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

Teresa Giugliano,Vincenzo Piccolo,Claudia Santoro,Giuseppe Limongelli,Silverio Perrotta,Vincenzo Nigro,Daniela Melis,Mariarosa Anna Beatrice Melone,Salvatore Buono,Giulio Piluso,Anna Grandone,Maria Elena Onore,Annalaura Torella,Giulia Straccia,Francesca Del Vecchio Blanco

doi:10.3390/genes10080580

Abstract

Pigmentary manifestations can represent an early clinical sign in children affected by Neurofibromatosis type 1 (NF1), Legius syndrome, and other neurocutaneous disorders. The differential molecular diagnosis of these pathologies is a challenge that can now be met by combining next generation sequencing of target genes with concurrent second-level tests, such as multiplex ligation-dependent probe amplification and RNA analysis. We clinically and genetically investigated 281 patients, almost all pediatric cases, presenting with either NF1 (n = 150), only pigmentary features (café au lait macules with or without freckling; (n = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders (n = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The NF1 and SPRED1 genes were mutated in 73.3% and 2.8% of cases, respectively. The remaining 8.9% carried mutations in different genes associated with other disorders. We achieved a molecular diagnosis in 69.5% of cases with only pigmentary manifestations, allowing a more appropriate clinical management of these patients. Our findings, together with the increasing availability and sharing of clinical and genetic data, will help to identify further novel genotype–phenotype associations that may have a positive impact on patient follow-up.

Highlights

Molecular diagnostic testing for Neurofibromatosis type 1 (NF1; MIM 162200) has improved considerably since identification of the first genotype–phenotype associations and an overlap disease, Genes 2019, 10, 580; doi:10.3390/genes10080580 www.mdpi.com/journal/genesLegius syndrome (LS; MIM 611431) [1]
Approximately 600 patients suspected of being affected by NF1 or an NF1-like condition, or by RASopathies and other neurocutaneous disorders, were clinically evaluated at our Neurofibromatosis Referral Center in accordance with the NIH diagnostic criteria
To optimize the use of genetic testing in discriminating NF1 versus LS and other neurocutaneous disorders in childhood, patients were classified into six groups and prioritized according to their clinical features

Summary

Introduction

Legius syndrome (LS; MIM 611431) [1] Both disorders belong to the RASopathies [2,3,4], a group of autosomal dominant and phenotypically overlapping disorders caused by mutations in genes encoding for components of the Ras/ mitogen activated protein kinase (MAPK) signaling pathway. Less common but potentially serious clinical manifestations are reported [5,6,7]. With a birth incidence of approximately 1:3000, Neurofibromatosis type 1 is caused by dominantly inherited mutations in NF1 (MIM 613113) [8], a complex gene [9] encoding for neurofibromin, a GTPase-activating protein that negatively regulates the Ras/MAPK signaling pathway [10]. Diagnosis of NF1 is still performed worldwide using clinical criteria formally codified in 1987 [6,11,12]

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