Noonan syndrome (NS) is a genetically heterogeneous disorder characterized by a broad spectrum of clinical features resulting from dysregulation of the RAS/MAPK pathway. Although complex genotypes are increasingly recognized in NS, cases harboring two distinct pathogenic variants in different NS genes remain extremely rare. We describe the case of a 53‐year‐old female presenting a severe NS phenotype—including short stature, facial dysmorphism, congenital heart defect, and developmental delay—and concurrent acute myeloid leukemia (AML). Targeted NGS analysis of a RASopathy‐specific gene panel identified a constitutional heterozygous PTPN11 variant (c.1472C>T, p.(Pro491Leu)) and a mosaic RIT1 variant (c.229G>C, p.(Ala77Pro), 16.45% VAF), both meeting criteria for pathogenicity. The RIT1 variant was validated via PCR‐RFLP across multiple tissues, excluding leukemia‐driven clonal expansion, and further quantified by high‐depth amplicon‐based sequencing. To our knowledge, this case represents a unique example of NS associated with pathogenic variants in two distinct RASopathy genes. Our findings underscore that comprehensive molecular characterization and multi‐tissue validation are essential for accurate diagnosis, genetic counseling, and personalized management, while also revealing that combinatorial RAS/MAPK alterations may influence disease severity and clinical outcomes.

Background: The melanocortin-1 receptor (MC1R) gene is a major determinant of skin and hair color. Although several MC1R variants increase the risk of skin tumors regardless of pigmentation, their role as genetic modifiers in ocular diseases remains poorly understood. Methods: Here, we analyzed a cohort of 48 Caucasian individuals using a custom next-generation sequencing (NGS) panel targeted for oculocutaneous disorders. Results: MC1R variants were identified in two probands selected from this cohort, exhibiting distinctly divergent pathological phenotypes. The first patient, an adult male with a pheomelanin-related trait and a history of early-onset skin cancer without ocular abnormalities, carried compound heterozygous MC1R variants: the novel frameshift c.537dupC (p.Ile180Hisfs*59) and the known c.880G>C (p.Asp294His). Conversely, the second patient, a young boy with severe vision-threatening features—including congenital nystagmus, foveal hypoplasia, and an atypical visual-pathway misrouting pattern—carried a candidate digenic genotype combining the same MC1R c.880G>C variant with the albinism-related c.1209G>T (p.Arg403Ser) variant in the tyrosinase (TYR) gene. Conclusions: While MC1R variants have previously been proposed as phenotypic modifiers in albinism, primarily in combination with the oculocutaneous type II melanosomal transmembrane protein (OCA2) encoding gene, our findings support a potential role for MC1R as a candidate modifier interacting with TYR in neuroretinal development. Although functional validation is required to establish causality, incorporating MC1R screening in patients with unresolved foveal hypoplasia may help clarify complex oligogenic mechanisms and optimize phenotypic classification.