The constitutive desmosomal plaque
protein desmoplakin plays a vital part in keratinocyte adhesion in linking the transmembranous
desmosomal cadherins to the cytoplasmic
keratin filament network. Recently, mutations in
desmoplakin have been shown to underlie some cases of the autosomal dominant disorder, striate
palmoplantar keratoderma, as well as an autosomal recessive condition characterized by
dilated cardiomyopathy, woolly hair, and keratoderma. Here, we describe two unrelated individuals with a new autosomal recessive genodermatosis characterized by focal and
diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, varying degrees of
alopecia, but no apparent cardiac anomalies. Mutation screening of
desmoplakin demonstrated compound heterozygosity for a non-sense/mis-sense combination of mutations in both cases, C809X/N287K and Q664X/R2366C, respectively. Heterozygous carriers of any of these mutations displayed no phenotypic abnormalities. Immunohistochemistry of skin biopsies from both affected individuals revealed that
desmoplakin was not just located at the cell periphery but there was also cytoplasmic staining. In addition, electron microscopy demonstrated
acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal
keratin intermediate filament network. Clinicopathologic and mutational analyses therefore demonstrate that
desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a mis-sense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations.