Genotype-Phenotype Analysis and New Clinical Findings in a Series of 24 Patients Presenting with Noonan Syndrome and...

RASopathies are a heterogeneous group of conditions of the RAS/mitogen-activated protein kinase pathway presenting with overlapping features such as growth deficiency, neurodevelopmental disorders, cardiac defects, craniofacial dysmorphisms, cutaneous and ocular abnormalities, and increased cancer risk.

This retrospective study analyzed the medical records regarding clinical and molecular data from 2018 to 2024 in a single center for rare diseases of individuals diagnosed with Noonan syndrome and related disorders previously submitted to diagnostic molecular analysis through next-generation sequencing techniques.

Twenty-four patients were enrolled with an even sex ratio distribution and ages ranging from 1 month to 16 years at first evaluation. The main reason for referral was diagnostic assessment due to a combination of dysmorphic features (24/24; 100%), growth deficiency (18/24; 75%), neurodevelopmental disorders (15/24; 62.5%), and/or heart disease (13/24; 54.1%). Final diagnoses included 15 individuals with Noonan syndrome (nine with variants in PTPN11, two in SOS1, and one each in LZTR1, A2ML1, and MRAS, besides one with variants in both LZTR1 and SOS1), two with Noonan syndrome with multiple lentigines (both with variants in PTPN11), two with Neurofibromatosis-Noonan (NF1), two with cardiofaciocutaneous syndrome (BRAF), and one each with Noonan syndrome-like with loose anagen hair (PPP1CB), Noonan syndrome-like (CBL), and Costello syndrome (HRAS); one individual presented with a double diagnosis of Noonan and Klinefelter syndromes.

Three pairs of unrelated patients presented recurrent variants in the PTPN11 gene, partially concordant in phenotypic correlation among the pairs but not fully concordant compared to previously described cases in the literature. Undescribed features in this group included myopathy and megacolon in a patient with Noonan syndrome-like, hypogonadotropic hypogonadism, and azoospermia in a patient with Noonan syndrome-like with loose anagen hair, and schizophrenia in a patient with Costello syndrome. One patient with Noonan syndrome had a novel variant of the A2ML1 gene (c.1829G>A), but the variant was strictly of uncertain significance, while c.2033G>A in the LZTR1 gene and c.1A>G in the NF1 gene are variants for the first time associated with features of Noonan syndrome.