Am J Clin Dermatol 2003; 4 (5): 315-331

THERAPY IN PRACTICE 1175-0561/03/0005-0315/$30.00/0

Adis Data Information BV 2003. All rights reserved.
Cutaneous Manifestations of Endocrine Disorders
A Guide for Dermatologists
Serge A. Jabbour
Division of Endocrinology, Diabetes and Metabolism, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
1. Thyrotoxicosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316
1.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
1.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317
1.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
2. Hypothyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
2.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
2.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
2.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3. Autoimmune Thyroid Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319
3.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
3.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320
4. Cushing Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
4.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
4.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
4.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
5. Addison Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
5.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
5.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
5.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
6. Acromegaly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
6.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
6.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
6.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
7. Androgen-Related Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
7.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
7.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
7.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
8. Hypopituitarism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
8.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
8.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
8.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
9. Parathyroid Hormone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
9.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
9.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
10. Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
10.1 Cutaneous Manifestations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
10.2 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 328
316 Jabbour
10.3 Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
11. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329
Dermatologists may commonly see skin lesions that reflect an underlying endocrine disorder. Identifying the Abstract
endocrinopathy is very important, so that patients can receive corrective rather than symptomatic treatment. Skin
diseases with underlying endocrine pathology include: thyrotoxicosis; hypothyroidism; Cushing syndrome;
Addison disease; acromegaly; hyperandrogenism; hypopituitarism; primary hyperparathyroidism; hypoparathy-
roidism; pseudohypoparathyroidism and manifestations of diabetes mellitus.
Thyrotoxicosis may lead to multiple cutaneous manifestations, including hair loss, pretibial myxedema,
onycholysis and acropachy. In patients with hypothyroidism, there is hair loss, the skin is cold and pale, with
myxedematous changes, mainly in the hands and in the periorbital region.
The striking features of Cushing syndrome are centripetal obesity, moon facies, buffalo hump, supraclavicu-
lar fat pads, and abdominal striae. In Addison disease, the skin is hyperpigmented, mostly on the face, neck and
back of the hands.
Virtually all patients with acromegaly have acral and soft tissue overgrowth, with characteristic findings, like
macrognathia and enlarged hands and feet. The skin is thickened, and facial features are coarser.
Conditions leading to hyperandrogenism in females present as acne, hirsutism and signs of virilization
(temporal balding, clitoromegaly).
A prominent feature of hypopituitarism is a pallor of the skin with a yellowish tinge. The skin is also thinner,
resulting in fine wrinkling around the eyes and mouth, making the patient look older.
Primary hyperparathyroidism is rarely associated with pruritus and chronic urticaria. In hypoparathyroidism,
the skin is dry, scaly and puffy. Nails become brittle and hair is coarse and sparse. Pseudohypoparathyroidism
may have a special somatic phenotype known as Albright osteodystrophy. This consists of short stature, short
neck, brachydactyly and subcutaneous calcifications.
Some of the cutaneous manifestations of diabetes mellitus include necrobiosis lipoidica diabeticorum,
diabetic dermopathy, scleredema adultorum and acanthosis nigricans.
Hormones are known to be essential in regulating physiologic
processes in each system of the body, including the skin. Endo-
crine diseases, through excess or deficiencies of hormones, result
in changes in cutaneous function and morphology. This paper
reviews many endocrinopathies and their associated skin condi-
tions. The overall clinical presentation is also discussed, as are the
appropriate diagnostic tests, and a brief overview of the treatments
related to these endocrine disorders.
1. Thyrotoxicosis
Thyrotoxicosis may be due to several conditions. The most
common cause is Graves disease (autoimmune disease); its fre-
quency ranging from 6090% of all thyrotoxic patients in different
regions of the world. Most of the remaining etiologies are caused
by a single toxic adenoma, a toxic multinodular goiter, several
types of thyroiditis (subacute thyroiditis, silent thyroiditis) or
excessive exogenous thyroid hormone ingestion. These other
Table I. Major symptoms and signs of thyrotoxicosis
Symptoms Signs
Fatigue Diffuse goiter (Graves), solitary nodule or
multinodular goiter
Heat intolerance Muscle weakness
Hyperactivity Ophthalmopathy (Graves)
Increased appetite Pretibial myxedema, acropachy
(Graves)
Increased perspiration Stare, lid lag and eyelid retraction
Menstrual disturbance Systolic hypertension
Neck pain (Subacute Tachycardia or atrial arrhythmia
thyroiditis)
Nervousness Thyroid tenderness
(subacute thyroiditis)
Palpitation Tremor and hyperreflexia
Tremor Warm, moist, smooth skin
Weakness
Weight loss
causes are rare.
[1-3]
The symptoms and signs of thyrotoxicosis are
summarized in table I.
[4]
Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (5)
Cutaneous Manifestations of Endocrine Disorders 317
In addition to the aforementioned cutaneous features of the
thyrotoxic state, patients with Graves disease may have distinct
cutaneous manifestations such as pretibial myxedema and ac-
ropachy. Pretibial myxedema or thyroid dermopathy (figure 2) is
almost always associated with Graves ophthalmopathy,
[25]
but it
was also reported in patients with Hashimoto thyroiditis.
[26]
It
occurs in a small percentage of patients with Graves disease
(0.54%), most frequently on the anterior tibia and dorsa of the
feet, and consists of nonpitting scaly thickening and induration of
the skin; it can also present as few well-demarcated pink, flesh-
colored or purple-brown papules or nodules.
[8,27]
Thyroid ac-
ropachy (figure 3) is a triad consisting of digital clubbing, soft
tissue swelling of the hands and feet, and periosteal new bone
formation.
[8]
It occurs in 0.11% of patients with Graves dis-
Fig. 1. Plummers nail, or onycholysis, is a separation of the nail plate from
the nail bed. The separated portion is white and opaque, in contrast to the
pink translucence of the attached portion.
ease.
[28]
It almost always occurs in association with
ophthalmopathy and pretibial myxedema.
