Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Germline mutations of the fumarate hydratase (FH, fumarase) gene are found in the recessive FH deficiency syndrome and in dominantly inherited susceptibility to multiple cutaneous and uterine leiomyomatosis (MCUL). We have previously reported a number of germline FH mutations from MCUL patients. In this study, we report additional FH mutations in MCUL and FH deficiency patients. Mutations can readily be found in about 75% of MCUL cases and most cases of FH deficiency. Some of the more common FH mutations are probably derived from founding individuals. Protein-truncating FH mutations are functionally null alleles. Disease-associated missense FH changes map to highly conserved residues, mostly in or around the enzyme's active site or activation site; we predict that these mutations severely compromise enzyme function. The mutation spectra in FH deficiency and MCUL are similar, although in the latter mutations tend to occur earlier in the gene and, perhaps, are more likely to result in a truncated or absent protein. We have found that not all mutation-carrier parents of FH deficiency children have a strong predisposition to leiomyomata. We have confirmed that renal carcinoma is sometimes part of MCUL, as part of the variant hereditary leiomyomatosis and renal cancer (HLRCC) syndrome, and have shown that these cancers may have either type II papillary or collecting duct morphology. We have found no association between the type or site of FH mutation and any aspect of the MCUL phenotype. Biochemical assay for reduced FH functional activity in the germline of MCUL patients can indicate carriers of FH mutations with high sensitivity and specificity, and can detect reduced FH activity in some patients without detectable FH mutations. We conclude that MCUL is probably a genetically homogeneous tumour predisposition syndrome, primarily resulting from absent or severely reduced fumarase activity, with currently unknown functional consequences for the smooth muscle or kidney cell.

Dogger Bank Itch and cyclosporin.

Two cases of Dogger Bank Itch responding to oral cyclosporin (Neoral) are reported. The first, a 42-year-old shell-fisherman, presented with eczema on his face, forearms and hands. Oral prednisolone was ineffective and in subsequent years systemic steroids and topical clobetasol propionate allowed him to continue his work. In the shellfishing season of 1996, cyclosporin (Neoral) was introduced and the eczema was subsequently satisfactorily controlled. The second fisherman, aged 46, presented with an irritant eczema of the hands and forearms. Initial treatment with emollients and potent topical steroids had little effect. A subsequent course of cyclosporin provided good control of the eczema.

Pyoderma gangrenosum complicating bilateral mammaplasty.

Pyoderma gangrenosum (PG) is an idiopathic necrotising cutaneous disorder. It is associated with systemic diseases like inflammatory bowel disease, monoclonal gammopathy, arthritides and haematological malignancy. PG occurring at sites of trauma, a phenomenon called pathergy, is well described. One of the manifestations of pathergy is PG occurring at sites of surgery. We describe a case of PG at sites of reduction mammaplasty and review the literature so far.

Vitamin D receptor polymorphisms are associated with altered prognosis in patients with malignant melanoma.

Calcitriol [1,25(OH)2D3], the hormonal derivative of vitamin D3, is an antiproliferative and prodifferentiation factor for several cell types, including cultured melanocytes and malignant melanoma (MM) cells. Several polymorphisms of the vitamin D receptor (VDR) gene have been described including a FokI RFLP in exon 2, BsmI, and ApaI polymorphisms in intron 8 and an adjacent TaqI RFLP in exon 9. Alterations in vitamin D/1,25(OH)2D3 levels and polymorphisms of the VDR have been shown to be associated with several systemic malignancies. We hypothesize that polymorphism in this gene may be associated with altered susceptibility and outcome in patients with MM. A hospital-based case-control study, using 316 MM cases and 108 controls, was used to assess associations with MM susceptibility. Breslow thickness, the most important single prognostic factor in MM, was used as the outcome measure. Polymorphisms at the FokI and TaqI restriction sites were determined using PCR-based methods. Polymorphism at the FokI, but not TaqI, RFLP was associated with an altered risk of MM (P = 0.014). More importantly, variant alleles were associated with increased Breslow thickness. Thus, homozygosity for variant alleles at both RFLP (ttff genotype combination) was significantly associated with thicker tumors. (> or = 3.5 mm; P = 0.001; odds ratio = 31.5). Thus, polymorphisms of the VDR gene, which would be expected to result in impaired function, are associated with susceptibility and prognosis in MM. These data suggest that 1,25(OH)2D3, the ligand of the VDR, may have a protective influence in MM, as has been proposed for other malignancies.

Guidelines for the management of basal cell carcinoma. British Association of Dermatologists.

These guidelines on the management of basal cell carcinoma have been prepared for dermatologists on behalf of the British Association of Dermatologists. They present evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiological aspects, diagnosis and investigation.

A clinical review of 209 pilomatricomas.

BACKGROUND: Pilomatricomas have a wide variety of clinical characteristics and are often misdiagnosed. This can result in extensive surgery for an essentially benign condition. OBJECTIVE: The purpose of this study was to define the clinical and histologic spectrum of these tumors to aid diagnosis. METHODS: Two hundred nine cases were analyzed retrospectively with regard to age at presentation, site, size, and physical appearance. RESULTS: Pilomatricomas appear at any age, with peak presentation bimodally in the first and sixth decade. Their most common site is the head and neck. Presentation is of a hard nodule, either deeply subcutaneous and invisible or superficial with possible erosion through the skin surface. This may lead to a false diagnosis of malignancy or of an epidermoid cyst. An association with myotonic dystrophy has been confirmed, as is the rare occurrence of malignant transformation. CONCLUSION: Careful clinical examination and a high index of suspicion results in an accurate diagnosis, appropriate treatment, and the avoidance of unnecessarily extensive surgery.

A prospective study of Mohs' micrographic surgery in two English centres.

In this study we report the results of using Mohs' micrographic surgery (MMS) to treat 228 basal cell carcinomas (BCCs) in both a teaching and a district general hospital. The criteria for case selection and the 5-year recurrence rate of 3.8% are comparable with figures from the U.S.A. Our experience shows that high cure rates in difficult and, especially, recurrent tumours are obtainable using MMS in both a teaching and a district general hospital setting. Such treatment should be more widely available in the U.K. particularly as the incidence of BCCs is rising.

The nature and distribution of daffodil pickers' rash.

The rash associated with picking daffodils has long been recognized, but the distribution and differing types of lesions have not been explained. This study, from observations in the field, attempts to clarify the position. The method of picking and then gathering the flowers explains the development of the rash at the points of contact of plant sap with skin. Crystals of calcium oxalate in the sap, in conjunction with alkaloids, act as an irritant, and also cause the characteristic sores.