Adapted from the Dermatology Progress in Foundation Dermatology Editor: Alan N. Moshell, MD. Epidermolytic Hyperkeratosis: Applied Molecular Genetics John J. DiGiovanna and Sherri J. Bale* Dermatology Branch, Division of Cancer Biology, Diagnosis, and Centers, National Cancer Institute; and ' Genetic Studies Section, Skin Biology Branch, National Institute of Arthritis and Musculoskeletal and Skin Disease, Bethesda, Maryland, U.S.A. Epidermolytic hyperkeratosis is an autosomal dominant ich­ in keratin 10 were found in other families with EHK. We thyosis characterized by blistering, especially at birth and have examined 52 patients from 21 families and have identi­ during childhood, and hyperkeratosis. Epidermolytic hyper­ fied at least six clinical phenotypes. The most useful distin­ keratosis presents striking clinical heterogeneity, particularly guishing feature was the presence or absence of severe hyper­ between families. Several avenues of research have impli­ keratosis of the palms and soles. We and others are cated an abnormality of epidermal differentiation in the continuing to search for and characterize mutations in kera­ pathogenesis of this disease. In a three-generation family tin 1 and 10 in patients with epidermolytic hyperkeratosis. with 20 affected individuals, we tested a variety of candidate Correlation of the clinical disease types with the specific loci and identified linkage to the type II keratin region on mutations should lead to a better understanding of the rela­ chromosome 12. Further investigation revealed a mutation tionship between keratin structure and function in normal in the H1 subdomain of the keratin 1 gene as the cause of and diseased epidermis. Key words: ichthYOSis/keratin/genoder­ EHK in this family. Because keratin 10 is the co-expressed matosis.] Invest Dermatol102:390-394, 1994 partner of keratin 1, it was not surprising when abnormalities istorically, the clinical classification of skin disease pathogenesis of several diseases. Through dermatopathology, d~r­ was the mainstay of dermatology. A first step in matologists had an additional perspective to understand and claSSify understanding the etiology of skin diseases was to diseases. Similarly, understanding the biochemical alterations un­ define the clinical spectrum of disorders to deter­ derlying the metabolically induced dermatoses, such as the por­ mine which presentations were manifestations of phyrias, led to elucidation of their etiology. With the maturing of theH same disease, and which identified different conditions. In these molecular genetics the ability to categorize diseases based upon the early attempts to understand disease processes the main tools were specific underlying gene mutation has become a reality. observation, description, and classification. The development of OVERVIEW OF THE ICHTHYOSES various medical and scientific disciplines created tools to probe the mechanisms underlying disease pathogenesis. Advances in microbi­ Ichthyosis is a general term used to describe a heterogeneous groUP ology allowed the identification of organisms involved in infectious of skin disorders. The term is derived from the Greek word for fish, diseases, such as syphilis, resulting in a better understanding of the ichth),s, and relates to the characteristic dry, scaly appearance of the skin in these conditions. Ichthyosis may be acquired, for example, resulting from cancer, endocrine disease, or severe nutritional defi­ Reprint requests to: Dr. John J. DiGiovanna, Dermatology Branch, ciencies. However, most types of ichthyosis have a genetic basis and National Cancer Institute, Building 10, Room 12N238, Bethesda, MD 20892. present at birth. Unfortunately, little is known about the pathogel~­ Abbreviations: ClE, congenital ichthyosiform erythroderma; EBS, epi­ esis of the ichthyoses. In x-linked ichthyosis the pattern of inheri­ dermolysis bullosa simplex; EHK, epidermolytic hyperkeratosis; IV, ichthy­ tance is known, as is the underlying abnormality, steroid sulfatase osis vulgaris; KIF, keratin intermediate filaments; LI, lamellar ichthyosis; deficiency. However, what is unknown is the mechanism through NPS, no palm/sole hyperkeratosis; PS, palm/sole hyperkeratosis; XLR, X­ which this enzyme deficiency leads to the clinical presentation of linked recessive (ichthyosis). ichthyosis. Copyright © 1994 by Dermatology Foundation, 1560 Sherman Avenue, Evanston, Illinois 60201 390 VOL. 102, NO.3 MARCH 1994 EPIDERMOLYTIC HYPERKERATOSIS 391 Classification schemes for the ichthyoses have been proposed causative gene and subsequently to search for its function. Genetic based on clinical features, pattern of inheritance, or histology and linkage analysis is a statistical method that involves analyzing fami­ cell kinetics. Williams