Clinical consensus guidelines for the management of Noonan syndrome in Japan.

Abstract

Noonan syndrome (NS) is a multisystem RASopathy marked by characteristic facies, congenital heart disease, short stature, and variable neurodevelopmental and systemic complications. Although molecular and clinical knowledge has advanced, evidence-based clinical guidance in Japan has been limited. A multidisciplinary committee in pediatric endocrinology, clinical genetics, and pediatric cardiology developed consensus guidelines on diagnosis, comorbidity assessment, treatment, and transitional care. Clinical questions were defined, and the literature published through March 2024 was systematically reviewed. Evidence was graded in partial accordance with the Minds Clinical Practice Guideline Development Manual 2020 and the GRADE framework, with expert consensus supplementing areas of limited evidence. External review included patient groups and academic societies, and the guideline was approved in 2025. The guideline recommends expanding diagnostic panels to include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to established genes. It advises comprehensive childhood assessment for tumor predisposition, coagulation abnormalities, hearing and ophthalmologic problems, neurodevelopmental features, and endocrine and cardiovascular complications, with strong emphasis on cardiac evaluation. Growth hormone therapy is recommended for short stature with careful monitoring for malignancy risk. MEK inhibitors may help selected patients with refractory hypertrophic cardiomyopathy or lymphatic abnormalities. Lifelong multidisciplinary surveillance and structured transition to adult care are strongly emphasized.