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A new type of corneal dystrophy with various oculocutaneous symptoms and other signs is described. Snowflake dystrophy is characterized by hundreds of small, round, oval or cork-screw-like white opacities in the endothelium and Descemet's membrane. The length of the opacities is 5-20 mu and they form an even layer throughout the posterior membrane. 44% of the patients above the age of 70 years had also pseudoexfoliation of the lens capsule. Corneal endothelial pigmentation advance with the age but are not even in elderly patients necessarily present. A wide range of cutaneous disturbances of melanin metabolism was noted in 4/5 of the cases: intradermal nevi, lentigines, nevus spilus, melasma, vitiligo, early alopecia and early graying of the hair. Photosensitivity reactions like solar urticaria were noted in 5 cases. The skin was often wrinkled, dry and inelastic. Conjunctival wrinkling and Bitot's spots, ovarial cysts, frequently recurrent tonsillitis and several cholecystectomies suggest a generalized involvement of mucous membranes in this syndrome. Degenerative joint disease was constated in 2/5 of cases. The genetic analysis of 59 persons revealed an autosomal dominant mode of inheritance. The prevalence of the gene was high in the province of Satakunta in western Finland.
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PMID:Inherited corneal snowflake dystrophy with oculocutaneous pigmentation disturbances and other symptoms. 387 58

Keratins are obligate heterodimer proteins that form the intermediate filament cytoskeleton of all epithelial cells. Keratins are tissue and differentiation specific and are expressed in pairs of types I and II proteins. The spectrum of inherited human keratin diseases has steadily increased since the causative role of mutations in the basal keratinocyte keratins 5 and 14 in epidermolysis bullosa simplex (EBS) was first reported in 1991. At the time of writing, mutations in 15 epithelial keratins and two trichocyte keratins have been associated with human diseases which include EBS, bullous congenital ichthyosiform erythroderma, epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, diffuse and focal non-epidermolytic palmoplantar keratoderma, pachyonychia congenita and monilethrix. Mutations in extracutaneous keratins have been reported in oral white sponge naevus and Meesmann's corneal dystrophy. New subtleties of phenotype-genotype correlation are emerging within the keratin diseases with widely varying clinical presentations attributable to similar mutations within the same keratin. Mutations in keratin-associated proteins have recently been reported for the first time. This article reviews clinical, ultrastructural and molecular aspects of all the keratin diseases described to date and delineates potential future areas of research in this field.
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PMID:Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation. 1035 17

Keratins are the type I and II intermediate filament proteins which form a cytoskeletal network within all epithelial cells. They are expressed in pairs in a tissue- and differentiation-specific fashion. Epidermolysis bullosa simplex (EBS) was the first human disorder to be associated with keratin mutations. The abnormal keratin filament aggregates observed in basal cell keratinocytes of some EBS patients are composed of keratins K5 and K14. Dominant mutations in the genes encoding these proteins were shown to disrupt the keratin filament cytoskeleton resulting in cells that are less resilient and blister with mild physical trauma. Identification of mutations in other keratin genes soon followed with attention focussed on disorders showing abnormal clumping of keratin filaments in specific cells. For example, in bullous congenital ichthyosiform erythroderma, clumping of filaments in the suprabasal cells led to the identification of mutations in the suprabasal keratins, K1 and K10. Mutations have now been identified in 18 keratins, all of which produce a fragile cell phenotype. These include ichthyosis bullosa of Siemens (K2e), epidermolytic palmoplantar keratoderma (K1, K9), pachyonychia congenita (K6a, K6b, K16, K17), white sponge nevus (K4, K13), Meesmann's corneal dystrophy (K3, K12), cryptogenic cirrhosis (K8, K18) and monilethrix (hHb6, hHb1).In general, these disorders are inherited as autosomal dominant traits and the mutations act in a dominant-negative manner. Therefore, treatment in the form of gene therapy is difficult, as the mutant gene needs to be inactivated. Ways of achieving this are actively being studied. Reliable mutation detection methods from genomic DNA are now available. This enables rapid screening of patients for keratin mutations. For some of the more severe phenotypes, prenatal diagnosis may be requested and this can now be performed from chorionic villus samples at an early stage of the pregnancy. This review article describes the discovery of, to date, mutations in 18 keratin genes associated with inherited human diseases.
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PMID:The molecular genetics of keratin disorders. 1268 39