Outline

Growth
Laurie E. Cohen, M.D.

Normal growth rates Growth patterns Growth hormone deficiency

short stature --- less than 2 stdev below the normal

Childrens Hospital Boston

What is Short Stature?

Definition:
Height < 2 SDS below the mean for age and sex Approximately 3% of all children

Human Variation
Hormones play a
major role in human growth, but not the only factor. Genetics, nutrition, psychological wellbeing, and other factors also determine ultimate adult height.

www.hcc.hawaii.edu/~pine/variation.htm

Postnatal Growth
Rapid growth velocity that declines Frequent crossing of percentiles as
prenatal influences diminish
in utero growth in v. rapid . first 6 mos v rapid growth

Ranges of Normal Growth Velocity (Tanner and Davies)

boys girls

progressively after birth

+2

-2

slow: <25th percentile

Page 1

Adolescence
Rapid and highly variable growth rate
due to increased production of adrenal and gonadal hormones Pubertal development occurs earlier in girls (10 yrs) than boys (12 yrs) Pubertal growth spurt in girls is a relatively earlier event in pubertal progression

Adolescence

Late Adolescence / Early Adulthood Growth rate declines markedly after

puberty
Bone growth ceases Epiphyseal plates fuse Height is stable (barring presence of degenerative disease/condition or trauma)

Monitoring Growth

Josef Gast, University of Pennsylvania Gazette, Jan/Feb 2002

Monitoring Growth
Accurate
measurements at regular intervals Correct data recording
Record and plot data Use correct growth charts Plot data at correct age

Proper equipment

Page 2

Calculating Target Heights

Midparental height Girls: (F + M) - 13 cm* 2 Boys: (F + M) + 13 cm 2 F = fathers height (cm) M = mothers height (cm) Target height = midparental height 1.88 SD (1 SD = 5 cm**)
* 13 cm 5 inches, ** 5 cm 2 inches

Familial (Genetic) Short Stature

Family history of short stature Normal birth length and weight Height < 3rd percentile for chronologic Normal annual growth rate Predicted adult height < 3rd percentile Normal onset of puberty No other cause of growth failure
age

late bloomer -- late, really short kid , who is now very tall

Bone Age

MPH M

http://emedicine.medscape.com/article/924411-diagnosis

Constitutional Delay
Late Bloomer

Slowing of growth during first 2-3 years

of life, but normal annual growth rate thereafter Family history of similar pattern of growth and delayed puberty Delayed bone age closer to height age Normal predicted adult height in context of family pattern

MPH M

height age -age at which child height is 50 percentile

Page 3

Normal Patterns of Growth

Familial or genetic short stature Constitutional growth delay

parents are really high so child may not get up there! so be concerend

Turner Syndrome
Multiple nevi Low posterior hairline Increased carrying angle Webbed neck Widely spaced nipples Cardiac abnormalities Renal abnormalities
Horseshoe kidney Duplicated collecting system Aortic coarctation Left-sided defects
postive correlation betwen parental height and height of turner syndrome patients.

From Behrman: Nelson Textbook of Pediatrics, 16th ed., W. B. Saunders Company, 2000

Turner Syndrome
Characteristic phenotypic features may
not be present Should be considered in any girl who presents with unexplained short stature and no FH of short stature Positive correlation between parental height and height of Turner syndrome patient Definitive diagnosis is made with chromosomal testing

Primary Growth Disturbances

Intrauterine growth Genetic disorders
Chromosomal defects / other syndromes Turner syndrome Down syndrome Noonan syndrome Prader-Willi syndrome Russell-Silver syndrome

retardation

Disproportionate short
stature
Skeletal dysplasias Spinal irradiation

Page 4

this child --- under nutrition !!!

Systemic Disorders
Decreased weight-to-height ratio generally Absolute or relative nutritional deficiency
IBD and celiac disease may otherwise be asymptomatic

indicates a systemic illness

typically results in decrease in rate of weight gain or weight loss prior to decreased linear growth

Other chronic illnesses impair growth related

to their disease activity

Systemic Disorders
Hypocaloric
Malnutrition Gastrointestinal disease Malabsorption IBD Celiac disease Poorly controlled IDDM

Metabolic
Renal RTA Nephrogenic DI Renal failure Hepatic Cardiac (cyanotic) Hematologic (chronic anemias) Respiratory CF Severe asthma Chronic infections

height affected more! but weight has fallen off.

