Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer.

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1-2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1-5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles.

Dystrophinopathy in girls with limb girdle muscular dystrophy phenotype.

OBJECTIVES: Limb girdle muscular dystrophy (LGMD) is a diverse group of myopathic disorders characterized by proximal muscle weakness and hyperCKemia. Mutations encoding sarcoglycans and numerous other proteins have been shown to be responsible for most cases. We report a series of girls with a negative family history for boys with Duchenne muscular dystrophy, demonstrating an LGMD phenotype associated with dystrophinopathy. METHODS: A retrospective chart review of all girls presenting with the LGMD phenotype to our clinic between January 2001 and September 2007 was conducted. Patients 18 years old or younger with dystrophinopathy proven by muscle biopsy and/or gene mutations and a negative family history for affected boys were included in the review. RESULTS: Five patients, 4 to 10 years of age at presentation, were included in the series. Four had an LGMD phenotype at presentation. All five patients had hyperCKemia, all five patients had gene mutations, and four patients had muscle biopsy consistent with dystrophinopathy. CONCLUSION: Dystrophinopathy is an important cause of LGMD phenotype in girls and should be considered in the differential diagnosis.