Keratoderma, Palmoplantar, With Deafness

A number sign (#) is used with this entry because of evidence that palmoplantar keratoderma with deafness is caused by heterozygous mutation in the gene encoding connexin-26 (GJB2; 121011) on chromosome 13q12.

Clinical Features

Sharland et al. (1992) reported a family that appeared to validate a syndrome of palmoplantar hyperkeratosis and sensorineural deafness as an autosomal dominant disorder. Male-to-male transmission was observed. Progressive, bilateral, high-frequency sensorineural hearing loss had its onset in early childhood. Progressive hyperkeratosis of the palms and soles, the only ectodermal feature, had its onset in mid-childhood.

Verbov (1987) described a 3-generation pedigree of hereditary palmoplantar keratoderma with deafness. The father of the proband was incorrectly shown as being deaf in the 1987 publication due to misinformation regarding parentage. Fitzgerald and Verbov (1996) corrected the pedigree and provided follow-up on the affected individuals and subsequently born affected children.

Kelsell et al. (1997) studied the kindred reported by Verbov (1987) and Fitzgerald and Verbov (1996). From a clinical reevaluation, they concluded that it was unlikely that the same mutation resulted in both palmoplantar keratoderma and deafness, since there were 3 individuals who had the skin disorder but not the profound hearing loss. Haplotype analysis suggested linkage of the skin disorder with microsatellite DNA markers located on 13q11-q12. Three disease loci had been localized to this area: autosomal dominant nonsyndromic deafness (DFNA3; 601544), autosomal recessive nonsyndromic deafness (DFNB1; 220290), and the autosomal dominant skin disease Clouston hidrotic ectodermal dysplasia (129500).

Inheritance

The transmission pattern of palmoplantar hyperkeratosis and sensorineural deafness in the family reported Sharland et al. (1992) was consistent with autosomal dominant inheritance.

Molecular Genetics

Heathcote et al. (2000) identified a missense mutation in the GJB2 gene (121011.0015) segregating with the phenotype in the family reported by Sharland et al. (1992) with deafness and palmoplantar keratoderma. Heathcote et al. (2000) proposed that the mutation, which lies in a highly conserved region of the gene, may disrupt the structure of an extracellular loop and, consequently, gap junction formation.

In a 4-generation Turkish family segregating autosomal dominant deafness and palmoplantar keratoderma, Uyguner et al. (2002) identified a missense mutation in the GJB2 gene (121011.0026). The age of onset and progression of hearing loss were variable among affected family members, but they all had more severe impairment at higher hearing frequencies.

In a 40-year-old German woman, her 9-year-old daughter, and her 2-year-old son with focal palmoplantar keratoderma and severe progressive sensorineural deafness, de Zwart-Storm et al. (2008) identified heterozygosity for a mutation in the GJB2 gene (H73R; 121011.0038). The affected sibs had much less pronounced skin alterations than their mother. The mutation was not found in unaffected family members or in 100 unrelated German controls.