PROGRESSIVE

 

SYMMETRIC

 

ERYTHROKERATODERMIA

 

Progressive symmetric erythrokeratodermia , first definitively described by Darier in 1911, is characterized by well-demarcated, erythematous, hyperkeratotic plaques that are symmetrically distributed over the extremities and buttocks, and often the face. The trunk tends to be spared, but palms and soles may be involved. The plaques appear shortly after birth, progress slowly during the first few years, and then stabilize in early childhood. The plaques usually remain stable in location and appearance but may undergo partial regression at puberty. The variable, migratory erythema that defines erythrokeratodermia variabilis is absent. The disorder is inherited in an autosomal dominant pattern but with incomplete penetrance and variable expressivity. A mutation in the cornified envelope protein loricrin was found in one family, although the diagnosis (and the distinction from erythrokeratodermia variabilis) has been disputed.

Keratitis, Ichthyosis, and Deafness Syndrome

KID syndrome is a rare disorder characterized by keratitis (with progressive corneal opacification), ichthyosis, and deafness (neurosensory). Involvement of multiple ectodermal tissues qualifies KID syndrome as an ectodermal dysplasia. Most cases are compatible with autosomal dominant inheritance. However, occurrence in an inbred sibship suggests the existence of an autosomal recessive form. The disease is characterized by discrete erythematous plaques, and there may be a mild, generalized hyperkeratosis. The distinctive plaques may have a discrete border and a verrucous appearance with crusting and may be conspicuously figurate and symmetric on the face . Furrowing about the mouth results in characteristic faces. There may be prominent follicular hyperkeratosis, which can result in a scarring alopecia of the scalp. “Leather-like” palmar/plantar keratoderma is almost always seen . Several authors have suggested that because the plaques do not scale, this disorder is more accurately designated an erythrokeratodermia rather than an ichthyosis. Descriptions of nail changes vary from absent, delayed appearance after birth, atrophic, or brittle to thickened, with loss of or “rough” cuticles, subungual hyperkeratosis, and leukonychia. The teeth may be small. Auditory evoked potential studies allow detection of the hearing deficit in infancy. Affected individuals can have an increased susceptibility to bacterial, fungal, or viral infections. Squamous cell carcinoma of the skin and tongue has also been reported. In contrast to many other ichthyotic conditions, treatment of these patients with oral retinoids has been reported to be of little benefit and possibly to exacerbate the corneal neovascularization.

Richard et al. discovered dominant mutations in GJB2, the gene encoding connexin-26, in eight sporadic cases and one family with KID syndrome. Functional studies of cells expressing mutated connexin-26 demonstrated failure of a fluorescent tracer to pass through gap junction channels to neighboring cells, consistent with disruption of intercellular communication. Different mutations in the same gene (GJB2) encoding connexin-26 have also been found in a family with a mutilating palmoplantar keratoderma (Vohwinkel syndrome) and deafness (without ichthyosis), and a mutation in GJB6, the gene for connexin-30, has been demonstrated in one child with KID syndrome. Connexin proteins aggregate to form gap junction channels, which span the cell membrane between adjacent cells. These channels are flexible structures that are constantly remodeled, and enable a direct cytoplasmic connection that allows the passage of a variety of small molecules between cells. The identification of mutations in the genes encoding a variety of connexin proteins has highlighted the role of connexin-mediated intercellular communication through gap junctions in the development and maintenance of ectodermal tissues. Connexins-26, -30, and -31 are expressed in the stratified epithelia of the cochlea and epidermis, and abnormalities in these proteins can cause sensorineural hearing impairment and/or skin disorders.