Proliferative Vasculopathy and Hydranencephaly-Hydrocephaly Syndrome via the FLVCR2 Gene

Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, also known as Fowler syndrome or encephaloclastic proliferative vasculopathy, is a rare vascular brain disorder with prenatal onset. As of 2010, only around 40 cases had been reported. The major symptoms include hydrocephalus; hydranencephaly; diffuse clastic ischemic lesions and calcifications in the brain stem, basal ganglia, and spinal cord; glomeruloid vasculopathy in the brain and retinal vessels; and intrauterine death. In addition, patients also present with other symptoms such as polyhydramnios and fetal akinesia deformation sequence with muscular neurogenic atrophy. Prenatal ultrasound reveals ventriculomegaly, hydranencephaly, joint contractures in upper and lower limbs, cystic hygroma, and intrauterine death (Meyer et al. 2010. PubMed ID: 20206334; Lalonde et al. 2010. PubMed ID: 20518025; Soster et al. 2015. PubMed ID: 25131804).   

As proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome presents with variable and overlapping phenotypes, it can be difficult to diagnose by clinical manifestation and image studies only. An accurate molecular diagnosis is critical for treatment, prognosis, and prediction of recurrence risk as well as future family planning.

FLVCR2-related proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is inherited in an autosomal recessive manner. Pathogenic variants in FLVCR2 include missense, nonsense, splicing, small deletions and duplications, and large deletions (Human Gene Mutation Database; Thomas et al. 2010. PubMed ID: 20690116). Missense variants and truncating variants are equally common. No de novo variants have been reported.

FLVCR2 encodes feline leukemia virus subgroup c receptor 2, a transmembrane transporter. This receptor is hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis (Meyer et al. 2010. PubMed ID: 20206334). A knock-out mice model showed Flvcr2 was essential for angiogenic sprouting in the brain, leading to vascular malformations. Brain hypovascularization was associated with hypoxia and tissue infarction, which eventually resulted in hydrocephalus and death of mice (Santander et al. 2020. PubMed ID: 32369453). FLVCR2 has been cited as a conditionally essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Clinical sensitivity of FLVCR2 in a large cohort of patients with FLVCR2-related disorder relevant phenotypes is unavailable in the literature, because most studies are case reports. However, analytical sensitivity should be high.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the FLVCR2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).