The musculoskeletal manifestations of familial Mediterranean fever in children genetically diagnosed with the disease.

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.

A single nucleotide polymorphism in the RAD51 gene modifies cancer risk in BRCA2 but not BRCA1 carriers.

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 and/or 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 (135C/G) 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 and/or 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 and/or 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.

Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women.

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, hyperhomocysteinaemia and increased risk for atherosclerosis in homozygotes. We examined the frequency of this mutation and its association with disease pattern in 491 Jewish women with either sporadic (n = 355; 72%) or hereditary (n = 136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2 mutation carriers, genotyped for the three predominant Jewish founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes were equally distributed among women with sporadic breast and/or ovarian cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205; 21.0%) (P=non-significant). 677T homozygotes were equally distributed among women diagnosed with breast cancer prior to (22/122; 18.0%) and after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes in manifesting cancer (32/136; 23.5%) and asymptomatic individuals (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among women with bilateral breast cancer and those with both breast and ovarian carcinoma than among those with unilateral breast cancer (64/365; 17.5%). Differences in morbidity (one versus multiple breast/ovarian tumours) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations. Confirmation of these data, namely, that the 677T allele is significantly more common in cases of bilateral breast cancer or combined breast and ovarian cancer would have important clinical implications.

Prenatal diagnosis of X-linked hyper-IGM syndrome by direct detection of mutation Q220X in the CD40L gene using PCR-mediated site directed mutagenesis.

We present the first report of prenatal diagnosis of X-linked hyper-IgM syndrome by PCR-mediated site directed mutagenesis (PSM) in a woman known to carry the Q220X mutation in the CD40L gene. Using the simple PSM assay, the Q220X mutation was identified by chorionic villous sampling (CVS) at 11 weeks' gestation and the pregnancy was terminated.

Association of the I1307K APC mutation with hereditary and sporadic breast/ovarian cancer: more questions than answers.

The frequency of the APC I1307K mutation and its association with disease pattern was examined in 996 Ashkenazi women consisting of individuals with either sporadic (n = 382) or hereditary (n = 143) breast and/or ovarian cancer; asymptomatic BRCA1/2 mutation carriers (185delAG, 5382insC and 6174delT) (n= 53) and healthy controls (n= 418). The I1307K allele was equally distributed among women with sporadic (17/382; 4.6%) and inherited (10/143; 7%) breast and/or ovarian cancer irrespective of their being diagnosed before or after 42 years of age and among asymptomatic (7/53; 13.2%) and cancer manifesting BRCA1/2 carriers (10/143; 7%). Taken together, the prevalence of the I1307K allele was significantly higher in BRCA1/2 carriers compared to non-BRCA1/2 carriers (17/196; 8.7% and 40/800, 5%; respectively). The high prevalence of the I1307K allele among BRCA1/2 carriers is not associated with increased cancer risk but seems to be genetically connected because of Jewish ancestry.

Familial Mediterranean fever: high gene frequency and heterogeneous disease among an Israeli-Arab population.

OBJECTIVE: Familial Mediterranean fever (FMF) is an autosomal recessive disease that primarily affects non-Ashkenazi Jews, Armenians, Arabs, and Turks. The FMF (MEFV) gene responsible for the disease has been recently identified. Four missense mutations in exon 10 of the FMF gene seem to account for 86% of the DNA variations identified in patients with FMF. We conducted a phenotype/genotype correlation study in a homogenous population of Israeli-Moslem Arab patients with FMF and performed a mutational screening analysis on DNA samples from healthy individuals of this ethnic group. METHODS: Sixty-five patients clinically diagnosed as having FMF underwent molecular genetic studies using polymerase chain reaction and restriction endonuclease digestion methods to detect the presence of the 4 mutations (M694V, V726A, M680I, M694I). We then correlated the presence of each mutation with age of onset, clinical manifestations, and disease severity; patients whose allelic combination included M694V were then excluded from further statistical analysis, since the association of severe disease with the M694V allele has already been shown. In addition, we screened for FMF mutations the DNA samples from 318 healthy Moslem Arab individuals for the presence of these mutations. RESULTS: Among the 65 patients who were clinically diagnosed as having FMF, 78.5% had one or 2 mutation-bearing chromosomes. The most prevalent mutation was V726A, followed by M680I, M694V, and M6941. No significant difference in phenotypic characteristics was found between the patients with the diverse mutations. The total carrier frequency for the 4 mutations was 10.4% (95% confidence interval 0.07 to 0.137). CONCLUSION: A high FMF gene frequency was found among an Israeli-Moslem Arab population. Among the FMF patients from this ethnic group, several mutations were detected, none of which was found to correlate with a severe course of the disease.