gout, hyperlipidaemia, insulin resistance, hepatic adenomas, renal disease, pulmonary hypertension.
17
Glucose-6-phosphatase translocase
Synonym: Glycogenosis type Ib (GSD Ib).
Phenotype: As for GSD type Ia, recurrent infections, neutropenia, impaired neutrophil function, inammatory bowel disease.
18
Amylo 1-6 glucosidase deciency (glycogenosis type IIIa and type IIIb)
Synonyms: Type IIIa: liver and muscle debrancher deciency, limit dextrinosis, Cori or Forbes disease. Type IIIb: liver debrancher deciency (GSD III).
Phenotype: Type IIIa: hepatomegaly, hypoglycaemia, growth failure, muscle weakness, cardiomyopathy, hyperlipidaemia. Type IIIb: no muscle symptoms.
19
Branching enzyme
Synonyms: Glycogen storage disease type IV, branching enzyme deciency, amylopectinosis, Andersens disease (GSD IV).
Phenotype: Failure to thrive, hepatosplenomegaly, portal hypertension, muscle weakness, cardiomyopathy, progressive stenosis, elevated transaminase levels.
81
20
Liver phosphorylase deciency

Synonyms: Glycogen storage disease type VI, Hers disease (GSD VI).
Phenotype: Hepatomegaly, diminishing with age, growth retardation, mild hypoglycaemia and hyperlipidaemia, ketosis.
21
Phosphorylase kinase deciency

Synonym: Glycogen storage disease type IX (GSD IX).
Phenotype: Hepatomegaly, growth retardation, mild muscle weakness, mild hypoglycaemia, mild
hyperlipidaemia. A few cases have been reported with isolated involvement of muscle or heart.
Comment: Sometimes included in GSD type VI.
22
Hepatic glycogen synthase deciency

Synonym: Glycogen synthetase deciency.
Phenotype: Early morning drowsiness, fatigue, fasting hypoglycaemia, ketosis, postprandial hyperglycaemia.
23
Hereditary fructose intolerance, fructose-1,6-bisphosphatase deciency

Synonym: Fructosaemia, fructose-1,6-diphosphatase deciency.
Phenotype: Symptoms after exposure to fructose. Neonate: Poor feeding, vomiting, hypoglycaemia,
hepatomegaly, liver failure, bleeding, renal tubular dysfunction. Older child: Episodic, provoked by
fasting: hepatomegaly, poor growth, aversion for sweet food. Hyperventilation due to acidosis, hypoglycaemia, encephalopathy.
24
Phosphoenolpyruvate carboxykinase (PEPCK) deciency

Phenotype: Lactic acidaemia, hypoglycaemia, hypotonia, failure to thrive.
Comment: Some published cases have actually had respiratory chain defects or hyperinsulinism.
25
Pyruvate carboxylase deciency

Phenotype: Type A: lactic acidaemia, hepatomegaly, mental retardation; type B: lactic acidaemia,
hepatomegaly, hyperammonaemia, citrullinaemia, hyperlysinaemia, death by 3 months; type C: intermittent lactic acidaemia.
Comment: Hypoglycaemia is not a prominent feature.
26
Very-long-chain acyl-CoA dehydrogenase (VLCAD) deciency

Phenotype: Fasting hypoglycaemia, cardiomyopathy, episodic rhabdomyolysis.
Comment: Many cases were previously labelled as long-chain acyl-CoA dehydrogenase (LCAD) deciency.
27
Medium-chain acyl-CoA dehydrogenase (MCAD) deciency

Phenotype: Fasting hypoglycaemia and encephalopathy, unexpected infant death.
28
Long-/short-chain-L-3-hydroxy-acyl CoA (LCHAD) deciency

Synonym: Trifunctional protein deciency.
Phenotype: Fasting hypoglycaemia and encephalopathy, hypertrophic cardiomyopathy, myopathy
and episodic rhabdomyolysis, pigmentary retinopathy and neuropathy (long-term), acute fatty liver
of pregnancy or HELLP syndrome (women carrying an aected foetus).
82
29
Carnitine deciency
Synonym: Carnitine transport defect.
Phenotype: Cardiomyopathy, muscle weakness, fasting hypoglycaemia.
Comment: Secondary carnitine deciency occurs in many -oxidation defects.
30
Carnitine palmitoyltransferase type I (CPT I) deciency

Phenotype: Fasting hypoglycaemia and encephalopathy.
31
Carnitine palmitoyltransferase type II (CPT II) deciency

Phenotype: Infants: fasting hypoglycaemia and encephalopathy, cardiomyopathy, congenital
anomalies (kidneys, brain); adolescents, young adults: myopathy and episodic rhabdomyolysis.
32
Carnitine-acylcarnitine translocase deciency

Phenotype: Hypoketotic hypoglycaemia and encephalopathy, hyperammonaemia, cardiomyopathy, heart block, arrhythmias.
33
Galactosaemia
Phenotype: Diarrhoea, vomiting, failure to thrive, cataracts, liver disease, intellectual retardation
(especially aecting speech). Ovarian failure.
Comment: Probably only causes hypoglycaemia as a complication of severe liver failure.
34
Maple syrup disease (MSUD)

Phenotype: Neonatal: lethargy, anorexia, encephalopathy leading to seizures and coma, ketosis,
odour; intermittent: episodic encephalopathy; intermediate: developmental delay and/or ts, episodic ketoacidosis.
35
3-Hydroxy 3-methylglutaryl-CoA (HMG-CoA) lyase deciency

Phenotype: Recurrent episodes of encephalopathy, acidosis and hypoketotic hypoglycaemia, liver
dysfunction.
36
3-Methylcrotonyl-CoA carboxylase deciency

Synonym: 3-Methylcrotonylglycinuria.
Phenotype: Recurrent episodes of encephalopathy, acidosis and hypoketotic hypoglycaemia, liver
dysfunction.
37
Glutaric aciduria type 2

Synonyms: Glutaric acidaemia type II, multiple acyl-CoA dehydrogenase deciency (severe or mild),
ethylmalonic-adipic aciduria (late onset cases).
Phenotype: Neonatal onset with congenital anomalies: hypotonia, metabolic acidosis, odour; hypotonia; hepatomegaly; renal cysts, dysmorphism. Neonatal onset without congenital anomalies: hypoglycaemia, metabolic acidosis, odour; hepatomegaly; cardiomyopathy. Late onset cases: Episodic
vomiting, hypoglycaemia and acidosis; myopathy.
38
Ethanol toxicity
Phenotype: In children, alcohol can cause hypoglycaemia after relatively short fasts. Other symptoms of ethanol ingestion: confusion, vomiting, inebriation.
83
39
Salicylate toxicity
Synonym: Aspirin toxicity.
Phenotype: Hypoglycaemia can occur with overdoses or with therapeutic doses in young children
(<3 years), especially if fasting. Other symptoms of toxicity: tinnitus, vomiting, tremor, sweating,
confusion, hyperventilation.
40
Idiopathic ketotic hypoglycaemia (diagnosis of exclusion)

Synonym: Accelerated starvation.
Phenotype: Fasting hypoglycaemia, sometimes leading to seizures.
Comments: This is a diagnosis of exclusion. It comprises a heterogeneous group of patients. Some
may represent the lower end of the normal distribution for fasting blood glucose concentrations,
whilst others may have as yet unrecognised metabolic or endocrine defects.
41
Fulminant hepatic failure

Phenotype: Hypoglycaemia can occur in acute hepatic failure from any cause but only in severe
cases, accompanied by encephalopathy. The clinical picture will be that of hepatic failure (jaundice,
anorexia, vomiting, bleeding and encephalopathy).
42
Reyes syndrome
Phenotype: Vomiting; encephalopathy, seizures; hepatic dysfunction with hyperammonaemia and
coagulopathy; hypoglycaemia; preceding viral illness and/or aspirin exposure.
Comment: This is a diagnosis of exclusion, many suspected cases actually having inborn errors of
metabolism (-oxidation or urea cycle defects or organic acidaemias).
43
Jamaican vomiting sickness

Synonym: Hypoglycin toxicity.
Phenotype: Vomiting and encephalopathy; hypoglycaemia and acidosis; liver dysfunction.
Comment: Hepatic steatosis and glycogen depletion due to unripe ackee fruit (West Indies).
44
Genetic hyperlipoproteinaemias (hyperlipidaemias)

Comments: In each textbook, a somewhat dierent classication is used. The hyperlipidaemias have
traditionally been classied as Fredrickson types IV on the basis of the type of lipoprotein particle
that is increased in plasma. However, as a classication scheme it is now generally felt unhelpful.
Hyperlipidaemias can be subdivided into primary (resulting from inherited defects in lipid metabolism) and secondary hyperlipidaemias (resulting from acquired metabolic conditions). In the ESPE
classication the genetic hyperlipoproteinaemias are classied according to Oskis Pediatrics, ed 4;
in McMillan JA, Feigin RD, DeAngelis C, Jones MD (eds). Philadelphia, Lippincott Williams & Wilkins,
2006.
45
Familial hypercholesterolaemia (FH)

Synonym: Autosomal-dominant hypercholesterolaemia, type IIa hyperlipoproteinaemia, LDL receptor disorder.
Phenotype: Heterozygotes: Tendon xanthomas, xanthelasma and arcus corneae appear at the age
of 20 years or later; coronary atherosclerosis from 30 years of age. Homozygotes: Cutaneous xanthomas by 4 years of age; coronary heart disease in childhood; aortic valve stenosis.
84
46
Familial defective apolipoprotein B-100

Synonyms: Autosomal-dominant hypercholesterolaemia, type B; familial defective apolipoprotein B.
Phenotype: Increased risk of coronary heart disease; raised plasma cholesterol and LDL.
47
Polygenic hypercholesterolaemia
Phenotype: Cholesterol and LDL are moderately elevated, lipoprotein electrophoretic pattern usually IIa type, or IIb.
Comments: Multifactorial etiology. Occurs in 5% of the adult population.
48
Familial combined hyperlipidaemia

Phenotype: Early coronary heart disease; raised apolipoprotein B-100 levels and plasma VLDL, LDL
or both.
49
Familial hypertriglyceridaemia
Phenotype: In the mild forms of this condition symptoms usually not evident during childhood. Environmental factors may potentiate symptoms in aected adults. Plasma triglycerides are elevated
moderately. VLDL is elevated, but cholesterol is not. Lipoprotein electrophoretic patterns of type IV
or occasionally type V. The severe form presents also in childhood, and is characterised by elevated
triglycerides, fasting chylomicronaemia, eruptive xanthomas, recurrent abdominal pain and pancreatitis, and a type V lipoprotein pattern.
Comments: Mild forms: Autosomal dominant that aects 0.20.3% of the population, associated
with mutations in the HTGS gene. Severe forms: Autosomal dominant, resulting from mutations at
the apoE gene locus that lead to defective binding with the LDL receptor and other LDL receptorrelated proteins.
50
Apolipoprotein A disorders
Phenotype: Severe coronary atherosclerosis, cutaneous and tendinous xanthomas, and corneal
clouding, low levels of HDL, normal LDL and cholesterol.
Comment: Familial apoA-I deciency is a rare autosomal-recessive disorder.
51
Abetalipoproteinaemia
Synonym: Bassen Kornzweig disease.
Phenotype: Steatorrhoea; failure to thrive; spinocerebellar ataxia, peripheral neuropathy, pigmentary retinopathy, ceroid myopathy; absent VLDL and LDL, absent apoB-48 and apoB-100 in plasma.
Comment: Due to absence of a microsomal triglyceride transfer protein (MTP) involved in the assembly, processing, or secretion of apoB-containing lipoproteins.
52
Familial hypobetalipoproteinaemia
Phenotype: Homozygotes: steatorrhoea; failure to thrive; spinocerebellar ataxia, peripheral neuropathy, pigmentary retinopathy, ceroid myopathy; absent VLDL and LDL; heterozygotes: sometimes
ataxia or pigmentary retinopathy; low LDL and cholesterol levels.
53
Chylomicron retention disease

