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Clin Genet. 2018 Jan;93(1):138-143. doi: 10.1111/cge.13047. Epub 2017 Sep 15.

Multiple spinal nerve enlargement and SOS1 mutation: Further evidence of overlap between neurofibromatosis type 1 and Noonan phenotype.

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Dipartimento della Donna, del Bambino e della Chirurgia generale e specialistica, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Dipartimento di Biochimica, Biofisica e Patologia Generale, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Divisione di Neurologia, Dipartimento Medico-Chirurgico di Internistica Clinica e Sperimentale "F. Magrassi e A. Lanzara", Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Centro Interuniversitario di Ricerca in Neuroscienze (CIRN), Naples, Italy.
Prima Divisione di Neurologia, Dipartimento di Scienze Mediche, Chirurgiche, Neurologiche, Metaboliche e dell'Invecchiamento, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.
Dipartimento di Salute Mentale, Fisica e Medicina Preventiva, Clinica di Neuropsichiatria Infantile, Università degli Studi della Campania "Luigi Vanvitelli", Naples, Italy.


Neurofibromatosis type 1 (NF1) has long been considered a well-defined, recognizable monogenic disorder, with neurofibromas constituting a pathognomonic sign. This dogma has been challenged by recent descriptions of patients with enlarged nerves or paraspinal tumors, suggesting that neurogenic tumors and hypertrophic neuropathy may be a complication of Noonan syndrome with multiple lentigines (NSML) or RASopathy phenotype. We describe a 15-year-old boy, whose mother previously received clinical diagnosis of NF1 due to presence of bilateral cervical and lumbar spinal lesions resembling plexiform neurofibromas and features suggestive of NS. NF1 molecular analysis was negative in the mother. The boy presented with Noonan features, multiple lentigines and pectus excavatum. Next-generation sequencing analysis of all RASopathy genes identified p.Ser548Arg missense mutation in SOS1 in the boy, confirmed in his mother. Brain and spinal magnetic resonance imaging scans were negative in the boy. No heart involvement or deafness was observed in proband or mother. This is the first report of a SOS1 mutation associated with hypertrophic neuropathy resembling plexiform neurofibromas, a rare complication in Noonan phenotypes with mutations in RASopathy genes. Our results highlight the overlap between RASopathies, suggesting that NF1 diagnostic criteria need rethinking. Genetic analysis of RASopathy genes should be considered when diagnosis is uncertain.


NF1; NGS; RASopathies; SOS1; genotype-phenotype correlation; plexiform neurofibromas

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