To present a unique case and systematic-review regarding the rare co-occurrence of NF type 1 and 2 and MS. 

Neurofibromatoses are neurocutaneous disorders characterized by mutations in the NF1 and NF2 tumor suppressor genes, predisposing patients to benign and malignant neoplasms. The coexistence of NF and multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system, is exceptionally rare, with approximately 69 reported cases. The interaction between immunosuppressive disease-modifying therapies (DMTs) for MS and NF-related tumor behavior remains poorly understood.

We report the case of a 42-year-old female with NF1 diagnosed at age 14 who developed relapsing-remitting MS (RRMS). After initial steroid therapy, she began cladribine as maintenance treatment. Two months following the first cladribine cycle, she experienced an increase in the number and size of cutaneous neurofibromas, which continued after the second cycle before stabilizing. Serial magnetic resonance imaging (MRI) revealed no central nervous system neurofibromas. This case represents the first documented occurrence of neurofibroma proliferation following cladribine therapy in a patient with NF1 and MS.

Across all published cases, no prior reports described neurofibroma growth or secondary malignancy following MS immunomodulatory therapy. Female predominance and relapsing-remitting MS were common findings.

This case presentation and review highlights a previously unreported association between cladribine therapy and neurofibroma proliferation in NF1. While causality cannot be established, immunosuppression may play a contributory role in tumor growth in genetically susceptible individuals. Further research is warranted to elucidate the biological mechanisms linking NF and MS and to guide therapeutic decisions in this rare comorbidity.