BRCA1 and BRCA2 carriers are at increased risk for both breast and ovarian cancer, but estimates of lifetime risk vary widely, suggesting their penetrance is modified by other genetic and͞or environmental factors. The BRCA1 and BRCA2 proteins function in DNA repair in conjunction with RAD51. A preliminary report suggested that a single nucleotide polymorphism in the 5 untranslated region of RAD51 (135C͞G) increases breast cancer risk in BRCA1 and BRCA2 carriers. To investigate this effect we studied 257 female Ashkenazi Jewish carriers of one of the common BRCA1 (185delAG, 5382insC) or BRCA2 (6174delT) mutations. Of this group, 164 were affected with breast and͞or ovarian cancer and 93 were unaffected. RAD51 genotyping was performed on all subjects. Among BRCA1 carriers, RAD51-135C frequency was similar in healthy and affected women [6.1% (3 of 49) and 9.9% (12 of 121), respectively], and RAD-135C did not influence age of cancer diagnosis [Hazard ratio (HR) ‫؍‬ 1.18 for disease in RAD51-135C heterozygotes, not significant]. However, in BRCA2 carriers, RAD51-135C heterozygote frequency in affected women was 17.4% (8 of 46) compared with 4.9% (2 of 41) in unaffected women (P ‫؍‬ 0.07). Survival analysis in BRCA2 carriers showed RAD51-135C increased risk of breast and͞or ovarian cancer with an HR of 4.0 [95% confidence interval 1.6 -9.8, P ‫؍‬ 0.003]. This effect was largely due to increased breast cancer risk with an HR of 3.46 (95% confidence interval 1.3-9.2, P ‫؍‬ 0.01) for breast cancer in BRCA2 carriers who were RAD51-135C heterozygotes. RAD51 status did not affect ovarian cancer risk. These results show RAD51-135C is a clinically significant modifier of BRCA2 penetrance, specifically in raising breast cancer risk at younger ages. G erm-line mutations in the BRCA1 and BRCA2 genes increase susceptibility for both breast and ovarian cancer. Penetrance of these mutations is incomplete and age-dependent, thus cancer risk in carriers continues to increase with age even though the mean age of cancer diagnosis is younger in BRCA1͞ BRCA2 carriers compared with noncarriers (1). Estimates of penetrance have varied widely, perhaps as a result of different ascertainment schemes and͞or allelic effects. In families ascertained for multiple affected individuals suitable for linkage analysis, lifetime cancer risk (by age 70) was 85% for breast cancer in both BRCA1 and BRCA2 carriers (2, 3), 63% for ovarian cancer in BRCA1 carriers (2), and 27% for ovarian cancer in BRCA2 carriers (3). Significantly lower risk estimates were obtained in studies performed in less selected families or at the population level, with a 36-56% lifetime risk for breast cancer (4-7) and a 16% lifetime risk for ovarian cancer (5). These studies were performed in specific ethnic groups (Ashkenazi Jewish and the Iceland population) that harbor a limited number of specific mutations and could therefore be representative of these alleles, rather than reflect the general penetrance of BRCA1͞BRCA2 mutations. Such differences suggest that penetrance of BRCA1...

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Objective Familial Mediterranean fever (FMF) is characterized by recurrent episodes of peritonitis, pleuritis, and synovitis. Its most common musculoskeletal manifestation is acute recurrent monarthritis, but other manifestations have also been described. We describe the articular and musculoskeletal manifestations in a group of patients who were found by genetic screening to be homozygous for the FMF gene. Methods We surveyed 136 pediatric patients of Mediterranean extraction who were evaluated for a variety of musculoskeletal symptoms, and in whom genetic studies confirmed a diagnosis of FMF. Two groups of patients emerged: group 1 contained 107 patients who displayed a classic picture of FMF, and group 2 comprised 29 patients whose symptoms did not fulfill the criteria for a clinical diagnosis of FMF. Fifty‐nine patients were Sephardic Jews and 77 were Arabs. The Jewish patients were all homozygous or compound heterozygous for the M694V mutation, while the Arab patients were homozygous or compound heterozygous for any 1 of the 5 mutations tested (M694V, V726A, M680I, M694I, and E148Q). Results Acute episodes of monarthritis occurred in 42 (71%) of the Jewish children and 31 (40%) of the Arab children; 70% of these patients had the M694V mutation. Acute monarthritis occurred in 73 (68%) of the patients of group 1, but in none of the patients from group 2. Ten (34%) of the 29 patients from group 2 exhibited diverse musculoskeletal manifestations. Thirteen patients in our series (10%) presented with a variety of musculoskeletal symptoms, including febrile myalgia syndrome in 6 patients. Conclusion Acute episodes of monarthritis are the most common musculoskeletal manifestation of FMF in children bearing the M964V mutation, which predominates among Sephardic Jews, although children with the M694V mutation may also present with diverse nonspecific musculoskeletal manifestations. Genetic screening for FMF appears indicated in the evaluation of unexplained musculoskeletal symptoms in children of Mediterranean extraction.

The high incidence of 11-OHD in MJ, therefore, is only partially explained by the presence of R448H as a founder mutation.