In This Issue: The Complexity of Genetics in Heritable Skin Diseases

Over the past decade, with the advent of molecular genetics in general and completion of the Human Genome Project in particular, spectacular progress has been made in understanding the genetic basis of a number of heritable skin diseases. Mutations have now been identified in close to 200 distinct genes important for development and function of human skin, and in many cases explain the cutaneous manifestations associated with these disorders (see Pulkkinen et al, 2002). This knowledge has provided novel means for an updated and refined classification of genodermatoses on molecular and etiological grounds, for widespread availability of molecular diagnostic tests, prenatal diagnosis and improved genetic counseling, as well as for the development of new therapeutic approaches (Uitto et al, 2002). Nevertheless, molecular genetics alone is not the ‘‘silver bullet’’ solving all diagnostic problems and pathogenetic mysteries. As more genetic information is gathered, the reliable classification of some disorders seems to become more difficult, as in the case of erythrokeratodermas, and genotype–phenotype correlations may be complex, as illustrated by cutaneous connexin 26 disorders. In this issue, two letters argue the pros and cons of autosomal recessive EKV and highlight some of the fundamental problems of molecular genetic studies in rare genodermatoses. In response to a recent publication by Terrinoni et al (2004), which reported only the second family with autosomal recessive EKV because of a novel missense mutation in the connexin 31 gene (GJB3), van Steensel and van Geel (p. 268) question the validity of the clinical diagnosis and the pathogenicity of the connexin 31 mutation in lieu of functional studies of the mutant protein. The latter authors’ comments underscore the scarcity of solid diagnostic criteria for EKV and the difficulties encountered even by experienced dermatologists in distinguishing EKV from other disorders with similar or overlapping features, such as progressive symmetric erythrokeratoderma, localized (abortive) forms of non-bullous congenital ichthyosiform erythroderma, or epidermolytic hyperkeratosis with cyclic ichthyosis. In their invited response, Terrinoni and Melino (p. 270) provide convincing clinical and histological information supporting the diagnosis of EKV in their family, and additional molecular data exclude a causative mutation in the keratin 1 gene, refuting the diagnosis of epidermolytic hyperkeratosis with cyclic ichthyosis. Nevertheless, the observations on patients with overlapping or new, distinctive features, together with reports of mutations in different genes (connexins, loricrin, transglutaminase 1) resulting in erythrokeratodermas as well as other disorders of cornification, have fueled recent debates on the classification and nomenclature of erythrokeratodermas (Hohl, 2000; van Steensel, 2004). Yet, a complex understanding of the different erythrokeratoderma phenotypes and their etiology beckons further thorough clinical and molecular analyses in larger cohorts of patients. With the mounting evidence provided by Terrinoni et al (2004) and Gottfried et al (2002) that pathogenic connexin 31 mutations may be inherited in an autosomal recessive fashion, nature has thrown us another curve ball, challenging our emerging understanding of the pathological mechanisms of cutaneous gap junction disorders.