Vohwinkel Syndrome, Variant Form

A number sign (#) is used with this entry because of evidence that the variant form of Vohwinkel syndrome, mutilating keratoderma with ichthyosis, is caused by heterozygous mutation in the gene encoding loricrin (152445), a component of the epidermal differentiation complex (EDC), on chromosome 1q21.

Classic Vohwinkel syndrome (VOWNKL; 124500) is caused by mutation in the gene for connexin-26 (GJB2; 121011). A form of mutilating palmoplantar keratoderma with periorificial keratotic plaques (Olmsted syndrome; 614594) is caused by mutation in the TRPV3 gene (607066).

Clinical Features

Maestrini et al. (1996) studied a large kindred with a variant form of Vohwinkel syndrome without hearing loss, associated with ichthyosiform dermatosis. The kindred, which originated in the central Ohio region of the US, had previously been reported as 3 presumably unrelated families by Camisa and Rossana (1984) and Camisa et al. (1988). By genealogic tracing it was possible for Maestrini et al. (1996) to connect the 3 families to a common ancestor who originated in the United Kingdom 8 generations previously in the mid-1700s, and an historical photograph showed pseudoainhum in a family member living in the 1800s. Examination of affected family members in 4 living generations revealed that the youngest was 18 months old and the oldest was 92 years old. Males and females were equally affected. The phenotype appeared fully penetrant even at 18 months, and there was some interfamilial variation in expressivity and clinical severity. However, each affected individual displayed the characteristic palmar and plantar honeycomb hyperkeratosis, with some having starfish keratoses. Nearly all affected family members showed evidence of pseudoainhum of the fifth digit of the hands; some individuals had pseudoainhum of all the digits of the hands, whereas others displayed bilateral autoamputation of the fifth toe. In addition to these characteristic findings of Vohwinkel syndrome, several individuals also had a diffuse generalized ichthyosiform dermatosis, and none of the affected individuals had hearing impairment. Skin histopathology in 2 affected individuals demonstrated the pathognomonic finding of hyperkeratosis with round retained nuclei, together with hypergranulosis.

Ishida-Yamamoto et al. (1997) described a 3-generation Japanese family with what was initially believed to be a form of erythrokeratodermia (PSEK; see 133200). The proband was a 27-year-old woman who had diffuse facial erythema and erythrokeratotic plaques with white pityriasiform scales on the extensor and flexor surfaces of the extremities, abdomen, and buttocks. Her palms and soles showed waxy hyperkeratosis, with a honeycomb pattern on the palms. Pseudoainhum was present on the distal interphalangeal joints of both fifth fingers, with mild constrictions on the joints of other fingers. Her 57-year-old father had well-demarcated and widespread erythematous plaques on his extremities, hyperkeratosis of the palms and soles, and mild constrictions on the distal interphalangeal joints. There were no migratory or blistering lesions, and hair, teeth, nails, and hearing were all normal. Light microscopy of skin samples showed marked hyperkeratosis with parakeratosis and intranuclear granules in the upper granular cells. Immunoelectron microscopy demonstrated that the intranuclear granules were loricrin immunoreactive. Although the erythematous hyperkeratotic plaques of the proband and her father were similar to those seen in PSEK, Richard et al. (2000) suggested that the phenotype represented a form of Vohwinkel syndrome because of the presence of mutilating palmoplantar keratoderma (pseudoainhum), which is usually not seen in PSEK.

Matsumoto et al. (2001) described what they designated as the sixth reported family with loricrin keratoderma. A 14-year-old Japanese boy and his 11-year-old sister were both born as collodion babies (see 242300) and were initially diagnosed as having nonbullous congenital ichthyosiform erythroderma (242100), but they later developed palmoplantar keratoderma with pseudoainhum. Their father was similarly affected. Hair, eyes, teeth, and nails were normal, and audiograms showed no hearing impairment. Light microscopy of palmar skin revealed marked compact hyperkeratosis, with round retained nuclei and hypergranulosis, with no epidermolysis. Direct immunofluorescence confirmed the presence of mutant loricrin in the nuclei of differentiated keratinocytes in palmar and plantar skin from all 3 affected individuals.

Mapping

Terminal keratinocyte differentiation involves coordinated expression of several functionally interdependent genes, many of which have been mapped to the epidermal differentiation complex (EDC) on chromosome 1q21. In an extended pedigree with a variant form of Vohwinkel syndrome involving ichthyosis but no deafness, Maestrini et al. (1996) identified linkage to markers flanking the EDC region, with a maximum multipoint lod score of 14.3.

Korge et al. (1997) studied 2 families, one with typical Vohwinkel syndrome, including starfish keratoses and deafness, and the other with the variant form of Vohwinkel keratoderma. They demonstrated that the classic and variant forms of Vohwinkel syndrome are clinically and ultrastructurally distinct and that the classic form does not map to the loricrin locus.

Molecular Genetics

In an extended pedigree segregating an autosomal dominant variant form of Vohwinkel syndrome mapping to chromosome 1q21, Maestrini et al. (1996) sequenced the candidate gene loricrin and identified a heterozygous 1-bp insertion (730insG; 152445.0001). The authors stated that this was the first evidence for a defect in an EDC gene in human disease.

In a family with a variant form of Vohwinkel keratoderma, involving ichthyosis but no deafness and mapping to 1q21, Korge et al. (1997) analyzed the loricrin gene and identified heterozygosity for the same 1-bp insertion (730insG) in affected individuals.

In affected members of a 3-generation Japanese family with features of a progressive symmetric form of erythrokeratodermia (PSEK; see 133200), but who showed clinical and histologic similarities to the variant form of Vohwinkel keratoderma, Ishida-Yamamoto et al. (1997) identified heterozygosity for a 1-bp insertion in the loricrin gene (709insC; 152445.0002).