Proliferative Vasculopathy And Hydranencephaly-Hydrocephaly Syndrome

A number sign (#) is used with this entry because of evidence that proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as encephaloclastic proliferative vasculopathy, is caused by homozygous or compound heterozygous mutation in the FLVCR2 gene (610865) on chromosome 14q24.

Description

The proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a rare, autosomal recessive, usually prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation (summary by Meyer et al., 2010). Rarely, affected individuals may survive, but are severely impaired with almost no neurologic development (Kvarnung et al., 2016).

Clinical Features

In identical male twins, Moeschler and Marin-Padilla (1989) described a disorder that had been reported in 5 sibs by Fowler et al. (1972) and in 2 sibs by Harper and Hockey (1983). Of the sibs reported by Harper and Hockey (1983), one had hydranencephaly at birth; the other had a normal ultrasound examination at 22 weeks, but later developed hydranencephaly which was evident on ultrasound at 26 weeks. The twins reported by Moeschler and Marin-Padilla (1989) were born at 25 weeks' gestation and survived only 12 minutes. Ultrasound at 16 weeks was normal. Although the brain in each was normal on gross examination, CNS proliferative vasculopathy was noted on microscopic examination. Identical anomalies were found in the dorsolateral posterior region of the right frontal lobe. Distinctive 'glomeruloid' lesions representing abnormal focal vascularization of the cortical mantle by tufts of blood vessels had resulted from focal proliferation of endothelial cells. This proliferative vasculopathy damaged the developing CNS by disruption and disorganization of the developing organ, rupture of the pial/glial surface, and hemorrhagic necrosis. Moeschler and Marin-Padilla (1989) suggested that the twins would have eventually developed typical hydranencephaly but were born before the full evolution of this abnormality.

Witters et al. (2002) described a 13-week-old female fetus with early-onset fetal akinesia deformation sequence (FADS; 208150) and hydranencephaly. In a previous pregnancy, the same ultrasonographic findings were noted in the fetus at 13 weeks' gestation. Fetopathologic examination of both female fetuses confirmed FADS with severe arthrogryposis, multiple pterygia, and muscular hypoplasia. Neuropathologic examination showed massive cystic dilatation of the cerebral ventricles (hydranencephaly) with calcification of the basal ganglion and brainstem and a proliferative vasculopathy throughout the central nervous system. This represented the earliest echographic diagnosis of Fowler-type hydranencephaly and supported autosomal recessive inheritance of this distinct form of hydranencephaly.

Bessieres-Grattagliano et al. (2009) reported 16 fetuses from 8 unrelated families with Fowler syndrome, including 4 families that were consanguineous. Common ultrasound findings beginning as early as 12 weeks' gestational age showed showed hydrocephalus with macrocrania, decreased fetal movements, severe arthrogryposis with fetal akinesia sequence, and cystic hygroma. Cleft palate and/or microretrognathia were common. Neuropathologic examinations showed encephaloclastic proliferative vasculopathy (EPV), intracranial calcifications, thin-walled cerebral hemispheres, and hypoplastic brainstem, cerebellum, and spinal cord. Immunohistochemical studies of the proliferating cells showed endothelial cell CD34 staining but decreased staining for smooth muscle actin, which stains pericytes. Fourteen fetuses showed EPV changes in both the brain and spinal cord, whereas 2 sibs had more focal involvement only of the brain. Analysis of the cerebral vasculature showed that the normal thin-walled leptomeningeal superficial vascular channels were followed by a deeper sheet of thickened perforating vessels, with some endothelial cells containing PAS-positive bodies. In the brain parenchyma, the wall of abnormal vessels contained enlarged CD34-positive endothelial cells. The most striking abnormality, best seen in the glomeruloids, was the lack of a single vascular lumina, replaced by multiple small microcavities, containing few red blood cells. Bessieres-Grattagliano et al. (2009) suggested that the disorder may result from a defect in vascular remodeling during angiogenesis.