[29]
1.1 Cutaneous Manifestations
1.2 Diagnosis
In patients with thyrotoxicosis, the skin is usually warm, ery-
thematous and moist, with a smooth, silky texture.
[5-7]
The warmth,
The diagnosis of thyrotoxicosis is made by measuring serum
caused by increased cutaneous blood flow and peripheral vasodila-
thyroid-stimulating hormone (TSH) level, which is the most cost-
tion, may be responsible for episodic facial flushing and palmar
effective screening test.
[30]
A normal TSH almost excludes thyro-
erythema.
[8]
toxicosis, except in the rare case of TSH-secreting pituitary adeno-
The epidermis is thin but not atrophic.
[9]
Generalized hyperhi-
ma, where TSH is normal to high.
[30,31]
If TSH is suppressed to
drosis may be noted, but it is usually more prominent on the palms
below 0.1 IU/ml, free T4 (thyroxine) and free T3 (triiodothyro-
and soles.
[8,9]
Scalp hair is fine and soft, and holds a permanent
nine) should then be obtained. Because serum levels of total T4
wave poorly.
[5,8]
Diffuse loss of scalp hair occurs in 2040% of
and total T3 can be affected by some binding proteins (mostly
thyrotoxic patients, although the severity of the loss is not directly
thyroxine-binding globulin), free levels are more accurate and
related to the severity of the endocrine abnormality.
[10]
Alopecia
reflect the patients true thyroid state. Some patients may also have
areata and loss of axillary, pubic, body and eyebrow hair may also
T3-toxicosis, producing mainly T3; for this reason, free T3 should
be noted.
[11]
The nails become shiny, soft and friable. Many
always be measured, especially if TSH is suppressed and free T4 is
patients develop onycholysis (figure 1), that is, distal separation of
normal.
[30,31]
nail plate from its underlying bed with upward curvature, so-called
After a laboratory diagnosis of hyperthyroidism is made, a
Plummers nail; it usually begins under the distal central portion of
24-hour radioiodine uptake and scan is usually done to define the
the fourth fingernail, but may eventually involve any of the finger
and toe nails.
[12,13]
Onycholysis is not specific to thyrotoxicosis
and may be observed in patients with hypothyroidism, psoriasis,
trauma or allergic contact dermatitis.
[14]
Such nail changes are less
common in patients over 60 years of age.
[15]
Hyperpigmentation
has been noted in thyrotoxic patients from 2% to as high as 40% of
large series.
[2,16]
The hyperpigmentation can be diffuse or local-
ized, sometimes in a pattern similar to patients with Addison
disease.
[8]
Vitiligo of variable extent occurs in a substantial portion of
patients, and is seen especially in Graves disease, as a marker of
the autoimmune disease.
[17-19]
Other less frequently reported cutaneous changes are pruri-
tus,
[20]
eczematous dermatitis,
[21]
dermographism and urticaria,
[22]
purpura and erythematous eruptions,
[23]
and xanthelasma.
[24]
Fig. 2. Pretibial myxedema, a localized violaceous induration that usually
occurs on the shins.
Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (5)
318 Jabbour
locytosis.
[33]
The different types of thyroiditis are usually self-
limited and do not necessitate radioactive iodine or antithyroid
agents.
[34]
2. Hypothyroidism
Worldwide, iodine deficiency is the most common cause of
hypothyroidism.
[35]
In areas where iodine intake is adequate, the
most common causes are chronic autoimmune thyroiditis (goitrous
type or Hashimotos thyroiditis and atrophic type or primary
myxedema), radiation-induced thyroiditis (mostly after
131
I ther-
apy for thyrotoxicosis) and post-surgical hypothyroidism.
[35]
Other
rare causes are drug-induced (lithium, iodine), central hypothy-
roidism (pituitary or hypothalamic disease), and the hypothyroid
phase of certain thyroiditis (subacute, silent).
[35]
The symptoms
and signs of hypothyroidism are summarized in table II.
[36]
2.1 Cutaneous Manifestations
In hypothyroidism, the skin is cold and pale, due to cutaneous
vasoconstriction and reduced core temperature.
[9]
In over 80% of
patients with primary hypothyroidism, the epidermis is thin, dry,
rough, hyperkeratotic and covered with fine superficial scales.
[37]
These abnormalities are much less frequent in central hypothy-
roidism (<10%).
[38]
Fine wrinkling imparts a parchment-like quali-
ty to the skin, especially in hypothyroidism secondary to pituitary
failure.
[9]
A malar flush is seen in 50% of patients.
[37]
Yellowish
discoloration of the skin, especially the palms, soles and nasolabial
Fig. 3. Acropachy or clubbing of the nail.
folds, is caused by accumulation of carotene in stratum corneum,
secondary to carotenemia,
[39]
attributed to a hepatic defect in the
etiology, either Graves (high uptake, homogenous goiter), toxic
nodule(s) [high uptake, hot nodule(s)], or thyroiditis (low/sup-
pressed uptake, cold scan).
[30,31]
1.3 Treatment
Patients with symptomatic thyrotxicosis can be given a beta-
adrenoreceptor antagonist (beta-blocker), unless contraindicated
(such as patients with asthma). The definite treatment of hyperthy-
roidism depends on the etiology. In Graves disease and toxic
nodule(s), radioactive iodine is the favorite option for most en-
docrinologists, because it has a good safety profile and is very
effective.
[32]
However, it may lead to post-ablative hypothyroidism
and weight gain. In Graves disease, when patients refuse radioac-
tive iodine, antithyroid agents (methimazole, propylthiouracil) are
another option,
[33]
but induce a remission in only 3040% of
patients after a treatment period of 18 months. They also have
adverse effects that include rash, pruritus, urticaria, arthralgias,
fever, nausea and vomiting; but the most serious effect is agranu-
Table II. Major symptoms and signs of hypothyroidism
Symptoms Signs
Arthralgia Ascites
Cold intolerance Bradycardia
Constipation Carotenemia
Decreased appetite Diastolic hypertension
Decreased perspiration Diffuse or nodular goiter
Depression Dry, coarse skin
Dry skin Hoarseness
Fatigue and lethargy Hyporeflexia and delayed relaxation of
reflexes
Hoarseness Loss of lateral third of eyebrows
Menstrual disturbances Nonpitting edema (myxedema)
Mental impairment Pleural effusions
Paresthesia Puffy face
Sleepiness Slow movements
Weight gain Slow speech
Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (5)
Cutaneous Manifestations of Endocrine Disorders 319
conversion of beta-carotene to vitamin A. Scleral sparing is a clue
to hypercarotenemia as opposed to jaundice.
