Endocrine disorders and the skin

Hyperthyroidism

Box 23.1 summarizes the various cutaneous changes that may be seen in hyperthyroidism. This disorder is most often caused by an autoimmune thyroid condition: Graves disease. It may also be associated with a hyperfunctioning thyroid nodule, thyroid multinodular goiters, non-Graves thyroiditis, excessive thyroxine intake, or hypersecretion of thyroid-stimulating hormone (TSH). Cutaneous features occur most commonly in association with Graves disease, and these manifestations may more often be the result of autoimmune mediation rather than direct effects of thyroid hormones.

The clinical features of hyperthyroidism include nervousness, emotional lability, tachycardia and palpitation, heat intolerance, weakness, fatigue, tremors, hyperactivity, increased appetite, weight loss, increased systolic and pulse pressure, accelerated growth, sleep disturbances, school problems, vomiting, diarrhea, and occasionally exophthalmos. An enlarged thyroid gland is often present. Specific findings that suggest Graves disease include thyroid ophthalmopathy, pretibial myxedema (PTM), and acropachy. The ophthalmopathy is secondary to periorbital deposition of glycosaminoglycans and may present with proptosis, ocular paralysis, or lid lag.

Pretibial myxedema

PTM (also known as thyroid dermopathy ) manifests as plaques on the anterior tibial surfaces and is related to localized accumulation of acid mucopolysaccharides. Other locations of involvement are occasionally reported, including the dorsal feet. The majority of patients with PTM have ophthalmopathy. ^, The onset of PTM usually follows the diagnosis of hyperthyroidism. Examination reveals nonpitting edema, nodules, and plaques with pink to purple to yellow-brown discoloration ( Fig. 23.1 ). The overlying epidermis is thin with a waxy and sometimes translucent quality. Hypertrichosis with dilated hair follicles and a “ peau d’orange ” appearance may be noted. Polypoid or elephantiasis forms occur less commonly. Although the pretibial surfaces are most commonly involved, other areas, including the face, scalp, upper extremities, and trunk, may reveal similar changes. The differential diagnosis may include cellulitis, trauma, erythema nodosum, or other mucinoses, and PTM can be confirmed by tissue examination of skin biopsy material in conjunction with laboratory findings. Histologic evaluation may reveal mucin deposition and reduced elastic fibers.

Thyroid acropachy

Thyroid acropachy is more common in adults with hyperthyroidism; only occasionally occurs in children; and classically presents as the triad of digital clubbing, soft-tissue swelling of the hands and feet, and periosteal changes. Examination reveals thickening of the soft tissues over the distal extremities and (secondary to diaphyseal periosteal proliferation) of the distal bones. Drumstick-like clubbing, enlargement of the hands and feet, and radiographic changes (fluffy, spiculated, or homogeneous subperiosteal thickening with new bone formation) may be seen. Associated extremity and joint pain may be reported, and nail clubbing may also be seen. Thyroid acropachy and diabetic dermopathy (DD) are indicators of more severe Graves ophthalmopathy. ^,

Less specific cutaneous changes in hyperthyroidism include skin that is warm, velvety, moist, and smooth. Hair may be fine and thin. Facial flushing, increased sweating (particularly of the palms and soles), and palmar erythema are common, especially in the advanced state of the disease, called thyrotoxicosis . The nails grow rapidly, are shiny, and may reveal onycholysis (separation or loosening of the nail plate from the nailbed) with distal upward curvature (Plummer nails). Koilonychia (spoon-shaped nails; Fig. 23.2 ) and clubbing may also be noted. Chronic urticaria and generalized pruritus are uncommon manifestations of thyrotoxicosis, and chronic active hyperthyroidism can be complicated by Addison disease–like hyperpigmentation. However, the hyperpigmentation of hyperthyroidism is distributed differently, primarily on the shins ( Fig. 23.3 ), posterior feet, and nailbeds. Patients with hyperthyroidism may also have an increased incidence of alopecia areata and/or vitiligo. ^, Gynecomastia may be present in males and may be caused by increased conversion of testosterone to estradiol. Scleromyxedema, a condition marked by white-yellow papules, weight loss, monoclonal gammopathy, esophageal dysmotility, myopathy, and Raynaud phenomenon, has also been reported in patients (mainly adults) with hyperthyroidism.