Williams et al. (2010) reported 14 fetuses from 10 families with Fowler syndrome. Sibs were affected in 4 families, and 6 families were consanguineous, indicating autosomal recessive inheritance. The gestational age at diagnosis ranged from 13 to 27 weeks. All had the characteristic finding of glomeruloid cerebral vascular proliferation involving various brain regions, such as brainstem, cerebellum, germinal matrix, deep cerebral gray matter, white matter, cortex, and spinal cord. Within the vascular proliferation, endothelial cells contained diastase-resistant intracytoplasmic globular inclusions. Other brain features were variable but included ventriculomegaly, agenesis of the corpus callosum, hypoplastic cerebellum, and dystrophic calcification. Although ultrasound indicated hydranencephaly, histologic studies showed a hemispheric mantle in all cases, more consistent with severe hydrocephalus. Extraneurologic manifestations included intrauterine growth retardation, limb contractures, reduced muscle bulk, pterygia, low-set ears, and micrognathia.

Lalonde et al. (2010) reported a fetus, born of unrelated French Canadian parents, with Fowler syndrome ascertained at 23 weeks' gestation by the finding of ventriculomegaly and limb deformities. Postmortem examination showed fetal akinesia deformation sequence, muscular atrophy, and cutaneous webbing. Neuropathologic examination showed bag-like cerebral hemispheres with no internal structures, such as basal ganglia or thalami. The brain parenchyma showed microcalcifications and hyperplastic microvessels forming glomeruloid structures. Residual brain parenchyma was highly disorganized. Another fetus from this family had been similarly affected.

Kvarnung et al. (2016) reported 2 sibs, born of consanguineous parents from Somalia, with a severe neurologic disorder. One child had unremarkable ultrasound findings at 18 weeks' gestation, whereas the other child showed microcephaly, profound ventriculomegaly, and lissencephaly at 32 weeks' gestation. After birth, the first child was noted to have similar brain abnormalities; both also had intracranial calcifications in the cortex, cerebellum, and brainstem. Both had basically normal development until about 2 months, when they showed hypotonia, severely delayed or even absent development, and onset of seizures associated with hypsarrhythmia on EEG. Neither patient developed functional movements or communication, and both had central visual impairment. The older sib died at age 3 years, whereas the younger sib was still alive at age 6, but had refractory seizures and needed a feeding tube. Kvarnung et al. (2016) emphasized that the findings indicated that PVHH may be compatible with life.

Inheritance

The transmission pattern of PVHH in the family reported by Kvarnung et al. (2016) was consistent with autosomal recessive inheritance.

Mapping

By genomewide linkage analysis of 2 consanguineous Pakistani families with PVHH, Meyer et al. (2010) identified a locus on chromosome 14q24 (maximum combined lod score of 3.69 at D14S61).

Molecular Genetics

By candidate gene sequencing, Meyer et al. (2010) identified a homozygous mutation in the FLVCR2 gene (T430R; 610865.0001) in 5 fetuses with PVHH from 3 consanguineous Pakistani families. Two additional fetuses of northern European origin with the disorder were each found to be compound heterozygous for 2 mutations in the FLVCR2 gene (610865.0002-610865.0005).

Using exome sequencing, Lalonde et al. (2010) identified compound heterozygosity for 2 mutations in the FLVCR2 gene (610865.0006 and 610865.0007) in a fetus with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome.

By genomewide linkage analysis followed by high-throughput sequencing of 7 families with Fowler syndrome, Thomas et al. (2010) identified homozygous or compound heterozygous mutations affecting the FLVCR2 gene (see, e.g., Y134X, 610865.0008). Two of the families, of Turkish origin, carried a large deletion. The patients and families had previously been reported by Bessieres-Grattagliano et al. (2009).

In 2 sibs, born of consanguineous Somalian parents, with Fowler syndrome, Kvarnung et al. (2016) identified a homozygous missense mutation in the FLVCR2 gene (T430M; 610865.0009). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Kvarnung et al. (2016) noted that both of these affected children survived beyond birth, although they had essentially no neurologic development. Functional studies of the variant and studies of patient cells were not performed.