Giulio Piluso

Noonan syndrome is an autosomal dominant developmental disorder characterized by peculiar facial dysmorphisms, short stature, congenital heart defects, and hypertrophic cardiomyopathy. In 2001, PTPN11 was identified as the first Noonan syndrome gene and is responsible for the majority of Noonan syndrome cases. Over the years, several other genes involved in Noonan syndrome (KRAS, SOS1, RAF1, MAP2K1, BRAF, NRAS, RIT1, and LZTR1) have been identified, acting at different levels of the RAS-mitogen-activated protein kinase pathway. Recently, SPRED2 was recognized as a novel Noonan syndrome gene with autosomal recessive inheritance, and only four families have been described to date. Here, we report the first Italian case, a one-year-old child with left ventricular hypertrophy, moderate pulmonary valve stenosis, and atrial septal defect, with a clinical suspicion of RASopathy supported by the presence of typical Noonan-like facial features and short stature. Exome sequencing identified a novel homozygous loss-of-function variant in the exon 3 of SPRED2 (NM_181784.3:c.325del; p.Arg109Glufs*7), likely causing nonsense-mediated decay. Our results and the presented clinical data may help us to further understand and dissect the genetic heterogeneity of Noonan syndrome.

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.