Renal cancer and pneumothorax risk in Birt-Hogg-Dubé syndrome; an analysis of 115 FLCN mutation carriers from 35 BHD families.

BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant condition caused by germline FLCN mutations, and characterised by fibrofolliculomas, pneumothorax and renal cancer. The renal cancer risk, cancer phenotype and pneumothorax risk of BHD have not yet been fully clarified. The main focus of this study was to assess the risk of renal cancer, the histological subtypes of renal tumours and the pneumothorax risk in BHD. METHODS: In this study we present the clinical data of 115 FLCN mutation carriers from 35 BHD families. RESULTS: Among 14 FLCN mutation carriers who developed renal cancer 7 were <50 years at onset and/or had multifocal/bilateral tumours. Five symptomatic patients developed metastatic disease. Two early-stage cases were diagnosed by surveillance. The majority of tumours showed characteristics of both eosinophilic variants of clear cell and chromophobe carcinoma. The estimated penetrance for renal cancer and pneumothorax was 16% (95% minimal confidence interval: 6-26%) and 29% (95% minimal confidence interval: 9-49%) at 70 years of age, respectively. The most frequent diagnosis in families without identified FLCN mutations was familial multiple discoid fibromas. CONCLUSION: We confirmed a high yield of FLCN mutations in clinically defined BHD families, we found a substantially increased lifetime risk of renal cancer of 16% for FLCN mutation carriers. The tumours were metastatic in 5 out of 14 patients and tumour histology was not specific for BHD. We found a pneumothorax risk of 29%. We discuss the implications of our findings for diagnosis and management of BHD.

Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis.

Heterozygous fumarate hydratase (FH) germline mutations cause hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant syndrome characterized by multiple cutaneous piloleiomyomas, uterine leiomyomas and papillary type 2 renal cancer. The main objective of our study was to evaluate clinical and genetic data from families suspected of HLRCC on a nationwide level. All families referred for FH mutation analysis in the Netherlands were assessed. We performed FH sequence analysis and multiplex ligation-dependent probe amplification. Families with similar FH mutations were examined for haplotype sharing. In 14 out of 33 families, we identified 11 different pathogenic FH germline mutations, including 4 novel mutations and 1 whole-gene deletion. Clinical data were available for 35 FH mutation carriers. Cutaneous leiomyomas were present in all FH mutation carriers older than 40 years of age. Eleven out of 21 female FH mutation carriers underwent surgical treatment for symptomatic uterine leiomyomas at an average of 35 years. Two FH mutation carriers had papillary type 2 renal cancer and Wilms' tumour, respectively. We evaluated the relevance of our findings for clinical practice and have proposed clinical diagnostic criteria, indications for FH mutation analysis and recommendations for management.

HPV type concordance in sexual couples determines the effect of condoms on regression of flat penile lesions.

We earlier demonstrated, in a randomised clinical trial, that the regression time of flat penile lesions in male sexual partners of women with cervical intraepithelial neoplasia (CIN) was shorter in men who used condoms compared to those who did not. To further evaluate this finding, we examined whether the effect of condom use on the regression of flat penile lesions depends on the presence of human papillomavirus (HPV) type concordance in sexual couples, as determined in cervical and penile scrapes by GP5+/6+ PCR testing. A Cox model with time-dependent covariates showed a beneficial effect of condoms on regression of flat penile lesions in concordant couples (hazard ratio 2.63, 95% CI 1.07-6.48) but not in those who were nonconcordant. When both partners harboured different HPV types, no effect of condoms was found (hazard ratio 0.90, 95% CI 0.27-2.96). Delayed regression of flat penile lesions was associated with either stable lesions or with new penile lesions developing at sites surrounding pre-existing lesions suggesting reinfection of the penile epithelium. We conclude that condom use blocks sexual HPV transmission by preventing reinfection and development of new penile lesions in men who are susceptible to the same type as present in the female partner.

Orofacial granulomatosis in a patient with Crohn's disease.

Orofacial granulomatosis encompasses the previously recognized clinical entities Melkersson-Rosenthal syndrome and cheilitis granulomatosa. We report the case of a 39-year-old patient with cheilitis granulomatosa, intestinal Crohn's disease, and optic neuropathy. Cheilitis granulomatosa and optic neuropathy represent 2 rare manifestations of orofacial granulomatosis in Crohn's disease.

