Genodermatoses

Introduction

The inherited skin disorders are individually rare, but in the aggregate comprise a significant proportion of dermatologic practice. Some are of minimal medical significance; others are life threatening, life shortening, or debilitating. For some, treatment is available. For others, there is no management beyond diagnosis. For a growing number of conditions, both the causal mutations and the specific perturbations in cellular function are known.

Genetic skin disorders are unique in that the diagnosis automatically invokes the issues of recurrent risk to relatives and prenatal diagnosis. These are topics not usually in the domain of the dermatologist. Identification of a genodermatosis may require referral for medical genetics evaluation and counseling. The availability and applicability of molecular (DNA) testing changes daily. Medical genetics centers are most likely to be aware of these resources. Online resources include:

GENE CLINICS http://www.geneclinics.org

This web site includes a listing of laboratories offering molecular testing for research and/or clinical purposes and for many disorders, a review that is clinically focused with molecular information as well, along with support group information.
OMIM http://www.ncbi.nlm.nih.gov/omim/

A catalog web site of Mendelian disorders in man with references, clinical synopses, and hyperlinks to other databases.

Many common skin disorders also have a significant genetic component. The risk for psoriasis, atopic dermatitis, vitiligo, alopecia areata, or systemic lupus erythematosus is much higher among close relatives of affected individuals than for the general population. Even acne and onychomycosis enjoy genetic contribution. These disorders are discussed in Chapters 13 and 33, respectively, and will not be further addressed here. This chapter will deal with only a handful of the many inherited skin disorders.

Disorders of Keratinization

Ichthyoses

The ichthyoses (Table 40-1; Figs. 40-1,40-2,40-3,40-4) share in common a thickened stratum corneum, which results in scaly skin. The distribution and severity of scaling, the presence of erythroderma, the mode of inheritance, and associated abnormalities differ among them. The degree to which life is impaired ranges from minimal to lethal. The genetic alterations responsible for some of these conditions are known. Treatment remains general and nonspecific. Use of keratolytics (α-hydroxy acids such as lactic acid, glycolic acid, and urea-based emollients) can be helpful. The oral retinoids are effective and should be considered in the more severe forms of ichthyoses. Their long-term use is limited by significant side effects including dryness of the mucous membranes, alterations in serum lipids, musculoskeletal pain, bony alterations, and teratogenicity.

Palmar-Plantar Keratodermas

Palmar-plantar keratodermas (PPK) (Figs. 40-5 and 40-6) are conditions in which thickening of the stratum corneum and scaling, with or without erythroderma, are limited primarily to the palms and soles. They are distinguished, as are the more generalized ichthyoses, by mode of inheritance and associated findings. One autosomal dominant form (Howell-Evans) is associated with esophageal carcinoma. Papillon-Lefèvre is an autosomal recessive PPK caused by mutations in the cathepsin C gene and is associated with gingivitis and premature tooth loss. Unna-Thost disease or nonepidermolytic hyperkeratosis results from mutations in KRT9 or KRT1. PPK with epidermolytic hyperkeratosis, Voener, can also be caused by mutations in KRT1 and by mutations in KRT16.

