Noonan Syndrome: current understanding, diagnostic challenges, and advances in treatment

Abstract

Noonan Syndrome is a common genetic disorder characterized by facial dysmorphisms, short stature, and congenital heart defects. Its incidence is estimated between 1:1,000 and 1:2,500 live births, making it one of the most frequent genetic causes of congenital heart disease. Inheritance is predominantly autosomal dominant, although de novo mutations account for a large proportion of cases. Clinical manifestations include hypertelorism, palpebral ptosis, webbed neck, shield chest, and cryptorchidism in boys. Cardiac defects, such as pulmonary valve stenosis and hypertrophic cardiomyopathy, are highly prevalent. Mutations in genes of the RAS-MAPK pathway, particularly PTPN11, are associated with the observed phenotypic changes. Diagnosis is clinical, based on the assessment of phenotypic patterns and family history, with genetic testing available for confirmation. Management requires a multidisciplinary approach, including cardiological, endocrinological, and genetic follow-up, aiming to address complications and improve patients' quality of life. Growth hormone therapy may be considered for optimizing final height, while surgical interventions might be necessary for correcting heart defects and other associated anomalies. Recent research has explored new therapeutic approaches, including inhibitors of the RAS-MAPK pathway, which may represent a promising alternative for syndrome management.