Hypothyroidism

Box 23.2 summarizes the various mucocutaneous changes that may be seen in hypothyroidism. Hypothyroidism in pediatric patients may be congenital or acquired. Clinical features of congenital hypothyroidism are shown in Box 23.3 . Symptoms may be subtle in both forms of hypothyroidism, but decreased linear growth is an important indicator of both types of disease. Hypothermia, lethargy, and poor feeding are all characteristic of congenital disease, which is most often diagnosed on routine newborn screening examinations. Children with acquired hypothyroidism tend to be quiet and well behaved and as a result often receive high grades in school.

Congenital hypothyroidism may develop as a result of agenesis or dysgenesis of the thyroid gland (the most common cause), defective synthesis of thyroid hormone caused by an enzymatic defect, the presence of antithyroid antibodies in a pregnant mother, the lack of maternal iodine during pregnancy (endemic goiter), or the ingestion of antithyroid medications such as propylthiouracil or methimazole by a pregnant woman being treated for thyrotoxicosis. Iodine toxicity from iodine-containing skin antiseptic solutions has been implicated as a potential cause of transient hypothyroidism in newborn infants, although some studies refute this association. ^, Acquired hypothyroidism in children younger than 5 or 6 years of age may be caused by a delayed failure of thyroid remnants (with thyroid dysgenesis), by inborn defects of thyroid hormone synthesis, by ingestion of antithyroid agents, by thyroidectomy or ablation after radiation, or by chronic thyroiditis or hypothalamic-pituitary disease. After the age of 5 or 6 years, although the same etiologies may be involved, chronic lymphocytic thyroiditis (Hashimoto thyroiditis) is the most common cause. Although iodine deficiency is the most common cause of hypothyroidism worldwide, it is uncommon in the United States.

Cutaneous features of hypothyroidism reflect the hypometabolic state with reduced body temperature and reflex vasoconstriction. Patients often have dry, coarse, pale, and cool skin. Cutis marmorata (physiologic mottling) may be prominent. Hypohidrosis may lead to acquired palmoplantar keratoderma. Myxedema may occur in hypothyroidism, again as a result of mucopolysaccharide deposition in skin. It most commonly occurs in the hands, feet, and periorbital locations and may also be deposited in the tongue, giving rise to macroglossia. Generalized puffiness may be present, and the skin may take on a yellow hue as a result of carotenemia ( Fig. 23.4 ), especially on the palms, soles, and nasolabial folds. The hair is dull and brittle, and nails are ridged, brittle, and grow very slowly. Patients may have a dull, expressionless facies. Hypertrichosis of the back and shoulders may be seen, and alopecia may involve the lateral portions of the eyebrows (termed madarosis ) or occur in a more diffuse pattern. A collodion baby with concomitant congenital hypothyroidism has been reported.

Hyperparathyroidism

Primary hyperparathyroidism, one of the least common endocrine disorders of infancy and childhood, is rarely diagnosed in children younger than 16 years of age. When seen, it is usually the result of a familial, genetically determined hyperplasia of the parathyroid, which may present as an isolated hyperparathyroidism or as the hyperparathyroidism–jaw tumor syndrome, in which case ossifying tumors of the maxilla or mandible are present. A malignant neoplasm of the parathyroid or an association with some other disease, such as is seen in patients with multiple endocrine adenomatosis (multiple endocrine neoplasia [MEN]; see later) or chronic renal insufficiency, may also result in hyperparathyroidism. ^,

The majority of cases of hyperparathyroidism are sporadic, most often being caused by a single adenoma in the parathyroid gland. The clinical features of hyperparathyroidism include systemic effects of hypercalcemia: failure to thrive, muscular weakness, lethargy, anorexia, vomiting, fever, headache, constipation, weight loss, polydipsia, polyuria, mental retardation, metastatic calcification, and with marked hypercalcemia, stupor or death. Of these, metastatic calcification is the most common cutaneous manifestation, and in patients with sporadic hyperparathyroidism, this may be the only cutaneous finding. Hypercalcemia may also produce an ophthalmologic finding known as band keratopathy , which is the result of calcium and phosphate deposition beneath the Bowman capsule. Band keratopathy appears as a superficial corneal opacity resembling frosted or ground glass in a band-like configuration with white flecks or “holes” in the band resulting in a “Swiss cheese–like” appearance. It is not specific for hyperparathyroidism but may also be seen as a manifestation of hypercalcemia secondary to vitamin D intoxication, uremia, or sarcoidosis. It is not commonly found in patients with hyperparathyroidism when serum phosphorus levels are low and glomerular function is maintained.

