Proliferative vasculopathy and hydranencephaly–hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism

Abstract

BackgroundFowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly–hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi‐allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far.MethodsWe report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment.ResultsThe present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding.ConclusionOur data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.

Expanding the clinical spectrum of Fowler syndrome: Three siblings with survival into adulthood and systematic review of the literature

“…In addition, heme deficiency could determine severe anemia, leading to fetal fluid accumulation, and therefore to cystic hygroma and generalized edema. 2,3,8,9,[22][23][24] This is also supported by the presence of anemia in all our patients, even in the still living patient, which does not have feeding problems. Gene-expression studies from different brain regions of a crab-eating monkey recently showed that FLVCR2 has effects on brain and eye function and development.…”

“…[2][3][4][5][6][7][8] Although there is a strict correlation between the vascular and CNS lesions, the pathophysiology remains elusive. 1,3,[8][9][10][11][12] Three hypotheses have been proposed for the molecular pathogenesis of the syndrome: (a) impairment of calcium trafficking, 13 affecting the proliferation and motility of endothelial cells and altering angiogenesis and therefore calcifications are observed, (b) heme import impairment, which would affect neuronal migration 3 by impairing oxidative phosphorylation 2,14 and could also result in iron accumulation, possibly accounting for the severe bone abnormalities observed in some fetuses 14 and (c) a deficit in pericytes, interfering with normal stabilization and remodeling during CNS angiogenesis, 6,8 also resulting in calcifications. 15 Further studies are essential to explore these hypotheses, and to explain why the disease is confined only to the CNS.…”

“…Since its first description, only 69 patients have been reported on the basis of clinical, histological and/or molecular criteria. [1][2][3][4][5][6][7][8][9][10][11][12][16][17][18][19][20][21][22][23][24][25] The vast majority of previously described cases ended with voluntary termination of pregnancy. Thus, the disorder was previously considered to be prenatally lethal, 9 until Kvarnung et al in 2016 reported two siblings who survived beyond the neonatal period.…”

Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier

“…PVHH is an autosomal recessive prenatal lethal disorder characterized by severe hydrocephalus and thin cerebral cortex, glomeruloid vascular structures in the brain, and diffuse ischemic lesions in the brain stem and embryonic basal ganglia or ganglionic eminence (GE) (12). To date, there are 16 different reported FLVCR2 mutations in humans: 1 large deletion, 2 nonsense mutations, 1 splice-site mutation, 1 insertion/deletion change, and 11 missense variations (9,13,14). These are most likely loss-of-function mutations, since heterozygotes are not normally affected and, because most affected individuals are compound heterozygotes, having 2 different recessive alleles at the FLVCR2 locus.…”

Unraveling the Role of Heme in Neurodegeneration

“…Different kinds of mutations in the FLVCR2 gene have been reported ( Lalonde et al, 2010 ; Meyer et al, 2010 ; Thomas et al, 2010 ; Kvarnung et al, 2016 ), including missense and nonsense mutations, deletions and insertions. Homology modeling of FLVCR2 structure suggests that the missense mutations related with Fowler syndrome affect transmembrane domains that may modify the channel proper function or folding ( Radio et al, 2018 ). It has been proposed that the mutations might lead to alteration of heme-iron metabolism.…”