[40]
The most striking skin change is due to dermal accumulation of
mucopolysaccharides (myxedema), and is most marked in the
hands and in the periorbital region. The facial changes are almost
pathognomonic (figure 4). There is a non-pitting swelling or
puffiness around the eyes, with a very characteristic loss of the
outer third of the eyebrows. A drooping of the upper lid may occur
secondary to decreased sympathetic stimulation. The nose is
broadened, and the lips are thickened. The tongue is large. The
face lacks expressiveness; and changing emotions are registered
slowly.
[8,9,37]
The hair is dull, coarse and brittle, in part due to diminished
sebum secretion. Hair loss has been noted in up to 50% of
hypothyroid patients, resulting in a diffuse, partial alopecia.
[8,37]
There is also loss of genital and beard hair. Nail deformities are
reported in many patients with myxedema.
[37,41]
The nails are thin,
brittle and striated, with both longitudinal and transverse
grooves.
[42]
Other manifestations include vitiligo, alopecia areata,
and dermatitis herpetiformis.
[8,43]
2.2 Diagnosis
The diagnosis of hypothyroidism is made by measurement of
serum TSH, which is above normal in these patients. If the level is
normal, hypothyroidism is almost excluded, except in the rare
occurrence of central hypothyroidism, where TSH can be normal
or low; in this case, the diagnosis is made by adding free T4 level
to TSH.
[44,45]
When TSH is high, free T4 is also measured, but it Fig. 4. Hypothyroidism. This patient has many typical features of hypothy-
roidism: puffiness of the face with dry and pale skin.
may be normal in the early stages of hypothyroidism (subclinical
hypothyroidism). Antithyroid peroxidase antibodies (anti-TPO)
time, there is no cause-effect relationship demonstrated, but the
are obtained to document the diagnosis of Hashimoto thyroidi-
association is probably part of the same immune dysfunction.
tis.
[44,45]
24-hour thyroid uptake and scan is neither necessary nor
These associations may be in the patients or in other family
useful in patients with hypothyroidism.
members.
[47]
2.3 Treatment
3.1 Cutaneous Manifestations
L-thyroxine is given in a maintenance dose of 1.6 g/kg/day to
patients with hypothyroidism, except in patients with underlying
The most common clinical association of autoimmune thyroid
cardiac disease or older people (>60 years), where treatment is
disease is dyschromia, which generally has an autoimmune etiolo-
started at 25 g/day and increased progressively by 25g every
gy. The most frequent hyperchromia is melasma, a localized caf e-
24 weeks until the maintenance dose is reached. TSH levels are
au-lait hyperpigmentation over the forehead, upper lips, cheeks,
measured 6 weeks after the treatment is started or after any change
and chin. There is a strong association between thyroid autoim-
in dose.
[46]
Titration in dosage is made every 6 weeks until TSH
munity (microsomal thyroid autoantibodies) and melasma, mostly
reaches a normal level of around 12 IU/ml.
in women whose melasma develops during pregnancy or after
ingestion of oral contraceptive drugs.
[48]
Among hypochromias,
3. Autoimmune Thyroid Disease
the main expression is vitiligo, characterized by achromic areas
Many skin disorders can be seen in patients with autoimmune with hyperpigmented margins, located mainly in the back of the
thyroid disease, independently of thyroid function. Most of the hands, face, neck, folds and genitals. The prevalence of vitiligo in
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320 Jabbour
Graves disease; the prevalence of TSHR-Ab varies from 70
to100%, being higher in patients with hyperthyroidism.
[53]
Of course, TSH is also measured, as discussed in sections 1 and
2. If TSH is normal, but thyroid autoantibodies are present, the
patients is at higher risk of developing thyroid dysfunction; there-
fore, follow-up testing with yearly TSH measurements would be
indicated.
3.3 Treatment
If the patient has hyper- or hypothyroidism, then treatment is
aimed at correcting thyroid function (see sections 1 and 2). If the
patient is euthyroid, but has thyroid autoantibodies, treatment of
the autoimmune thyroid disease is not usually indicated. However,
a few investigators have reported patients with urticaria and
angioedema that resolved after L-thyroxine therapy, even if TSH
was initially within normal limits.
[51,52]
Therefore, in these pa-
tients, especially if they do not respond to other treatments, L-
thyroxine could be tried for 48 weeks;
[51,52]
care should be taken
Table III. Symptoms and signs of Cushing syndrome
Symptom or sign Reported incidence
(%)
Abdominal striae 5171
Acne, oily skin 2680
Ankle edema 2860
Backache, vertebral collapse, fracture 4050
Centripetal obesity 7997
Easy bruisability 2384
Facial plethora 5094
Glucose intolerance 3990
Headache 047
Hirsutism 6481
Hyperpigmentation 416
Hypertension 7487
Impotence 5580
Oligomenorrhea or amenorrhea 5580
Polydipsia, polyuria 2544
Psychological changes 3186
Renal calculi 1519
Weakness, proximal myopathy 2990
patients with Graves disease is 67%, whereas it is only 12% in
the general population.
[49]
Besides dyschromia, alopecia areata is classically associated
with thyroid diseases;
[50]
the main features are circumscribed bald
patches in the scalp or beard. Also, in patients with diffuse
alopecia, autoimmune thyroid disease is found in almost 60% of
the cases.
