Title: Clinical and Mutational Spectrum of Neurofibromatosis Type 1-like Syndrome
Authors: Messiaen, Ludwine
Yao, Suxia
Brems, Hilde
Callens, Tom
Sathienkijkanchai, Achara
Denayer, Ellen
Spencer, Emily
Arn, Pamela
Babovic-Vuksanovic, Dusica
Bay, Carolyn
Bobele, Gary
Cohen, Bruce H
Escobar, Luis
Eunpu, Deborah
Grebe, Theresa
Greenstein, Robert
Hachen, Rachel
Irons, Mira
Kronn, David
Lemire, Edmond
Leppig, Kathleen
Lim, Cynthia
McDonald, Marie
Narayanan, Vinodh
Pearn, Amy
Pedersen, Robert
Powell, Berkley
Shapiro, Lawrence R
Skidmore, David
Tegay, David
Thiese, Heidi
Zackai, Elaine H
Vijzelaar, Raymon
Taniguchi, Koji
Ayada, Toranoshin
Okamoto, Fuyuki
Yoshimura, Akihiko
Parret, Annabel
Korf, Bruce
Legius, Eric # ×
Issue Date: Nov-2009
Series Title: Journal of the American Medical Association vol:302 issue:19 pages:2111-2118
Abstract: 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.
ISSN: 0098-7484
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Neurofibromatosis Research
× corresponding author
# (joint) last author

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