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Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor-suppressor disorder caused by heterozygous NF1 variants. A rare but clinically significant complication is moyamoya disease (Moyamoya Syndrome), a progressive intracranial arteriopathy leading to ischemic and hemorrhagic strokes.
Several pediatric case reports describe individual NF1 patients presenting with moyamoya syndrome. A 5-year-old girl with café-au-lait spots and neurofibromas developed bilateral intracranial stenoses and collateral vessels characteristic of moyamoya syndrome (n = 1 proband) (PMID:24952383). A second pediatric patient with late-diagnosed NF1 and multiple neurofibromas presented with rapid ischemic stroke and radiologic features of moyamoya arteriopathy (n = 1 proband) (PMID:29364453).
An Italian-French multicenter cohort of 18 NF1 children with moyamoya syndrome further substantiates this association. Moyamoya was incidentally diagnosed in nearly half of these children, who manifested headache (n = 6), cerebral infarction (n = 2) and complex partial seizures (n = 2) (HP:0002315, HP:0001298, HP:0002384) (PMID:28422438). Two first cousins in this cohort shared familial NF1 and moyamoya, supporting segregation (affected relatives = 2) (PMID:28422438).
Molecular analysis identified NF1 variants in 16/18 children, encompassing missense, splice-site and truncating mutations. One recurrent missense variant is c.1845G>C (p.Lys615Asn) (PMID:28422438). No NF1 genotype–phenotype correlation distinguished children with or without moyamoya.
The pathogenesis of NF1-associated moyamoya likely reflects loss of neurofibromin–mediated Ras regulation in vascular smooth muscle cells, leading to proliferative arteriopathy. Modifier gene analysis (e.g., RNF213) did not implicate additional risk alleles in moyamoya occurrence within NF1 cohorts, suggesting neurofibromin haploinsufficiency is sufficient for vascular dysplasia.
Overall, the NF1–moyamoya association meets a Moderate ClinGen gene–disease validity (20 probands; 2 segregations; functional hypothesis) category. Genetic evidence is Moderate (20 probands; one segregation event). Functional evidence is Limited (pathophysiological model without dedicated vascular assays).
Key Take-home: Children with NF1 should undergo angiographic screening when presenting with focal neurologic signs to enable early moyamoya detection and intervention.
Gene–Disease AssociationModerate20 probands including two case reports and an 18-patient cohort; two segregations Genetic EvidenceModerate16 molecularly confirmed NF1 cases in moyamoya cohort; one familial segregation Functional EvidenceLimitedProposed neurofibromin-loss mechanism for vascular smooth muscle proliferation; no dedicated vascular functional studies |