Dystrophic epidermolysis bullosa (DEB) is a severe skin fragility disorder associated with trauma-induced blistering, progressive soft tissue scarring, and increased risk of skin cancer. DEB is caused by mutations in type VII collagen. In this study, we describe the generation of a collagen VII hypomorphic mouse that serves as an immunocompetent animal model for DEB. These mice expressed collagen VII at about 10% of normal levels, and their phenotype closely resembled characteristics of severe human DEB, including mucocutaneous blistering, nail dystrophy, and mitten deformities of the extremities. The oral blistering experienced by these mice resulted in growth retardation, and repeated blistering led to excessive induction of tissue repair, causing TGF-β1-mediated contractile fibrosis generated by myofibroblasts and pseudosyndactyly in the extremities. Intradermal injection of WT fibroblasts resulted in neodeposition of collagen VII and functional restoration of the dermal-epidermal junction. Treated areas were also resistant to induced frictional stress. In contrast, untreated areas of the same mouse showed dermal-epidermal separation following induced stress. These data demonstrate that fibroblast-based treatment can be used to treat DEB in a mouse model and suggest that this approach may be effective in the development of clinical therapeutic regimens for patients with DEB. IntroductionSkin integrity and resistance to mechanical stress rely on the function of the dermal-epidermal junction zone (DEJZ), which anchors the epidermis to the underlying dermal matrix. The supramolecular cell adhesion complexes at the DEJZ mediate interactions of the cytoskeleton in basal keratinocytes with the basement membrane and the extracellular anchoring fibrils, which emanate from the basement membrane into the dermis and entrap dermal collagen bundles, thus establishing stable dermal-epidermal cohesion (1).The main component of the anchoring fibrils is collagen VII, a homotrimeric collagen synthesized by keratinocytes and fibroblasts (2). Fibril formation and deposition at the DEJZ requires proteolytic processing of procollagen VII to mature collagen (3). Loss of collagen VII functions in dystrophic epidermolysis bullosa (DEB) leads to absence or anomalies of the anchoring fibrils and to dermal-epidermal tissue separation. DEB refers to a clinically heterogeneous group of disorders including recessively and dominantly inherited subtypes (4, 5). All forms of DEB are allelic and caused by mutations in the collagen VII gene, COL7A1. Early investigations demonstrated reduced amounts of anchoring fibrils and collagen VII in the skin of patients with mild and moderate, reces-

Here, we report on the first systematic long-term study of fibroblast therapy in a mouse model for recessive dystrophic epidermolysis bullosa (RDEB), a severe skin-blistering disorder caused by loss-of-function of collagen VII. Intradermal injection of wild-type (WT) fibroblasts in >50 mice increased the collagen VII content at the dermal-epidermal junction 3.5- to 4.7-fold. Although the active biosynthesis lasted <28 days, collagen VII remained stable and dramatically improved skin integrity and resistance to mechanical forces for at least 100 days, as measured with a digital 3D-skin sensor for shear forces. Experiments using species-specific antibodies, collagen VII-deficient fibroblasts, gene expression analyses, and cytokine arrays demonstrated that the injected fibroblasts are the major source of newly deposited collagen VII. Apart from transitory mild inflammation, no adverse effects were observed. The cells remained within an area

