Section 18. Endocrine Disorders and the Skin

Acanthosis nigricans (AN) is a diffuse, velvety thickening and hyperpigmentation of the skin, chiefly in axillae and other body folds, the etiology of which may be related to factors of hereditary, associated endocrine disorders, obesity, drug administration, and, in one rare form, malignancy.

Classification

• Type 1—Hereditary Benign AN No associated endocrine disorder.
• Type 2—Benign AN Associated with insulin resistance (IR): IR diabetes mellitus (DM), hyperandrogenism, acromegaly, gigantism, Cushing’s disease, glucocorticoid therapy, diethylstilbestrol, oral contraceptives, growth hormone, hypogonadism, Addison’s disease, hypothyroidism.
• Type 3—Pseudo-AN Obesity-induced IR, darker skin types.
• Type 4—Drug-induced AN Nicotinic acid, stilbestrol in young males, oral contraceptives.
• Type 5—Malignant AN Paraneoplastic, usually adenocarcinoma; less commonly, lymphoma.

Epidemiology

Age Any age. Peak: puberty to adulthood.

Gender M = F.

Incidence 7% of the population.

Race African Americans > Hispanics > Caucasians.

Pathophysiology

Epidermal changes of AN are likely caused by triggers that stimulate keratinocyte and fibroblast proliferation. In type 2, benign AN, the trigger is likely insulin or an insulinlike growth factor. In type 5, malignant AN, the trigger is likely the tumor or tumor secretions.

History

AN has an asymptomatic, insidious onset. The first visible change is darkening of pigmentation which gradually progress to velvety plaques that may be pruritic.

Physical Examination

Skin Findings

Type Plaque.

Color Dark brown to black, hyperpigmented, skin appears dirty.

Palpation Velvety, rugose, mammillated.

Distribution Posterior neck (Fig. 18-1) > axillae, groin > antecubital, knuckles, submammary, umbilicus, areola.

Mucous Membranes Oral, nasal, laryngeal, and esophagus: velvety texture with delicate furrows.

Nails Leukonychia, hyperkeratosis.

Other Skin tags in same areas.

General Findings

Ocular Papillomatous lesions on the eyelids and conjunctiva.

Benign AN Obesity or underlying endocrine disorder.

Malignant AN Underlying malignancy, gastric adenocarcinoma (70%).

Differential Diagnosis

AN can be confused with confluent and reticulated papillomatosis of Gougerot and Carteaud (CRP), terre firme, hypertrichosis, Becker’s nevus, epidermal nevus, hemochromatosis, Addison’s, or pellagra.

Laboratory Examinations

Dermatopathology Papillomatosis, hyperkeratosis; epidermis thrown into irregular folds, showing varying degrees of acanthosis.

Course and Prognosis

• Type 1: Accentuated at puberty, and, at times, regresses when older.
• Type 2: Prognosis related to severity of IR. AN may regress subsequent to treatment of the IR state.
• Type 3: AN may regress subsequent to significant weight loss.
• Type 4: Resolves when causative drug discontinued.
• Type 5: Poor prognosis, since the underlying malignancy is often aggressive. Adults with new-onset AN have an average survival time of 2 years.

Management

Treatment of AN should include a careful workup to exclude any underlying endocrine disorder. In children, AN is rarely a sign of an underlying malignancy. Correction of any underlying disorder (obesity, endocrine disease) improves the skin condition. Cosmetically, AN is difficult to treat, but some improvement may be gained with topical keratolytics (retinoic acid). In severe cases, systemic retinoids (etretinate, isotretinoin), metformin, dietary fish oil, dermabrasion, and laser therapy have reported successes. In adults, malignant AN may respond to cyproheptadine because it may inhibit the release of tumor products.

Necrobiosis lipoidica (NL) is a cutaneous disorder characterized by distinctive, sharply circumscribed, red–brown plaques with palpable rims and yellow–brown atrophic centers occurring on the lower legs. It is sometimes associated with DM.

Synonyms Necrobiosis lipoidica diabeticorum (NLD).

Epidemiology

Age Any age, peak: 30 years. Seen earlier in juvenile diabetic patients.