Patients with chronic renal failure may experience several types of cutaneous manifestations. The skin of the patient with uremia may be pruritic, dry, scaly, sallow, and hyperpigmented; the sallow appearance is partially caused by anemia, and the hyperpigmentation appears to be the result of decreased renal clearance of melanocyte-stimulating hormone (MSH). Hyperparathyroidism secondary to chronic renal failure results from impaired synthesis of 1,25-dihydroxyvitamin D ₃ , which leads to hypocalcemia from impaired intestinal calcium absorption and, ultimately, increased levels of PTH. Hyperphosphatemia may result in a high serum calcium phosphate product and produce secondary calcification of the skin. This calcinosis cutis (see Chapter 9 ) manifests as hard calcium deposits in skin and subcutaneous tissues, especially in periarticular locations. These lesions may resolve spontaneously with correction of the serum calcium and phosphate levels. In addition to being seen in hyperparathyroidism, it may be noted in association with paraneoplastic hypercalcemia, milk alkali syndrome, sarcoidosis, and hypervitaminosis D. Calcinosis cutis has also been reported in the setting of normocalcemic primary hyperparathyroidism , in which case it represents preferential target organ deposition of calcium despite normal serum levels of calcium and phosphorus.

When the calcification is more progressive and involves blood vessels, ischemic necrosis of skin and soft tissues occurs and is termed calciphylaxis . This rare (especially in children) and life-threatening condition results from vascular calcification and is most commonly reported in patients with end-stage renal disease. Clinically, it manifests as ecchymotic or infarcted areas of skin, bullous lesions, and plaques of calcinosis with periodic extrusion of calcium. Lesions of pediatric calciphylaxis are most commonly noted on the upper and lower extremities. They are very painful, and mortality related to gangrene and sepsis is high. Extensive calcification in the heart and lungs may result in cardiorespiratory failure. Parathyroidectomy is often, but not always, useful in this setting. Histologically, calciphylaxis shows calcification of the walls of small and medium-sized blood vessels in the dermis and subcuticular regions.

The diagnosis of hyperparathyroidism is established by consistent elevations of total serum calcium above 12 mg/dL, the reduction of serum phosphorus concentrations below 4 mg/dL, and elevated levels of PTH. High alkaline–phosphatase levels usually indicate bone disease. This complication of hyperparathyroidism may be demonstrated radiographically by generalized demineralization of bones, destructive changes at the growing ends of long bones, subperiosteal erosions (particularly in the phalanges, metacarpals, and lateral portions of the clavicles), and in more advanced disease, generalized rarefaction, cysts, tumors, fractures, and deformities. Radiographs of the abdomen may reveal renal calculi or nephrocalcinosis, and ultrasonography and radioisotope scanning can confirm the diagnosis of primary hyperparathyroidism associated with an isolated parathyroid adenoma. In infants with parathyroid hyperplasia, cupping and fraying at the ends of long bones and ribs may suggest rickets, and severe demineralization and pathologic fractures are common.

Hypoparathyroidism/DiGeorge syndrome

Hypoparathyroidism is characterized by hypocalcemia and inappropriate response of the parathyroid glands or, less often, with elevated PTH levels and lack of response to the hormone (see Pseudohypoparathyroidism/Albright Hereditary Osteodystrophy section). In childhood, hypoparathyroidism may develop as a congenital idiopathic disorder but usually appears in the neonatal period, in later infancy, or during childhood or as an acute condition after inadvertent removal or damage of the parathyroid glands during thyroid surgery. Congenital hypoparathyroidism may occur alone; may be seen as an autoimmune disorder, where it may occur alone or with other endocrine disorders; or may be a hereditary condition associated with an increased familial incidence of other endocrinologic disorders (Addison disease, pernicious anemia, and Hashimoto thyroiditis), candidiasis, and/or vitiligo. When associated with hypoplasia of the thymus and immunologic defects, the condition is known as DiGeorge syndrome (see later).