Phenotype: Steatorrhoea, occasional neurological problems.
85
54
Apolipoprotein C-II deciency

Phenotype: Recurrent pancreatitis; chylomicroanaemia, raised plasma triglycerides.
55
Familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia)

Phenotype: Cutaneous xanthomas; peripheral and coronary atherosclerosis in adults; raised plasma
cholesterol and triglycerides with excess -VLDL.
56
Type V hyperlipoproteinaemia (HLP)

Phenotype: Increased risk of coronary heart disease; raised plasma Lp(a).
57
Lp(a) disorders
Comments: Lp(a), a variant of LDL, consists of an LDL-like molecule that has one or two copies of
the glycoprotein Lp(a) attached to its apoB-100. Approximately 20% of the general population have
high levels of Lp(a) that double the risk for premature atherosclerosis.
58
Tangier disease
Synonym: Familial high-density lipoprotein deciency.
Phenotype: Hyperplastic orange tonsils; splenomegaly, relapsing neuropathy; low plasma cholesterol and HDL.
59
Lipoprotein lipase deciency

Phenotype: Recurrent pancreatitis; cutaneous xanthomas; hepatosplenomegaly; chylomicronaemia.
60
Familial lecithin-cholesterol acyltransferase (LCAT) deciency

Synonym: Fish eye disease (mild variant).
Phenotype: LCAT deciency: corneal opacities; anaemia; proteinuria and sometimes renal failure.
Fish eye disease: corneal opacities. Little 1 and no pre--lipoprotein bands, unusual LDL particles
with high unesteried cholesterol and phosphatidylcholine.
61
Cerebrotendinous xanthomatosis
Phenotype: Tuberous and tendon xanthomas; dementia, ataxia, paraparesis; atherosclerosis; cataracts.
62
Sitosterolaemia
Synonym: Phytosterolaemia.
Phenotype: Tuberous and tendon xanthomas; premature coronary atherosclerosis.
86
ESPE Code Diagnosis
OMIM
ICD10
12
D I SO R D E R S O F BO N E
M E TABO LISM , I N CLU D I N G
C ALCI UM/ PH OS PHATE
M E TABO LISM
12A
T R A N S I E N T H Y P O C A L C A E M I A ( N E O N AT A L )
E83.5
12A.1
Early neonatal1
Prematurity 2
Asphyxia
Infant of diabetic mother
Perinatal stress or trauma
P71.1
Late neonatal3
Conditions classified under permanent hypocalcaemia,
hypomagnesaemia
High milk phosphate load
P71.1
12A.1a
12A.1b
12A.1c
12A.1d
12A.2
12A.2a
12A.2b
P71.0,
P71.1
12A.2h
Parenteral nutrition
Exchange transfusions
Chronic alkalosis or bicarbonate treatment
Maternal hypercalcaemia
Maternal vitamin D deficiency
Transient hypoparathyroidism
12B
PERMANENT HYPOCALCAEMIA
12B.1
Genetic disorders of the calcium-sensing receptor

Autosomal-dominant hypocalcaemia
Autosomal-dominant hypocalcaemia with Bartter-like features
12A.2c
12A.2d
12A.2e
12A.2f
12A.2g
12B.1a
12B.1b
12B.2
12B.2a
12B.2b
Hypoparathyroidism
DiGeorge syndrome types 1 and 2 (14B.10)
Autoimmune polyglandular syndrome type 1 (APECED syndrome)
(14C.4a)
X-linked hypoparathyroidism
Disorders of Bone Metabolism, Including Calcium/Phosphate Metabolism
P71.4
#146200
+601199
E20.9
E20.8
%307700
E20.8
87
ESPE Code Diagnosis

12B.2c
12B.2c.1
12B.2c.2
12B.2c.3
12B.2c.4
12B.2c.9
12B.2d
12B.2e
12B.2f
12B.2f.1
12B.2f.2
12B.2f.9
12B.2g
12B.2g.1
12B.2g.2
12B.2g.3
12B.2g.4
12B.2z
Mitochondrial disorders
Kearns-Sayre
MELAS
Pearson marrow-pancreas syndrome
tRNA-Leu mutation
Other
Hypoparathyroidism, deafness and renal anomalies (Barakat
syndrome)
Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD
deficiency) [primary 11B.5d]
Other familial syndromes
Kenny-Caffey syndrome type 1
Sanjad-Sakati
Acquired hypoparathyroidism
Parathyroid surgery
Isolated autoimmune hypoparathyroidism
Iron overload
Other specified acquired forms
Idiopathic
12B.3
PTH defects
(autosomal-dominant or autosomal-recessive familial isolated
hypoparathyroidism)
12B.4
PTH/PTHrP receptor defects4

Pseudohypoparathyroidism type 1b
Other PTH/PTHrP receptor defects, unspecified
12B.4a
12B.4z
12B.5
12B.5a
12B.5b
12B.5c
12B.5d
12B.6
12B.6a
12B.6b
12B.6c
12B.6d
Post-receptor defects
Classified elsewhere:
Pseudohypoparathyroidism type Ia (Albrights hereditary
osteodystrophy, 14B.2)
Pseudohypoparathyroidism type Ic
Pseudohypoparathyroidism type II
Pseudohypoparathyroidism with testotoxicosis
Magnesium deficiency5
Familial primary hypomagnesaemia
Familial hypomagnesaemia with hypercalciuria,
nephrocalcinosis, and severe ocular involvement
Isolated renal magnesium wasting
Hypomagnesaemia with secondary hypocalcemia
OMIM
ICD10
#530000
#540000
#557000
*590050
#146255
*600890
E20.8
#244460
#241410
E20.0
#146200
E20.8
#603233
E20.1
#103580
E20.1
%203330
E20.1
#176410
E20.1
E83.4
#248250
#248190
#154020
#602014
88
ESPE Code Diagnosis

12B.6e
Gitelman syndrome [primary 14B.15]
12B.7
Calciopenic rickets (see 12C.1)
12B.8
12B.8z
Systemic conditions associated with hypocalcaemia

Tumour lysis syndrome
Renal osteodystrophy6
AIDS
Other conditions, unspecified
12C
RICKETS
12C.1
Calciopenic rickets
Nutritional (vitamin D deficiency)
Malabsorption
Liver disease
Anticonvulsant treatment (phenobarbital, phenytoin)
Renal osteodystrophy6
Calcium deficiency rickets7
Genetic
Vitamin D 1-hydroxylase deficiency (formerly known as
pseudo-vitamin D-deficiency rickets, vitamin D-dependent
rickets type I)
Hereditary 1,25(OH)2D-resistant rickets (formerly known as
pseudo-vitamin D-deficiency rickets type II, vitamin
D-dependent rickets type II, calcitriol-resistant rickets)
12B.8a
12B.8b
12B.8c
12B.8y
12C.1a
12C.1a.1
12C.1a.2
12C.1a.3
12C.1a.4
12C.1a.5
12C.1b
12C.1b.1
12C.1b.2
12C.2
12C.2a
12C.2b
12C.2b.1
12C.2b.2
12C.2b.3
12C.2b.4
12C.2c
12C.2d
12C.3
Phosphopenic rickets
McCune-Albright syndrome (14B.22)
Renal tubular disorders Fanconi renotubular syndrome (14B.13)
Familial hypophosphataemic rickets
X-linked hypophosphataemic rickets8
Autosomal-dominant hypophosphataemic rickets9
Hereditary hypophosphataemic rickets with hypercalciuria10
Hypophosphataemic nonrachitic bone disease
Tumour-induced osteomalacia11
Decreased phosphate intake12
Hypopophosphatasia
(if not associated with rickets, classify under 12E.5l)
OMIM
ICD10
#263800
N25.0
E55.0
N25.0
#264700
E83.3
#277400
E83.3
E83.3
#307800
#193100
#241530
%146350
#146300
E83.3
#241500
89
ESPE Code Diagnosis
12D
OSTEOPOROSIS
12D.1
Genetic defects
Ehlers-Danlos syndrome (14B.11)
Marfan syndrome [primary 14B.20, other secondary 2A.2a]
12D.1a
12D.1b
Osteogenesis imperfecta (types IVII)
OMIM
ICD10
M81.9
#166200
#166210
#166220
#166240
#259420
12D.1d
Homocystinuria [if tall, classify also as 2A.2c]

Other genetic defects
12D.2
Chromosomal defects
M82.8
12D.3
Endocrine disorders
M82.0
12D.4
Iatrogenic causes
M81.4
12D.5
Nutritional disorders
M81.3
12D.6
Chronic diseases
M82.8
12D.7
Malignancies
M82.8
12D.8
Disuse
M81.2
12D.9
Other specified disorders, e.g. muscle and neuromuscular

disorders
M81.8
12D.10
Idiopathic juvenile osteoporosis13
M81.5
12E
HYPERCALCAEMIA
E83.5
12E.1
Disorders of the calcium-sensing receptor

Familial benign hypercalcaemia (familial hypocalciuric
hypercalcaemia)
Neonatal severe primary hyperparathyroidism
Calcium-sensing receptor blocking antibodies
12D.1c
12E.1a
12E.1b
12E.1c
+236200
#145980
#239200
90
ESPE Code Diagnosis

12E.2
12E.2a
12E.2b
12E.2c
12E.2d
12E.2e
12E.2f
12E.2y
12E.3
12E.3a
12E.4y
12E.4
12E.4a
12E.4b
12E.5
12E.5a
12E.5b
12E.5c
12E.5d
12E.5e
12E.5f
12E.5g
12E.5h
12E.5i
12E.5j
12E.5k
12E.5l
12E.5m
12E.5y
12E.5z
OMIM
Disorders of the parathyroid glands/PTH oversecretion

Multiple endocrine neoplasia type 1 (14C.5a)
Multiple endocrine neoplasia type 2a (14C.5b)
Multiple endocrine neoplasia type 2b (14C.5c)
Familial isolated hyperparathyroidism, type 1
Familial isolated hyperparathyroidism, type 2 (jaw tumour)
Sporadic parathyroid adenomas
Parathyroid carcinomas
Tertiary hyperparathyroidism
Other PTH abnormalities (specified)
#145000
PTH/PTHrP Receptor abnormalities

Metaphyseal chondrodysplasia, Jansen type
Other PTH/PTHrP receptor abnormalities (specified)
#156400
Abnormal vitamin D metabolism

Williams-Beuren syndrome (14B.37)
Idiopathic infantile hypercalcaemia14
Miscellaneous causes of hypercalcaemia in childhood
Vitamin D (or vitamin D metabolite) intoxication15
Sarcoidosis, other granulomatous diseases
Immobilisation16
Hypercalcaemia of malignancy
Subcutaneous fat necrosis
Excessive calcium supplementation
Congenital lactase deficiency
Disaccharidase deficiency
Endocrine forms (adrenal insufficiency, severe congenital
hypothyroidism, thyrotoxicosis) (primarily classified elsewhere)
Down syndrome
AIDS
IMAGe syndrome
Hypophosphatasia
Other disorders (unspecified)
ICD10
E21
#145001
E21.0
E21.0
E21.4
E21.4
E21.4
E21.4
Q78.9
#19405
E83.5
E67.3
D86.9
E83.5
E83.5
#223000
#222900
#190685
Q90
B24
300290
#241500
E83.3
91
Early neonatal hypocalcemia (ENH) (<72 h)

