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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. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that the kinetics of activation and deactivation of rod phototransduction are altered in children with Smith-Lemli-Optiz syndrome (SLOS), a common genetic disorder caused by an inborn error in cholesterol biosynthesis., Methods: Thirteen patients with SLOS (median age, 4 years) were studied by means of scotopic full-field electroretinography. The kinetics of activation and deactivation of rod phototransduction were derived from the electroretinographic a-wave. Postreceptoral electroretinographic components were also evaluated., Results: The kinetics of activation were below normal limits in all but 3 of the 13 patients. Rod cell recovery (deactivation) in SLOS was slower than normal in all 8 patients in whom it was studied. Postreceptoral sensitivity was below normal limits in all but 1 of the 13 patients., Conclusions: The kinetics of phototransduction are slow in children with SLOS. This is likely a consequence of altered sterol composition in the cell membranes of the rod photoreceptors. To our knowledge, this is the first demonstration of altered kinetics of a membrane-bound signaling system in SLOS. Investigation of other membrane-bound signaling systems may be warranted in the quest to understand development and phenotype of individuals with SLOS.