TABLE 40-1 ▪ Ichthyoses

Disorder	Inheritance	Basic Defect	Major Dermatologic Findings	Associated Features	Miscellaneous
Ichthyosis vulgaris	AD	Unknown	Mild-to-moderate white scales Spares flexures and neck; involves face Keratosis pilaris Atopic dermatitis (50%)	None	Improves with age and warm weather
X-linked ichthyosis (sterol sulfatase deficiency)	XLR	Mutation/deletion of steroid sulfatase gene	Moderate-to-severe white-brown scale Spares face; involves neck	Corneal opacities Possible increased risk of testicular malignancy	Pregnancies with affected males have low to absent estriol levels; failure of spontaneous initiation of labor is common
Bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis)	AD	Mutations in K1 or K10 (suprabasal keratins)	Red skin with blisters and scale evident at birth Marked hyperkeratosis Face usually least affected Inter- and intrafamilial variability	Secondary skin infection, bacterial and fungal common	Skin is tender; skin fragility improves with age
Lamellar ichthyosis/nonbullous congenital ichthyosiform erythroderma/congenital autosomal recessive ichthyosis	AR	Heterogenous. Some caused by mutations in transglutaminase 1 (TGM1), 12-R lipoxygenase (ALOX12B), lipoxygenase-3 (ALOXE3), ATP-binding cassette transporter 2 (ABCA2)	LI: mild erythroderma; brown, adherent plate-like scale NCIE: Erythroderma; fine, white scale Many cases with overlap in phenotype	Secondary tinea infection common	Collodion membrane common at birth Ectropion/ecla-bium common
Harlequin fetus	AR	Unknown; probably heterogenous	Severe, armor platelike hyperkeratosis In survivors, phenotype becomes similar to BCIE	Among survivors, mental retardation has been noted in a few	Rare spontaneous survival; handful of survivors treated with oral retinoids
Conradi Hunermann	XLD AR	XLD: mutation in gene encoding delta(8)-delta(7) sterol isomerase emopamilbinding protein AR: mutations in PEX7 gene	Feathery scale on erythrodermic base Follicular atrophoderma	Seizures; MR Chondrodysplasia punctata Cataracts	Asymmetry typical in XLD form
Sjögren-Larsson syndrome	AR	Fatty aldehyde dehydrogenase deficiency	Mild-to-moderate fine, adherent scale Pruritus	Progressive spastic paraparesis Mild retardation Glistening white dots on retina
Netherton syndrome	AR	Mutations in SPINK5 gene	Variable erythroderma and scale Classic pattern of ichthyosis linearis circumflexa	Trichorrhexis invaginata (bamboo hair)	Failure to thrive Food allergies
Collodion baby	AR if isolated Otherwise, depends on underlying disorder	Heterogenous	Plastic wrap-like membrane peels within few weeks after birth, revealing underlying skin, which may range from minimally xerotic to lamellar ichthyosis	This is a feature of many disorders including lamellar ichthyosis, hypohidrotic ectodermal dysplasia, Gaucher disease and lamellar exfoliation of the newborn
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; BCIE, bullous congenital ichthyosiform erythroderma; XLR, X-linked recessive; K, keratin; MR, mental retardation.

FIGURE 40-1 ▪ X-linked ichthyosis. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

FIGURE 40-2 ▪ A young girl with nonbullous congenital ichthyosiform erythroderma. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

FIGURE 40-3 ▪ A newborn with Harlequin ichthyosis. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

Disorders of Adhesion

The epidermolysis bullosa syndromes (Table 40-2; Figs. 40-7,40-8,40-9) are mechanobullous disorders that share in common fragility of the skin. They are distinguished, one from the next, by the histologic level of blister formation, mode of inheritance, and associated cutaneous features. Most present at birth or soon thereafter. Scarring is primarily limited to the dystrophic forms, where the separation of the skin occurs below the basement membrane of the dermis. Extensive involvement in the newborn period can occur in epidermolysis bullosa simplex Dowling-Meara (EBS-DM), recessive epidermolysis bullosa dystrophica (REBD), and in junctional epidermolysis bullosa (JEB). Neonatal or infant death due to sepsis or intestinal protein loss and inanition is common in the most severe forms. Respiratory mucosa is often involved in the Herlitz form of JEB. Accurate diagnosis requires electron microscopy and/or immunofluorescence studies. Treatment consists of protection of skin surfaces and avoidance of trauma, lancing of small blisters to prevent lateral spread by the pressure of blister fluid, topical antibiotics, and nonadherent dressings. More severe forms may require a team approach to management of complications.

FIGURE 40-4 ▪ The feathery scale of X-LD Conradi Hunermann disease. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

FIGURE 40-5 ▪ Palmar-plantar hyperkeratosis. The hands and soles are thickened, with erythroderma evident at the margins. A young girl shares the same condition as her father. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

FIGURE 40-6 ▪ Palmar-plantar hyperkeratosis with severe palm/sole involvement and extension onto the wrists and shins. Some of these patients have involvement of the elbows, knees, and gluteal cleft. (Reprinted from Sybert VP. Genetic Skin Disorders. New York: Oxford University Press; 1997.)

TABLE 40-2 ▪ Epidermolysis Bullosa

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