Phenotype: Specic signs: tetany, generalised or focal clonic seizures, frequent twitches or jerking
of limbs, hyperacusis, laringospasm, jitteriness, irritability; nonspecic signs: apnoea, tachycardia,
tachypnoea, cyanosis, oedema; may be asymptomatic. Serum-Ca (), P (+), Mg (), PTH (+), CT (+),
25-OHD (), 1,25(OH)2D ().
Comments: The mechanism(s) of ENH is uncertain; possible pathogenetic factors are exaggerated
postnatal depression of circulating Ca levels, transient pseudohypoparathyroid-like state probably
due to an immaturity of renal and bone response to PTH, and exaggerated rise in CT levels. Reduced
25-OHD and 1,25(OH)2D levels may be contributing factors. Conditions at risk to develop ENH: diabetes in the mother, pre-eclampsia, perinatal asphyxia, and prematurity.
Metabolic bone disease (MBD) of prematurity

Synonym: Rickets of prematurity, osteopenia of prematurity.
Phenotype: Asymptomatic, or hypotonia, signs of rickets and/or osteopenia, fractures of the ribs or
long bones, skeletal deformities (rib cage softening, altered head shape), respiratory distress syndrome, growth delay. Serum-Ca (/N), P (/N), alkaline phosphatase (+/N), PTH (+/N), 25-OHD (/N),
1,25(OH)2D (+ if Ca and P are reduced, in case of substrate deciency), urine-Ca (+ in phosphate
depletion syndrome), urine-P (+ in secondary hyperparathyroidism, in phosphate depletion syndrome or normal). Hormonal ndings may vary on the basis of the amount of Ca and P supplied
by the preterm formula, fortied human milk, or parenteral nutrition, the degree of vitamin D deciency, and the adaptative mechanisms in response to the dietary mineral insuciency.
Comments: MBD of prematurity mainly arises from insucient dietary minerals (Ca and P). Copper
deciency, as a result of abnormal collagen metabolism, has also been implicated in this condition.
Phosphate depletion syndrome mainly occurs in preterm neonates who are fed unfortied human
milk or during parenteral nutrition.
Late neonatal hypocalcemia (> 72 h)

Phenotype: Asymptomatic, or symptoms similar to those of early neonatal hypocalcaemia. SerumCa (), P (+), Mg (), PTH (/+), CT (N), 25-OHD (), 1,25(OH)2D ().
Comments: Possible pathogenetic factors seem to be excessive dietary P load in neonates fed cows
milk or cows milk based formula with Ca/P molar ratio 34 times that of human milk, inability of
the immature kidney to excrete P eciently, insucient PTH response to hypocalcaemia, and materno-foetal vitamin D deciency. Late neonatal hypocalcaemia is less frequent than early neonatal
hypocalcaemia. The incidence of late neonatal hypocalcaemia is greater in full term than in preterm
infants. Infants of diabetic mother and infants with transient hypoparathyroidism due to maternal
hypercalcaemia secondary to primary hyperparathyroidism may be at risk for late neonatal hypocalcaemia.
PTH/PTHrP receptor defects

Comment: A congenital defect of the PTH/PTHrP receptor is Blomstrand chondrodysplasia, a perinatally lethal condition, that does not present with hypocalcaemia.
Magnesium deciency
Comment: Only some conditions, such as familial primary hypomagnesaemia and hypomagnesaemia with secondary hypocalcaemia, show hypocalcaemia.
92
Renal osteodystrophy (ROD)

Phenotype: Growth failure, bone pain, muscle weakness, skeletal deformities (scoliosis, kyphosis,
genu valgum, distorsion of the thoracic cage), bone fractures (ribs, hips, vertebral bodies), extraskeletal calcications (periarticular, vascular, subcutaneous, and visceral). Serum-P (+), Ca (), Mg (+),
alkaline phosphatase (+), PTH (+), 25-OHD (/N), 1,25(OH)2D (). Osteitis brosa (subperiosteal erosions, osteosclerosis, slipped epiphyses), rickets-like lesions.
Comments: ROD is determined by the skeletal eect of secondary hyperparathyroidism associated
with a reduced 1,25(OH)2D production. Reduced GFR ] decreased urinary loss of P ] mild hyperphosphataemia ] hypocalcaemia ] secondary hyperparathyroidism. As renal function continues
to decline, hypocalcaemia is further aggravated by a resistance to the action of PTH on bone. In
addition, the set-point for the inhibition of PTH secretion by extracellular calcium is raised in chronic renal failure, making it more dicult to turn o the secondary hyperparathyroidism. Reduced
1,25(OH)2D production derives from a decline in the functioning renal mass available to perform
1-hydroxylation of 25-OHD, hyperphosphataemia suppressing renal 1-hydroxylase activity, and
metabolic acidosis. The signs and symptoms of ROD are rather nonspecic, and laboratory and radiological abnormalities often do not correspond to the severity of the clinical manifestations.
Calcium deciency rickets

Phenotype: Clinical features are identical to those observed in patients with vitamin D deciency
rickets. Calcium deciency rickets usually occurs after the age of 18 months. Serum-Ca (/N), P (/N),
alkaline phosphatase (+), PTH (N/+), 25-OHD (N/), 1,25(OH)2D (+).
Comments: Low dietary calcium intake, often exacerbated by a high oxalate and phytate content in
the diet that impairs intestinal calcium absorption, is not able to ensure calcium demand for growth
plate mineralisation. Reduced calcium intake ] hypocalcaemia ] secondary hyperparathyroidism
] increased 1,25(OH)2D production. Reduced 25-OH-D levels due to increased catabolism.
X-linked hypophosphataemic rickets (XLH)

Synonyms: Hypophosphataemic vitamin D-resistant rickets.
Phenotype: Growth failure with disproportionate short stature, lower limbs deformities, dental and
periodontal lesions. Serum-P (), alkaline phosphatase (+), PTH (N), 25-OHD (N), 1,25(OH)2D ( or
inappropriately normal relative to hypophosphataemia), TmP/GFR (), urine-P (+), urine-Ca (N). Osteomalacia in both cortical and trabecular bone, increase in osteoid volume, areas of hypomineralisation around osteocytes in the lamellar cortical bone.
Comment: Defective tubular reabsorption of P associated with abnormal renal vitamin D metabolism caused by mutations in the PHEX (phosphate-regulating gene with homology to endopeptidases) gene, which is located on Xp22.1.
Autosomal-dominant hypophosphataemic rickets (ADHR)

Synonym: Vitamin D-resistant rickets.
Phenotype: Clinical features are similar to those observed in patients with XLH. In contrast to XLH,
ADHR shows incomplete penetrance, variable age at onset (childhood to adult), and resolution of
the phosphate-wasting defect in rare cases.
Comments: Autosomal dominant. It is caused by mutation in a gene encoding a member of the
broblast growth factor family (FGF23).
93
10
Hereditary hypophosphataemic rickets with hypercalciuria (HHRH)

Synonym: Hypercalciuric hypophosphataemic rickets.
Phenotype: Stunted growth, lower limbs deformities. Serum-P (), PTH (N), 25-OHD (N), 1,25(OH)2D
(+), TmP/GFR (), urine-P (+), urine-Ca (+).
Comments: Defective tubular reabsorption of P ] hypophosphataemia ] increased 1,25(OH)2D
production ] increased intestinal calcium absorption ] hypercalcaemia ] increased calcium ltered load and PTH suppression ] hypercalciuria. A signicant number of asymptomatic family
members showed idiopathic hypercalciuria alone without associated bone disease. Complete remission of the disease on P therapy alone.
11
Tumour rickets and osteomalacia

Synonyms: Tumour-associated rickets and osteomalacia, tumour-induced rickets, oncogenic hypophosphataemic osteomalacia (OHO), oncogenic rickets and osteomalacia.
Phenotype: Stunted growth, bone and muscle pain, muscle weakness, fatigue, gait disturbances,
skeletal abnormalities (bowing of the lower limbs), recurrent fractures of long bones (occasionally).
The majority of patients have benign or malignant tumours of mesenchymal origin of either soft
tissues or bone, carcinomas of epidermal or endodermal origin; occasionally, epidermal naevus, von
Recklinghausen neurobromatosis. Serum-P (), 25-OHD (N), 1,25(OH)2D ( or inappropriately normal relative to hypophosphatemia), TmP/GFR (), urine-P (+). Occasionally glycinuria, glucosuria,
and hyperaminoaciduria.
Comments: Production of a humoral factor(s) known as phosphatonin (FGF-23, matrix extracellular
phosphoglycoprotein, frizzled-related protein 4), that may aect multiple functions of the proximal
renal tubule, including P reabsorption. Complete resection of the tumour restores normophosphataemia.
12
Decreased phosphate intake

Synonyms: Dietary phosphate deciency, nutritional phosphate deciency.
Phenotype: Severe serum-P (): red cell dysfunction (haemolytic anaemia), leukocyte dysfunction
[chemotaxis (), phagocytosis (), bacterial killing ()]; platelet dysfunction (thrombocytopenia);
musculo-skeletal: rhabdomyolysis, reversible cardiomyopathy and myopathy; CNS: metabolic encephalopathy; metabolic acidosis, rickets/osteomalacia/osteopenia. Serum-P ().
Comments: The signs and symptoms of severe hypophosphataemia may be related to a decrease in
2,3-diphosphoglycerate and/or ATP content in tissues. Main causes: total parenteral nutrition (nutritional recovery syndrome) in which aluminium loading may be a complicating factor, low-phosphate feedings in low-birthweight infants (phosphate depletion syndrome), malabsorption.
13
Idiopathic juvenile osteoporosis

Phenotype: Diuse bone pain, mainly in the back, hips, and feet, and a characteristic gait with difculty in walking, associated with radiological evidence of osteoporosis and fractures of the vertebrae and long bones, mostly at metaphyseal sites. Idiopathic juvenile osteoporosis may have a
spontaneous recovery, usually within 35 years.
Comments: The diagnosis of idiopathic juvenile osteoporosis is based on the exclusion of the other
known causes of osteoporosis. It may be dicult to distinguish from mild forms of osteogenesis
imperfecta. Bone biopsy may be useful for the correct diagnosis.
94
14
Idiopathic infantile hypercalcaemia

Synonyms: Lightwood type (mild form) and Fanconi-Schlesinger type (severe forms).
Phenotype: Similar to patients with Williams-Beuren syndrome; the distinction between the two
syndromes remains problematic.
Comment: A disorder in vitamin D metabolism with increased vitamin D sensitivity with respect to
gastrointestinal transport of Ca has been postulated in some cases. Elevated serum PTHrP levels at
the time of hypercalcaemia have been reported.
15
Vitamin D intoxication
Synonym: Hypervitaminosis D.
Phenotype: Asymptomatic or symptoms of hypercalcaemia/hypercalciuria. Excessive storage of vitamin D in adipose tissue and voluntary muscle. Serum-Ca (+), P (N/+), PTH (), 25-OHD (+ if vitamin
D or 25-OHD is ingested), 1,25(OH)2D (N), urine-Ca (+).
Comment: Increased action of vitamin D metabolites on intestinal Ca absorption and Ca mobilisation from bone.
16
Immobilisation
Synonyms: Immobilisation-induced hypercalciuria, immobilisation-induced hypercalcaemia and
osteopenia.
Phenotype: Asymptomatic or symptoms related to hypercalcaemia/hypercalciuria. Osteopenia. Serum-Ca (N/+), alkaline phosphatase (N/+), PTH (N), 1,25(OH)2D (), urine-Ca (+), urine-P (+), GFR (),
metabolic alkalosis.
Comment: Uncoupling of bone cells activity for increased osteoclastic bone resorption and decreased osteoblastic bone formation.
95
ESPE Code Diagnosis
13
D I SO R D E R S O F WATE R
BAL ANCE
13A
D I S O R D E R S C H A R A C T E R I S E D B Y P O LY D I P S I A
A N D P O LY U R I A
13A.1
Central diabetes insipidus

