Genetic skin diseases (genodermatoses) present a wide spectrum of clinical manifestations ranging from relatively mild to extremely severe which can affect exclusively the skin or be part of a multi-organ pathology. Genodermatoses can be categorized according to (i) the involved tissue (e.g. disorders of the epidermis, dermis, skin appendages), or (ii) the abnormal tissue/cell function (e.g. disorders in DNA repair) or (iii) a combination of both (e.g. epithelial adhesion disorders, keratinization disorders). GENESKIN focuses on five major groups of genodermatoses: epithelial adhesion disorders, keratinization disorders, connective tissue disorders affecting the skin, DNA repair diseases and ectodermal dysplasias, Current knowledge concerning the molecular basis, function of defective proteins and pathogenesis of these disorders has reached significantly different levels. Consequently diagnosis, genetic counselling and possible treatment vary considerably from disease to disease.
The best characterized category of genodermatoses is the epithelial adhesion disorders, a clinically and genetically heterogeneous group of diseases manifesting in skin fragility and blister formation. They include the different forms of inherited epidermolysis bullosa and the Kindler syndrome. Epidermolysis bullosa is transmitted as an autosomal dominant or recessive trait and manifests with skin and mucous membrane trauma-induced blistering lesions. To date, mutations in 10 distinct genes, encoding for structural proteins involved in epithelial-mesenchymal adhesion, have been shown to underlie the different forms of epidermolysis bullosa. Recent studies have demonstrated that Kindler syndrome is caused by recessive mutations in the KIND1 gene encoding for a protein implicated in linking the basal keratinocyte actin cytoskeleton to the extracellular matrix.
Keratinization disorders group a variety of inherited diseases caused by abnormalities in the epithelial differentiation process (i.e. keratinization) and stratum corneum formation which lead to scaling and hyperkeratotic skin lesions. They may present at birth or later in life, and can be limited to the skin or be part of a multi-system disorder. To date, the genes of several keratinisation disorders have been identified, demonstrating the functional importance and interactions of several proteins involved in epidermal differentiation and barrier formation and maintenance. Affected proteins include major structural keratinocyte components (e.g. keratins, loricrin, connexins), membrane transporters (e.g. ABCA12), and enzymes involved in lipid metabolism (e.g. transglutaminase 1, steroid sulfatase, ALOXE3, ALOX12B, NSDHL), protein catabolism (e.g. LEKTI) and peroxisomal biogenesis and function (e.g. phytanoyl-CoA hydroxylase). However, the causative gene of some keratinization disorders (e.g. a sub-group of autosomal recessive congenital ichthyoses, specific forms of palmoplantar keratoderma) is still unknown and the pathogenesis of a number of these conditions remains poorly understood.
The ectodermal dysplasia syndromes is a group of morphogenesis disorders resulting from the abnormal development of two or more ectodermal derivatives (e.g. hair, teeth, nails, sweat glands) and manifesting with a wide range of signs and symptoms as a result of the impaired function and growth of these structures. It represents the most complex and both clinically and genetically most heterogeneous group of genodermatoses, with more than 150 clinically recognizable conditions. As other categories of inherited skin diseases, these disorders can also affect other tissues or organs. To date, about 40 ectodermal dysplasias have been explained at molecular level by mutations in single genes, following any one of the major inheritance patterns (i.e. autosomal dominant, autosomal recessive and X-linked). The majority of these genes are implicated in the embryonic development of the skin, which is regulated by the interaction between the mesenchyme and overlying epithelium. The pathways which orchestrate this interaction include cell-cell signalling, cell adhesion and transcription regulation. Furthermore, recent discoveries also highlight the involvement of causative genes for ectodermal dysplasias in other biological pathways, such as DNA replication. However, the molecular basis of a large number of ectodermal dysplasias is still unknown and the classification of these disorders remains one of the most confusing in medical literature.
The inherited connective tissue diseases predominantly affecting the skin include the Ehlers-Danlos syndrome, pseudoxanthoma elasticum, cutis laxa, and lipoid proteinosis. The Ehlers-Danlos syndrome comprises a group of disorders characterized by a variable association of skin hyperelasticity and fragility with increased bruisability, dystrophic scars, joint hyperlaxity and generalized fragility of other connective tissues. The current classification recognizes six major subtypes (classical, hypermobility, vascular, kyphoscoliotic, arthrochalasis and dermatosparaxis) plus additional rare variants. While some of these have been associated to mutations in collagens or collagen modifying enzyme genes, others still await elucidation at molecular level. Pseudoxanthoma elasticum manifests with skin, eye, and cardiovascular abnormalities. The recently identified causative gene encodes for a putative membrane transporter protein with unknown function. Hereditary cutis laxa is a heterogeneous group of diseases characterized by loose and sagging skin with reduced elasticity. The inheritance of cutis laxa includes autosomal dominant and recessive forms, with mutations in elastin and fibulin-5 genes, respectively. An X-linked recessive type of hereditary cutis laxa, currently termed occipital-horn disease, results from mutation in the ATP7A gene. Lipoid proteinosis, characterized by skin scarring and infiltration, hoarseness and respiratory distress, results from mutations in the extracellular matrix protein 1, a glycoprotein expressed in the skin and other tissues.
DNA repair disorders comprise xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome. They all result from defective DNA-repair after ultraviolet light-induced cellular injury and are characterised by sun hypersensitivity and increased genetic instability. While xeroderma pigmentosum patients have an extremely elevated incidence of early skin cancer, both Cockayne syndrome and trichothiodystrophy are systemic disorders showing many features of premature ageing with no significant predisposition to skin cancer. Xeroderma pigmentosum is a group of diseases caused by mutations in either any one of the seven genes (XPA-G) involved in the nucleotide excision repair (NER) of DNA damage, or in the DNA polymeraseh gene (XPV), whose product is required to replicate damaged DNA. Cockayne syndrome is due to mutations in the NER sub-pathway genes (CSA and CSB), required to remove damage from the transcribed strand of active genes. As for trichothiodystrophy, mutations in two genes (XPB and XPD) previously associated to xeroderma pigmentosum have been recently identified in some patients. In addition, a few trichothiodystrophy cases show mutations in a further gene encoding the TFB5 component of the transcription factor complex TFIIH.