Gender F > M, 3:1.

Incidence 0.3% of patients with diabetes.

Etiology 65% patients with diabetes. Posttraumatic.

Pathophysiology

NL is a granulomatous inflammatory reaction caused by alterations in the collagen. The exact cause is unknown, but in DM, NL is thought to be secondary to diabetic microangiopathy. In non-DM cases, the trigger may be posttraumatic, postinflammatory, metabolic, or vasculitic antibody-mediated.

History

NL skin lesions evolve slowly and enlarge over months to years. The skin lesions are typically asymptomatic, but ulcerated lesions are painful. Diabetes may or may not be present at the time of onset of lesions and is present in up to 65% of NL patients.

Physical Examination

Skin Findings

Type Papules, plaques, ulcers.

Size 1 to 3 mm up to several centimeters.

Color Brownish-red border; yellow atrophic center (Fig. 18-2).

Shape Serpiginous, annular, irregularly irregular.

Arrangement Often symmetrical.

Distribution Legs and feet (80%) > arms, trunk, face, and scalp.

Other Decreased sensation, hypohidrosis, and alopecia.

Laboratory Examinations

Dermatopathology Interstitial and palisaded granulomas with reduced intradermal nerves, thickened blood vessel walls, and endothelial cell swelling in the dermis. Granulomas consist of histiocytes, multinucleated lymphocytes, plasma cells, and eosinophils.

Immunofluorescence IgM, IgA, C3, and fibrinogen in the walls of the small blood vessels.

Differential Diagnosis

NL can be confused with xanthomas, xanthogranuloma, sarcoidosis, rheumatoid nodules, stasis dermatitis, injection granulomas, and granuloma annulare (GA).

Course and Prognosis

The lesions are indolent and can enlarge to involve large areas of the skin surface unless treated. Up to 30% of the patients have clinical DM, but the severity of NL is not to diabetic severity or control. NL is chronic with variable scarring, and rarely squamous cell carcinomas have been reported.

Management

Most patients are most upset by the clinical appearance of the lesions rather than the symptoms. Because localized trauma can precipitate NL, elastic support stockings and leg rest may be helpful. Lesions can be improved with topical or intralesional steroids. Antiplatelet aggregation therapy (aspirin, dipyridamole, pentoxifylline, stanozolol, inositol nicotinate, nicofuranose), TNF agents (etanercept, infliximab), thalidomide, topical bovine collagen, topical GM–CSF, cyclosporine, PUVA or UVA, mycophenolate mofetil, ticlopidine, nicotinamide, clofazimine, local heparin injections, surgical grafting, and laser therapy all have cases of reported success. Screening for DM is warranted if systemic symptoms are present.

GA is a self-limited dermatosis of unclear etiology, clinically characterized by dermal papules arranged in an annular configuration commonly on the dorsa of the hands, feet, elbows, and knees.

Insight

Annular lesions are frequently called “ringworm” and treated as such. For an annular lesion that is not scaly, GA must be considered.

Classification

GA can be classified into several clinical variants:

1. 1. Localized GA (most common): Solitary annular plaques on extremities of young people.

   2. Generalized GA (15%): Numerous papules on trunk/extremities in patients younger than 10 years or aging between 30 and 60 years.

   3. Subcutaneous GA: Occurs in children younger than 6 years. Nodules on pretibial area (75%), hands, buttocks, scalp.

   4. Perforating GA (5%): Occurs in children. Papules with crusting/ulceration on dorsal hands/fingers.

   Synonyms Pseudorheumatoid nodule.

Epidemiology

Age Children, young adults, 67% in those who are younger than 30 years.

Gender Female-to-male ratio of 2:1.

Genetics Familial cases reported. HLA-Bw35, HLA-A29, HLA-B8.

Pathophysiology

GA has been reported to follow insect bites, trauma, viral infections (EBV, VZV, HIV), sun exposure, PUVA therapy, tuberculin skin test, malignancy. Generalized GA may be associated with DM. It is thought that GA may be an immune-mediated necrobiotic inflammation of collagen and elastin fibers, a TH1 reaction-eliciting matrix degeneration, an immune complex vasculitis, or an abnormality of tissue monocytes.

History

The solitary skin lesions appear sporadically, are asymptomatic, and most self-resolve in a few months to years. More generalized GA can persist for years and have a more recalcitrant course, improving in the winter and worsening in the summer.

Physical Examination

Skin Lesions

Type Papules, plaques, nodules.

Size 1 to 5 cm.

Color Flesh-colored, pink to violaceous.

Arrangement Annular (Fig. 18-3) or arciform.

Distribution Dorsal upper extremities (60%) > lower extremities (20%) > trunk (5%).

Differential Diagnosis

The differential diagnosis for GA is broad since it has several different clinical manifestations. The list includes lichen planus, tinea, psoriasis, papular sarcoid, annular erythema, subacute lupus erythematosus (SCLE), erythema multiforme, erythema chronicum migrans, necrobiosis lipoidica, rheumatoid nodule, xanthomas, eruptive histiocytomas, pityriasis lichenoides et varioliformis acuta (PLEVA), cutaneous T-cell lymphoma (CTCL), elastosis perforans serpiginosa, and perforating collagenosis.

Laboratory Examinations

Dermatopathology Early GA: Interstitial pattern with histiocytes scattered between collagen fibers. Later GA: Palisading granulomas in the upper/mid reticular dermis with a central zone of necrobiotic collagen surrounded by histiocytes, lymphocytes, and a few giant cells. Rare cases of sarcoidal GA are also described.

Course and Prognosis

Since solitary lesions of GA are asymptomatic and 50% spontaneously resolve by 2 years, reassurance is all that is needed. Recurrences can happen. Disseminated GA has a more recalcitrant course, but uncommonly seen in children. Twenty-one percent of patients with generalized GA have DM.

Management

The skin lesions are typically asymptomatic and will eventually self-resolve, thus treatment is unnecessary. Symptomatic or extensive lesions can be treated with topical/intralesional steroids, tacrolimus, pimecrolimus, or cryotherapy. Generalized GA may need more aggressive management with PUVA, UVA1, isotretinoin, dapsone, systemic steroids, pentoxifylline, hydroxychloroquine, cyclosporine, fumaric esters, γ-IFN, potassium iodide, nicotinamide, or laser therapy.

Alopecia areata (AA) is an autoimmune-mediated nonscarring loss of scalp hair in round or oval patches without any visible inflammation. Alopecia totalis is the loss of all the scalp hair and alopecia universalis is the loss of the scalp and all body hair.

Insight

Although it is a relatively rare finding, if hair adjacent to an area of alopecia are gray or white suggesting pigment loss, the diagnosis is almost certainly AA.

Epidemiology

Age Children are frequently affected; 60% of patients present before age 20 years.

Gender M = F.

Incidence 158 per 100000, 0.2% of the population.

Genetics One in five AA patients have 1 FHx for AA.

Etiology Genetic and environmental factors. HLA-DQB1, HLA-DRB1.

Pathophysiology

AA is thought to be an autoimmune disease of T cells directed against follicular antigens. It may be associated with other autoimmune disorders such as vitiligo, IBD, atopy, polyendocrinopathy syndrome type 1, and thyroid disease (Hashimoto’s disease). Stress (e.g., life crises) reportedly precipitates some cases of AA.

History

Patients usually report abrupt hair loss and will present with an asymptomatic bald spot on the scalp. More spots may appear and in severe cases, can lead to loss of all the scalp and/or body hair. Most cases of localized areas in the scalp slowly regrow hair over a period of weeks to months.

Physical Examination

Skin Lesions

Type Nonscarring macules, patches (Fig. 18-4).

Shape Round to oval.

Size 1 cm to several centimeters.

Distribution Localized (AA), regional (alopecia totalis), generalized (alopecia universalis).

Sites of Predilection Scalp, eyebrows, eyelashes, pubic hair, beard.

Hair Proximally-tapered short “exclamation point hairs” (Fig. 18-5).

Nails “Hammered brass” pitting (Fig. 18-6), trachyonychia, brittle nails, onycholysis, koilonychia.