[47]
Other skin disorders described in patients with autoimmune
thyroid diseases are pemphigus, bullous pemphigoid, dermatitis
herpetiformis, lupus erythematosus, scleroderma, and Sj ogren
syndrome.
The association of chronic urticaria and angioedema with thy-
roid autoimmunity has also been observed, and resolution of
chronic urticaria was achieved after L-thyroxine treatment, even in
euthyroid patients.
[51,52]
3.2 Diagnosis
The presence of one or more of the skin disorders previously
listed in section 3.1 should prompt the screening for autoimmune
thyroid disease by the use of antithyroid peroxidase antibodies,
which replaced the former antithyroid microsomal and an-
tithyroglobulin antibodies. These antibodies are present in almost
9598% of patients with Hashimoto thyroiditis and in almost 80%
of patients with Graves disease. A more expensive test, autoan-
tibodies against the TSH receptor (TSHR-Ab), is more specific for
Fig. 5. Plethoric moon facies in Cushing syndrome.
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Cutaneous Manifestations of Endocrine Disorders 321
skin eventually becomes fragile and, in extreme case, peels off
after being covered with adhesive tape (Liddle sign).
[61]
Minor
wounds heal slowly.
[55]
Loss of subcutaneous connective tissue
results in easy bruising after minimal trauma.
[61]
One sign that is virtually pathognomonic for Cushing syndrome
is the presence of purple (violaceous) striae >1cm in diameter
(figure 7). They are most commonly seen on the abdomen and
lower flanks but can also occur on the upper arms, shoulders,
axillae, breasts, hips, buttocks and upper thighs. These violaceous
striae must be differentiated from those often seen in obese or
pregnant patients, which are pink, reddish or silvery, less pig-
mented and thinner.
[56]
Fig. 6. Buffalo hump and supraclavicular fat pad in Cushing syndrome.
Hyperpigmentation is also seen and is dependent upon both the
duration and the degree of increase in ACTH secretion.
[55]
It
not to render the patient thyrotoxic by titrating L-thyroxine in
occurs most often in patients with the ectopic ACTH syndrome,
order to keep the TSH in the lower range of normal.
less often with pituitary hypersecretion of ACTH, and not at all
with adrenal Cushing syndrome.
[55]
It may be generalized, but is
4. Cushing Syndrome
most evident in areas exposed to light (face, neck, back of the
Defined as the constellation of clinical signs and symptoms
hands) or to chronic mild trauma or pressure (shoulders, midriff,
resulting from chronic glucocorticoid excess, Cushing syndrome
waist, elbows, knuckles, spine, knees). Patchy pigmentation may
can be caused mainly by pituitary hypersecretion of adrenocortico-
occur on the inner surface of lips and the buccal mucosa along the
tropic hormone (ACTH) [Cushing disease], ectopic secretion of
line of dental occlusion.
[55,61]
As in any condition that causes
ACTH by non-pituitary tumors, adrenal hypersecretion of
hyperinsulinism and insulin resistance, acanthosis nigricans may
glucocorticoids or exogenous administration of corticosteroids.
be found in Cushing syndrome.
[62,63]
The axillae are the most
Other etiologies are very rare.
[54]
The clinical manifestations of
frequent sites, but also the sides of the neck, under the breasts, the
Cushing syndrome are summarized in table III.
[55,56]
belt line and the groin.
[56]
The most common change in body hair in Cushing syndrome is
4.1 Cutaneous Manifestations
the development of villous hypertrichosis of the forehead and
upper cheeks.
[56]
When there is concomitant androgen excess
One of the striking features of glucocorticoid excess is the
(most common with carcinomas), women with Cushing disease
change in the appearance and body habitus. The most common
show signs of hirsutism, oily facial skin, acneiform rash on the
feature is progressive central (centripetal) obesity, usually involv-
face, neck and shoulders, temporal balding and other signs of
ing the face, neck, trunk, abdomen and internally, the mesentery
virilization.
[55,56]
and mediastinum.
[55]
Significant fat deposits may also appear in
the cheeks resulting in moon facies often accompanied by pleth-
ora over the cheeks, anterior neck, and sun-exposed chest (figure
5), in the dorsocervical area known as buffalo hump (figure 6), or
in the supraclavicular fossae (figure 6) resulting in supraclavicu-
lar fat pads.
[56]
Retro-orbital fat deposition may result in exoph-
thalmos.
[57]
The centripetal obesity is accompanied by wasting of the ex-
tremities.
[9]
Corticosteroids inhibit epidermal cell division,
[58]
and
decrease collagen synthesis.
[59]
The stratum corneum is thinned
and there is loss of subcutaneous fat in the extremities.
[60]
These
alterations in skin cell physiology lead to several dermatological
changes, including cutaneous atrophy, which is often promi-
nent.
[56]
On physical examination, a fine cigarette paper wrin-
kling may be seen on the dorsum of the hand and the elbow.
[56]
The
Fig. 7. Abdominal striae (wide and purple) in Cushing syndrome.
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322 Jabbour
ing, adrenal carcinoma) or drugs which block steroid synthesis
(ketoconazole, metyrapone, aminoglutethimide).
5. Addison Disease
The most common cause of chronic primary adrenal insuffi-
ciency (Addison disease) was formerly tuberculous adrenalitis, but
now it is autoimmune adrenalitis (slow destruction of the adrenals
by cytotoxic lymphocytes).
[66]
Other etiologies (infection, hemor-
rhage, neoplasia) are less common. Addison disease should not be
confused with secondary adrenal insufficiency, where the damage
is in the hypothalamic/pituitary axis (tumors, chronic steroid in-
take, etc.). The clinical manifestations are shown in table IV.
[66-68]
5.1 Cutaneous Manifestations
The most striking cutaneous change of chronic primary adrenal
insufficiency is hyperpigmentation (figure 8 and figure 9), which
occurs almost uniformly,
[9]
with some exceptions.
[69]
In many
Table IV. Clinical manifestations of Addison disease
Amenorrhea
Anorexia
Associated autoimmune disorders (vitiligo, Hashimotos thyroiditis etc.)
