4080 Background: Germline mutations in the CDH1 gene lead to the hereditary diffuse gastric cancer syndrome (HDGC), with strongly increased risk of developing gastric cancer (GC) and lobular breast cancer (LBC). We report on the geno-/phenotypical data of all Dutch families with germline mutations in the CDH1 gene. Methods: Index patients of families suspect for HDGC were tested for CDH1 mutations in a central molecular genetics laboratory. Of families with CDH1 mutations all cancer data were retrieved. Surgical data of prophylactic gastrectomies were collected. Pathologic investigation was performed according to the Swiss roll technique by expert pathologists. Results: In 6 families 6 different CDH1 mutations were found. Symptomatic GC was diagnosed in 26 individuals. Mean age at diagnosis was 40 years (range 23-65 years), with 3 GCs < 30 years. Of 18 confirmed GCs, 17 were diffuse cancers, one intestinal type. Symptomatic LBC was diagnosed in 1 carrier. Forty out of 79 tested family members carried a CDH1 mutation. Twenty-four of these carriers, aged 18-61 years, underwent prophylactic gastrectomy, in 2/24 combined with prophylactic mastectomy. In 1 patient a small focus of invasive diffuse gastric cancer and an in situ carcinoma were found. Multiple foci of intramucosal cancer and one GIST were diagnosed in 13 other patients. In 8 patients no cancer cells were found. Foci of invasive LBC and multifocal LCIS were found in all mastectomy specimens. Two out of 40 carriers were diagnosed with GC or precursor lesions at gastroscopy before planned gastrectomies. Re-laparotomy was necessary in 3 subjects because of abdominal infection, anastomotic leakage or residual gastric mucosa. Clefts of lip and/or palate were reported in 6 individuals from 3 families (3 proven mutation carriers). Conclusions: The age at onset of GC in our families is highly variably, which has to be included in the counselling on planning prophylactic gastrectomies. A multidisciplinary approach is obligatory in the care for HDGC patients in order to maximize the quality and to minimize the physical impact of prophylactic procedures. Taking a family history should include clefts in gastric cancer families. No significant financial relationships to disclose.
Six cases of Kabuki syndrome (KS) with ocular anomalies are reported and the variety of ocular features reported in the literature for this syndrome is described. Routine ocular examinations are recommended for every patient with KS because of the high proportion of ocular anomalies found in these patients, the presence of which can hamper development if not adequately addressed.
Eur J Clin Invest 2010; 40 (5): 433–439 Abstract Background In most cases of renal cell carcinoma there is no family history of renal cancer and no hereditary cause of the disease. Hereditary renal cancer accounts for about 2–4% of cases. Recognition of this subgroup by clinicians is important because of the possibility of severe medical consequences for patients and their relatives. Materials and methods We review the latest data about different genetic conditions characterized by an increased risk of developing renal cancer and we formulate tools to recognize high‐risk families. Results In general, a positive family history, young age at diagnosis of renal cancer, multiple and/or bilateral renal tumours and combined occurrence of different histological types of renal tumours should raise suspicion of a hereditary renal tumour syndrome. In addition, the presence of specific extrarenal symptoms in patients could assist in differentiating between tumour syndromes. Conclusions A detailed medical and family history, along with physical examination are key factors to diagnose hereditary renal cancer syndromes. When a genetic predisposition for renal cancer is suspected, referral to a Family Cancer Clinic is warranted to initiate genetic examination and counselling on preventive options.
Endoscopic ultrasonography (EUS) and MRI are promising tests to detect precursors and early-stage pancreatic ductal adenocarcinoma (PDAC) in high-risk individuals (HRIs). It is unclear which screening technique is to be preferred. We aimed to compare the efficacy of EUS and MRI in their ability to detect clinically relevant lesions in HRI.
Design
Multicentre prospective study. The results of 139 asymptomatic HRI (>10-fold increased risk) undergoing first-time screening by EUS and MRI are described. Clinically relevant lesions were defined as solid lesions, main duct intraductal papillary mucinous neoplasms and cysts ≥10 mm. Results were compared in a blinded, independent fashion.
Results
Two solid lesions (mean size 9 mm) and nine cysts ≥10 mm (mean size 17 mm) were detected in nine HRI (6%). Both solid lesions were detected by EUS only and proved to be a stage I PDAC and a multifocal pancreatic intraepithelial neoplasia 2. Of the nine cysts ≥10 mm, six were detected by both imaging techniques and three were detected by MRI only. The agreement between EUS and MRI for the detection of clinically relevant lesions was 55%. Of these clinically relevant lesions detected by both techniques, there was a good agreement for location and size.
Conclusions
EUS and/or MRI detected clinically relevant pancreatic lesions in 6% of HRI. Both imaging techniques were complementary rather than interchangeable: contrary to EUS, MRI was found to be very sensitive for the detection of cystic lesions of any size; MRI, however, might have some important limitations with regard to the timely detection of solid lesions.
An unclassified variant (UV) in exon 1 of the MLH1 gene, c.112A > C, p.Asn38His, was found in six families who meet diagnostic criteria for Lynch syndrome. The pathogenicity of this variant was unknown. We aim to elucidate the pathogenicity of this MLH1 variant in order to counsel these families adequately and to enable predictive testing in healthy at-risk relatives.We studied clinical data, microsatellite instability and immunohistochemical staining of MMR proteins, and performed genealogy, haplotype analysis and DNA testing of control samples.The UV showed co-segregation with the disease in all families. All investigated tumors showed a microsatellite instable pattern. Immunohistochemical data were variable among tested tumors. Three families had a common ancestor and all families originated from the same geographical area in The Netherlands. Haplotype analysis showed a common haplotype in all six families.We conclude that the MLH1 variant is a pathogenic mutation and genealogy and haplotype analysis results strongly suggest that it is a Dutch founder mutation. Our findings imply that predictive testing can be offered to healthy family members. The immunohistochemical data of MMR protein expression show that interpreting these results in case of a missense mutation should be done with caution.
