Moyamoya syndrome (MMS) is a rare cerebrovascular disease characterized by progressive intracranial arterial stenosis, with significant morbidity due to ischemic and hemorrhagic stroke. Several genetic etiologies have been identified including RASopathies, alterations in the Notch signaling pathway, and mutations in genes involved in angiogenesis and inflammation. Management of MMS includes antiplatelet therapies and surgical revascularization.

Case report and literature review

This patient had a history of macrocephaly, developmental delay, and bilateral retinal arterial narrowing. He presented at 6 years of age with unilateral facial droop and slurred speech. Imaging showed bilateral middle cerebral artery stenoses with collateral lenticulostriate vessels, consistent with MMS. His sister had previously been diagnosed with MMS and had non-diagnostic whole exome sequencing. His father also had macrocephaly, retinal vascular changes, and cerebral white matter changes, although no MMS. Whole genome sequencing identified a heterozygous pathogenic deletion in PTEN (chr10:89642208_89657754 [GRCh37]) in all three individuals, diagnostic of PTEN-related hamartoma tumor syndrome (PHTS). Manifestations of PHTS include macrocephaly, white matter abnormalities, developmental delays, and benign soft tissue tumors. Vascular malformations are seen in 20-50% of people with PHTS, including in the central nervous system, but MMS has not been described. No other pathogenic variants were reported in this patient or his sister.

Pathogenic mutations in PTEN are known to cause vascular anomalies. We describe siblings with MMS and PHTS, raising the possibility that MMS could be a clinical manifestation of PHTS. This may offer new treatment opportunities with mTOR/PI3K pathway inhibitors, which have been shown to be effective for vascular anomalies in some children with PHTS. It is also possible that these siblings carry an unidentified MMS risk factor. This case highlights the importance of whole genome sequencing in identifying pathogenic genetic alterations not detected on exome sequencing.