A 49-year-old man with a family history of early myocardial infarction presented with a 2-month history of a pruritic eruption of yellowish papules on the elbows, the other extensor surfaces of the limbs, and the buttocks. The papules were focally grouped, particularly over the elbows, each measuring approximately 4-6 mm in diameter. They were dome-shaped, slightly red with a yellow hue in the centre, and surrounded by erythematous halos (Fig. 1a). Two years previously, the patient had been diagnosed with metabolic syndrome, comprising obesity (body mass index 42), diabetes mellitus type 2, arterial hypertension, hyperuricaemia and hyperlipidaemia. He had a 66 pack-year smoking history and consumed alcohol regularly.Laboratory investigations carried out after 12 h of fasting revealed a total triglyceride level of 10 270 mg ⁄ dL (normal range 20-200), total cholesterol of 1082 mg ⁄ dL (normal range 120-240 and 10.8% glycosylated haemoglobin (normal range 4-6%). A sample of whole blood refrigerated overnight developed a creamy supernatant indicative of lipaemic plasma (Fig. 1b), which did not allow lipid serum electrophoresis to be performed.A biopsy was taken from a lesion on the elbow, and histological examination found dermal accumulation of lipid-laden macrophages characterized by an abundant vacuolated cytoplasm (Fig. 1c).A diagnosis of eruptive xanthomas was made, based on the markedly raised hypertriglyceridaemia and hyperglycaemia. Triglyceride-lowering therapy with 145 mg ⁄ day fenofibrate was started and the existing antidiabetic therapy intensified. At the 4-month followup, the xanthomas had almost completely resolved, leaving only small indented scars. The total triglyceride and cholesterol levels had decreased to 678 mg ⁄ dL and 320 mg ⁄ dL, respectively, and glycosylated haemoglobin had decreased to 8.5%.Eruptive xanthomas most often occur in the context of chylomicronaemia and hypertriglyceridaemia caused by primary and secondary forms of dyslipidaemia.

Acute and chronic UV exposure is an important risk factor leading to photocarcinogenesis, photoimmuno suppression and photoaging (1, 2). Patients with Gorlin syndrome (GS) harbour a hereditary predisposition to develop basal cell carcinomas (BCC) and are, therefore, advised that effective sun protection is essential and can help reduce skin cancer risk (1-4). On the other hand, adherence to strict sunprotection habits can result in vitamin D deficiency, which has been demonstrated in many patients with GS (2, 3). Vitamin D deficiency is associated with an increased risk of osteomalacia, bone fractures, autoimmune diseases, cancer and cardiovas cular disease (1). CASE REPORTHere, we report a 54yearold man with GS who was admitted to our hospital for surgical treatment of multiple BCC (Fig. 1). Characteristic features of GS were present in the form of multiple BCC since youth, palmoplantar pits, an odontogenic cyst, calcification of the falx cerebri, and positive family history (5). DNA analysis by multi plex ligationdependent probe amplification revealed a novel heterozygous deletion of exons 11 and 12 within the PTCH1 gene, leading to a frame shift and premature termination codon. Moreover, the patient's medical his tory revealed that within the past decades, multiple bone fractures had occurred after minimal trauma, suggesting a bone calcification disorder. The patient reported of his strict photoprotection habits by daily textile and cosmetic sun protection measures as well as trying to avoid sun exposure. Laboratory workup including parameters of bone turnover and metabolism showed serum 25(OH)D levels of < 4 ng/ml, far below the normal range (30-70 ng/ml), elevated alkaline phosphatase and low serum phosphate concentrations. Serum calcium, parathyroid hormone and vitamin A, E and K concentrations were within normal ranges. Dualenergy Xray absorptiometry (DEXA) was consistent with severe osteoporosis ac cording to the WHO classification, with a mean T-score of -3.6 measured from the hip (Fig. 2). Based on these observations, we concluded that the patient suffered from a disorder of bone mineralisation caused by vitamin D deficiency. Substitution therapy was initiated with a single dose of intramuscularly administered vitamin D3 derivative (cholecalciferol 100,000 IU) followed by longterm daily oral substitution of 2,000 IU of vitamin D3. The 25(OH)D level was within the normal range 3 months after initiation of therapy.Vitamin D deficiency has been described in GS pa tients and is thought to be related to strict sun protection habits (1-3). The time of vitamin D measurement in our patient was spring (April), where probands usually have higher vitamin D levels than during winter (2), but they were still below the detection limit of the labora tory test. Normal serum levels of the other lipophilic vitamins (vitamins A, E, K) argue against an intestinal malabsorption disorder or an imbalanced overall nu tritional vitamin supply in our patient. There were no signs of renal or hepatic insufficiency which could have...

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