Endocrine Disorders
Preserved weight gain or frank obesity
associated with poor linear growth suggests an endocrine disorder

Hypothyroidism
Symptoms Signs
Fatigue Cold intolerance Constipation Myxedema Dry, coarse skin & nails Decreased heart rate Delayed DTR relaxation phase
From Brown RS. Disorders of the Thyroid Gland in Infancy, Childhood and Adolescence in Thyroid Disease Manager. http://www.thyroidmanager.org/Chapter15/15-frame.htm accessed 1/13/11
Hypothyroidism

Page 5

Hypothyroidism
Onset of signs and symptoms may be An overtly enlarged thyroid gland may Once treatment with L-T4 is initiated,
not be present there is a rapid increase in growth velocity A permanent height deficit may remain related to duration of thyroid hormone deficiency before treatment subtle

Growth Hormone (GH) Deficiency

Immature
endocrine disorder wt maintained height lost

Large calvarium
nasal bridge fat

appearance

Underdeveloped

(frontal bossing)

Ripply abdominal
From Shulman DI, Bercu BB. Contemporary Pediatrics 1998. 15:95-110

Growth Hormone
Synthesized and secreted by
cell types

GH and its Receptor

Receptors are present in a variety of Required for bone and soft tissue
growth after the postnatal period

somatotrophs in the anterior pituitary

uses janus kinase to phosp

Page 6

GH Receptor
Cytokine family of receptors
Class I cytokine receptor (hematopoietinreceptor family) Includes erythropoietin, GH, many interleukins Class II cytokine receptor Many are receptors for interferon or interferon-like cytokines TNF-receptor family Chemokine-receptor family

GH Receptor Signaling
nucleus

-IGF1

IGF-1 Levels

IGF levels increase in adolescence short children low levels of IGF 1

From Shulman DI, Bercu BB. Contemporary Pediatrics 1998. 15:95-110

IGF from liver circulates IGF BP -3 carrier for IGF 1 -- used to screening test for GH secretion

IGFBP-3 Levels
Technically simpler
assay Circulates in plasma at high levels (g/ ml) Age dependent, but varies only modestly with age Less nutritionally dependent than IGF-1
From Smith et al. J Clin Endocrinol Metab 77:1294, 1993

GH Deficiency
1/4,000 - 1/10,000 live births Normal birth weights and lengths Severe GH deficiency may be associated with
multiple anterior pituitary hormone deficits and characterized in the newborn period by:
Hypoglycemia Conjugated hyperbilirubinemia, neonatal hepatitis Small phallus in boys

Mild GH deficiency usually presents after 6

months of age with subnormal growth rate

Page 7

Etiologies of GH Deficiency: Congenital

Syndromes CNS abnormalities
Septo-optic dysplasia Cleft lip palate Empty sella syndrome Holoprosencephaly, anencephaly Pituitary aplasia, hypoplasia Thin or absent pituitary stalk Hydrocephalus

Single Central Incisor

Genetic Idiopathic

Ectopic Posterior Pituitary Bright Spot with GH Deficiency

GH Deficiency

ectopic ADH highly suggestive of GH deficiney

Hesx1, Ptx2, Lhx3, Lhx4, Prop-1, Pit-1 GH gene mutations

IGF-1 Deficiency: Abnormalities GH Receptor Signaling

extracellular domain
transmembrane domain

IGF-1 Deficiency
Laron Dwarfism IGF-1 mutations

GH binding dimerization trafficking to cell membrane anchoring (mutant GHR containing extracellular domain only) Signaling defects (stat5b mutation) GHR

IGF-1 rec. mutations

Signal transduction (lacks stat5b activation)
IGF-1 IGFBP-3

intracellular domain

ALS

ALS mutations

Page 8

Impact of SNPs on Short Stature

A single IGF-1 allele
is a major determinant of size in small dogs

Etiologies of GH Deficiency: Acquired

Trauma Infections
Perinatal events Head injury Meningitis Granulomatous disease Histiocytosis Sarcoidosis

Neoplasms
Craniopharyngioma Germinoma Hypothalamic astrocytoma/optic glioma

Infiltrative
Sutter NB et al. Science 2006. 316(5821):112

Cranial irradiation

Craniopharyngioma

Short Stature
A common clinical problem A symptom, not a disease May represent a variant of normal May indicate pathology
growth

UNC Radiology Teaching File

Page 9