(vasopressin deficiency)1
[primary] [secondary 6C]
Genetic causes
Mutations in the AVP-NPII gene2
Familial autosomal-dominant neurohypophyseal diabetes
insipidus
Autosomal-recessive neurohypophyseal diabetes insipidus
Wolfram syndrome/DIDMOAD3 [primary 14B.38] [other
secondary 11A.3h.4]
Congenital intracranial anatomic defects
Septo-optic dysplasia4
[primary 6E.1a] [other secondary 14B.30]
Midline craniofacial defects
Holoprosencephalic syndromes5
Agenesis of the pituitary
Acquired causes (for detailed classification use codes in 6E and 6F)
Neoplasms
Inflammatory/infiltrative
Infectious
Traumatic injury
Idiopathic
Adipsic diabetes insipidus6
13A.1a
13A.1a.1
13A.1a.1a
13A.1a.1b
13A.1a.2
13A.1b
13A.1b.1
13a.1b.2
13a.1b.3
13a.1b.4
13A.1c
13A.1c.1
13A.1c.2
13A.1c.3
13A.1c.4
13A.1c.9
13A.1d
13A.2
13A.2a
13A.2a.1
13A.2a.2
13A.2a.3
13A.2b
13A.2b.1
13A.2b.2
13A.2b.3
Nephrogenic diabetes insipidus

Genetic
X-linked recessive (AVP-V2 receptor)7
Autosomal recessive (aquaporin-2)8
Autosomal dominant (aquaporin-2)
Acquired
Drugs, e.g. lithium, foscarnet, demeclocycline
Metabolic, e.g. hyperglycaemia, hypercalcaemia, hypokalaemia,
protein malnutrition
Renal
OMIM
ICD10
E23.2
#125700
#222300
#182230
%236100
N25.1
#304800
#125800
#125800
96
ESPE Code Diagnosis
OMIM
ICD10
Primary polydipsia9
Psychogenic10
Dipsogenic11
Iatrogenic12
R63.1
13B
DISORDERS CHAR AC TERISED BY

H Y P E R N AT R A E M I A
E87.0
13B.1

Central diabetes insipidus (13A.1)
Nephrogenic diabetes insipidus (13A.2)
13B.2
Adipsic hypernatraemia13
13B.3
Physical obstacles to drinking
13B.4
Excessive free water loss (other than diabetes insipidus)

e.g. after gastroenteritis with prolonged vomiting and diarrhoea
13B.5
Excessive sodium intake

Salt poisoning (child abuse)
Other causes
13A.3
13A.3a
13A.3b
13A.3c
13B.5a
13B.5b
13C
DISORDERS CHAR AC TERISED BY

H Y P O N AT R A E M I A
E87.1
13C.1
Inappropriate AVP secretion (syndrome of inappropriate

antidiuretic hormone, SIADH)14
Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)15
Tumours
Drugs
CNS disorders
Non-malignant pulmonary disorders
Post-operative hyponatraemia
Adrenal insufficiency [primary 8A]
Hypothyroidism [primary 7A]
E22.2
13C.1a
13C.1b
13C.1c
13C.1d
13C.1e
13C.1f
13C.1g
13C.1h
13C.2
13C.2a
13C.2a.1
Appropriately increased secretion of vasopressin

Hypovolaemic hyponatraemia from salt and water depletion
Salt and water depletion
Disorders of Water Balance
#300539
E87.1
97
ESPE Code Diagnosis
OMIM
ICD10
13C.2b
Primary sodium deficiency

Hypervolemic hyponatraemia
13C.3
Water intoxication
E87.7
13C.4
Cerebral salt wasting16
E87.1
13C.2a.2
Central diabetes insipidus

Synonyms: Hypothalamic, neurogenic, pituitary, neurohypophyseal diabetes insipidus.
Phenotype: Polyuria (exceeding 2 litres/m2/day), nocturia, enuresis, thirst, increased uid intake,
especially water. If water is restricted hypernatraemia occurs.
Familial central diabetes insipidus

Phenotype: Polyuria and polydipsia usually after the rst year of life. Undetectable AVP.
Comments: Defect in the arginine vasopressin gene (AVP-neurophysin II gene). An X-linked form of
neurohypophyseal diabetes insipidus has been suggested, but the evidence is weak.
Wolfram syndrome (DIDMOAD)

Phenotype: (Partial) diabetes insipidus, gradual onset of diabetes mellitus, optic atrophy, deafness.
In addition, neurogenic bladder, ataxia, psychiatric disorders. Signs outside the nervous system: hypogonadism, pigmented retinopathy, cardiomyopathy, sideroblastic anaemia, thrombocytopenia.
Frequently, insulin dependence, no autoimmune phenomena. Serum AVP (). DNA: heterogeneous
with mitochondrial and nuclear mutations.
Comments: Caused by mutation in the gene encoding wolframin (WFS1). Another locus for the
disorder has been mapped to 4q (WFS2).
Septo-optic dysplasia (De Morsier Syndrome)

Comment: HESX1 mutations have been found in only a few cases.
Holoprosencephalic syndromes
Phenotype: Etiologically heterogeneous entity which varies widely from cyclopia to almost no manifestation except perhaps a single middle incisor.
Comments: Frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions.
There are teratogenic causes, maternal diabetes being the most signicant, giving a 200-fold increased risk. Genetic factors are indicated by familial occurrence, the occurrence of holoprosencephaly in some mendelian genetic syndromes, and the association with non-random chromosomal aberrations. One of the genetic syndromes that includes holoprosencephaly as a feature is
98
Smith-Lemli-Opitz syndrome. Several loci for holoprosencephaly have been mapped to specic
chromosomal sites and the molecular defects in some cases of HPE have been identied. Holoprosencephaly-1 (HPE1) maps to 21q22.3, HPE2 is caused by a mutation in the SIX3 gene, HPE3 is caused
by a mutation in the sonic hedgehog gene (SHH), HPE4 is caused by a mutation in the TGIF gene,
HPE5 is caused by a mutation in the ZIC2 gene, HPE6 maps to 2q37.1, HPE7 is caused by a mutation
in the PTCH1 gene, HPE8 maps to 14q13, and HPE9 is caused by a mutation in the GLI2 gene.
6
Adipsic diabetes insipidus

Phenotype: Diabetes insipidus in combination with absent thirst. This can manifest itself as adipsic
hypernatraemia in case of insucient water intake (see 13B.2).
X-linked recessive nephrogenic diabetes insipidus

Synonym: Renal diabetes insipidus.
Phenotype: Polyuria, polydipsia, nocturia, compulsive drinking. In infants: failure to thrive, fever, weight
loss, irritability. High serum ADH, activation of the renin-angiotensin-aldosterone system (RAAS).
Comments: Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to
absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopression (AVP).
Approximately 90% of patients are males with the X-linked recessive form, type I, which is caused by
a mutation in the gene encoding the vasopressin V2 receptor (AVPR2).
Autosomal-recessive nephrogenic diabetes insipidus

Synonym: Renal diabetes insipidus.
Phenotype: Polyuria, polydipsia, nocturia, compulsive drinking. In infants: failure to thrive, weight
loss, fever. High serum ADH, activation of the renin-angiotensin-aldosterone system (RAAS).
Comments: Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts
to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin
(AVP). 10% of patients have the autosomal form, type II, caused by mutation in the AQP2 gene. Both
autosomal dominant and autosomal recessive forms have been reported.
Primary polydipsia
Synonym: Primary polyuria.
Phenotype: Excessive water drinking, resulting in decrease of plasma osmolality. Normalisation of
renal concentrating capacity by stepwise reduction of water intake. Hypernatraemia is never seen.
Therapy with dDAVP may cause water intoxication to develop rapidly.
10
Psychogenic polydipsia
Phenotype: Can occur as part of a general cognitive defect associated with schizophrenia or other
psychiatric disorder or compulsive water drinking.
11
Dipsogenic polydipsia
Phenotype: Increased water consumption is due to an increase in thirst, e.g. in diseases involving
the hypothalamus.
.
12
Iatrogenic polydipsia
Phenotype: Primary polydipsia can also be prompted by incorrect advice or incorrect understanding of advice oered by physicians, etc.
Disorders of Water Balance
99
13
Adipsic hypernatraemia
Phenotype: Primary adipsia is usually caused by lesions in the anterior hypothalamus. The water
intake associated with a normal diet is insucient to match obligate renal, bowel, and insensible
water losses, and absent thirst can lead to hypernatraemic dehydration.
14
Inappropriate AVP secretion (syndrome of inappropriate antidiuretic hormone, SIADH)

Phenotype: Euvolaemic hyponatraemia, concentrated urine, sodium concentration >20 mmol/l,
low serum uric acid and urea concentration. Can be caused by ADH-producing tumours, pulmonary
and CNS disorders of dierent origin, drugs, and others. Inappropriately high serum ADH, elevated
serum ANF.
Comments: The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common
cause of hyponatraemia. The syndrome manifests as an inability to excrete a free water load, with
inappropriately concentrated urine and resultant hyponatraemia, hypo-osmolality, and natriuresis.
SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deciency
of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with
drug use or a lesion in the central nervous system or lung.
15
Nephrogenic syndrome of inappropriate diuresis (NSIAD)

Comments: Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterised by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP. The disorder is caused
by gain-of-function mutations in the gene encoding the vasopression V2 receptor (AVPR2). Constitutive activation of the receptor results in antidiuresis.
16
Cerebral salt wasting

Comment: Following CNS injury, a syndrome of hyponatraemia associated with increased urine
sodium concentration, increased urine volume, and volume depletion known as salt wasting can
develop.
100
ESPE Code Diagnosis
OMIM
ICD10
14
SYN D ROM ES WITH

E N DOCR I NE FE ATUR ES 1
14A
CHROMOSOMAL ABNORMALITIES
(deletions or duplications of complete or half chromosomes)
14A.1
Chromosome 18q deletion syndrome2

If associated with short stature: also classify as 1A.1a
#601808
Q93.5
14A.2
Down syndrome, trisomy 213

If associated with any other disorder, also classify there
For example:
If associated with obesity: also classify as 5B.3a
If associated with autoimmune hypothyroidism: also classify as
7A.3b
If associated with diabetes mellitus: also classify as 11A.3h.1
#190685
Q90
14A.3
Klinefelter syndrome (47,XXY)4

If associated with tall stature: also classify as 2A.1a
If associated with hypogonadism: also classify as 9A.0
Q98.0
14A.4
Mixed gonadal dysgenesis (45,X/46,XY)5

If associated with disorder of sex development, primarily classify as
4A.1
Q99.9
14A.5
Turner syndrome (Ulrich-Turner syndrome)

(45,X or variants)6
If associated with gonadal dysgenesis: also classify as 10A.1a
Q96.9
14A.6
XYY syndrome7
Q98.5
Syndromes with Endocrine Features
101
ESPE Code Diagnosis
OMIM
ICD10
14B
C O N G E N I TA L DY S M O R P H I C S Y N D R O M E S
14B.1
Aarskog-Scott syndrome8
If associated with shawl scrotum: also classify as 9F.2
100050
Q87.1
14B.2
Albrights hereditary osteodystrophy,

pseudohypoparathyroidism9
If associated with hypocalcaemia:also classify as 12B.5a
If associated with short stature: also classify as 1A.3y
#103580
E20.1
14B.3
Alstrm syndrome10
If associated with obesity: also classify as 5A.2a
#203800
Q87.8
14B.4
Bannayan-Riley-Ruvalcaba syndrome11
#153480
Q87.3
14B.5
Beckwith-Wiedemann syndrome12
If associated with tall length/stature: also classify as 2A.4a
If associated with hypoglycaemia: also classify as 11B.1a.5
#130650
Q87.3
14B.6
Bloom syndrome13
#210900
Q82.8
14B.7
Carpenter syndrome14
%201000
Q87.0
14B.8
Cohen syndrome15
#216550
Q87.8
14B.9
Cornelia de Lange syndrome16

