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

Abstract

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.

The Importance of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants in NF1 Gene and CRX Gene. Case Report and Short Literature Review

“…Peduto et al also demonstrated that large gene deletions correlate with a severe phenotype and that not all mutational variants have the same effects. Genotype-phenotype associations are on an upward curve at present, changing at a slower but profound pace the clinical and genetic approach to NF patients [3,24]. The splice site pathogenic variant identified in our patient has not been described in populational databases, so we cannot make an exact genotype-phenotype correlation.…”

“…The prevalence of pathogenic variants in the NF1 gene is over 0.5% (31 different pathogenic variants), but the percentage of extremely rare or privately encountered variants is over 46% [22,23]. On the other hand, 90% of mutations occur in the intragenic region, with less than 10% being deletions that span the entire gene or are located in lacking genomic regions [24].…”

The Surprises of Molecular Testing in Neurofibromatosis Type 1: Rare Association between Two Mutational Variants

“…The prevalence of pathogenic variants in the NF1 gene is over 0.5% (31 different pathogenic variants), but the percentage of extremely rare or privately encountered variants is over 46% [20,21]. On the other hand, 90% of mutations occur in the intragenic region, with less than 10% being deletions that span the entire gene or are located in lacking genomic regions [22].…”

Drosophila Contributions towards Understanding Neurofibromatosis 1

“…NF1 predominantly presents with benign tumors of the peripheral nervous system, called plexiform neurofibromas, as well as increased susceptibility to development of other brain and nerve tumors, including optic pathway gliomas and malignant peripheral nerve sheath tumors (MPNSTs) [14]. While typically considered an oncogenic predisposition syndrome, it is also associated with a number of non-tumor manifestations, including skeletal and skin pigmentation abnormalities (intense freckling, multiple Café-au-lait spots-CALSs), reduced overall growth, or short stature [14][15][16][17]. Neuronal impairments include executive and higher-order functions such as planning, visuospatial skills, reading/vocabulary, and motor coordination, sleep, learning, and cognitive impairments, including autism-like symptoms and attention deficits [18][19][20][21][22][23].…”