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An analysis of the findings in 21 patients with the Cowden syndrome or the multiple hamartoma syndrome is presented. The Cowden syndrome is a cancer‐associated genodermatosis with characteristic mucocutaneous findings and a wide array of associated abnormalities including a high incidence of breast cancer in female patients. Genetic studies confirmed autosomal dominant inheritance with a high penetrance in both sexes and moderate interfamilial and intrafamilial differences in the expressivity of a number of symptoms. Familial occurrence was present in 4 of the 7 families. There was a strong predominance of female patients (6:1), which may be fortuitous. Mucocutaneous changes were the most constant (100% incidence) and characteristic findings; they almost invariably became manifest in the second decade. Four of our 18 female patients (22%) were treated for breast cancer, a lower incidence than reported previously. No increased incidence of other types of malignancies was found. Craniomegaly (high head circumference) was found to be the most common extracutaneous manifestation (80% incidence); craniomegaly appears to be an important early marker. We also found high incidences of gastrointestinal polyps (approximately 60%) and cutaneous fibromas (76%), while the incidence of thyroid abnormalities, thus far regarded as the most common extracutaneous finding, was similar to that reported previously (62%). G‐banded karyotype and preliminary DNA‐repair studies revealed no clear abnormalities. No linkage with the loci of HLA, and immunoglobulin haplotypes was found.

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.

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.

The management of cheilitis granulomatosa remains a challenge. As this study revealed a low chance of developing Crohn's disease, it does not seem justified to inform patients with cheilitis granulomatosa of the possibility that they might develop Crohn's disease. Patients with a negative history of gastrointestinal complaints should not be exposed to routine investigations of the gastrointestinal tract.