Genodermatoses



Genodermatoses


Amy Y. Jan MD, PhD

Virginia P. Sybert MD



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 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.



  • 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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May 28, 2016 | Posted by in Dermatology | Comments Off on Genodermatoses
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Disorder


Mode of Inheritance


Basic Defect Mutations In


Major Dermatologic Findings


Associated Features


Electron Microscopy


EBS-WC (Weber-Cockayne) (localized)


AD


Basal keratins (KRT 5) (KRT 14)


Blisters primarily limited to hands and feet. Onset can be at birth but usually thereafter.


Occasionally delayed until adolescence. Palmar-plantar hyperkeratosis may occur


None


Level of split within basal keratinocyte