Idiopathic or congenital hypoparathyroidism usually first manifests with tetany or seizures and in 25% to 50% of patients, ectodermal defects. The skin of affected individuals is rough, dry, thick, and scaly; the hair and eyebrows are sparse; and the nails are short and thin with brittleness, crumbling, or longitudinal grooving. When hypoparathyroidism occurs during tooth development, pitting, ridging, absence of dental enamel, and absence or hypoplasia of the permanent teeth may result. Extensive calcification of skin and subcutaneous tissues has been reported in an infant with congenital primary hypoparathyroidism, although this is exceedingly rare. Other clinical manifestations include convulsions, carpopedal spasm, muscle cramps and twitching, numbness or tingling of the extremities, laryngospasm or bronchospasm, exfoliative dermatitis, mental retardation, chronic diarrhea (especially in infants), photophobia, keratoconjunctivitis, blepharospasm, and cataracts. Mucocutaneous candidiasis is seen as a complication in 15% of patients with idiopathic hypoparathyroidism. Electrocardiography may reveal prolongation of the QT interval, and head imaging may show calcifications of the basal ganglia. The combination of candidiasis, endocrinopathy, and ectodermal dysplasia has been termed autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy (APECED) as well as autoimmune polyglandular syndrome (APS) type 1 or autoimmune polyendocrinopathy syndrome type 1 and is discussed in more detail in the section Autoimmune Polyglandular Syndromes (see also Chapter 17 ).

The cutaneous manifestations of hypoparathyroidism associated with surgical removal or injury of the parathyroid glands differ from those seen in patients with idiopathic or congenital hypoparathyroidism. These include thinning or loss of hair, the development of horizontal grooves (Beau lines) in the nails, or a complete loss of nails after episodes of tetany (these abnormalities revert to normal when hypocalcemia is controlled). Hyperpigmentation (predominantly on the face and distal extremities) may resemble melasma, pellagra, or Addison disease and also may occur in cases of postthyroidectomy hypoparathyroidism. Although cutaneous calcification has been noted, this complication is relatively uncommon. In a series of 21 patients with acquired hypoparathyroidism, the most common cutaneous manifestations were hair loss (especially axillary and pubic), coarsening of body hair, and dry skin.

DiGeorge syndrome is a T-cell deficiency disorder that develops as a result of faulty embryologic development of the thymus and the parathyroid glands (a congenital malformation of the third and fourth pharyngeal pouches and the surrounding arches). The classic triad consists of cardiac malformation, hypocalcemia, and T-cell immunodeficiency. Defects of the great vessels may include truncus arteriosus, interrupted aortic arch, double aortic arch, or aberrant subclavian artery. Oral candidiasis is an almost constant finding in patients with this disorder, and overwhelming fungal, viral, or bacterial infection may lead to death early in infancy. Hypocalcemia and tetany may occur at an early age, and other features include chronic diarrhea, interstitial pneumonia, failure to thrive, micrognathia, hypertelorism, low-set ears, bifid uvula, shortened philtrum, bowed mouth, chronic purulent rhinitis, mental retardation, calcification of the central nervous system, and nephrocalcinosis.

DiGeorge syndrome is associated with a deletion in the long arm of chromosome 22 and is also referred to as 22q11.2 deletion syndrome (22q11DS) or velocardiofacial syndrome. The candidate gene for this disorder is termed TBX1 , which encodes the T-box transcription factor 1. Approximately half of patients with DiGeorge syndrome are hemizygous for 22q11, and they have occasionally been found to have overlapping deletions in the 10p13/14 boundary. ^, These patients are at increased risk for developing psychiatric disorders, with one in four developing schizophrenia and one in six developing major depressive disorders. Other reported psychiatric morbidities include attention-deficit/hyperactivity disorder, oppositional defiant disorder, and anxiety disorders. Patients with 22q11DS may have varying rates of intellectual disability, especially with regard to visuospatial memory, face processing, and attention. Camptodactyly (fixed flexion of the proximal interphalangeal joints) may be a feature. When the immunodeficiency is severe, thymic or bone marrow transplantation should be considered.

