Fowler syndrome—A clinical, radiological, and pathological study of 14 cases

Abstract

We report on 14 fetuses from 10 families with the autosomal recessive syndrome of proliferative vasculopathy and hydranencephaly-hydrocephaly (Fowler syndrome). In four families sibs were affected and in six the parents were consanguineous. Antenatal ultrasonography showed hydrocephaly in all except two fetuses, but hydranencephaly was diagnosed in only one case. Postural abnormalities were seen in 10 fetuses and structural brain abnormalities were suspected in 3. At autopsy the cerebral cortex appeared as a translucent membranous structure (hydranencephaly) in most fetuses. However, in one case, the ventricles were dilated but the cortical mantle was relatively well preserved. Histology of the brain showed the characteristic glomeruloid vascular proliferation of Fowler syndrome in all cases, but with variable extent of involvement of the central nervous system. Dystrophic calcification and necrosis were always present. Extra-cranial anomalies included micrognathia (10 fetuses), cleft palate (1 fetus), cystic hygroma (2 fetuses), joint contractures (12 fetuses), and pterygia (11 fetuses). The typical proliferative vasculopathy was never observed outside the central nervous system and karyotypes were normal in the 10 fetuses studied. Fowler syndrome should be considered in the differential diagnosis of lethal multiple pterygium syndrome, fetal akinesia, and hydrocephalus in addition to classical hydranencephaly. Autopsy and study of the brain are essential to differentiate autosomal recessive Fowler syndrome from other causes of hydrocephaly and hydranencephaly, which may have a lower recurrence risk.

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

“…Subsequent reports have shown that hydranencephaly–hydrocephaly resulted from the destruction of brain tissue due to vascular anomalies, while other features were likely secondary to CNS injuries. The disorder is almost invariably prenatally lethal, usually detected by ultrasound between the 13 and 27 weeks of gestation (Williams et al., ). Only a single brother–sister pair has been reported, who survived beyond the neonatal period (Kvarnung et al., ).…”

High-throughput sequencing of a 4.1 Mb linkage interval reveals FLVCR2 deletions and mutations in lethal cerebral vasculopathy

“…Since its first description, 42 cases from 26 families have been reported on the basis of histological criteria of PGV [Bessieres-Grattagliano et al, 2009;Williams et al, 2010]. In the 16 fetuses of our series born to eight unrelated families, neuropathological analysis defined a diffuse form of encephaloclastic prolifrative vasculopathy (EPV), affecting the entire CNS and resulting in classical PGV with pterygia and a severe fetal akinesia deformation sequence in 14 cases.…”

“…Arthryogryposis, when present, appears to be a secondary result of CNS motoneuron degeneration, itself one potential outcome of perfusion failure. Since its earliest description, 42 PGV cases from 26 families have been reported on the basis of histological criteria [Bessieres-Grattagliano et al, 2009;Williams et al, 2010].…”

Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy

“…Histopathologic examination of the CNS of these fetuses invariably shows a glomeruloid vascular proliferation, a finding that is considered pathognomonic for Fowler syndrome. The histopathological changes usually extend into the spinal cord, but spare tissues outside the CNS . Arthrogryphosis secondary to fetal akinesia is a common finding in fetuses, but a few fetal cases show a milder phenotype without joint contractures .…”

“…Proliferative vasculopathy and hydranencephalyhydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, first described in 1972 by Fowler et al who reported five fetuses with a distinct clinical and histological phenotype (1). Hallmarks of the disorder are severe hydrocephaly-hydranencephaly and a specific glomerular vasculopathy in the central nervous system (CNS) along with secondary hypokinesia/akinesia and arthrogryphosis (2,3). The syndrome is further characterized by early prenatal onset and is considered lethal based on findings from all histologically verified cases reported to date (n = 42) that consistently comprise fetuses at different gestational ages, ranging from week 12 to 40 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12).…”