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S5 | Skin Diseases, Freitag, 10. März 2006 08:30–10:00

The ichthyoses: from genes to the clinic

Heiko Traupe
Münster, Germany

Ichthyoses are generalized hereditary keratinization disorders. They are grouped together because they share a conspicuous scaling which affects the entire integument. Ichthyoses are uncommon diseases and apart from the more frequent mild forms such as ichthyosis vulgaris (prevalence 1 : 1000) or X-linked recessive ichthyosis (male restricted prevalence 1 : 4000) - they have an overall prevalence of 1 : 100.000 only. Ichthyoses are severe congenital skin conditions which result in early and chronic disease. In particular newborns with congenital ichthyosis are often born as “collodion baby”, suffer from erythroderma and significant transepidermal water loss and throughout their life from marked disfigurement. Biochemical and molecular genetic research has unravelled fascinating new insights into biologic mechanisms underlying these diseases. Mutations in keratins – the pre-eminent proteins of the epidermis – can result in a number of “keratin disorders” which are characterized by loosened epidermal adhesion and by hyper proliferation and inflammatory scaling such as is the case in bullous congenital ichthyosiforme erythroderma (K1 and K10 deficiencies) or ichthyosis bullosa Siemens (K2e deficiency). The cornified envelope is a structure giving stability to corneocytes and responsible for the epidermal barrier. The cornified envelope is assembled in the stratum granulosum by transglutaminase-1 and other transglutaminases. A deficiency of TG-1 results in a certain type of lamellar ichthyosis. Other causes of lamellar ichthyosis include mutations in the lipoxigenases ALOX12B and ALOX E3 which are involved in the hepoxilin pathway and in the gene ichthyin. Lamellar bodies are lipid and enzyme containing vesicles that greatly contribute to the formation of the stratum corneum. A model disease of this structure is Harlekin ichthyosis, which is caused by severe stop codon mutations in the lipid transporter gene ABCA12. Disturbed cholesterol biosynthesis can result in CHILD syndrome (mutations in NSDHL gene) and Conradi-Hünermann-Happle syndrome (mutations in EBP). The importance of balanced proteases for epidermal homeostasis is highlighted by the protease inhibitor LEKTI which is encoded by SPINK5 and is deficient in the Netherton syndrome.