Reproductive impairment in males with neurofibromatosis-noonan syndrome: a systematic review

Neurofibromatosis-Noonan syndrome (NFNS) is an ultra-rare phenotype associated predominantly with pathogenic variants in the NF1 gene. Male reproductive complications in affected individuals have long been largely overlooked, and no systematic review has yet focused specifically on male reproductive impairment in this population. This systematic review was performed in accordance with PRISMA 2020 guidelines, and the review protocol was prospectively registered in PROSPERO (CRD420261465574). PubMed and Web of Science were searched from inception to March 2026, and 26 eligible original clinical studies were included after screening 219 records. Twenty-six eligible clinical studies were included. Cryptorchidism was the most consistently reported male reproductive abnormality, although reporting of testicular status was incomplete across studies. In the primary descriptive analysis, 5 of 26 male records with explicitly documented testicular status had cryptorchidism (19.2%). This is a report-level proportion rather than a population prevalence estimate. Evidence regarding delayed puberty, gonadal dysfunction, and impaired fertility was limited and derived from individual NFNS reports and, for several outcomes, from Noonan syndrome or other RASopathy cohorts. These findings indicate that reproductive abnormalities have been reported in NFNS, while their frequency, clinical spectrum, and underlying mechanisms remain incompletely characterized. Male reproductive abnormalities have been reported in NFNS, particularly cryptorchidism, but the available clinical evidence remains limited and heterogeneous. Findings from related RASopathies provide useful biological context for understanding potential gonadal involvement, whereas direct NFNS-specific evidence remains insufficient. Further studies with standardized reproductive and endocrine phenotyping are needed.