Exp Dermatol 1998: 7: 268–272 Copyright C Munksgaard 1998 Printed in Denmark ¡ All rights reserved ISSN 0906-6705 Monilethrix: a keratin hHb6 mutation is co-dominant with variable expression Zlotogorski A, Horev L, Glaser B. Monilethrix: a keratin hHb6 mutation A. Zlotogorski 1 , L. Horev 1 is co-dominant with variable expression. and B. Glaser 2 Exp Dermatol 1998: 7: 268–272. C Munksgaard, 1998 Departments of 1 Dermatology and 2 Endocrinology & Metabolism, Hadassah Abstract: Monilethrix is a rare autosomal dominant disease characterized University Hospital, Jerusalem, 91120, Israel by hair fragility and hyperkeratotic papules. Mutations in type-II hair spe- cific keratins hHb6 and hHb1 have recently been reported. We describe a large family with a E410D mutation in the evolutionary conserved helix termination motif of keratin hHb6 that was variably expressed among 12 Key words: monilethrix – intermediate heterozygous members, and severely expressed among 3 homozygous mem- filaments – hair keratins – dominance – bers. These 3 patients had essentially complete lack of scalp hair since the homozygous mutation – genodermatosis age of 2 months with no improvement over time as well as follicular Abraham Zlotogorski, Department of keratotic involvement extensively expressed over the scalp and large body Dermatology, Hadassah University Hospital, areas. The variability seen in heterozygous patients, along with seasonal Jerusalem 91120, Israel. and pregnancy-related improvement suggest that other genetic or environ- Tel.: π972–2–6777111 Fax: π972–2–6434434 mental factors may modify keratin gene expression. This represents the e-mail: zloto/cc.huji.ac.il first report of a co-dominant keratin hHb6 mutation resulting in severe disease. Accepted for publication 5 July 1998 Introduction Monilethrix is a rare autosomal dominant in- herited defect of the hair shaft resulting in hair fra- gility and loss. The clinical picture ranges from lo- calized regions of hair loss, to total lack of scalp hair. In some cases, body hair is also involved. Light microscopic examination is diagnostic and reveals alternating regions of thin and thick hair, which result from abnormalities in hair shaft pro- teins. Based on electron microscopic ultrastruc- tural findings, keratin intermediate filament (KIF) became a prime candidate in the pathogenesis of monilethrix (1). Subsequently, several monilethrix pedigrees were linked to the type II keratin gene locus on chromosome 12q13 (2). Since this locus also harbors type II hair keratin genes, it was sug- gested that the disease may be caused by a hair keratin defect. There are seven type-I [hHa1, hHa2, hHa3-I, hHa3-II, hHa4, hHa5 and hHRa1] and 4 type-II human hair keratins [hHb1, hHb3, hHb5 and hHb6] (3). Recently, the first 2 muta- tions in the hair cortex keratin hHb6 were reported by Winter et al. (4). Keratins have highly homo- logous central alpha-helical rod domain flanked by variable-sized head and tail domains. The bound- ary peptides at the extremities of the rod domain, 268 the helix initiation motif (HIM) of the 1A subdo- main and the helix termination motif (HTM) of the 2B subdomain, are highly conserved and cru- cial for structure and function. Pathogenic muta- tions appear most disruptive in the HIMs or HTMs of keratins. The first 2 mutations associated with monilethrix were described in 2 unrelated families, one British and one French, and were located in the highly conserved HTM motif of hHb6. Both mutations were in the same glutamic acid codon (E410K and E410D). Subsequently, a Canadian family was described with clinically similar disease and a mutation in the parallel glu- tamic acid codon (E403K) of another hair keratin, hHb1, was identified (5). These discoveries have proven the importance of these 2 specific proteins in hair integrity. Individuals homozygous for mutations of domi- nant human disease are rarely encountered. Examples of more severe disease in homozygous patients when compared to their heterozygous relatives have been previously described (6), e.g. in Waardenburg syndrome (7), achondrodysplasia (8), spinocerebellar ataxia type 6 (9) and Mach- ado–Joseph disease (10). Recently, few dominant disorders have been reported in which homozy- gotes and heterozygotes are affected to a similar