A mutation in the glycine-rich cornified envelope protein loricrin has recently been reported in Vohwinkel's keratoderma (honeycomb keratoderma with pseudoainhum), in a pedigree amongst whom ichthyosis was also a feature. We have studied two further families with Vohwinkel's keratoderma for evidence ofloricrin mutations. Our first family (VK1) also had ichthyosis but not deafness. In lesional and nonlesional skin, granular and transitional cell layers were increased. In immunoelectron-microscopic studies cornified envelopes were abnormally thin and were labeled densely by anti-involucrin antibodies, but only sparsely by antiloricrin antibodies; however, abnormal intranuclear granules seen in granular and cornified layer cells were labeled by antibodies to both C- and N-terminal loricrin. Microsatellite markers in VK1 supported linkage to the loricrin locus in the epidermal differentiation complex at 1q21 (Zmax = 2.48). The loricrin gene was sequenced, identifying a heterozygous mutation as previously reported: a G insertion producing a frameshift after codon 231 and an abnormal C-terminal peptide lacking residues necessary for cross-linking. In our second family (VK2), affected members had sensorineural deafness but not ichthyosis. Immunoelectron-microscopic studies showed normal loricrin distribution, and assuming complete penetrance, linkage to 1q21 was excluded. Vohwinkel's keratoderma is thus clinically and genetically heterogeneous. Only the variant with ichthyosis appears to be due to loricrin mutation. As the arginine-rich domain in C-terminal loricrin caused by the frameshift contains several potential bipartite nuclear localization signals, we suggest that the intranuclear accumulation of loricrin in VK1 is due to these motifs, and may be unique to insertional mutation.