Differential Diagnosis

The differential diagnosis of AA includes telogen effluvium, trichotillomania, traction alopecia, androgenetic alopecia, secondary syphilis (“moth-eaten” appearance in beard or scalp), or tinea capitis.

Laboratory Examinations

Dermatopathology Peribulbar lymphocytic infiltrate, miniaturized hairs with fibrous tracts, and pigment incontinence. There is also a decreased anagen-to-telogen ratio.

Course and Prognosis

In the majority of patients, hair will regrow in less than 1 year without treatment. Total alopecia is rare. Recurrences of alopecia, however, are frequent and 7% to 10% of cases can have a chronic form of the condition. Repeated attacks, nail changes, and total alopecia before puberty are poor prognostic signs.

Management

No treatment changes the course of AA, but some palliative options include topical, intralesional, or systemic steroids; topical irritants (anthralin, tazarotene, azelaic acid); topical minoxidil; topical immunotherapy (diphenylcyclopropenone or squaric acid); PUVA; laser, photodynamic therapy; or systemic cyclosporine.

Confluent and reticulated papillomatosis of Gougerot and Carteaud (CRP) is a benign chronic, relapsing rash characterized by elevated, hyperpigmented scaly plaques that begin on the upper trunk, coalesce, and spread slowly with a reticulated pattern over the body.

Insight

A helpful way to conceptualize this sesquipedalian entity is to place it between acanthosis nigricans and tinea versicolor; clinically, it has features reminiscent of both but not quite right for either one.

Synonyms Atrophie brilliante, erythrokeratodermia papillaris et reticularis, parakeratose brilliante, pigmented reticular dermatosis of the flexures.

Epidemiology

Age Adolescence, average age: 17 years.

Gender F > M, 2:1 except in Japan M > F.

Incidence Rare.

Race Darker skin types > lighter skin types.

Family Several cases affecting multiple family members.

Etiology Abnormal keratinocyte maturation and differentiation.

Pathophysiology

CRP may represent an endocrine abnormality, an atypical response to an infection, a disorder of keratinization or a hereditary disorder. CRP lesions show elevated keratin production of the skin and increased skin turnover. Hormones seem to play a role since the rash is associated with puberty, and at times with abnormal glucose tolerance, thyroid problems, menstrual problems, Cushing disease, obesity, or hirsutism. In some cases, yeast (Malassezia, Pityrosporum ovale, Pityrosporum orbiculare) or bacteria (actinomycete Dietzia) have been isolated and thought to play a pathogenic role.

History

Patients with CRP usually report an asymptomatic or mildly pruritic rash that slowly spreads upper trunk to the rest of the body. CRP typically is chronic with relapses, but responds well to therapies.

Physical Examination

Skin Lesions

Type Papules, plaques, scale.

Color Gray, brown, blue.

Shape Round to oval, coalescing, reticulated (Fig. 18-7).

Size 1 mm to 1 cm.

Palpation Elevated, warty.

Distribution Neck, upper trunk > breasts, armpits, abdomen > shoulders, pubic area, gluteal cleft, face.

Differential Diagnosis

The differential diagnosis of CRP includes tinea versicolor, acanthosis nigricans, verrucae, Darier disease, seborrheic keratoses, epidermal nevus syndrome, pityriasis rubra pilaris, or erythrokeratodermia variabilis.

Laboratory Examinations

Dermatopathology Compact hyperkeratosis (+/− yeast forms), decreased granular cell layer, papillomatosis, mild perivascular infiltrate.

Wood’s Lamp Yellow fluorescence if yeast organisms are present.

Course and Prognosis

CRP is a benign skin disorder that results in cosmetic dyspigmentation which can be distressing to the patient. The condition is chronic with exacerbations and remissions. In some cases, after spreading slowly for a few years, the lesions remain permanently unchanged and cause no symptoms.

Management

Several therapies have been used in an attempt to clear the CRP and prevent it from recurring. Systemic antibiotics (minocycline, tetracyclines, macrolides, or cephalosporins) show the most improvement. Topical antifungal agents (ketoconazole shampoo, antifungal creams), topical calcipotriol, topical or systemic retinoids are sometimes effective. Weight loss may also be helpful.