Tammie Ferringer

Pseudoxanthoma elasticum

Pseudoxanthoma elasticum is an autosomal-recessive and, less commonly, autosomal-dominant disorder due to a mutation in the ABCC6 transporter gene. It results in calcification of the elastic fibers of the skin, eyes, and artery walls. The skin changes become apparent around the second decade and simulate “plucked chicken skin” in the flexural areas. Biopsy of a scar may reveal the elastic tissue abnormalities in a patient with no cutaneous lesions. Eye changes include angioid streaks and retinal hemorrhage that may cause blindness. The vascular changes may lead to hypertension, stroke, myocardial infarction, mitral valve prolapse, and gastrointestinal hemorrhage.

Similar histologic findings can also be seen after topical exposure to calcium salts. Periumbilical perforating pseudoxanthoma elasticum (perforating calcific elastosis) affects multiparous black women but is limited to an isolated area. Patients on long-term penicillamine for Wilson’s disease may develop altered elastic fibers with overlapping features of pseudoxanthoma elasticum and elastosis perforans serpiginosa. The penicillamine-induced, altered elastic fibers have small lateral buds arranged perpendicularly to the primary elastic fiber resembling the twigs on a bramble bush.

Ichthyosis vulgaris

In most other conditions, hyperorthokeratosis is associated with a prominent granular layer and parakeratosis is associated with a diminished or absent granular layer. Ichthyosis vulgaris (in which there is little to no granular layer despite hyperkeratosis) and axillary granular parakeratosis (in which there is a granular layer despite the presence of parakeratosis) are exceptions to this rule.

Ichthyosis vulgaris is an autosomal-dominant disorder with retention of the stratum corneum (rather than hyperproliferation) resulting in hyperkeratosis. There is a deficiency in profilaggrin resulting in inadequate keratohyaline granule synthesis. There are fine brown to transparent scales that spare the flexures. Accentuation of the palmoplantar creases, keratosis pilaris, and coexisting atopic dermatitis may be present.

Acquired ichthyosis in association with malignancy, especially Hodgkin’s lymphoma, may clinically and histologically mimic ichthyosis vulgaris. Acquired ichthyosis may also occur with niacin therapy.

Incontinentia pigmenti (Bloch–Sulzberger syndrome)

This X-linked dominant disorder is typically lethal in males. A mutation in the NEMO gene leads to defective nuclear factor kappa-B (NF-κB) activation. There is evolution through overlapping stages. At birth or soon after, there are linear vesicular lesions that evolve into verrucous lesions weeks to months later. At 3–6 months of age there are streaks and whorls of hyperpigmentation that do not correlate with the areas of prior vesicles. The pattern has been likened to marble cake. Hypopigmentation may replace the hyperpigmentation decades later. Other cutaneous findings include alopecia and nail dystrophy. Ocular, dental (peg teeth), skeletal, and neurologic abnormalities may be present.

Mastocytosis

Mastocytosis comprises a spectrum of diseases. A solitary mastocytoma may occur in childhood with a tendency to spontaneous involution. Urticaria pigmentosa is a sporadic rather than inherited disorder, characterized by multiple tan macules, papules, or nodules. There is a congenital or early-onset form that is rarely associated with systemic disease and typically clears by puberty. In contrast, adult-onset urticaria pigmentosa persists and can be associated with systemic involvement, especially bone marrow. The majority of lesions urticate with stroking (Darier’s sign). Mutations in c-kit have been found in sporadic adult cases and in children with extensive or persistent disease but not in typical pediatric urticaria pigmentosa. TMEP is a rare adult form of mastocytosis with erythema, telangiectasia, and faint tan macules on the trunk and extremities, rarely with a Darier’s sign.

In macular and TMEP lesions, the mast cells are limited to a superficial perivascular infiltrate. The mast cells may have small round nuclei with ample cytoplasm and resemble fried eggs or they may be spindle-shaped and simulate large hyperchromatic fibroblasts. The presence of more than five perivascular mast cells around each vessel is suggestive of mastocytosis. Special stains are recommended for identification. Mast cells can be identified with Leder stain (ASD-chloroacetate esterase) or via metachromatic staining of granules with toluidine blue and Giemsa methods. Immunohistochemistry for CD117 (the c-kit encoded tyrosine kinase receptor) and mast cell tryptase also identifies mast cells. Lesions degranulated by stroking (Darier’s sign) may show no intracellular granules with Giemsa staining. A Leder stain is preferred in this setting.

Multiple or solitary nodular lesions reveal closely packed, uniformly spaced, round to cuboidal mast cells that fill the papillary dermis and may extend into the reticular dermis and subcutaneous tissue. These mast cells may be visibly granular and may have a “fried-egg” appearance with a central nucleus and eosinophilic to pale gray cytoplasm. A scattering of eosinophils is usually present and basal hyperpigmentation may be identified. These lesions can be distinguished from Langerhans cell histiocytosis by the absence of epidermal involvement, absence of folliculotropism, absence of reniform nuclei, and with special stains. The cuboidal cells may resemble nevus cells but mast cell lesions lack junctional and dermal nesting and lack the nuclear pseudoinclusions typical of melanocytes.

Epidermolytic ichthyosis (bullous congenital ichthyosiform erythroderma)

Epidermolytic hyperkeratosis is a histologic pattern that can be seen in several clinical settings, including palmoplantar keratoderma, solitary epidermolytic acanthoma, and epidermolytic ichthyosis. Not uncommonly, epidermolytic hyperkeratosis is an incidental finding in biopsies of another lesion such as a dysplastic nevus.

Epidermolytic ichthyosis is an autosomal-dominant condition characterized by widespread blistering and erythema at birth that evolve into generalized furrowed hyperkeratosis with accentuation in the flexures. There is a wide morphologic spectrum. Mutations in keratin genes (K1 and K10) have been identified. This generalized disorder has been reported in the offspring of patients with linear epidermal nevi that histologically reveal epidermolytic hyperkeratosis, suggesting that these “epidermal nevi” represent mosaicism for the trait.

Further reading