Decreased axillary and pubic hair
Diarrhea
Hyperpigmentation
Hypoglycemia
Hyponatremia, hyperkalemia and acidosis
Hypotension
Loss of libido
Lymphocytosis, eosinophilia
Mild normocytic anemia
Myalgias and arthralgias
Nausea and vomiting
Psychiatric manifestations
Tiredness and weakness
Weight loss
patients, it may be the first sign of the disease.
[70]
It is caused by
increased melanin content in the skin, due to the melanocyte-
4.2 Diagnosis
stimulating activity of the high plasma ACTH concentration.
[71,72]
The hyperpigmentation is generalized, but is most conspicuous in
When the index of suspicion is high for Cushing syndrome, the
areas exposed to light (such as face, neck, back of hands), areas
screening test of choice is a 24-hour urinary free cortisol (UFC). A
exposed to chronic pressure (elbows, knees, spine, knuckles,
level of at least three times the upper limit of normal is diagnostic
waist, midriff, shoulders), in the palmar creases and in sexual areas
of Cushing syndrome.
[64,65]
Intermediate values necessitate repeat-
(nipples, areolae, axillae, perineum and genitalia).
[9,67,68]
Patchy
ing the test. The UFC is 95100% sensitive and specific.
[65]
pigmentation also appears on mucosal surfaces, especially the
Another screening test is the overnight dexamethasone suppres-
buccal mucosa, inner surfaces of lips, gums and tongue.
[9]
Genera-
sion test, where 1mg of dexamethasone is given at 11.00pm and a
lized buccal, vaginal and anal mucosal membrane hyperpigmenta-
serum cortisol is obtained the next morning at 8.00am. A value of
tion is usually seen only in patients whose skin is normally
>3 g/dl is abnormal. This test is only 80% specific, because it
pigmented, such as African Americans and native Americans.
[67]
carries many false positives, especially in certain psychiatric con-
Scars acquired after the onset of Addison disease are permanently
ditions like major depression.
[65]
For this reason, even when abnor-
pigmented. Hair may darken and longitudinal pigmented bands
mal, the overnight dexamethasone suppression test needs to be
confirmed by doing a UFC.
[64,65]
After the diagnosis of Cushing
syndrome is made, serum ACTH should be measured to define the
source, either adrenal (low ACTH), pituitary (normal to high
ACTH), or ectopic (very high ACTH). Subsequently, appropriate
imaging is performed.
[64,65]
Sometimes, the ACTH level is not very
diagnostic, and further sophisticated tests are necessary (beyond
the scope of this article).
4.3 Treatment
The treatment of Cushing syndrome is directed at the source.
Surgery on the pituitary, adrenal or ectopic tumor (if not metastat-
ic) is performed. Occasionally, it may be necessary to use radiation
therapy (pituitary tumor), chemotherapy (metastatic ectopic Cush-
Fig. 8. Hyperpigmentation, mostly marked on areas exposed to light, such
as face and neck in Addison disease.
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Cutaneous Manifestations of Endocrine Disorders 323
going surgery or a major procedure, stress dose corticosteroids
must be given.
[76]
6. Acromegaly
Acromegaly is the clinical syndrome that results from exces-
sive secretion of growth hormone (GH). More than 99% of cases
result from a pituitary adenoma.
[77]
The clinical features of acro-
megaly are summarized in table V.
[77,78]
6.1 Cutaneous Manifestations
Virtually all patients with acromegaly have acral and soft tissue
overgrowth, although the extent of the overgrowth varies. The
characteristic findings (figure 10 and figure 11) are an enlarged
Fig. 9. On the left, hand of a patient with Addison disease, showing a
darker skin and hyperpigmented knuckles. On the right, hand of the pa-
tients mother.
jaw (macrognathia), and enlarged, swollen hands and feet, which
result in increasing shoe and glove size and the need to enlarge
appear on the nails.
[9]
Decreased axillary and pubic hair is com-
rings.
[78]
The skin is thickened and has a doughy feel. Furrowing
mon in women, in whom androgen production primarily occurs in
and accentuation of folds contributes to the coarsening of the facial
the adrenal glands.
[73]
Patchy, often bilaterally symmetrical areas
features. Deepening of creases on the forehead and nasolabial
of vitiligo, the result of autoimmune destruction of dermal melano-
folds gives the patients a scowling, somber expression.
[9]
Eyelids
cytes, occur on the trunk or extremities in 1020% of patients with
are thick, the lower lip is enlarged and there is macroglossia.
[78]
autoimmune-based disease but not those with other causes of
Folds of skin over bony prominences on the hands are accentuated.
adrenal insufficiency.
[67,74]
The pads of the digits become fleshy, and fingers assume a blunted
shape. The heel pads on the feet are thickened.
[9]
The overgrowth
5.2 Diagnosis
of fibrous tissue leads to production of small fibromas that are
found in 2030% of patients.
[79]
Nails become thick and hard.
The diagnosis of Addison disease is made by performing a
Hyperhidrosis is present in 50% of patients, and is often malodor-
short cosyntropin (synthetic ACTH) stimulation test: A baseline
serum cortisol is obtained, then the patient is injected with cosyn-
tropin 0.25mg intramuscularly or intravenously; 1 hour later,
another serum cortisol is obtained. A normal response is a 1-hour
cortisol value of at least 20 g/dl. If it is <20 g/dl it is diagnostic
of adrenal insufficiency, either primary or secondary.
[75]
Addition-
ally, plasma ACTH is elevated (>100 ng/L) in patients with
Addison disease, while it is normal (952 ng/L) or low in patients
with secondary adrenal insufficiency. Typical routine laboratory
tests in Addison disease show hyponatremia, hyperkalemia and
hyperchloremic metabolic acidosis.
[75]
After the diagnosis of Ad-
dison disease is made, imaging of the adrenals (computed tomog-
raphy [CT] scan) is done to exclude any hemorrhage, infection and
metastatic cancer.
