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Birt-Hogg-Dubé (BHD) syndrome is a cancer disorder caused by a pathogenic FLCN mutation characterized by fibrofolliculomas, lung cysts, pneumothorax, benign renal cyst, and renal cell carcinoma (RCC). In this case we describe a patient with bilateral renal tumour and a positive familial history for pneumothorax and renal cancer. Based on this clinical presentation, the patient was suspected for BHD syndrome, which was confirmed after molecular testing. We discuss the importance of recognizing this autosomal dominant cancer disorder when a patient is presented at the urologist with a positive family history of chromophobe renal cell cancer or a positive familial history for renal cell cancer and pneumothorax.

Previously, we proposed that familial multiple trichodiscomas is distinct from Birt-Hogg-Dubé syndrome (BHD). We now studied the cutaneous findings in eight additional families and renamed the condition familial multiple discoid fibroma (FMDF) to emphasize the distinction from BHD. FMDF is characterized by early age of onset, prominent involvement of the pinnae and typical discoid fibromas without the follicular epithelial component seen in the fibrofolliculoma/trichodiscoma spectrum of BHD. Associated internal abnormalities and FLCN germline mutations are absent and using segregation analysis we could exclude involvement of the FLCN locus.

AIMS: To investigate the occurrence of preinvasive neoplastic lesions in ovarian surface epithelium and ovarian inclusion cyst epithelium of women with a hereditary predisposition to the development of female adnexal (ovarian and fallopian tube) carcinoma and to assess the expression of differentiation and proliferation related proteins within putative sites of origin of serous ovarian carcinoma, the ovarian surface epithelium and ovarian inclusion cyst epithelium.METHODS: Twenty-one ovaries, prophylactically removed from 11 women predisposed to the development of female adnexal cancer (cases) were compared with 22 ovaries from 11 women without such predisposition (controls). Archival histological specimens were screened for hyperplastic and dysplastic epithelial lesions. In both the ovarian surface and inclusion cyst epithelia, the percentage of cells was determined that stained positively for Ki67, p21, p27, p53, cyclin A, cyclin D1, bcl-2 and the presence of HER-2/neu, oestrogen (ER-alpha) and progesterone receptors (PR).RESULTS: No preinvasive neoplastic lesions were detected. However, hyperplastic areas were found in three cases and in four controls (NS). ER-alpha (P = 0.013), PR (P < 0.001), bcl-2 (P = 0.008), p21 (P = 0.046) and p27 (P = 0.008) were expressed in a significantly higher percentage of cells in inclusion cyst epithelium than in ovarian surface epithelium (both groups). The latter showed higher bcl-2 expression in cases (P = 0.05) compared with controls. The inclusion cyst epithelium of cases showed higher expression of bcl-2 (P = 0.006) and PR (P = 0.039) compared with controls. Proliferation was low in both cases and controls as reflected by low Ki67 expression. Over-expression of p53, cyclin D1 and HER-2/neu was not detected.CONCLUSIONS: Premalignant changes are not a common feature of ovaries removed prophylactically from women predisposed to the development of female adnexal carcinoma. Increased expression of p21, p27, and ER-alpha is seen in inclusion cyst compared with ovarian surface epithelium of women with and without an inherited risk of adnexal carcinoma. This is most probably caused by the different intraovarian hormonal milieu of inclusion cyst epithelium. However, the increased expression of bcl-2 and PR in the inclusion cyst epithelium of patients with a hereditary predisposition may reflect early disruption of hormonal balance and growth control.

