Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.

CONTEXT: Autosomal dominant inactivating sprouty-related EVH1 domain-containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with café au lait macules (CALMs), axillary freckling, and macrocephaly. The extent of the clinical spectrum of this new disorder needs further delineation. OBJECTIVE: To determine the frequency, mutational spectrum, and phenotype of neurofibromatosis type 1-like syndrome (NFLS) in a large cohort of patients. DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional study, 23 unrelated probands carrying a SPRED1 mutation identified through clinical testing participated with their families in a genotype-phenotype study (2007-2008). In a second cross-sectional study, 1318 unrelated anonymous samples collected in 2003-2007 from patients with a broad range of signs typically found in neurofibromatosis type 1 (NF1) but no detectable NF1 germline mutation underwent SPRED1 mutation analysis. MAIN OUTCOME MEASURES: Comparison of aggregated clinical features in patients with or without a SPRED1 or NF1 mutation. Functional assays were used to evaluate the pathogenicity of missense mutations. RESULTS: Among 42 SPRED1-positive individuals from the clinical cohort, 20 (48%; 95% confidence interval [CI], 32%-64%) fulfilled National Institutes of Health (NIH) NF1 diagnostic criteria based on the presence of more than 5 CALMs with or without freckling or an NF1-compatible family history. None of the 42 SPRED1-positive individuals (0%; 95% CI, 0%-7%) had discrete cutaneous or plexiform neurofibromas, typical NF1 osseous lesions, or symptomatic optic pathway gliomas. In the anonymous cohort of 1318 individuals, 34 different SPRED1 mutations in 43 probands were identified: 27 pathogenic mutations in 34 probands and 7 probable nonpathogenic missense mutations in 9 probands. Of 94 probands with familial CALMs with or without freckling and no other NF1 features, 69 (73%; 95% CI, 63%-80%) had an NF1 mutation and 18 (19%; 95% CI, 12%-29%) had a pathogenic SPRED1 mutation. In the anonymous cohort, 1.9% (95% CI, 1.2%-2.9%) of individuals with the clinical diagnosis of NF1 according to the NIH criteria had NFLS. CONCLUSIONS: A high SPRED1 mutation detection rate was found in NF1 mutation-negative families with an autosomal dominant phenotype of CALMs with or without freckling and no other NF1 features. Among individuals in this study, NFLS was not associated with the peripheral and central nervous system tumors seen in NF1.

Comparing knowledge of beta-thalassemia in samples of Italians, Italian-Americans, and non-Italian-Americans.

The purpose of this study was to determine the level of beta-thalassemia awareness among Italians living on the eastern side of Sicily (Bronte, Catania, and Tortorici, Messina), Italian-Americans, and Americans of other ethnic backgrounds (Other-Americans). A questionnaire was developed which asked respondents knowledge questions about both beta-thalassemia and Down Syndrome. Five hundred questionnaires were distributed, and 456 were ultimately returned and analyzed (150 Italians, 156 Italian-Americans, 150 Other-Americans). Italians answered an average of 55% of the beta-thalassemia correctly compared to scores of 17 and 24% for the Italian-Americans and Other-Americans, respectively. The groups did not differ in their knowledge of Down Syndrome (all answered between 58 and 60% of the questions correctly on average). Over 80% of the Italian respondents had heard of beta-thalassemia compared to only 19% of the Italian-Americans. beta-Thalassemia education programs in Italy appear to have dramatically increased awareness of the disorder. Similar programs need to be developed for at-risk populations in the United States.