#122470
Q87.1
#300590
#610759
14B.10
DiGeorge/velocardiofacial syndrome syndrome

(part of CATCH 22 complex)17
If associated with hypocalcaemia: also classify as 12B.2a
#188400
Q87.1
102
ESPE Code Diagnosis
14B.11
Ehlers-Danlos syndrome18
If associated with osteoporosis: also classify as 12D.1a
OMIM
ICD10
#130000
Q79.6
(to 80)
#225400
%229200
%305200
14B.12
Elejalde syndrome19
200995
Q87.3
14B.13
Fanconi renotubular syndrome20

If associated with short stature: also classify as 1B.3a.0
If associated with rickets: also classify as 12C.2a
%134600
E72.0
14B.14
Fragile X syndrome21
#300624
Q99.2
14B.15
Gitelman syndrome22
If associated with hypocalcaemia: classify as 12B.6e
#263800
14B.16
Kallmann syndrome23
Primarily classified as 6A.3a.1
If associated with tall stature: also classify as 2B.6a
+308700
14B.17
Klippel-Trenaunay-Weber syndrome24
%149000
Q87.2
14B.18
Laurence-Moon-Bardet-Biedl syndrome25
245800
Q87.8
14B.19
Leri-Weill dyschondrosteosis26
#127300
Q77.8
14B.20
Marfan syndrome27
If associated with osteoporosis: also classify as 12D.1a
#154700
Q87.4
14B.21
Marshall-Smith syndrome28
602535
E23.0
#147950
#244200
#209900
103
ESPE Code Diagnosis
OMIM
ICD10
14B.22
McCune-Albright syndrome29
#174800
If associated with tall stature: also classify as 2B.1b
If associated with pseudoprecocious puberty: also classify as 3A.2c.0
If associated with hyperthyroidism: also classify as 7B.1d.1
If associated with phosphogenic rickets: also classify as 12C.2a
Q87.1
14B.23
Nevo syndrome30
#601451
E87.3
14B.24
Noonan syndrome31
#163950
Q87.1
14B.25
Prader-Willi(-Labhart) syndrome32
If associated with hypogonadotrophic hypogonadism: also classify
as 6A.3d
If associated with hypothalamic-pituitary disorders: also classify as
6E.2a
#176270
Q87.1
14B.26
Proteus syndrome33
#176920
Q87.3
14B.27
Von Recklinghausens disease (neurofibromatosis type 1)34

If associated with precocious puberty: also classify as 3A.1a and
6F.1a.5
+162200
Q85.0
14B.28
Rieger syndrome35
If associated with growth hormone deficiency: also classify as
1B.3a.0
If associated with ACTH deficiency: also classify as 6A.1
If associated with TSH deficiency: also classify as 6A.2
If associated with gonadotrophin deficiency: also classify as 6A.3d
#180500
Q87.1
14B.29
Rubinstein-Taybi syndrome36
#180849
Q87.2
104
ESPE Code Diagnosis
OMIM
ICD10
14B.30
Septo-optic dysplasia37
Primarily classified as 6E.1a
If associated with short stature: also classify as 1B.3a.3
If associated with diabetes insipidus: also classify as 13A.1b.1
#182230
Q04.4
14B.31
Silver-Russell syndrome38
If associated with precocious or delayed puberty: also classify
according to the codes in chapter 3
%180860
Q87.1
14B.32
Simpson-Golabi-Behmel syndrome (mutations in GPC3)39

#312870
Q87.3
14B.33
Smith-Lemli-Opitz syndrome40
If associated with a disorder of sex development: also classify as
4B.2a
If associated with low cholesterol level: also classify as 11C.4a
#270400
Q87.1
14B.34
Sotos syndrome41
#117550
Q87.3
14B.35
Steinerts disease, myotonic dystrophy 142

If associated with precocious puberty: also classify as 3A.1y
If associated with delayed puberty: also classify as 3D.0
If associated with hypothyroidism: also classify as 7A.3y
If associated with hyperthyroidism: also classify as 7B.2a
If associated with adrenal insufficiency: also classify as 8A.3a
#160900
G71.1
14B.36
Weaver syndrome43
#277590
Q87.3
14B.37
Williams-Beuren syndrome44
If associated with hypercalcaemia: also classify as 12E.4a
#194050
Q87.1
14B.38
Wolfram syndrome (DIDMOAD)45

If associated with diabetes insipidus: also classify as 13A.1a.2
#222300
E10
E23.2
105
ESPE Code Diagnosis
14C
N O N - DYSM O R PH I C SY N D RO M E S
14C.1
Cushing syndrome46
Primarily classified as 8C.1
If associated with short stature: also classify as 1B.5a
If associated with diabetes mellitus: also classify as 11A.3d.2
14C.2
Mauriac syndrome47
Primarily classified as 11A
If associated with short stature: also classify as 1B.5a
If associated with obesity: also classify as 5C.0
14C.3
Polycystic ovary syndrome48

Primarily classified as 10A.2a
If associated with hirsutism: also classify as 3C.2a
If associated with obesity: also classify as 5C.0
14C.4
Autoimmune polyglandular syndromes

Autoimmune polyglandular syndrome type 1 (APECED)49
If associated with autoimmune thyroiditis: also classify as 7A.3b
If associated with autoimmune adrenalitis: also classify as 8A.3a
If associated with autoimmune hypergonadotrophic hypogonadism:
also classify as 9A.2a or 10A.1a
If associated with type 1 diabetes mellitus: also classify as 11A.1a
If associated with hypoparathyroidism: also classify as 12B.2a
Autoimmune polyglandular syndrome type 250
If associated with autoimmune adrenalitis: also classify as 8A.3a
Immune dysregulation, polyendocrinopathy, and enteropathy
(X-linked) syndrome (IPEX)52
Autoimmune lymphoproliferative syndrome (ALPS)53
14C.4a
14C.4b
14C.4c
14C.4d
14C.4e
OMIM
ICD10
E24
#184700
E28.2
M35.9
#240300
M35.9
269200
M35.9
M35.9
#304790
M35.9
#601859
M35.9
106
ESPE Code Diagnosis
OMIM
ICD10
%147920
M35.9
14C.4f
Kabuki make-up syndrome54

If associated with growth hormone deficiency: also classify as
1B.3a.0
If associated with Hashimotos thyroiditis: also classify as 7A.3b
If associated with primary ovarian dysfunction: also classify as
10A.1c.8
14C.5
Multiple endocrine neoplasia (MEN) syndromes

Multiple endocrine neoplasia 155
+131100
If associated with hyperparathyroidism: also classify as 12E.2a
If associated with prolactinoma: also classify as 6B.3a
If associated with growth hormone-secreting tumour: also classify as
2B.1b
If associated with insulinoma: also classify as 11B.1b.7
If associated with adrenal cortical tumour (carcinoma): also classify
as 8C.1b.4
If associated with thyroid adenoma: also classify as 7D.1
MEN2A56
#171400
If associated with medullary thyroid carcinoma: also classify as
7D.2c.2
If associated with phaeochromocytoma: also classify as 8D.2a
If associated with hyperparathyroidism: also classify as 12E.2a
MEN2B57
#162300
If associated with medullary thyroid carcinoma: also classify as
7D.2c.3
If associated with phaeochromocytoma: also classify as 8D.2a
14C.5a
14C.5b
14C.5c
M8360/1
M8360/1
M8360/1
Syndromes with endocrine features

Comments: Endocrine syndromes without signicant other features are not classied in this chapter, but only in the pertinent organ-specic chapters. Information in this chapter is mainly derived
from the OMIM database, in which more detailed and updated information can be found.
Chromosome 18q deletion syndrome

Synonyms: Chromosome 18q- syndrome, 18q- syndrome.
Phenotype: The phenotype is highly variable, but is characterised by mental retardation, short
stature, hypotonia, hearing impairment, and foot deformities. Tapered digits and wide mouth have
been described.
Comments: Its basis is assumed to be in haploinsuciency of multiple genes. It is a terminal deciency or macrodeletion syndrome.
107
Down syndrome
Synonyms: Trisomy 21, trisomy-21-syndrome, mongolism.
Phenotype: (1) Dysmorphic features (brachycephaly, Brusheld spots, simian crease, gap between
1st and 2nd toe, high arched palate, strabismus, broad short neck, small teeth, short broad hands,
hypoplasia of the middle phalange V); (2) psycho-motor (mental retardation, hypotonia); (3) short
stature (approximately 100%); (4) cardiac anomalies (40% atrio-ventricularis communis); (5) infertility (100%); (6) frequent obesity, leukaemia (1%), urinary tract malformations and hypothyroidism.
Comments: Trisomy of chromosome 21, additional (maternal) chromosome free or translocated
(3%) mosaicism (2%). Full clinical picture in trisomy 21p22. Mostly sporadic except for maternal
translocation. Incidence 1:650, increasing with age of mother.
Klinefelter syndrome (47,XXY)

Phenotype: From childhood: normal/tall stature in comparison to parental heights, with or without
mild learning diculties and behavioural problems, small head circumference, testes normal/small.
In adolescence: obesity, long legs, prolonged growth resulting in tall stature, gynaecomastia, female
pubic hair distribution, testes small and rm. Basal LH (+), FSH (+), GnRH response (+) by mid-puberty. T response (/N) to hCG. Partial Leydig cell failure. Adulthood: Infertility + gynaecomastia
(15%) with weak facial hair growth, obesity. Progressive loss of sperm cells, Sertoli cells. Hyalinisation of seminiferous tubules with relative preservation of Leydig cells. Azoospermia/oligospermia.
Karyotype: 47,XXY or 46XY/47XXY or mosaicism.
Comments: 1 in 600 male births. Testosterone replacement during adolescence may lessen disproportion and tall stature. Mosaicism may occur, and results in a milder clinical picture.
Mixed gonadal dysgenesis (MGD)

Phenotype: Variable degree of impaired masculinisation (4A.1), from almost female (in case of complete female phenotype classify as Turner syndrome (14A.5)) to normal male genitalia (14A.4). Hypospadias, cryptorchidism may be present. At puberty FSH and LH are usually elevated and testosterone decreased. Secondary to sex chromosomal mosaicism in a male, the gonads have become
dysgenetic in combinations ovary/testis, or testis/streak. Sometimes a tumour is found instead of a
gonad.
Comments: The term MGD can be used when the above chromosomal mosaicism (or, in rare cases,
45,X/46,XY/47,XYY) is found, even if gonadal dysgenesis has not been proven anatomically.
Turner syndrome (TS) or Ullrich-Turner syndrome (UTS)

Phenotype: Female appearance, short stature (95%), gonadal dysgenesis (90%), dysmorphic stigmata (pterygium colli, cubitus valgus), coarctation of the aorta, renal and urinary tract malformation. Great variability in physical appearance. In early infancy and from 10 years LH and FSH (+) and
E2 (). Karyotype: loss or abnormality of one X chromosome or mosaicism (typical karyotype: 45,X).
Comment: Approximately 1:2,000 (female births).
XYY syndrome
Phenotype: Often no specic symptoms, sometimes behavioural problems. Adulthood: FSH (N/+),
reduced fertility. Histology: quantitatively reduced spermatogenesis.
Comment: 1/900 newborn males.
108
Aarskog-Scott syndrome
Phenotype: Short stature, hypertelorism, shawl scrotum, delayed puberty, cryptorchidism, stretchable skin.
Comment: X-linked recessive inheritance or autosomal dominant.
Albrights hereditary osteodystrophy (AHO), pseudohypoparathyroidism

