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


METHODS
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.


METHODS
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.
Messiaen
Ludwine
L
Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, 720 20th St S, Birmingham, AL 35294, USA. lmessiaen@genetics.uab.edu
Yao
Suxia
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Brems
Hilde
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Callens
Tom
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Sathienkijkanchai
Achara
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Denayer
Ellen
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Spencer
Emily
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Arn
Pamela
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Babovic-Vuksanovic
Dusica
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Bay
Carolyn
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Bobele
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Cohen
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Escobar
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Eunpu
Deborah
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Theresa
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Greenstein
Robert
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Hachen
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Kronn
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Lemire
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Leppig
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Lim
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McDonald
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Narayanan
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Pearn
Amy
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Pedersen
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Powell
Berkley
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Lawrence R
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Skidmore
David
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Tegay
David
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Thiese
Heidi
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Zackai
Elaine H
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Vijzelaar
Raymon
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Taniguchi
Koji
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Ayada
Toranoshin
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Okamoto
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D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D019080:Cafe-au-Lait Spots / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D004252:DNA Mutational Analysis; D005260:Female; D016514:Genes, Neurofibromatosis 1; D056726:Genetic Association Studies; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D009456:Neurofibromatosis 1 / Q000175:diagnosis* / Q000235:genetics*; D010641:Phenotype; D013577:Syndrome; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C504812:SPRED1 protein, human