Pseudohypoparathyroidism/Albright hereditary osteodystrophy

Pseudohypoparathyroidism (PHP) is a hereditary disorder in which there is decreased target tissue responsiveness in the receptor tissues, particularly the kidneys and skeletal system, to PTH (rather than a true deficiency). PHP is subclassified into types Ia, Ib, Ic, and type II (which involves a different mechanism of resistance to PTH). Albright hereditary osteodystrophy (AHO) refers to PHP in conjunction with a clinical constellation of physical features, including short stature, central obesity, brachydactyly, ectopic ossification, and variable degrees of mental retardation. ^,

Pseudopseudohypoparathyroidism (PPHP) is a term used to describe individuals with AHO who have normal end-organ responsiveness to PTH. These patients do not develop hypocalcemia and tetany. PHP and PPHP are caused by different types of mutations in the GNAS gene, and the presence of genetic imprinting may lead to quite diverse clinical phenotypes. ^, Specifically, maternal inactivating mutations result in PHP-Ia, whereas paternal inactivating mutations result in PPHP and the disorder progressive osseous heteroplasia (POH), a disease of severe heterotopic ossifications of the subcutaneous tissues, skeletal muscles, and deep connective tissues (see Chapter 9 ). This observation suggests that expression of the guanine nucleotide regulatory protein (Gsα) from the paternal and maternal alleles is not equivalent in the various tissues which depend on this hormonal mediation.

Patients with PHP have hypocalcemia, hyperphosphatemia, and elevated serum levels of PTH. Hypothyroidism secondary to TSH resistance may be seen in PHP-Ia. Patients may also display resistance to other hormones, including gonadotropins and growth hormone (GH)–releasing hormone. Ectopic calcification is common, and intracranial lesions usually involve the basal ganglia and occasionally other regions. Calcinosis cutis may occur and presents with multiple small papules, plaques, or nodules with a predilection for the scalp, hands and feet, periarticular regions, and chest wall. Soft-tissue ossification (osteoma cutis) may be present at birth or develop during infancy or childhood ( Fig. 23.5 ) and is often a presenting feature of the disease, along with hypothyroidism. The subcutaneous calcifications or ossifications may occasionally present very early in life (even by 2 weeks of age) and in those patients ( Fig. 23.6 ) may be vital to early recognition and diagnosis of PHP. Dermal or subcutaneous hypoplasia may occasionally be noted in areas of cutaneous calcification.

The characteristic features of AHO include short stature, obesity, and characteristic facial features, including round face, flat nasal bridge, and a short neck. Brachymetaphalangism refers to shortening of the fourth and fifth metacarpals and may be recognized by knuckle dimples when the patient makes a clenched fist. In addition, the fourth and fifth fingers and toes may appear shortened ( Fig. 23.7 ). Plain radiography may confirm this feature when the clinical findings are subtle. Mental retardation may be present and may be less common with aggressive and early treatment for the hypocalcemia.

Addison disease

Addison disease (primary adrenal insufficiency) is caused by the absence of glucocorticoids and mineralocorticoids despite an increased concentration of adrenocorticotropic hormone (ACTH) and is characterized by weakness, anorexia, weight loss, hypotension, decreased serum sodium and chloride, increased serum potassium, hypoglycemia, and hyperpigmentation of the skin and mucous membranes. Sporadic and recurrent “flu-like” episodes may provide a clinical clue to the diagnosis, especially in the setting of pigmentary alterations. Hyperpigmentation in Addison disease is the result of increased production of proopiomelanocortin, which is cleaved to form MSH and ACTH. This overproduction in the pituitary gland occurs as a compensatory phenomenon associated with decreased cortisol production by the adrenal glands. The hyperpigmentation of Addison disease occurs in the setting of primary adrenocortical failure, as opposed to secondary adrenal insufficiency, in which case ACTH levels are low and mineralocorticoid production remains relatively intact.