and Elias define twenty-four "disorders of lies with the disease along with genetic markers whose chromo­ cornification" in which clinical, genetic, or biochemical data somal location is known. This allows the localization of the disease strongly suggest a distinct genetic entity [1]. However, no single locns within a genetic map of the markers used. This map is the schema has been universally accepted. result of determining in offspring the frequency of recombination . On a practical basis, when a patient presents to a physician, the that occurred during parental meiosis that produced gametes. The disease is often characterized clinically based on appearance and estimate of the distance between the disease locus and the markers pattern of inheritance. The most common ichthyoses inherited as (or between the markers themselves) is derived from observation of aUtosomal dominant traits include ichthyosis vulgaris (IV) and epi­ the frequency of meiotic recombination. Markers that are inherited dermolytic hyperkeratosis (EHK). In contrast, lamellar ichthyosis with the disease tend to be located in close physical proximity to the ~LI) and congenital ichthyosiform erythroderma (CIE) are inherited disease gene. Markers that are distant from the disease locus are In an autosomal recessive manner. Steroid sulfatase deficiency is an more likely to have undergone recombination with the disease gene X-linked recessive ichthyosis. In addition to these, there are several during meiosis. Markers can be genes with known function (i.e., Ichthyoses observed in association with syndromes. genes for cell surface markers [HLA, ABO blood group], enzymes, . IV is the most common of the hereditary scaling disorders, affect­ serum proteins) or they may be random pieces of DNA whose I~g one in 250-300 persons. As an autosomal dominant trait, the location is all that is known. If there are specific genes of known n.sk to each offspring of an affected parent is 50%. Clinically, the function that are suspected to be involved in the etiology of the disease is usually not present at birth, but presents in the first year. disease, i.e., candidate genes, they may also be used as genetic link­ Sbn involvement in IV is usually mild and manifested by xerosis age markers. a.nd a fine, white scale. IV is notable for its widely variable expres­ Linkage analysis does not allow specific identification of the Sion, even within affected members of the same family. Histopatho­ physical location of the gene, only its genetic relationship to known logic examination of affected skin frequently reveals a decreased or markers. However, once the general location of the disease gene is akbsent granular layer [2]. The molecular basis of the disease is un- known, other studies (i. e., physical mapping includirIg chromo­ nown to date. some walking and jumping) may allow for identification of the EHK, also known as bullous congenital ichthyosiform erythro­ disease gene itself. The gene may then be cloned, characterized, and derma, occurs in 1 : 200,000 - 300,000 people. As many as one half sequenced, and its function sought. the cases of EHK represent new mutational events, where both Information derived from a variety of approaches, including his­ parents are unaffected [3]. The disorder is evident at birth, and may tology, ultrastructure, and molecular genetic studies in mice and present with blistering, redness, and peeling. Over time patients humans have led to the recent identification of the underlying de­ develop a generalized hyperkeratosis. In contrast to the other ich­ fects in one ichthyosis, epidermolytic hyperkeratosis. t?yoses, the histopathologic picture ofEHK is distinctive, and con­ Epidermolytic Hyperkeratosis-Clinical and Histologic Features: EHK Sists of epidermal hyperkeratosis with a characteristic degeneration is characterized by blistering, especially at birth and during child­ of the granular layer. hood, and hyperkeratosis. EHK presents striking clinical heteroge­ .~ - l inked recessive (XLR) ichthyosis was distinguished from the neity between families, particularly regarding extent of body chmcally similar, but more common, IV by clinical and pedigree surface involvement, quality of scale, presence or absence of itudies This disease occurs almost exclusively in males, with at [4,5]. erythroderma, and palmar/plantar involvement. Histologic exami­ ~ast males being affected. Manifestations ofXLR ichthyo­ 1 : 6000 nation of hematoxylin-eosin stained sections of EHK skin show a SIS a.re not always confined to the skin and may include asympto­ tremendously thickened stratum corneum and vacuolar degenera­ matic corneal opacities and cryptorchidism [6,7]' The underlying tion of the upper epidermis, leading to the histologic term "epi­ ~Iochemical