Neurofibromatosis Type 1: Pediatric Aspects and Review of Genotype-Phenotype Correlations

Simple Summary In the last few years, an increasing number of genotype-phenotype correlations has been described for neurofibromatosis type 1 (NF1), impacting on the clinical follow-up of patients, especially in pediatric age. The widespread use of molecular diagnosis, made easier by next generation sequencing technology, now allows very early confirmation of clinical diagnosis, even in the case of non-canonical presentation of the disorder with other overlapping conditions. Here, we review the main clinical characteristics and complications related to NF1, particularly those occurring in children. We also describe currently known genotype-phenotype associations that need to be considered because of their effect on genetic counseling and prognosis. Molecular diagnosis is today fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes. Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000-3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype-phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype-phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes.

Automated summary

In recent years, there has been an increase in the description of genotype-phenotype correlations for neurofibromatosis type 1 (NF1), which affects the clinical follow-up of patients, especially children. The use of molecular diagnosis, facilitated by next generation sequencing technology, allows for early confirmation of clinical diagnosis, even in cases with atypical presentation or overlapping conditions. This article reviews the main clinical characteristics and complications of NF1, particularly in children, and discusses the genotype-phenotype associations that impact genetic counseling and prognosis. Molecular diagnosis is crucial for confirming clinical diagnoses, especially with recently revised diagnostic criteria, and for early identification of genotypes associated with specific phenotypes.