Synonyms: Albright syndrome, hereditary osteodystrophy, pseudohypoparathyroidism type Ia
(PHP Ia).
Phenotype: Short stature, obesity, round facies, subcutaneous ossications, brachydactyly, short IV
metacarpal, short thick neck, and other skeletal anomalies. Some patients have mental retardation.
AHO is often associated with pseudohypoparathyroidism, hypocalcaemia, tetany, hyperphosphataemia and PTH (+) (PHP Ia). Patients with pseudopseudohypoparathyroidism have normal calcium
metabolism and PTH levels with isolated AHO. T4 and T3 (N/), TSH (N/+), parathyroids normal or
hyperplastic, calcication of basal ganglia.
Comments: Heterogeneous group of disorders whose common feature is resistance to parathyroid
hormone (PTH). It is generally classied as types Ia, Ib, Ic, and II according to dierent phenotypes
and pathogenesis. Albright hereditary osteodystrophy (AHO), pseudohypoparathyroidism type Ia
(PHP Ia), and pseudopseudohypoparathyroidism (PPHP) are caused by mutations, including imprinting defects, in the GNAS1 gene. Pseudohypoparathyroidism should not be confused with polyostotic brous dysplasia, to which Albrights name is also attached.
10
Alstrm syndrome
Phenotype: Although this disorder bears many similarities (retinitis pigmentosa, progressive nerve
deafness, obesity, and diabetes mellitus) to the Bardet-Biedl syndrome there is no mental defect,
polydactyly, or hypogonadism. The retinal lesion causes nystagmus and early loss of central vision in
contrast to loss of peripheral vision rst, as in other pigmentary retinopathies. Hypogonadotrophic
hypogonadism (FSH (), LH ()), insulin resistance (insulin (+)), acanthosis nigricans, glomerulosclerotic renal disease.
Comment: Caused by mutation in the ALMS1 gene.
11
Bannayan-Riley-Ruvalcaba syndrome
Synonyms: Bannayan-Zonana, Ruvalcaba-Myhre, Riley-Smith, Bannayan-Riley-Ruvalcaba.
Phenotype: Prenatal overgrowth with large birth weight and length. Developmental delay with hypotonia and macrocephaly with frontal bossing. Downslanting palpable ssures. Pigmented macules on penis. Mesodermal hamartomas with angiolipomas/lipomas in GI tract, cranium, bone. Lipid
storage myopathy.
Comment: Caused by mutations in the PTEN gene.
12
Beckwith-Wiedemann syndrome (BWS)

Synonym: Beckwith syndrome.
Phenotype: Macrosomia particularly aecting tongue and kidneys, exomphalos, ear lobe creases
and pits. Pancreatic hyperplasia with hyperinsulinism. Hemihypertrophy and predisposition to tumours, especially Wilms (7%). Large muscle mass and thick subcutaneous tissue with organomegaly. Transient hyperinsulinism resulting in hypoglycaemia.
109
Comments: Genetic lesion probably causes imbalance between maternally imprinted IGF-2 growth
enhancer gene and paternally imprinted H19 growth suppressor gene, leading to foetal overgrowth.
Aected infants require clinical, ultrasound, and alpha-foetoprotein monitoring until growth is completed to pre-empt tumour development, particularly Wilms.
13
Bloom syndrome
Phenotype: Bloom syndrome is an autosomal-recessive disorder characterised by proportionate
pre- and postnatal growth deciency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin;
predisposition to malignancy; and chromosomal instability.
Comment: Caused by mutations in the gene encoding DNA helicase RecQ protein-like-3.
14
Carpenter syndrome
Synonym: Acrocephalopolysyndactyly.
Phenotype: Acrocephaly, peculiar facies, brachysyndactyly of the ngers, preaxial polydactyly
and syndactyly of the toes, hypogenitalism, obesity and mental retardation, short stature. LH (),
FSH ().
15
Cohen syndrome
Phenotype: Nonprogressive mild to severe psychomotor retardation, motor clumsiness, microcephaly, characteristic facial features, childhood hypotonia and joint laxity, progressive retinochoroidal
dystrophy, myopia, intermittent isolated neutropenia, and a cheerful disposition. Characteristic
facial features include high-arched or wave-shaped eyelids, a short philtrum, thick hair, and low
hairline.
Comments: Rare autosomal-recessive disorders that are overrepresented in the Finnish population.
Some patients with Cohen syndrome have mutations in the COH1 gene.
16
Cornelia de Lange syndrome

Phenotype: The de Lange syndrome is recognised on the basis of characteristic facies (low anterior
hairline, synophrys, anteverted nares, maxillary prognathism, long philtrum, carp mouth) in association with prenatal and postnatal growth retardation, mental retardation and, in many cases, upper limb anomalies.
Comments: Can be caused by mutation in the NIPBL gene, which encodes a component of the cohesin complex. About half of the cases of CDLS are due to mutations in this gene. An X-linked form
of the disorder (CDLS2) can be caused by mutation in the SMC1L1 gene, which also encodes a component of the cohesin complex. A mild variant of Cornelia de Lange syndrome (CDLS3) has been
related to mutation in the SMC3 gene, which encodes another component of the cohesin complex.
17
DiGeorge syndrome
Synonym: 22q11.2 deletion syndrome, hypoplasia of thymus and parathyroids, third and fourth
pharyngeal pouch syndrome, takao vcf syndrome, catch22.
Phenotype: DiGeorge syndrome (DGS) comprises hypocalcaemia arising from parathyroid hypoplasia, thymic hypoplasia, and outow tract defects of the heart. Disturbance of cervical neural crest
migration into the derivatives of the pharyngeal arches and pouches can account for the phenotype. Most cases result from a deletion of chromosome 22q11.2 (the DiGeorge syndrome chromosome region, or DGCR). Several genes are lost including the putative transcription factor TUPLE1
110
which is expressed in the appropriate distribution. This deletion may present with a variety of phenotypes: Shprintzen or velocardiofacial syndrome; conotruncal anomaly face (or Takao syndrome);
and isolated outow tract defects of the heart including tetralogy of Fallot, truncus arteriosus, and
interrupted aortic arch. A collective acronym CATCH22 has been proposed for these diering presentations. A small number of cases of DGS have defects in other chromosomes, notably 10p13.
Comments: DiGeorge syndrome is caused by a 1.5- to 3.0-Mb hemizygous deletion of chromosome
22q11.2. Haploinsuciency of the TBX1 gene in particular is responsible for most of the physical malformations. There is evidence that point mutations in the TBX1 gene can also cause the disorder.
18
Ehlers-Danlos syndrome
Phenotype: The main features of classic Ehlers-Danlos syndrome, which includes EDS I and EDS
II, are loose-jointedness and fragile, bruisable skin that heals with peculiar cigarette-paper scars.
Most persons are born prematurely due to premature rupture of foetal membranes. A spontaneous
carotid-cavernous stula and rupture of large vessels, hiatus hernia, spontaneous rupture of the
bowel, diverticula of the bowel and retinal detachment have been reported.
Comments: According to the classication used by McKusick, 11 types of EDS were distinguished.
In a later classication major and minor diagnostic criteria were dened for each type and complemented whenever possible with laboratory ndings. Six main descriptive types were substituted for
earlier types numbered with Roman numerals: classic type (EDS I and II), hypermobility type (EDS
III), vascular type (EDS IV), kyphoscoliosis type (EDS VI), arthrochalasia type (EDS VIIA and VIIB), and
dermatosparaxis type (EDS VIIC). Six other forms were listed, including a category of unspecied
forms. At least some cases of the syndrome are caused by mutation in the collagen alpha-1(V) gene
(COL5A1), the collagen alpha-2(V) gene (COL5A2), or the collagen alpha-1(I) gene (COL1A1).
19
Elejalde syndrome
Synonyms: Acrocephalopolydactylous dysplasia, acrocephalopolydactyly renal dysplasia syndrome.
Phenotype: Excessive birth weight, a swollen globular body with thick skin, apparently short limbs,
polydactyly, craniosynostosis with acrocephaly, omphalocele, and abnormal face. At autopsy abdominal organomegaly, ascites, and cystic renal dysplasia, with excessive amounts of connective
tissue and perivascular proliferation of nerve bers in many organs.
Comment: Not to be confused with Elejaldes disease (neuroectodermal melanolysosomal disease).
20
Fanconis syndrome (FS)

Phenotype: Anorexia, vomiting, polydipsia, polyuria, constipation, unexplained fever (may reect
episodic dehydratation), delayed psychomotor development, growth failure, bone disease (rickets
resistant to doses of vitamin D that are ordinarily adequate for treatment of vitamin D deciency
rickets, bone pain, osteopenia, fractures), muscle weakness and episodic paralysis due to severe
hypokalaemia, nephrolithiasis, nephrocalcinosis, symptoms related to the cause of the disorder. Excessive renal excretion of Na, K, P, Ca, glucose, aminoacids, bicarbonate, uric acid, citrate and other
organic acid, and low-molecular-weight proteins (<50.000 Da), chronic hyperchloraemic metabolic
acidosis; serum-P (), K (), Ca (N/), alkaline phosphatase (+ if rickets is present), 25-OHD (N/ if
hepatic damage is present), 1,25(OH)2D (/N).
Comments: Generalised defect in renal proximal tubule transport capacity; vitamin D resistance may
be due to an impaired 1,25(OH)2D production by abnormal proximal tubular cells in the presence of
111
metabolic acidosis. Most commonly it is idiopathic, or related to genetically transmitted inborn errors of metabolism (cystinosis, fructose intolerance, galactosaemia, glycogenosis, Lowe syndrome,
tyrosinaemia, Wilsons disease), or acquired. FS may be associated with renal tubular acidosis.
21
Fragile X syndrome
Phenotype: Moderate to severe mental retardation (possibly worse with age); particularly delayed
speech development; behavioural changes; seizures. Large forehead and head (circumference
>97th centile), prominent chin, long nose and ears; increased birth weight, tall stature in childhood
but adult height tends to shortness; macro-orchidism in males (15% prepubertally, 80% by adulthood up to 120 ml); increased risk of mitral valve prolapse, aortic root dilatation and hernias; soft
skin; joint hypermobility. Testes are usually histologically and functionally normal; increased size
may be due to interstitial oedema or connective tissue; normal size penis. Generally normal gonadal
function, normal GH axis, no precocious puberty. Chromosomal analysis: Xq27 folate-sensitive fragile site in 520% of cells.
Comments: Basically inherited as an X-linked recessive disorder, i.e. a female may carry the trait and
pass it on to her sons; only 50% of obligatory female carriers demonstrate fragile sites. 1/1,000
1,500 males; 5% of autistic males; second commonest cause of mental retardation (after Down
syndrome); up to one third of female heterozygotes may show some manifestation of the disorder
(<10% of all female mild mental retardation).
22
Gitelman syndrome
Phenotype: It has been proposed that Bartter syndrome, dened generically as an autosomal-recessive disorder featuring hypokalaemic metabolic alkalosis with salt wasting, is a heterogeneous
entity with at least 2 subsets, Gitelman syndrome and true Bartter syndrome. Gitelman syndrome
refers to the numerically predominant subset of patients with hypokalaemic alkalosis in conjunction
with hypocalciuria and hypomagnesaemia, while true Bartter syndrome refers to patients with normal or hypercalciuria and typically normal magnesium levels. True Bartter patients usually present
under the age of 5 years with signs of vascular volume depletion, while Gitelman syndrome patients
typically present at older ages without overt hypovolaemia.
Comment: The Gitelman variant of Bartter syndrome is caused by mutation in the thiazide-sensitive
Na-Cl cotransporter (SLC12A3).
23
Isolated hypogonadotrophic hypogonadism and anosmia (Kallmann syndrome)

