Intrafamilial neurovascular heterogeneity in pediatric NF1-associated moyamoya syndrome: a three-generation pedigree study and pattern-oriented synthesis

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Neurofibromatosis type 1-associated moyamoya syndrome (NF1-MMS) is an important pediatric cerebrovascular phenotype. Early symptoms may be nonspecific, and vascular lesions can be detected before clear focal neurologic deficits. The value and timing of cerebrovascular screening in asymptomatic children with NF1 remain uncertain. We report a 32-month-old girl, the older twin, admitted for progressive brain imaging abnormalities more than 14 months after a single focal-to-bilateral tonic-clonic seizure around 18 months of age. She had no recurrent seizures, hemiparesis, definite transient ischemic attacks, or other focal neurologic deficits during available follow-up. Serial MRI/MRA showed persistent ischemic white-matter changes, left-sided linear sulcal FLAIR hyperintensity suggestive of an ivy sign, and narrowing of the terminal left internal carotid artery and proximal left anterior/middle cerebral arteries with collateral formation. Whole-genome sequencing and familial Sanger validation identified a heterozygous NF1 NM_000267:c.6947T > G, p.(Leu2316Arg) variant. The variant was present in four relatives across three generations: the paternal grandmother, father, proband, and twin sister. The paternal grandmother, father, and twin sister had no overt neurovascular symptoms during one year of clinical follow-up, although cerebrovascular imaging was unavailable for the paternal grandmother and twin sister. Representative pediatric NF1-MMS studies show recurrent patterns of clinically silent or atypical presentation, early unilateral involvement, and imaging signs of chronic hypoperfusion. This family illustrates possible intrafamilial neurovascular variability under the same familial NF1 variant background. These observations should be interpreted cautiously and warrant prospective multicenter studies to clarify the role of baseline cerebrovascular imaging in high-risk NF1 families.

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