The pigmentation of Addison disease is most intense in the flexures, at sites of pressure and friction, in the creases of the palms and soles ( Fig. 23.8 ), in the nails, in sun-exposed areas, and in normally hyperpigmented areas such as the genitalia and areolae. Pigmentation of the conjunctivae and vaginal mucous membranes is common, and pigmentary changes of the oral mucosae ( Fig. 23.9 ) include spotty or streaked blue-black to brown hyperpigmentation of the gingivae, tongue ( Fig. 23.10 ), hard palate, and buccal mucosa. In addition, increased pigmentation may be noted in existing nevi. The pigmentation may be quite diffuse in some children. Labial pigmentation and longitudinal pigmentary streaks of the fingernails similar to those in Laugier–Hunziker syndrome have been observed. Because the pigmentation may in some cases be subtle, comparison of the patient to other family members may be useful in highlighting the clinical findings. In one series of 18 pediatric patients with primary adrenal insufficiency at one institution, 12 (67%) exhibited cutaneous hyperpigmentation. Primary adrenal insufficiency without hyperpigmentation has been reported and may result in a delay in the diagnosis of Addison disease. Loss of body hair may be another cutaneous finding in this disorder.

The diagnosis of chronic adrenocortical insufficiency is suggested by the clinical features and confirmed by serum electrolyte studies and cortisol level determinations after stimulation by ACTH (the ACTH stimulation test). A morning serum cortisol (“am cortisol”) level is a convenient and simple test but may be insensitive as a screening tool. There are multiple potential causes of Addison disease, including adrenal dysgenesis (which may be related to a variety of genetic mutations), diseases resulting in adrenal destruction, or impaired steroidogenesis (disorders of cholesterol or steroid biosynthesis, including several forms of congenital adrenal hypoplasia). Although the majority of cases of Addison disease in the past century were attributed to tuberculosis, autoimmune disease currently accounts for most cases presenting outside of the newborn period. APS types 1 and 2 may both present with this disorder as one component. Other nonautoimmune causes include infection, metabolic and infiltrative or metastatic diseases, and drug-induced damage. The incidence of Addison disease is elevated in vitiligo probands and their first-degree relatives. When these two disorders occur concurrently, patients may have a striking presentation of hypopigmentation and hyperpigmentation.

Cushing syndrome

CS is a rare disorder caused by long-term glucocorticoid excess, which may be caused by a variety of different etiologies. It is divided into ACTH-dependent types (including pituitary-dependent Cushing disease, ectopic ACTH syndrome, and adrenal hyperplasia) and non-ACTH-dependent types (including adrenal adenoma, adrenal carcinoma, and adrenal hyperplasia). The most common form is pituitary-dependent bilateral adrenal hyperplasia, termed Cushing disease. Endogenous CS is fairly uncommon in children, and the lack of classic features of hypercortisolism in pediatric patients may delay diagnosis and treatment. In all patients with CS, there is loss of diurnal variation of ACTH and cortisol secretion, which leads to sustained hypercortisolism. Growth retardation to complete linear growth arrest is the hallmark of the disease in children and growing adolescents, although in a large review of children with CS, the majority had normal or advanced skeletal maturation. ^, CS may also result from the systemic administration of exogenous glucocorticoids (including oral, parenteral, or, rarely, topical) or ACTH and should be suspected by the findings of suppressed ACTH and cortisol with no response to corticotropin-releasing hormone (CRH) or ACTH, respectively. CS has occurred after intralesional corticosteroid injections for keloids in a child. The authors have observed CS in a few children after topical application of ultrapotent corticosteroids for extensive alopecia areata/totalis and severe atopic dermatitis. Neonatal CS is rare and may be associated with adrenocortical tumors or genetic syndromes, including Li–Fraumeni, McCune–Albright, or Beckwith–Wiedemann syndromes. A variety of genetic causes of (and syndromic associations with) CS are being identified.