Phenotype: Clinically and genetically heterogeneous disorder with a wide spectrum of reproductive function and anosmia. Absence of puberty, anosmia. Histologically immature gonads. LH (),
FSH (), T (), inhibin-B (). Hypoplasia of the bulbus olfactorius in MRI. In severe forms hypoplastic
genitalia.
Comments: Lack of GnRH neurones. X-linked mutations in KAL-1 gene (encodes anosmin-1, a protein
involved in olfactory and neuronal migration). Autosomal-dominant loss of function mutations in FGFR1 gene. Anosmia occurs in all KAL-1 mutations but only a small percentage of FGFR-1 mutations.
24
Klippel-Trenaunay-Weber syndrome
Phenotype: Triad of (1) cutaneous vascular naevus; (2) varicosity over trunk or limbs (usually lower)
in asymmetrical distribution; (3) hypertrophy of soft tissue and bone. Naevus formation and bone
hypertrophy do not always overlap. Occasional neurological involvement with meningocortical angiomata.
112
Comments: Somatic mutation aecting factor involved in embryonic vascular development. Usually sporadic but increased familial incidence of hemi-hypertrophy in some families.
25
Laurence-Moon-Bardet-Biedl syndrome
Synonyms: Laurence-Moon syndrome; Bardet-Biedl syndrome (it is assumed that these may be two
separate entities).
Phenotype: Retinal dystrophy (retinitis pigmentosa), polydactyly or syndactyly, increased appetite,
mental retardation, mild obesity, hypogonadism, defective pubertal development. Renal abnormalities are frequent in the Bardet-Biedl syndrome. FSH (N, ), LH (N, ), T ().
Comment: Mutations have been found in genes at the BBS1, BBS2, BBS3, BBS4, BBS5, BBS6, BBS7,
BBS8, BBS9, BBS10, BBS11, and BBS12 loci.
26
Leri-Weill dyschondrosteosis
Synonym: Leri-Weill syndrome.
Phenotype: Mesomelic (shortening of forearms and lower legs) short stature, with Madelungs deformity. Heterogeneity of the clinical expression, e.g. short fourth metacarpals, scoliosis, exostoses.
Adult height of males 156171 cm, females 135164 cm.
Comments: DNA: haploinsuciency of SHOX. A complete (homozygous) defect of SHOX causes
Langer mesomelic dwarsm. Heterozygous SHOX mutations or deletions have been described in
2.5% of short children previously labeled idiopathic short stature.
27
Marfan syndrome
Phenotype: A heritable disorder of brous connective tissue, Marfan syndrome shows striking pleiotropism and clinical variability. The cardinal features occur in 3 systems skeletal, ocular, and cardiovascular. Increased height, disproportionately long limbs and digits, anterior chest deformity,
mild to moderate joint laxity, vertebral column deformity (scoliosis and thoracic lordosis), and a
narrow, highly arched palate with crowding of the teeth are frequent skeletal features. Tall stature
with characteristic phenotype arachnodactyly, long face, high palate. Hyperextensible joints with
hypotonia, kyphoscoliosis, pes planus. Upward lens subluxation, myopia, retinal detachment. Aortic
root dilatation leading to rupture, mitral valve prolapse. Aortic histology shows swelling and fragmentation of elastic bres. Microbrillopathy with abnormal and reduced microbril production in
connective tissues.
Comments: All cases of the true Marfan syndrome appear to be due to mutation in the brillin-1
gene (FBN1) gene. Incidence: 1 in 20,000. Variable phenotype reects dierent mutations. Cardiac
ultrasonography is a useful screening test in children with unexplained tall stature/mildly marfanoid
habitus. NB: Several rare syndromes described with marfanoid habitus and other features (e.g. mental retardation, craniosynostosis, X linked inheritance).
28
Marshall-Smith syndrome
Phenotype: Prenatal onset acceleration in linear growth with failure to thrive, developmental delay,
unusual facies, including prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge,
and micrognathia. Respiratory diculties causing early death from pneumonia. Radiology: accelerated skeletal maturation, broad proximal and middle, with narrow distal, phalanges. Cerebral anomalies (macrogyria, cerebral atrophy, absent corpus collosum, cerebellar hypoplasia).
113
29
McCune-Albright syndrome (MAS)

Phenotype: The classic triad is caf-au-lait spots, polyostotic brous dysplasia and gonadotrophin
independent precocious puberty. Also thyrotoxicosis, pituitary gigantism, and Cushing syndrome
can be part of the syndrome.
Comments: The mosaic distribution of the GNAS1 mutation in dierent tissues results in the peculiar occurrence of skin, skeletal and endocrine abnormalities. In the ovary autonomous functioning
cysts will initiate precious puberty.
30
Nevo syndrome
Phenotype: Increased growth, kyphosis, prominent forehead, volar oedema, spindle-shaped ngers, wrist drop, talipes, hyperbilirubinemia, and generalised hypotonia. Developmental delay in
some but not all cases reported. Long face, large extremities, cryptorchidism.
Comment: Mutation in the gene encoding lysyl hydroxylase (PLOD1) and is therefore allelic with, or
in the view of some identical to, the kyphoscoliotic type of Ehlers-Danlos syndrome.
31
Noonan syndrome
Phenotype: Autosomal-dominant dysmorphic syndrome characterised by Turner-like dysmorphic
features (chest deformity, a short neck with webbing or redundancy of skin, hypertelorism, epicanthic folds, ptosis, downslanting palpebral ssures, and low-set posteriorly rotated ears). Other
features include short stature (50%), cardiac malformations (typically: pulmonary artery stenosis),
deafness, motor delay, moderate mental retardation, behavioural problems, a bleeding diathesis,
visual disturbance, hearing impairment, often cryptorchidism, anorchia, testicular atrophy, defective pubertal development, decreased fertility occurrence in males and females (1:1). In adulthood
FSH (N, +), LH (N, +), T (N, ).
Comments: One form of Noonan syndrome, that which maps to 12q24.1, is due to mutations in
PTPN11, a gene encoding the nonreceptor protein tyrosine phosphatase SHP2, which contains 2 Src
homology-2 (SH2) domains. Mutations in the PTPN11 gene account for about half the patients studied. Mutations in the neurobromin gene (NF1), which is the site of mutations causing classic neurobromatosis type I, have been found in neurobromatosis-Noonan syndrome (NFNS). De novo
germline mutations of the KRAS gene have also been found in individuals with Noonan syndrome
(NS3), but account for less than 5% of Noonan syndrome cases. A form of Noonan syndrome (NS4) is
caused by mutation in the SOS1 gene. Sporadic (80%) or autosomal dominant (20%). 1:1,0002,500
livebirths.
32
Prader-Willi-Labhart syndrome or Prader-Willi syndrome (PWS)

Synonyms: Hyperphagia, hypotonia, hypogonadism, obesity (HHHO) syndrome.
Phenotype: (1) Diminished foetal activity, neonatal/infantile central hypotonia; (2) feeding problems/failure to thrive in infancy; (3) weight gain and hyperphagia after 12 months, obesity; (4) narrow bifrontal diameter, almond-shaped eyes; (5) moderate developmental delay (IQ <80); (6) hypogonadism, incomplete pubertal development; (7) short stature in approximately 50% of cases; (8)
small hands and feet. Hypogonadotrophic hypogonadism: FSH (N, +, ), LH (N, +, ), testosterone
(N, ). Insulin resistance due to obesity.
Comments: Autosomal-dominant disorder caused by deletion or disruption of a gene or several
genes on the proximal long arm of the paternal chromosome 15 or maternal uniparental disomy 15,
because the gene(s) on the maternal chromosome(s) 15 are virtually inactive through imprinting.
114
Contiguous gene syndrome resulting from deletion of the paternal copies of the imprinted SNRPN
gene, the necdin gene, and possibly other genes.
33
Proteus syndrome
Phenotype: Hemihypertrophy/partial gigantism particularly aecting hands and feet; exostoses of
skull, ear canals, nasal bridge, alveolar ridge; macrocephaly, skull asymmetry; vascular abnormalities
(verrucous hamartomas, haemangiomas, lymphangiomas). Developmental delay in 50%. The skin
changes are papillomatous epidermal nevi.
Comments: Somatic mosaicism with alterations in genes aecting muscle dierentiation/paracrine
growth factors. Imaging studies useful in distinguishing from hemihyperplasia. A germline mutation in the tumour suppressor gene PTEN was found in 1 patient with Proteus syndrome.
34
Von Recklinghausens disease (type 1), neurobromatosis type 1 (NF1)

Synonyms: Neurobromatosis, NF1 microdeletion syndrome.
Phenotype: Neurobromatosis is an autosomal-dominant disorder characterised particularly by
cafe-au-lait spots and bromatous tumours of the skin. Other features are variably present. Criteria:
(1) six or more caf-au-lait spots >0.5 cm (prepubertal) or >1.5 cm (pubertal) in diameter; (2) two or
more neurobromas (any), or at least one plexiforme neurobroma; (3) freckling in axilla; (4) glioma
nervi optici; (5) bone lesions; (6) one 1st-degree relative with NF1. Benign tumours of perineural tissue (Schwann cells and other cells).
Comments: Neurobromatosis type I (NF1) is caused by mutation in the neurobromin gene. Several young children with some features of NF1 and hematologic malignancies have been identied
with homozygous mutations in the mismatch repair genes MLH1 and MSH2. Autosomal dominant,
50% new mutations. Incidence approximately 1:2,500.
35
Rieger syndrome
Phenotype: Hypodontia (partial anodontia), malformation of the anterior chamber of the eye (microcornea with opacity, hypoplasia of the iris, and anterior synechiae), myotonic dystrophy, anal
stenosis, characteristic facies. It has been suggested to label the combination of short stature, facial
anomalies, Rieger anomaly, midline anomalies, and enamel defects the short-FRAME syndrome.
Comments: There may be more than one genetic form of Rieger syndrome. Rieger syndrome type
1 is caused by mutations in a homeobox transcription factor gene, PITX2. Linkage studies indicated
that a second type of Rieger syndrome maps to chromosome 13q14 (RIEG2). Autosomal dominant
inheritance.
36
Rubinstein-Taybi syndrome
Phenotype: Mental retardation, broad halluces, broad thumbs, facial abnormalities, congenital or
juvenile glaucoma, persistent foetal pads of the ngers, shawl scrotum, frequent fractures, constipation, diculties in sleep and anaesthesia by easily collapsible laryngeal walls, short upper lip, pouting lower lip, high slit-like palate.
Comment: Can be caused by mutation in the gene encoding the transcriptional coactivator CREBbinding protein (CREBBP) or in the EP300 gene.
115
37
Septo-optic dysplasia (De Morsier syndrome)

Comments: HESX1 mutations were found only in a few cases.
38
Silver-Russell syndrome (SRS) or Russell-Silver syndrome

Phenotype: Congenital hemihypertrophy, low birth weight, short stature (postnatal shortness with
an adult height of about 4 SDS), and elevated urinary gonadotrophins, characteristic facial features, including triangular shaped face with a broad forehead and pointed, small chin with a wide,
thin mouth; clinodactyly V; 4. asymmetry. Variable phenotype.
Comment: Chromosomal analysis: sporadic, maternal uniparental disomy of chromosome 7 has
been described in approximately 10% of the cases.
39
Simpson-Golabi-Behmel syndrome
Phenotype: Pre- and postnatal overgrowth with mild-to-moderate psychomotor delay. Hypotonia
with macrocephaly. Postaxial polydactyly, partial syndactyly. Macroglossia, cleft lip/palate, hypertelorism. Cardiac conduction defects. Gastro-intestinal defects. Ambiguous genitalia. Renal defects
with enlarged cystic kidneys, dysplasia, duplex systems, hydronephrosis, increased risk of embryonal
tumours. Lab: Increased maternal alphafoetoprotein. Disorder of glypican (GPC3 + 4) metabolism.
Comment: Similar to Beckwith-Wiedemann syndrome but distinguished by facial dysmorphism,
broad thumb and great toe, and polydactyly.
40
Smith-Lemli-Opitz syndrome
Phenotype: Hypospadias, failure to thrive, mental retardation, photosensitivity, abnormal sleep pattern, microcephaly, short or proximally placed thumbs, syndactyly, second-third toe syndactyly, congenital cardiac abnormalities (e.g. atrioventricular septal defect), visceral abnormalities. The typical
facial appearance (coarse facies) becomes less obvious with age. Variable phenotype of the external
genitalia. Serum 7-dehydrocholesterol level does not correlate with clinical severity.
Comments: Caused by mutations in the sterol delta-7-reductase gene (DHCR7). This syndrome is the
rst true metabolic syndrome of multiple congenital malformations. Frequency: Approximately 1 in
20,000 to 30,000 births in populations of northern and central European background.
41
Sotos syndrome (cerebral gigantism)