About 5% of all ovarian-cancer cases are caused by a genetic predisposition, in particular as a component of the autosomal dominant hereditary breast-ovarian-cancer syndrome. This syndrome is usually due to germline mutations in the BRCA1- or BRCA2-gene. Ovarian and endometrial cancer also occur in families with hereditary non-polyposis colorectal cancer (HNPCC). This syndrome is caused by germline mutations in DNA mismatch-repair genes. Women at high risk of gynaecological cancer based upon familial clustering of disease or a demonstrated pathogenic germ-line mutation are candidates for surveillance: annual gynaecological examinations, including vaginal echoscopy and serum carcinoma antigen CA125 testing. Prophylactic surgery in the form of adnexectomy leads to a marked, but not complete, reduction of ovarian-cancer risk in high-risk cases. There is insufficient evidence to advise against the use of oral contraceptives or hormonal substitution after adnexectomy for healthy women with a genetic predisposition to breast cancer. Recommendations for surveillance and prevention should only be given after genetic-risk counselling, based on a detailed family study and DNA-based diagnosis

OBJECTIVE: familial ovarian cancer patients have been found to differ from sporadic cases, clinically as well as in the molecular make-up of the tumour. Here, a case control study is performed to analyse potential differences in survival.STUDY DESIGN: 31 families with a strong history of ovarian and/or breast cancer presenting to a family cancer clinic 44 ovarian cancer patients were included. Each patient was matched for age and stage with controls from a cancer registry. Survival rates and the effect of several prognostic factors were analysed.RESULTS: median survival in the study group differed significantly from controls. A survival benefit for familial cases was maintained up to 5 years after diagnosis. Long-term survival was equally poor in both groups.CONCLUSION: the difference in survival between familial ovarian cancer cases and matched controls may reflect differences in biological behaviour. This may have important implications for the management and prevention of familial ovarian cancer.

In a 35-year old man with deep venous thrombosis liver metastases of an adenocarcinoma were observed. The primary tumour was not found. The patient had pigmentations on the lips and hamartomatous polyposis of the intestine. These findings indicate Peutz-Jeghers syndrome. In this syndrome there is an increased risk of, notably, gastrointestinal malignancy at an early age. Recent investigations have shown that Peutz-Jeghers syndrome is associated with a mutation in the STK11 gene on chromosome 19.

OBJECTIVES: Our purpose was to determine the prevalence of BRCA1 and BRCA2 germline mutations among patients from ovarian cancer families and to evaluate age at diagnosis, histologic diagnosis, and International Federation of Gynecology and Obstetrics stage in this group.STUDY DESIGN: We reviewed 50 ovarian cancer patients from 30 ovarian cancer families and compared relevant clinical characteristics with those of a cancer registry reference group. BRCA1 (exons 2 to 24) and BRCA2 (exon 11) germline mutations were detected by a protein truncation test and sequencing of BRCA1 exon 2 (185delAG mutation) in 25 of the 30 families.RESULTS: Ten (40%) of 25 families tested revealed a germline BRCA1 or BRCA2 mutation. Patients with ovarian cancer from the study group were young with an advanced International Federation of Gynecology and Obstetrics stage at diagnosis and had a relatively high frequency of serous adenocarcinoma.CONCLUSION: Direct mutation analysis of BRCA1 and BRCA2 revealed a high frequency of germline mutations in ovarian cancer families. Some clinical characteristics of hereditary ovarian cancer may differ from those of sporadic disease.

We have identified 79 mutations in BRCA1 in a set of 643 Dutch and 23 Belgian hereditary breast and ovarian cancer families collected either for research or for clinical diagnostic purposes. Twenty-eight distinct mutations have been observed, 18 of them not previously reported and 12 of them occurring more than once. Most conspicuously, a 2804delAA mutation has been found 19 times and has never been reported outside the Netherlands. A common haplotype spanning greater than or equal to 375 kb could be identified for each of the nine examined recurrent mutations, indicating the presence of multiple BRCA1 founder mutations in the Dutch population. The 2804delAA mutation has been estimated to have originated similar to 32 generations ago, No specific breast or ovarian cancer phenotype could be assigned to any of the common mutations, and the ovarian cancer incidence among 18 families with the 2804delAA mutation was heterogeneous.

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