The clinical findings in CS are multiple and usually suggest the presence of hypercortisolism. Noncutaneous signs and symptoms include truncal obesity, diminution of the linear growth rate, diabetes mellitus or glucose intolerance, gonadal dysfunction, hypertension (in around 50% of patients), muscle weakness, fatigue, mood disorders, sleep disturbances, menstrual irregularities, osteoporosis, delayed or accelerated bone age, edema, polydipsia, polyuria, and fungal infections. ^{, ,} The typical growth chart in a child with CS reveals a severely diminished linear growth curve, with continued weight gain across percentiles. This is in distinction to the growth chart in a child with exogenous obesity, which reveals increasing linear growth. ^,

The cutaneous features of CS are listed in Box 23.4 . Addison disease–like pigmentation (particularly on the face and neck) has been noted in 6% to 10% of patients and is seen primarily in the ACTH-dependent forms of the disease. Other skin findings include a characteristic plethoric “moon” facies with telangiectasias over the cheeks; increased fine lanugo hair on the face and extremities; purplish striae (stretch marks, see later) at points of tension such as the lower abdomen, flanks, thighs, buttocks, upper arms, and breasts; fragility of dermal blood vessels with an increased tendency toward bruising at sites of minimal trauma; poor wound healing; and steroid acne. The latter usually presents as red papules or small pustules distributed primarily on the upper trunk ( Fig. 23.11 ), arms, neck, and to a lesser degree, the face. Temporal scalp hair regression may be present. There is a tendency to develop cutaneous fungal infections (e.g., tinea corporis, onychomycosis, candidiasis, pityriasis versicolor), and disseminated mycobacterial infection has been reported. Patients with CS classically have fatty deposits over the back of the neck, termed the buffalo hump ( Fig. 23.12 ).

CS is diagnosed based on suspicious clinical findings and the results of laboratory testing. A 24-hour urinary free-cortisol test is a widely used assay for diagnosing hypercortisolism and has a very high specificity and sensitivity. ^, Other diagnostic studies include plasma cortisol measurement (limited by diurnal variation), low-dose dexamethasone suppression test (excellent sensitivity but requires overnight hospitalization), high-dose dexamethasone suppression test, ACTH measurement (useful for discriminating between ACTH-dependent and ACTH-independent forms), late night salivary cortisol measurement, inferior petrosal sinus sampling, and the CRH stimulation test. ^{, ,} Radiographic imaging may be useful for assessing for pituitary or adrenal tumors. The treatment options for CS depend on the etiology and may include transsphenoidal pituitary surgery, external pituitary radiotherapy, excisional surgery (adrenal tumors), and mitotane (an adrenocytolytic agent). With the exception of striae, the cutaneous effects of CS most often completely heal after successful therapy. After treatment, glucocorticoid replacement and stress dosing of cortisol are often required.

Striae distensae (stretch marks), mentioned earlier, are linear depressions of the skin that are initially pink ( Fig. 23.13 ) or purple and later become more flesh-colored, translucent, and atrophic ( Fig. 23.14 ). They are most commonly seen in areas subject to stretching such as the lower back, buttocks, thighs, breasts, abdomen, and shoulders. Striae may develop physiologically in up to 35% of girls and 15% of boys between the ages of 9 and 16 years. Causes of striae include stretching exercises, rapid growth, obesity, adolescence, pregnancy, CS, and prolonged use of systemic or potent topical corticosteroids. They may be seen in patients with anorexia nervosa, mainly the restrictive (vs. the bulimic) form. They can occasionally be mistaken for nonaccidental injury or physical abuse. Although the precise cause of striae is unknown, their formation appears to be related to stress-induced rupture of connective tissue, alteration of collagen and elastin, and dermal scarring in which glucocorticoids suppress fibroblastic activity and newly synthesized collagen fills the gaps between ruptured collagen fibers. Elastic fibers are fine in early lesions and thickened in older lesions of striae. Treatment of striae is challenging, and most therapies are generally unsatisfactory. Many of the lesions that occur during adolescence tend to become less noticeable with time. It has been suggested that topical tretinoin cream may be helpful for some patients, although the results are mixed. Other topical agents reportedly effective in some patients include glycolic and trichloroacetic acid peels and topical hyaluronic acid preparations. The flashlamp-pumped pulsed-dye laser has also been used for treating these lesions, but data suggest that this modality should be reserved for patients with the more fair skin phenotypes (types II to IV). Other treatment modalities that have been reported for striae include intense pulsed light, excimer laser, copper–bromide laser, fractional photothermolysis, and microdermabrasion. ^{, ,}