Phenotype: Accelerated prenatal and infantile growth results in macrocephaly and rapid childhood
growth with bone age advance. Adult height not excessive mean 173 and 184 cm in females and
males, respectively. Developmental delay. Poor co-ordination. Unusual facies with long face, prominent chin and prominent forehead.
Comment: NSD1 haploinsuency in most characteristic cases.
42
Steinerts disease, myotonic dystrophy

Phenotype: Myotonia, muscular dystrophy, cataracts, hypogonadism, frontal balding, and ECG
changes.
Comment: Myotonic dystrophy-1 (DM1) is caused by mutation in the dystrophia myotonica protein
kinase gene (DMPK). The genetic defect in DM1 results from an amplied trinucleotide repeat in the
116
3-prime untranslated region of the protein kinase gene. Disease severity varies with the number
of repeats: normal individuals have 530 repeats, mildly aected persons have 5080 repeats, and
severely aected individuals have 2,000 or more copies. Amplication is frequently observed after
parent-to-child transmission, but extreme amplications are not transmitted through the male line.
This mechanism explains genetic anticipation and the occurrence of the severe congenital form
almost exclusively in the ospring of aected women. Dystrophia myotonica-2 (DM2l) is caused by
mutation in the ZNF9 gene.
43
Weaver syndrome
Phenotype: Primordial overgrowth syndrome with prenatal and infantile growth acceleration; hypertonia and developmental delay. Camptodactyly, with thin, deep-set nails and prominent nger
tip pads. Craniofacial dysmorphism (round face, hypertelorism, long philtrum, micrognathia, large
ears, down-slanting palpebral ssures). Talipes equinovarus. Radiology: Accelerated skeletal maturation, broad distal femur and ulna.
Comment: Some patients have a mutation in the NSD1 gene.
44
Williams-Beuren syndrome
Phenotype: Supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenoses, eln face,
mental and statural deciency, characteristic dental malformation, and infantile hypercalcaemia.
Comment: The disorder is a contiguous gene syndrome, autosomal-dominant inheritance. GTF2IRD1
and GTF2I are responsible for the main aspects of WBS, but other genes may also be involved (LIMK1,
RFC2, CYLN2).
45
Wolfram syndrome (DIDMOAD)

Phenotype: (Partial) Diabetes Insipidus, gradual onset of Diabetes Mellitus, Optic Atrophy, Deafness.
In addition, neurogenic bladder, ataxia, psychiatric disorders. Signs outside the nervous system: hypogonadism, pigmented retinopathy, cardiomyopathy, sideroblastic anaemia, thrombocytopenia.
Frequently insulin dependence, no autoimmune phenomena. Serum AVP (). DNA: heterogeneous
with mitochondrial and nuclear mutations.
Comments: Caused by mutation in the gene encoding wolframin (WFS1). Another locus for the
disorder has been mapped to 4q (WFS2).
46
Glucocorticoid excess (Cushing syndrome)

Phenotype: Truncal obesity and moon facies, acne, hypertension, striae, loss of muscle mass, decreased growth velocity, emotional instability. Cortisol (+), androgens (+), estrogens (N/+), aldosterone (+), ACTH (+/N/). Elevated blood glucose, hyperlipidaemia, insulin-resistant diabetes.
Comment: Symptoms of hypercortisolism are similar whatever its cause.
47
Mauriac syndrome
Phenotype: Short stature and glycogen-loaded liver in poorly controlled diabetes mellitus.
117
48
Polycystic ovary syndrome (PCO)

Synonym: Stein-Loewenthal syndrome.
Phenotype: Menstrual irregularity, amenorrhea, anovulatory cycles, hirsutism, obesity, decreased
fertility. Enlarged ovaries with multiple cysts, hyperthecosis. LH (+), FSH (N), LH:FSH ratio >3, T (+),
adrenal androgens (+), Prl (+), insulin resistance.
Comments: Not observed in prepubertal girls. No clear-cut diagnostic criteria during puberty.
49

Synonym: Autoimmune polyendocrinopathy syndrome (APS)1, autoimmune polyendocrine syndrome, type I, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), polyglandular autoimmune syndrome, type I (PGA I), hypoadrenocorticism with hypoparathyroidism
and supercial moniliasis, polyglandular deciency syndrome, autoimmune polyendocrinopathy
syndrome, type I.
Phenotype: 2 of 3 major clinical symptoms: Addisons disease, and/or hypoparathyroidism, and/or
chronic mucocutaneous candidiasis.
Comment: Caused by mutation in the autoimmune regulator gene (AIRE).
50

Phenotype: Dened by the presence of adrenalitis with either autoimmune thyroid disease (Schmidt
syndrome) or type 1 diabetes mellitus. Various combinations of other features, such as gonadal atrophy, hypoparathyroidism, alopecia, myasthenia gravis, pernicious anaemia, vitiligo, and Graves
disease.
Comments: The syndromal association may be due to unusual susceptibility to immunologic derangement because of a particular immune-response gene linked to (i.e. in linkage disequilibrium
with) HLA on chromosome 6.
51

Comment: Dened by the association between autoimmune thyroid disease and autoimmune disorders other than Addisons disease.
52
Immune dysregulation, polyendocrinopathy, and enteropathy (X-linked) syndrome (IPEX)

Phenotype: X-linked syndrome with various combinations of intractable diarrhoea, eczema, haemolytic anaemia, diabetes mellitus, or thyroid autoimmunity. Exaggerated responses to viral infections have been noted.
Comment: Caused by mutation in the FOXP3 gene.
53
Autoimmune lymphoproliferative syndrome (APLS)

Phenotype: Lymphadenopathy and splenomegaly associated with autoimmune haemolytic anaemia and thrombocytopenia.
Comments: Type IA is caused by mutations in the FAS gene (TNFRSF6, or CD95), and type IB by
mutations in the FAS ligand (FASL) gene (TNFSF6 or CD95L). Type IIA ALPS (ALPS2A) is caused by
mutations in the caspase-10 gene (CASP10), and type IIB by mutations in the CASP8 gene. Type III
ALPS comprises cases in which a mutation has not been identied.
118
54
Kabuki make-up syndrome

Phenotype: Congenital mental retardation syndrome with additional features, including postnatal
dwarsm, a peculiar facies characterised by long palpebral ssures with eversion of the lateral third
of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate,
scoliosis, short fth nger, persistence of ngerpads, radiographic abnormalities of the vertebrae,
hands, and hip joints, and recurrent otitis media in infancy.
55
MEN1
Synonyms: Multiple endocrine neoplasia, type Ia (MEN1a, MEN I); multiple endocrine adenomatosis
(MEA I), Wermer syndrome.
Phenotype: Autosomal-dominant disorder characterised by a high frequency of peptic ulcer disease and primary endocrine abnormalities involving the pituitary, parathyroid, and pancreas.
Comments: MEN1A is caused by a mutation in the MEN1 gene. MEN1B is caused by a mutation in
the CDKN1B gene.
56
MEN2A
Phenotype: Multiple endocrine neoplasia, type IIA, is an autosomal-dominant syndrome of multiple
endocrine neoplasms, including medullary thyroid carcinoma, phaeochromocytoma, and parathyroid adenomas.
Comment: Caused by a mutation in the RET oncogene.
57
MEN2B
Phenotype: Multiple true neuromas, phaeochromocytoma, thyroid carcinoma (medullary type),
sometimes caf-au-lait spots. The neuromas occur as pedunculated nodules on the eyelid margins,
lips and tongue. The lips are diusely hypertrophied. Features of Marfan syndrome (high arched palate, pectus excavatum, bilateral pes cavus, high patella and scoliosis), nodular goitre, pigmentation
of hands, feet and circumoral area, proximal myopathy, loose motions, and ushing attacks.
Comment: MEN2B is caused by a mutation in the RET gene.
119

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Official Journal of

ESPE European Society for Paediatric Endocrinology

Asia Pacific Pediatric Endocrine Society

Founded 1970 as Hormones by M. Marois

I.J.P. Arnhold, So Paulo

J.J. Heinrich, Buenos Aires

ESPE Council 20062007

Chairman of Clinical Practice

Fax +41 61 306 12 34

All rights reserved.

J. M.W. was supported by a grant of the Sabbatical Leave Programme of the

DISORDERS OF SEX DE VELOPMENT DSD

Primary Growth Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

Primary Growth Failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Sex Chromosome Disorders of Sex Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

OVERWEIGHT AND OBESIT Y

Simple Obesity, Common Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

ESPE Classification of Paediatric Endocrine Diagnoses

PITUITARY, HYPOTHAL AMUS, CENTR AL NERVOUS SYSTEM CNS

Section 2: Aetiological Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Primary Adrenal Insufficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

TESTICUL AR DISORDERS/DISORDERS OF MALE GENITALS

OVARIES, FEMALE REPRODUC TIVE TR AC T AND BREASTS

DISORDERS OF GLUCOSE AND TRIGLYCERIDE ME TABOLISM

DISORDERS OF BONE METABOLISM, INCLUDING C ALCIUM/

Transient Hypocalcaemia (Neonatal). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DISORDERS OF WATER BAL ANCE

SYNDROMES WITH ENDOCRINE FEATURES

ESPE Classification of Paediatric Endocrine Diagnoses

luminate understanding. In addition, when thinking about biological systems, there is

ESPE Classification of Paediatric Endocrine Diagnoses

Suggestions for coding are printed in italics.

Clinically defined syndromes

Small for gestational age (SGA) with failure of catch-up

Skeletal dysplasias (constitutional disorders of bone)3

Other specified disorders included in this group (thanatophoric

Other specified disorders included in this group

Insufficient nutrient intake (malnutrition)

Disorders in organ systems

ESPE Classification of Paediatric Endocrine Diagnoses

Muscular and neurological disorders, e.g. Duchenne muscular

Growth hormone deficiency (secondary IGF deficiency)5

Acquired growth hormone deficiency

Tumours outside the cranium, e.g. leukaemia, lymphoma

ESPE Classification of Paediatric Endocrine Diagnoses

Disorders of protein metabolism

Familial (idiopathic) short stature11

Non-familial (idiopathic) short stature13

2 Small for gestational age (SGA) with failure of catch-up growth

ESPE Classification of Paediatric Endocrine Diagnoses

Synonym (if combined with other deciencies): Hypothalamo-hypopituitarism, multiple congenital

Classical Idiopathic GHD

Idiopathic short stature (ISS)

Familial (idiopathic) short stature (FSS)

ESPE Classification of Paediatric Endocrine Diagnoses

Non-familial (idiopathic) short stature (NFSS)

Non-familial idiopathic short stature, onset of puberty not yet known

ESPE Code Diagnosis

PR I MARY G ROW TH D ISO R D E R S1

Clinically defined (dysmorphic) syndromes with sex

Other syndromes, unspecified

Dysmorphic syndromes due to metabolic/connective

Other dysmorphic syndromes with symmetrical overgrowth