Noonan Syndrome (NS) is a genetically heterogeneous developmental disorder characterized by cardiac defects, distinctive facial features, and short stature, along with additional features such as delayed puberty, bleeding disorders, cryptorchidism, behavioral or neurocognitive problems, chest malformations, and endocrine abnormalities. It is mainly an autosomal dominant condition, often due to de novo variants, and results from dysregulation of the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway. PTPN11 mutations account for about half of the cases, while variants in BRAF, KRAS, SOS1, RAF1, and NRAS contribute to others, collectively known as RASopathies. Â NS requires lifelong multidisciplinary care to manage the abnormalities related to development, endocrine, and cardiac.
However, several clinical guidelines for NS exist; an updated, integrated multidisciplinary framework covering care from fetal life to adulthood remains lacking. A recent study published in JAMA Network Open proposes a coordinated and lifelong care model designed for enhancing outcomes through collaboration of multidisciplinary experts. This study mainly provides the guidelines by Italian NS experts on key aspects of care, including transition management, growth hormone therapy, follow-up, and diagnosis.
In this study, guidelines were developed using a modified Delphi model under an accurate consensus reporting document (ACCORD) framework. A single-round evaluation incorporating structured discussions was conducted, and consensus was achieved in the first round, defined as ≥70% agreement. The steering committee and expert panel members were selected from the Italian multidisciplinary NS working group. A total of 25 clinicians participated: pediatric endocrinologists (n=6), geneticists (n=1), pediatricians (n=15), and cardiologists (n=3). Consensus was reached in the first voting round, and final recommendations were established in May 2024.
All 25 expert panel members completed the Delphi survey and produced 47 statements, which were rated using a 9-point Likert scale. Approximately 87% of statements received written comments, and more than half achieved agreement of>95%. Complete consensus (100% agreement) was reached on the key points, including the importance of molecular characterization for diagnosis, safety monitoring during recombinant human growth hormone (rhGH) therapy, heightened risk of hypertrophic cardiomyopathy, and the necessity of multidisciplinary care. This panel also agreed on the need for evaluation of adherence and assessment of genetically based risk.
Consensus statements were grouped into four domains: diagnosis (statements 1-10), transition (11-18), follow-up (19-31), and rhGH therapy (32-47). Accurate and early molecular diagnosis was emphasized for tailored care, timely referral, and genetic counseling. Lifelong and multidisciplinary management of NS was recommended for endocrine, cardiac, and behavioral complications. Regular follow-up assessments were considered essential for monitoring neurocognitive, oncologic, and cardiac risks. RhGH therapy was only approved for short stature in NS, should be individualized and preceded by cardiac evaluation, as well as monitored through growth and low insulin-like growth factor 1 (IGF-1) data for ensuring safety and efficacy. Additionally, magnetic resonance imaging was advised prior to initiating therapy.Â
The study’s limitations include that, although multidisciplinary, the predominantly Italian panel may limit global generalizability, and structured feedback might risk creating artificial consensus.
Overall, all these consensus statements highlight the value of early molecular testing, coordinated multidisciplinary care, and cautious use of rhGH treatment in NS patients for optimizing outcomes across the lifespan.
Reference: Stagi S, Cappa M, Gagliardi MG, Tartaglia M, Maghnie M. Multidisciplinary Treatment of Patients with Noonan Syndrome: A Consensus Statement. JAMA Netw Open. 2025;8(10):e2537603. doi:10.1001/jamanetworkopen.2025.37603
