VS is an autosomal dominant disorder with transgredient honeycomb keratoderma associated with digital strictures. A mutation in the loricrin gene has recently been found in a family of VS with ichthyosis. We have studied a different family with this phenotype using morphological analyses and molecular genetics. Both lesional and non-lesional skin showed characteristic structural and immunohistochemical abnormalities. N-terminal loricrin staining was rich in the nuclei of granular and cornified cells. C-terminal loricrin labels were observed diffusely with less marked nuclear staining. Immunoelectron microscopy demonstrated loricrin-positive intranuclear granules. Cornified cell envelopes were thinner and sparsely labeled with loricrin-, but densely with involucrin antibodies. Complete co-segregation of the disease with markers for 1q21 was observed resulting in a multipoint LOD score of 2.48. Sequencing of the loricrin gene revealed the same G insertion as the previous report. Our findings confirm that a specific defect in the loricrin gene can cause a variant of VS associated with ultrastructural and immunocytochemical evidence of altered keratinization.