Moyamoya angiopathy is a cerebral vasculopathy causing progressive stenosis of the internal carotid arteries and the compensatory development of collateral blood vessels, leading to brain ischemia and an increased risk of cerebral haemorrhage. Although multiple non-genetic causes have been associated with moyamoya syndrome, it can also be associated with rare genetic syndromes. Moyamoya Disease 4, characterised by a short stature, hypergonadotropic hypogonadism and facial dysmorphism (MYMY4, OMIM #300845), also referred to as BRCC3-associated moyamoya syndrome, has so far been described in 11 individuals. Here, we describe a 23-year-old male presenting with moyamoya syndrome, global developmental delay and intellectual disability, epilepsy, short stature and dysmorphic features, who after > 17 years of uninformative diagnostics was diagnosed with BRCC3-associated moyamoya syndrome after clinical RNA-seq. Transcriptome analysis showed reduced expression of the likely disease-causing gene BRCC3 in patient-derived fibroblasts, which was subsequently found to be caused by a ~ 26 kb Xq28 deletion. We furthermore review all reported cases of BRCC3-associated moyamoya syndrome, further delineating this clinical entity.

Severe hemophilia A and moyamoya (SHAM) syndrome is a rare condition that combines hemophilia A and moyamoya disease (MMD) due to an Xq28 microdeletion encompassing the F8 and BRCC3 genes. Here, we report the case of a 19-year-old male patient with hemophilia A and hypogonadism that presented with right-sided hemiparesis and dysarthria. Brain magnetic resonance imaging and angiography revealed an ischemic lesion in the left lobe and stenosis of both middle cerebral arteries with a concomitant thick vascular network, compatible with moyamoya disease. Next-generation sequence revealed a large Xq28 deletion compatible with SHAM syndrome. The patient was treated with acetylsalicylic acid and neurosurgical intervention was scheduled. Our patient is one of the few cases reported in the literature with Xq28 microdeletion encompassing the F8, hemophilia A causative gene, and BRCC3, responsible for MMD, presenting with a compound phenotype that included neurological manifestations and hypogonadism. In conclusion, diagnosis of MMD should be considered in any male, young patient with symptoms of ischemic stroke with no obvious explanation, and especially in patients with known hemophilia, since a relationship between the two conditions has been documented.

Moyamoya angiopathy, a rare cerebrovascular condition, can be primary (moyamoya disease) or secondary (moyamoya syndrome). Genetic factors, such as the ring finger protein 213 (RNF213), have been associated with moyamoya disease. However, X-linked moyamoya angiopathy/moyamoya syndrome and hypergonadotropic hypogonadism associated with moyamoya syndrome are rare. We report a case of a 14-year-old boy who presented with transient bilateral hemiparesis, recurrent seizures and cognitive decline. He previously had surgery for left-sided cryptorchidism and had been diagnosed with "epileptic attacks" or "functional movement disorders" in previous hospital admissions. Magnetic resonance angiography of the brain showed narrowing of supraclinoid portion of internal carotid arteries, as well as of middle and anterior cerebral arteries, and the presence of multiple collaterals. These findings were suggestive of moyamoya angiopathy. Laboratory investigations and karyotyping revealed a diagnosis of Klinefelter syndrome. This case presents a unique association of moyamoya angiopathy and Klinefelter syndrome in a boy from a poor socio-economic background, where the diagnosis and adequate treatment were delayed due to a lack of awareness and expertise.