Clinical and Mutational Spectrum of Neurofibromatosis Type 1–like Syndrome
- Ludwine Messiaen, PhD;
- Suxia Yao, MD;
- Hilde Brems, MS;
- Tom Callens, BSc;
- Achara Sathienkijkanchai, MD;
- Ellen Denayer, MD;
- Emily Spencer, BSc;
- Pamela Arn, MD;
- Dusica Babovic-Vuksanovic, MD;
- Carolyn Bay, MD;
- Gary Bobele, MD;
- Bruce H. Cohen, MD;
- Luis Escobar, MD;
- Deborah Eunpu, MS;
- Theresa Grebe, MD;
- Robert Greenstein, MD;
- Rachel Hachen, MD;
- Mira Irons, MD;
- David Kronn, MD;
- Edmond Lemire, MD, PhD;
- Kathleen Leppig, MD;
- Cynthia Lim, MS;
- Marie McDonald, MD;
- Vinodh Narayanan, MD;
- Amy Pearn, MS;
- Robert Pedersen, MD;
- Berkley Powell, MD;
- Lawrence R. Shapiro, MD;
- David Skidmore, MD;
- David Tegay, DO;
- Heidi Thiese, MS;
- Elaine H. Zackai, MD;
- Raymon Vijzelaar, MSc;
- Koji Taniguchi, MD, PhD;
- Toranoshin Ayada, MD, PhD;
- Fuyuki Okamoto, BSc;
- Akihiko Yoshimura, PhD;
- Annabel Parret, PhD;
- Bruce Korf, MD, PhD;
- Eric Legius, MD, PhD
- Author Affiliations: Department of Genetics, University of Alabama at Birmingham (Drs Messiaen, Yao, Sathienkijkanchai, and Korf, Mr Callens, and Ms Spencer); Department of Human Genetics, Catholic University Leuven, Leuven, Belgium (Ms Brems and Drs Denayer and Legius); Nemours Children's Clinic, Jacksonville, Florida (Dr Arn and Ms Eunpu); Medical Genetics, Mayo Clinic College of Medicine, Rochester, Minnesota (Dr Babovic-Vuksanovic); Division of Clinical/Biochemical Genetics and Dysmorphology, Department of Pediatrics, University of Kentucky, Lexington (Dr Bay); Driscoll Children's Hospital, Corpus Christi, Texas (Dr Bobele); Neurological Institute, Cleveland Clinic, Cleveland, Ohio (Dr Cohen); Medical Genetics and Neurodevelopment Center, St Vincent Children's Hospital, Indianapolis, Indiana (Dr Escobar); Phoenix Genetics Program and Child Neurology, St Joseph's Hospital and Medical Center, Phoenix, Arizona (Drs Grebe and Narayanan and Ms Lim); Department of Genetics and Developmental Biology, Division of Human Genetics, University of Connecticut Health Center, West Hartford (Dr Greenstein); Division of Human Genetics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia (Drs Hachen and Zackai); Division of Genetics, Children's Hospital Boston, Boston, Massachusetts (Dr Irons); Division of Medical Genetics and Inherited Metabolic Disease, Department of Pediatrics, New York Medical College and Maria Fareri Children's Hospital of Westchester Medical Center, Valhalla, New York (Drs Kronn and Shapiro); Department of Pediatrics, University of Saskatchewan, Saskatoon, Saskatchewan, Canada (Dr Lemire and Ms Pearn); Genetic Services, Group Health Cooperative, and Department of Pathology, University of Washington, Seattle (Dr Leppig and Ms Thiese); Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina (Dr McDonald); Tripler AMC, Honolulu, Hawaii (Dr Pedersen); Children's Hospital Central California, Madera (Dr Powell); Maritime Medical Genetics Service, Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada (Dr Skidmore); New York College of Osteopathic Medicine, Old Westbury, New York (Dr Tegay); MRC-Holland, Amsterdam, the Netherlands (Mr Vijzelaar); Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan (Drs Taniguchi, Ayada, and Yoshimura and Mr Okamoto); Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo, Japan (Drs Taniguchi and Yoshimura); Japan Science and Technology Agency, CREST, Chiyoda-ku, Tokyo, Japan (Drs Taniguchi and Yoshimura); Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany (Dr Parret).
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, 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.