5.3 Treatment
Treatment of Addison disease consists of replacing glucocorti-
coids (prednisone 57.5 mg/day or hydrocortisone 1520mg in the
morning and 510mg in the evening) and mineralocorticoids
(fludrocortisone 0.050.1 mg/day). During minor illnesses, pa-
tients should double/triple their glucocorticoid dose. When under-
Table V. Clinical manifestations of acromegaly
Acral overgrowth (enlarged hands and feet)
Amenorrhea in females, impotence and loss of libido in males
Arthralgias
Cardiomyopathy, left ventricular hypertrophy, arrhythmias
Carpal tunnel syndrome
Deepening of the voice
Excessive sweating
Glucose intolerance
Hyperphosphatemia
Hypertension
Increased risk of colonic polyps and gastrointestinal malignancies
Kidney stones
Macroglossia
Macrognathia, enlargement of nose and frontal bones
Malocclusion
New skin tags
Osteoporosis (if hypogonadism present)
Sleep apnea
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324 Jabbour
normal in 1050% of these women.
[83,84]
PCOS is the association
of androgenism (biochemical or clinical) with chronic anovulation
in women without specific underlying disease of the adrenal or
pituitary glands.
[85]
Less common causes include congenital adre-
nal hyperplasia (CAH), ovarian and adrenal tumors, and drugs
(anabolic steroids, progestogens, danazol).
[83,84]
Certain drugs, like
minoxidil, cyclosporine and penicillamine may rarely cause
hypertrichosis, or diffusely increased total body hair; which does
not represent true hirsutism.
[83,84]
The major clinical findings in
women with androgen-related disorders are summarized in table
VI.
[83,84]
7.1 Cutaneous Manifestations
Fig. 10. Acromegaly, showing coarse facial features and macrognathia.
The skin becomes thickened and coarse in patients with andro-
ous.
[78]
Hair growth increases and some women (<10%) complain
gen-related disorders. Pores on the face enlarge, and there is
of hirsutism.
[78]
Hyperpigmentation has been observed in about
excessive oiliness. Typically, acne vulgaris and seborrhea develop
40%. The increase in color is generalized but not marked.
[9]
(figure 12). Androgenetic alopecia may be seen, typically with
Acanthosis nigricans is associated with acromegaly in at least 10%
diffuse hair loss; alopecia is rarely complete. Hirsutism (increase
of patients.
[80]
in androgen-dependent terminal hair) occurs on the lip, chin, chest,
areolae, abdomen, linea alba, lower back, buttock, inner thighs and
6.2 Diagnosis
external genitalia.
[83,84]
Acanthosis nigricans can also be seen,
The diagnosis of acromegaly can be done by measurement of
especially in women with PCOS.
[62,63]
In addition, in patients with
serum insulin-like growth factor (IGF-1) which is GH-dependent,
severe hyperandrogenism (virilization), we can see temporal bald-
and serum GH after a glucose load. Serum IGF-1 is elevated in
ing, deepening of the voice, increased muscle mass, loss of female
virtually all patients with acromegaly and provides excellent dis-
body contour and clitoromegaly
[83]
(figure 13).
crimination from unaffected individuals.
[81]
However, poorly con-
trolled diabetes mellitus, starvation, and hepatic failure result in
7.2 Diagnosis
false underestimation of IGF-1 levels. In these cases, measurement
The tests that provide the most useful information in patients
of serum GH after a glucose load is the most specific dynamic test;
with androgen-related disorders are measurements of serum total
acromegalics do not suppress their GH levels to <1 g/L (mea-
testosterone, dehydroepiandrosterone-sulfate (DHEA-S) and pro-
sured by immunoradiometric [IRMA] assay) after ingestion of
lactin, although other tests may be indicated in selected patients.
[84]
75100g of an oral glucose solution.
[82]
When the laboratory
If total testosterone is greater than 200 ng/dl, an ovarian tumor is
diagnosis is made, a pituitary magnetic resonance imaging (MRI)
is done to define the size and extension of the tumor.
6.3 Treatment
Treatment of acromegaly consists essentially in resecting the
pituitary tumor.
[82]
If surgery is not curative, somatostatin ana-
logues can be used postoperatively.
[82]
Occasionally, radiation
therapy may offer some benefit.
[82]
7. Androgen-Related Disorders
Androgen-related disorders are most commonly due to in-
creased sensitivity of the pilosebaceous unit to normal plasma
levels of androgens with normal menstrual cycles.
[83]
When there
is androgen excess, polycystic ovary syndrome (PCOS) is the most
common cause, although plasma levels of androgens may be
Fig. 11. Same patient with acromegaly (see figure 10) with enlarged hands
and fingers.
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Cutaneous Manifestations of Endocrine Disorders 325
pituitary hormones. The most common cause is a pituitary tumor,
although infiltrative, vascular, cranial radiation therapy, hypotha-
lamic tumors and other disorders also cause hypopituitarism.
[86]
Most of the symptoms and signs are similar to those that occur
with a primary deficiency of that gland. ACTH deficiency results
in adrenal insufficiency (see previous section), except that
hyperpigmentation is absent. TSH deficiency results in symptoms
and signs of hypothyroidism (see previous section). Luteinizing
hormone (LH) and follicle-stimulating hormone (FSH) deficien-
cies lead to amenorrhea in females and erectile dysfunction with
hypogonadism in males. Loss of GH results in lack of vigor,
decreased tolerance to exercise and decreased social functioning.
Table VI. Clinical findings in women with androgen-related disorders
Acanthosis nigricans and obesity (especially in PCOS)
Acne vulgaris and seborrhea
Clitoromegaly
Deepening of voice
Galactorrhea (hyperprolactinemia)
Hirsutism (see section 7.1); androgenetic alopecia (diffuse)
Increased muscle mass
Irregular periods
Loss of female body contour
Striae, thin skin, bruising, truncal obesity (Cushing syndrome see
section 4)
Temporal balding
PCOS = polycystic ovary syndrome.
