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

Abstract

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-yearold 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. K E Y W O R D Sgenotype-phenotype correlation, NF1, NGS, plexiform neurofibromas, RASopathies, SOS1

Clinical and Genetic Findings in Children with Neurofibromatosis Type 1, Legius Syndrome, and Other Related Neurocutaneous Disorders

“…Further investigation of this mild phenotype in other patients with the same NF1 variant may help characterize a possible genotype-phenotype association. This case is illustrative of the diagnostic overlap between these two conditions, as well as in the recently reported case [64] of a child (Family ID 187) carrying an SOS1 variant inherited from his mother, who initially received a diagnosis of NF1 due to the spinal nerve enlargement resembling neurofibromas.…”

Understanding the Biological Activities of Vitamin D in Type 1 Neurofibromatosis: New Insights into Disease Pathogenesis and Therapeutic Design

“…In fact, some NF1 manifestations overlap with other RASopathies including Noonan syndrome, Noonan syndrome with multiple lentigines (i.e., LEOPARD syndrome) and Legius syndrome (LS) [ 241 , 372 , 373 ].…”

Neurodevelopmental Aspects of RASopathies

“…Gain-of-function mutation of SOS1 is usually found in patients with Noonan syndrome, and most of them are located in PH domain, which can inhibit the formation of auto-inhibitory conformation and results in the activation of RAS/MAPK pathway ( Sondermann et al, 2004 ; Tartaglia et al, 2007 ). SOS1 mutation-positive patients with Noonan syndrome have been reported to show neurological abnormalities such as mild cognitive impairment and spinal nerve enlargement ( Perrino et al, 2018 ; Santoro et al, 2018 ). However, the role of SOS1 in the neurodevelopment process has been poorly understood.…”