In two patients, a man aged 43 and a woman aged 40 years, who presented with a desmoid tumour, familial adenomatous polyposis (FAP) was diagnosed three and six years later, respectively. The second ...patient had developed metastatic rectal cancer. Desmoid-type fibromatoses usually develop sporadically, but may also be an extracolonic manifestation of FAP. All patients with desmoids diagnosed who are under age 60, or with desmoids located intra-abdominally or in the abdominal wall, should be referred for colonic and genetic evaluation. In all further patients with a desmoid tumour, the possibility of FAP should be considered and patient data and the family history should be evaluated thoroughly. If FAP is suspected, patients should be referred for colonoscopic examination and genetic evaluation.
Spontaneous pneumothorax can be due to Birt-Hogg-Dubé syndrome (BHD syndrome), an autosomal dominant predisposition for fibrofolliculomas, multiple lung cysts, pneumothorax and renal cancer. The ...syndrome is the result of germline mutations in the FLCN (folliculin) gene. Its clinical presentation is highly variable. Consequently, this syndrome is probably under-diagnosed. An illustrative kindred is presented in which the index patient, a man aged 26, had recurrent episodes of pneumothorax without apparent skin lesions or renal abnormalities. He had bilateral mostly basally-located lung cysts. There was a family history of fibrofolliculomas, lung cysts, pneumothorax and clear cell renal cancer. Recognition of BHD is important since carriers of the mutation can be offered surveillance for early detection and treatment of renal cancer.
Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, ...and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.
Hereditary non-polyposis colorectal cancer (HNPCC) is a common, autosomal dominant, cancer susceptibility condition characterized by early onset colorectal cancer. HNPCC is caused by germline ...mutations in one of five DNA mismatch repair genes (MMR): MSH2, MLH1, PMS1, PMS2 and MSH6. To date, more than 200 different predisposing mutations in these genes have been characterized in HNPCC patients, the majority of which occur in MSH2 and MLH1. Here, we report that genomic deletions at MSH2 also represent a frequent cause of HNPCC. In fact, these deletions comprise more than one-third of all pathogenic MSH2 mutations among Dutch HNPCC families and account for 6.5% of HNPCC defined by the Amsterdam criteria. In previous studies, we determined the prevalence of mutations at MSH2 and MLH1 among 184 kindreds, 92 of which comply with the Amsterdam criteria (AMS+) and 92 of which have a familial clustering of colorectal cancer reminiscent of HNPCC (AMS-). Approximately one-half (41) of AMS+ families revealed a pathogenic germline mutation in MSH2 or MLH1, whereas only 6 of 92 AMS-families had a mutation in either gene. In the present study, the remaining 137 families, 51 AMS+ and 86 AMS-, were investigated by Southern-blot analysis of genomic DNA.
