Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome.
Ludwine Messiaen,S. Yao,Hilde Brems,Tom Callens,Achara Sathienkijkanchai,Ellen Denayer,Emily Spencer,Pamela Arn,Dusica Babovic-Vuksanovic,Carolyn Bay,Gary Bobele,Bruce H. Cohen,Luis F. Escobar,Deborah L. Eunpu,Theresa A. Grebe,Robert M. Greenstein,Rachel K. Hachen,Mira Irons,David Kronn,Edmond G. Lemire,Kathleen A. Leppig,Cynthia Lim,Marie T. McDonald,Vinodh Narayanan,Amy Pearn,Robert Pedersen,Berkley R. Powell,Lawrence R. Shapiro,David Skidmore,David Tegay,Heidi Thiese,Elaine H. Zackai,Raymon Vijzelaar,Koji Taniguchi,Koji Taniguchi,Toranoshin Ayada,Fuyuki Okamoto,Akihiko Yoshimura,Akihiko Yoshimura,Annabel H. A. Parret,Bruce R. Korf,Eric Legius +41 more
TLDR
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, and NFLS was not associated with the peripheral and central nervous system tumors seen inNF1.Abstract:
Context Autosomal dominant inactivating sprouty-related EVH1 domain–containing protein 1 (SPRED1) mutations have recently been described in individuals presenting mainly with cafe 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, 22 unrelated probands carrying a SPRED1 loss-of-function (LOF) 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 40 SPRED1 LOF-positive individuals from the clinical cohort, 20 (50%; 95% confidence interval [CI], 34%-66%) 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 40 SPRED1 LOF-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: 26 pathogenic mutations in 33 probands and 8 probable nonpathogenic missense or silent mutations in 10 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.read more
Citations
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Journal ArticleDOI
Neurofibromatosis type 1.
David H. Gutmann,Rosalie E. Ferner,Robert Listernick,Bruce R. Korf,Pamela L. Wolters,Kimberly J. Johnson +5 more
TL;DR: Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.
Journal ArticleDOI
Noonan syndrome and clinically related disorders
TL;DR: An overview of clinical aspects of this disorder and closely related conditions, the molecular mechanisms underlying pathogenesis, and major genotype-phenotype correlations are provided.
Journal ArticleDOI
NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype†
Eric Pasmant,Audrey Sabbagh,Gillian Spurlock,Ingrid Laurendeau,Elisa Grillo,Marie-José Hamel,Ludovic Martin,Sébastien Barbarot,B. Leheup,Diana Rodriguez,Didier Lacombe,Hélène Dollfus,Laurent Pasquier,Bertrand Isidor,Salah Ferkal,Jean Soulier,Marc Sanson,Anne Dieux-Coeslier,Ivan Bièche,Béatrice Parfait,Michel Vidaud,Pierre Wolkenstein,Meena Upadhyaya,Dominique Vidaud +23 more
TL;DR: In this article, a high-resolution array comparative genomic hybridization (CGH) was used to characterize microdeletions in 70 unrelated NF1 microdeleted patients, compared to patients with intragenic truncating NF1 mutations and phenotyped in the same standardized way.
Journal ArticleDOI
The NF1 somatic mutational landscape in sporadic human cancers
TL;DR: The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.
Journal ArticleDOI
Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms
Marco Tartaglia,Bruce D. Gelb +1 more
TL;DR: An overview of the phenotypic spectrum associated with germline mutations perturbing RAS‐MAPK signaling is provided, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype–phenotype correlations are provided.
References
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Neurofibromatosis. Conference statement, National Institute of Health development conference
Journal ArticleDOI
The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2.
David H. Gutmann,Arthur S. Aylsworth,John C. Carey,Bruce R. Korf,Joan Marks,Reed E. Pyeritz,Allan E. Rubenstein,David Viskochil +7 more
TL;DR: The diagnostic criteria for neurofibromatosis 1 and neurof fibromaatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders are determined.
Journal ArticleDOI
The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2
Arthur S. Aylsworth,John C. Carey,Bruce R. Korf,J Marks,Reed E. Pyeritz,Allan E. Rubenstein,Dave Viskochil,David H. Gutmann +7 more
TL;DR: The diagnostic criteria for neurofibromatosis 1 and neurof fibromaatosis 2, recommendations for the care of patients and their families at diagnosis and during routine follow-up, and the role of DNA diagnostic testing in the evaluation of these disorders are determined.
Journal ArticleDOI
Epidemiology of neurofibromatosis type 1
TL;DR: The prevalence of neurofibromatosis type 1 is somewhat higher in young children than in adults, a difference that probably results in part from the early death of some NF1 patients.
Journal ArticleDOI
Spred is a Sprouty-related suppressor of Ras signalling
Toru Wakioka,Atsuo T. Sasaki,Reiko Kato,Reiko Kato,Takanori Shouda,Akira Matsumoto,Kanta Miyoshi,Kanta Miyoshi,Makoto Tsuneoka,Setsuro Komiya,Roland Baron,Akihiko Yoshimura,Akihiko Yoshimura +12 more
TL;DR: Spred may represent a class of proteins that modulate Ras–Raf interaction and MAP kinase signalling, and is described as a structurally similar tyrosine kinase substrates that contain a cysteine-rich domain related to Sprouty at the carboxy terminus.