Inherited disorders of keratinization

The term inherited disorders of keratinization encompasses a number of genetic skin disorders linked by the common finding of abnormal epidermal differentiation, often with aberrant formation of the cornified envelope (cornification). These disorders, such as ichthyoses, palmoplantar keratodermas, and erythrokeratodermas, have been classified traditionally on the basis of clinical morphology and the presence or absence of extracutaneous manifestations. In many cases the features do not facilitate easy segregation into a single distinct and well-defined group (eg, palmoplantar keratoderma and ichthyosis coexist in a number of conditions). These inherited disorders of keratinization may also feature epidermal fragility. Clinical, histologic, and ultrastructural morphologic characteristics of these conditions have been used to further classify and subdivide them. As none of these diseases is common, the morphologic approach has great benefit to the practicing clinician and offers a logical pathway to diagnosis when confronted with a patient for the first time in the clinic. Advances in genetic technology during the past 10 years have led to an enormous increase in understanding the basic molecular defects responsible for inherited disorders of keratinization, and these advances have made possible a new, molecular mechanism-based approach to their classification that complements the morphologic system. In the great majority of cases recent molecular insights have confirmed the accuracy of the original clinical distinctions and stand as testimony to the skilled and detailed observations made by generations of clinicians. As knowledge increases, however, the association of mutations in one gene with a distinct phenotype has become more complex. For example, clinically distinct conditions have been attributed to different mutations in the KRT1 gene (clinical heterogeneity). A further example of clinical heterogeneity is the spectrum of phenotypes attributable to mutations in the gene that encodes desmoplakin 1; dominantly acting mutations cause a skin-limited phenotype, but recessively acting mutations may cause a dilated cardiomyopathy and hair phenotype in addition to epidermal changes. In others, identical clinical phenotypes have been attributed to mutations in several genes (genetic heterogeneity), for example, with lamellar ichthyosis, in which 4 gene loci in addition to that encoding transglutaminase 1 have been identified. A sound knowledge of these issues is vital to the clinician involved in the care of patients with inherited disorders of keratinization. The direct benefits to patients of this increased knowledge are improved diagnostic certainty, an understanding of the biology underlying the gene defect, and more accurate genetic counseling. It is likely that this increased understanding will lead to the development of more rational treatments for many of these distressing conditions in the near future. Attempts at gene therapy have been limited to date, but ex vivo gene correction has succeeded for both lamellar ichthyosis and recessive X-linked ichthyosis in mouse models.