PRL (prolactin) is the only hormone under tonic inhibition in
suspected, and ovarian imaging (transvaginal ultrasound) should
normal conditions; in hypopituitarism, it becomes elevated and
be performed. If DHEA-S is more than 23 times the upper limit
results in galactorrhea.
[86]
Less commonly, deficiency in arginine
of normal, imaging of the adrenals (CT scan) is done to exclude a
vasopressin (AVP) results in diabetes insipidus.
virilizing adrenal mass. Prolactin is measured in women who,
besides hirsutism, have irregular menses, to exclude hyperprolac-
tinemia;
[84]
slightly elevated prolactin levels may be seen in wo-
men with PCOS, moderately elevated values (>40 ng/dl) should
prompt a search for other etiologies (hypothalamic/pituitary dis-
ease, renal or liver disease, primary hypothyroidism, and drugs,
mainly neuroleptics).
The diagnosis of PCOS does not require the presence of poly-
cystic ovaries on ultrasound, because 20% of normal ovulatory
women may have polycystic ovaries and up to 20% of women with
PCOS may have normal ovaries.
Testing for late-onset CAH (due to 21-hydroxylase deficiency)
should be considered in women with early onset of hirsutism or a
family history of CAH. Diagnosis is best established by measuring
serum 17-hydroxyprogesterone before and 60 minutes after 250g
of cosyntropin. A 60-minute value above 1000 ng/dl is diagnostic.
7.3 Treatment
In women who have PCOS or idiopathic hirsutism, oral contra-
ceptives, frequently in combination with antiandrogens (like spiro-
nolactone) are effective in controlling the hirsutism and regulating
the periods in most women.
[83-85]
Of course, hirsutism can also be
treated by physical methods (electrolysis, laser removal etc.).
Adrenal or ovarian tumors should be resected. In CAH, treatment
might include glucocorticoids and genetic counseling.
[85]
8. Hypopituitarism
Hypopituitarism results from a variety of conditions that com-
promise the anterior pituitary and therefore the elaboration of all
Fig. 12. Facial acne, hirsutism and greasy skin.
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326 Jabbour
volume, osmolarity and specific gravity; serum electrolytes are
also measured. Some of these tests have limitations, the discussion
of which is beyond the scope of this paper.
[86]
A pituitary MRI is
also performed to rule out the possibility of tumor or other destruc-
tive process in the sellar region.
8.3 Treatment
Treatment of hypopituitarism is directed at the underlying
process resulting in hypopituitarism. Most commonly, it is a
pituitary macroadenoma that needs to be removed surgically.
[86]
Hormonal deficiencies should also be replaced (thyroid hormones,
glucocorticoids, sex steroids, GH, and occasionally AVP).
[86]
9. Parathyroid Hormone
Primary hyperparathyroidism (hypersecretion of parathyroid
hormone [PTH] by parathyroid adenoma or hyperplasia) is not
associated with any cutaneous manifestations except, rarely, pruri-
tus and deposition of calcium.
[9]
In few case reports, chronic
urticaria was the initial manifestation of primary hyperpara-
thyroidism.
[87]
Hypoparathyroidism (failure of parathyroid glands) may be the
result of surgery, infiltrative disorders, autoimmune conditions, or
idiopathic. The clinical presentation of hypoparathyroidism is
shown in table VII.
[88]
Pseudohypoparathyroidism is a heritable disorder of target-
organ unresponsiveness to parathyroid hormone. It mimics hy-
poparathyroidism, with hypocalcemia and hyperphosphatemia,
Fig. 13. Enlargement of the clitoris.
but the PTH level is elevated.
[89]
Many of these patients have
8.1 Cutaneous Manifestations
Pallor of the skin with a yellowish tinge is a prominent feature
in patients with hypopituitarism, but mucous membranes retain
their normal hue unless the patient is anemic. The skin is dry but
softer than in primary hypothyroidism. The face may be puffy and
less expressive because of a reduction in skin folds. Thinness of
the skin and subcutaneous tissues results in fine wrinkling around
the eyes and mouth making the patient look older.
[9]
Loss of body hair occurs in all patients. Scalp hair tends to be
fine and dry. Sebaceous secretions and sweating also decrease.
[9]
8.2 Diagnosis
Screening studies include measurement of prolactin, TSH, free
T4, morning cortisol and ACTH, FSH, LH, testosterone (in
males), and dynamic testing for GH deficiency. In the right setting
(polyuria, polydipsia and absence of diabetes mellitus), screening
for diabetes insipidus is done by a 24-hour urine collection for
Table VII. Clinical manifestation of hypoparathyroidism
Abnormal dentition
Cataracts
Chvostek sign (twitching of the circumoral muscles in response to
tapping the facial nerve, just anterior to the ear)
Coarse brittle hair, alopecia
Dry, rough skin
Extrapyramidal signs
Laryngospasm and bronchospasm
Muscle cramps
Paresthesias
Personality disturbances
Prolonged Q-T interval on EKG
Pseudopapilledema
Seizures
Tetany
Trousseau sign (carpal spasm elicited by inflation of a blood pressure
cuff to 20mm Hg above the patients systolic pressure for 3 minutes)
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Cutaneous Manifestations of Endocrine Disorders 327
9.2 Diagnosis
The diagnosis of hypoparathyroidism (low calcium, high phos-
phorus and low PTH), pseudohypoparathyroidism (low calcium,
high phosphorus and high PTH) and primary hyperparathyroidism
(high calcium and high PTH) can be made by measuring serum
ionized calcium, phosphorus and intact PTH.
[88]
9.3 Treatment
In patients with symptomatic primary hyperparathyroidism,
surgery should be performed.
[91]
In asymptomatic patients, indica-
tions for surgery include: <50 years of age, bone disease, urine
calcium >400 mg/day, decreased kidney function, nephrocalci-
nosis, and low serum levels of 25-hydroxyvitamin D.
[91]
When
surgery is not performed, patients should stay well hydrated, and
keep a daily calcium intake of no more than 600800mg.
