Noonan Syndrome Spectrum Disorders Predispose to Systemic Lupus Erythematosus: Case Report and Critical Review of the Literature

RASopathies are clinically overlapping neurodevelopmental syndromes resulting from germline mutations in genes involved in the rat sarcoma/mitogen-activated protein kinases (RAS/MAPK) pathway. Historically, RASopathies have been described by clinical phenotypes, such as Noonan syndrome and Neurofibromatosis type I. There is emerging evidence of the association between Noonan syndrome spectrum disorders (NSSD) and systemic lupus erythematosus (SLE). Here, we present an SLE patient diagnosed with SOS1-associated Noonan Syndrome (c.806 T>C; p.Met269Thr) as part of a research study. Reviewing the literature, we identified further 16 cases of NSSD associated with SLE. Nine out of 16 cases (56%) had a confirmed molecular diagnosis, with pathogenic missense variants identified in KRAS, PTPN11, and SHOC2 genes, the majority in the last. Variants in SHOC2 are the cause of only a small proportion of all presentations of NSSD. Our case represents the first reported case of SLE in a patient with a SOS1 pathogenic variant. Compared to the general SLE population, SLE in the presence of NSSD develops at a younger age, with a similar prevalence among females and males, suggesting a contribution of the RAS/MAPK pathway in the development of SLE.