[Radiation-induced cutaneous hamartoma in a patient with Cowden syndrome. Clinical evidence for heterozygosity]. / Strahleninduzierte kutane Hamartome bei einer Patientin mit Cowden-Syndrom. Klinische Evidenz für Verlust der Heterozygotie.

A 56-year-old woman had typical features of Cowden syndrome in the form of hamartomas involving the skin, lips, and oral mucosa. At the age of 48, a mastectomy was performed for adenocarcinoma with a regional metastasis, and X-ray treatment was applied to the left axilla. Subsequently the patient developed approximately 30 skin-colored nodules surrounding the irradiated axillary region within several months. Histopathological examination of one of these lesions showed characteristic features of sclerotic fibroma. The multiple radiation-induced fibrous hamartomas observed may be best explained by multiple events of loss of heterozygosity (LOH), because molecular studies in other patients with Cowden syndrome have shown that both benign and malignant tumors originate from LOH. The X-ray treatment would have induced LOH in many cells, giving rise to either homo- or hemizygosity for the Cowden mutation.

Linear IgA bullous dermatosis in a patient with renal cell carcinoma.

Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal bullous disease with heterogeneous clinical manifestations, characterized by linear deposition of IgA along the epidermal basement membrane zone. We report a patient with a metastasized renal cell carcinoma who developed an extensive blistering eruption. The lesions showed immunopathological findings characteristic of LABD. The patient showed a fair response to prednisolone and dapsone. Treatment to control the LABD was no longer required when interferon-alfa was started as palliative therapy for the metastasized renal cell carcinoma. The association of LABD and malignancies has been documented before and is not due to mere chance alone.

Cheilitis granulomatosa.

Cheilitis granulomatosa is a rare inflammatory disorder with unclear aetiology. It is a disorder characterized by recurrent or persistent swelling of one or both lips that may be part of the Melkersson-Rosenthal syndrome or may be a manifestation of Crohn's disease. An overview of the clinical features, histopathology, differential diagnosis, management strategies and prognosis of cheilitis granulomatosa is presented and discussed with regard to the literature.

Paraneoplastic pemphigus caused by an epithelioid leiomyosarcoma and associated with fatal respiratory failure.

A patient is described who initially presented with pemphigus vulgaris, limited to the oral cavity, and weight loss. Although the various laboratory studies pointed to the diagnosis of paraneoplastic pemphigus (PNP), the underlying neoplasm was not detected until 6 months later, when the patient developed shortness of breath and routine physical examination on admission revealed an abdominal mass, which eventually was proven to be an epithelioid leiomyosarcoma. In spite of radical excision of the tumour and intensive treatment of the dyspnoea, the patient died of respiratory failure 19 months after the PNP had been diagnosed. Early diagnosis of PNP is stressed to possibly prevent fatal pulmonary involvement.

Granulomatous skin infection caused by Scopulariopsis brevicaulis.

A 14-year-old girl with a granulomatous infection of the cheek caused by Scopulariopsis brevicaulis is described. Treatment successively consisted of itraconazole and/or terbinafine for 19 months, after which clinical and mycologic cure seemed to be obtained. However, a relapse occurred 10 months later.

Eccrine syringofibroadenoma: multiple lesions representing a new cutaneous marker of the Schöpf syndrome, and solitary nonhereditary tumors.

BACKGROUND: Eccrine syringofibroadenoma (ESFA) is a rare eccrine tumor that has characteristic histopathologic features and variable clinical findings. OBJECTIVE: Our purpose was to define the clinical and histopathologic features of ESFA, to assess a possible syndromic association and heredity, and to propose a clinicopathologic classification. METHODS: Three solitary and five multiple cases of ESFA were analyzed and the findings compared with those of previously published cases. RESULTS: Clinically, solitary ESFA was typically a nonhereditary verrucous growth. Multiple examples presented as palmoplantar keratoderma and keratotic papules in a mosaic pattern. In the multiple form, four patients had the Schöpf syndrome (hydrocystomas of the eyelids, hypotrichosis, hypodontia, and nail abnormalities); one had an incomplete form of the syndrome. Histologically, ESFA showed a reticulate proliferation of thin strands of acrosyringeal cells with focal lumen formation, and a fibrovascular stroma. Malignant ESFA was present in one multiple case. CONCLUSION: Multiple (palmoplantar) ESFAs are a new cutaneous marker of the Schöpf syndrome.