In patients with hypoparathyroidism and pseudohypoparathy-
roidism, calcium and calcitriol (1,25-hydroxyvitamin D) are used
in combination.
[90]
10. Diabetes Mellitus
Diabetes mellitus is a group of metabolic diseases characterized
by hyperglycemia resulting from defects in insulin secretion (type
1 diabetes), insulin action or both (type 2 diabetes). The classic
symptoms are polyuria, polydipsia and unexplained weight
loss.
[92]
Other manifestations of diabetes mellitus are shown in
table VIII.
[92]
10.1 Cutaneous Manifestations
Fig. 14. Albright hereditary osteodystrophy: short stature, round face, short
neck and brachydactyly (short digits).
Certain skin disorders are more frequently associated with
Albright hereditary osteodystrophy. Pseudopseudohypoparathy-
diabetes mellitus. The best example of such an association is
roidism is the presence of Albright hereditary osteodystrophy
necrobiosis lipoidica diabeticorum (NLD) [figure 16]. Occurring
without any disorder of calcium metabolism.
[89]
in 0.3% of patients with diabetes mellitus, these lesions are distinc-
9.1 Cutaneous Manifestations
In hypoparathyroidism and pseudohypoparathyroidism, the
skin is dry, scaly, hyperkeratotic, and puffy. Nails become opaque,
brittle and develop transverse ridges. Hair becomes coarse and
sparse. Eczematous dermatitis, hyperkeratotic and maculopapular
eruptions have been reported.
[9]
Autoimmune hypoparathyroidism
may be associated with chronic mucocutaneous candidiasis.
[90]
Many patients with pseudohypoparathyroidism and all patients
with pseudopseudohypoparathyroidism have Albright hereditary
osteodystrophy (figure 14 and figure 15), which consists of short
stature, short neck, brachydactyly (short digits, mainly fourth and
fifth metacarpals), and subcutaneous ossifications.
[89]
Fig. 15. Brachydactyly in a patient with Albright hereditary osteodystrophy:
most often, there is shortening of the fourth and fifth metacarpals.
Adis Data Information BV 2003. All rights reserved. Am J Clin Dermatol 2003; 4 (5)
328 Jabbour
does not pit on pressure. It occurs mainly in obese patients with
diabetes mellitus with evidence of vascular complications. It may
not remit after a long period of time.
[99,100]
As many as one-third of patients with diabetes (both type 1 and
type 2) have tight, thickened, and waxy skin over the dorsa of the
hands.
[101]
Other cutaneous manifestations include reddening of
the face (rubeosis faciei) and of the extremities in patients with
long-standing diabetes mellitus, with occasional necrosis and de-
struction of the underlying bone,
[102]
bullous lesions of the feet,
xanthomatosis (secondary to hyperlipidemia, common in diabetes
mellitus), infections (most frequent are staphylococcal pyodermas,
candidiasis, erythrasma and epidermophytosis).
[9]
10.2 Diagnosis
There are three possible ways to diagnose diabetes mellitus,
and each must be confirmed, on a subsequent day, by one of the
Table VIII. Clinical manifestations in diabetes mellitus
Atherosclerotic heart disease (myocardial infarction, heart failure) and
peripheral vascular disease (lower extremity amputation)
Autonomic neuropathy (postural hypotension, gastroparesis, diarrhea,
neurogenic bladder, sexual dysfunction)
Intertriginous candidiasis (common in the obese) and oral candidiasis
(uncommon)
Neuropathic foot ulcers with secondary infections and diabetic Charcots
foot (degenerative change of the bony structure of the foot)
Peripheral neuropathy (sensory deficit, burning and tingling sensations)
Polyuria, polydipsia, polyphagia
Renal failure
Retinopathy (blurred vision, decreased visual acuity, visual loss)
Skin lesions and infections (see section 10.1)
Strokes
Unexplained weight loss
Vaginitis (usually due to monilial infection)
other two methods. The three methods are: (i) fasting plasma
glucose at least 7.0 mmol/l (126 mg/dl); (ii) symptoms of diabetes
tive, oval or irregularly shaped, indurated plaques with central
atrophy and yellow pigmentation; peripherally along the margins
there is either red-brown or violaceous pigmentation. The lesions
usually occur on the anterior and lateral surfaces of the lower
legs.
[9]
The differential diagnosis includes granuloma annulare,
which presents as asymptomatic annular red plaques on the dor-
sum of the extremities or posterior neck, but lacking a yellow
discoloration. Even histologically, it might be difficult to differen-
tiate between NLD and granuloma annulare. NLD occurs in pa-
tients with both type 1 and type 2 diabetes. The majority of
patients have diabetes mellitus when NLD develops; in most of the
rest, diabetes mellitus appears later.
[93]
Progression of lesions does not correlate with normalization of
hyperglycemia.
[9]
Acanthosis nigricans has been associated with
type 2 diabetes, type A and type B syndromes of insulin-resistance
(in type A, there is a defect in insulin receptor; in type B, there are
blocking antibodies to the insulin receptor).
[62,63,94]
Acanthosis
nigricans (figure 17) consists of diffuse velvety thickening and
hyperpigmentation of the skin, chiefly in the axillae, neck, in-
framammary folds, groin, perineum, and less often, nipples and
areolae.
[95]
Vitiligo occurs with greater than expected incidence in
patients with diabetes, either type 1
[96]
or type 2.
[97]
Diabetic
dermopathy consists of asymptomatic, irregularly shaped patches
occurring on the anterior lower legs; their surfaces are depressed
and they are a light brown color.
[98]
They are often accompanied
by significant microangiopathy elsewhere.
[9]
Scleredema
adultorum consists of induration of the skin beginning on the
posterior and lateral neck. This painless swelling may gradually
spread to the face, shoulders, anterior neck, and upper torso; it may
eventually involve the abdomen, arms and hands. The hard skin
Fig. 16. Necrobiosis lipoidica diabeticorum with multiple lesions showing
an atrophic and necrotic center with a raised brownish-red border.
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