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.

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Keywords Fumarate hydratase, Hereditary leiomyomatosis and renal cell cancer, Multiple cutaneous and uterine leiomyomas, Papillary type 2 renal cell cancer
Persistent URL dx.doi.org/10.1111/j.1399-0004.2010.01486.x, hdl.handle.net/1765/33560
Journal Clinical Genetics: an international journal of genetics and molecular medicine
Smit, D.L, Mensenkamp, A.R, Badeloe, S, Breuning, M.H, Simon, M.E.H, van Spaendonck, K.Y, … Menko, F. (2011). Hereditary leiomyomatosis and renal cell cancer in families referred for fumarate hydratase germline mutation analysis. Clinical Genetics: an international journal of genetics and molecular medicine, 79(1), 49–59. doi:10.1111/j.1399-0004.2010.01486.x