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

• Published in: Genes Vol. 10; no. 8; p. 580
• Main Authors: Giugliano, Teresa, Santoro, Claudia, Torella, Annalaura, Del Vecchio Blanco, Francesca, Grandone, Anna, Onore, Maria Elena, Melone, Mariarosa Anna Beatrice, Straccia, Giulia, Melis, Daniela, Piccolo, Vincenzo, Limongelli, Giuseppe, Buono, Salvatore, Perrotta, Silverio, Nigro, Vincenzo, Piluso, Giulio
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 31.07.2019; MDPI
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adolescent; Adult; Age; Cafe-au-Lait Spots - genetics; Cafe-au-Lait Spots - pathology; Child; Child, Preschool; Children; Design; Diagnosis; Female; Genes; Genetic disorders; Genomics; Genotype & phenotype; Genotypes; Humans; Infant; Kinases; Male; Mutation; Neurofibromatosis; Neurofibromatosis 1 - genetics; Neurofibromatosis 1 - pathology; Neurofibromin 1 - genetics; Neurological disorders; Next-generation sequencing; Patients; Pediatrics; Phenotype; Phenotypes; Proteins; Recklinghausen's disease; RNA probes; Tumors; United States > US; Germany; neurofibromatosis type 1; RASopathies; Legius syndrome; next generation sequencing; RNA analysis; multiplex ligation-dependent probe amplification
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes10080580

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 ( = 150), only pigmentary features (café au lait macules with or without freckling; ( = 95), or clinical suspicion of other RASopathies or neurocutaneous disorders ( = 36). The causative variant was identified in 239 out of the 281 patients analyzed (85.1%), while 42 patients remained undiagnosed (14.9%). The and 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.