ESPE Abstracts

Background: Noonan Syndrome (NS; OMIM 163950) is a common autosomal dominant disorder distinguished by facial dysmorphism, short stature, heart defects, chest deformities, and learning disabilities or mental retardation. NS stems from heterozygous germline causative variants in genes regulating the RAS/MAPK signaling pathway, including PTPN11, SOS1, RAF1, RIT1, KRAS, NRAS, BRAF, LZTR1, and SOS2. The condition exhibits considerable clinical variability and shares phenotypic overlap with related syndromes such as cardiofaciocutaneous syndrome (CFC), Costello syndrome (CSTLO), NS with multiple lentigines (NSML), NS-like disorder with loose anagen hair (NS-LAH), Legius syndrome (LGSS), and Neurofibromatosis 1 (NF1), all collectively termed RASopathies. The RAS/MAPK pathway governs critical cellular processes in response to external stimuli, and mutations in this pathway are implicated in oncogenesis. Epidemiological studies suggest an elevated cancer risk in individuals with NS, particularly for hematologic malignancies, neuroblastoma, and primary brain tumors.

Case report: We present a case of NS in a male patient with a pathogenic variant in the PTPN11 gene, diagnosed at age six based on characteristic facial features and short stature. Cardiac malformations were absent, and genetic testing confirmed the PTPN11 (NM_002834.5):c.1507G>A: p.Gly503Arg variant. Recombinant human growth hormone (rhGH) therapy was initiated at age 9.7 years due to short stature related to NS, following confirmation of growth hormone deficiency and unremarkable pituitary MRI. At age 11, the patient presented with seizures, and a subsequent brain MRI revealed a multifocal dysembryoplastic neuroepithelial tumor (DNET). Anticonvulsant medication was commenced, and the patient demonstrated partial seizure control. At age 14, the patient developed painless cervical lymphadenopathy, which a biopsy confirmed as Classical Hodgkin's Lymphoma. Chemotherapy with the ABVD protocol was initiated with a favorable response, and no radiation therapy was required. Subsequent imaging showed persistent DNET, prompting plans for resection.

Conclusion: Our case highlights the association between NS and cancer, particularly hematologic malignancies and central nervous system tumors like DNET. While specific gene variants in NS are associated with increased cancer risk, the exact prevalence and mechanisms remain unclear. The safety of rhGH therapy in NS patients regarding tumor development is debated, necessitating cautious monitoring and consideration of individual risk factors. Guidelines recommend regular surveillance for cancer, especially in patients with specific gene variants associated with increased risk. Long-term safety data on rhGH therapy in NS patients must be improved, warranting further investigation.