Fowler syndrome: a case report

Case presentation: A 10-year-old boy, presented with early onset epilepsy, at three months of age, characterized by myoclonic and tonic seizures, associated with global developmental delay. He has never developed gait or speech. Neurologic examination showed spastic tetraparesis. Cranial resonance imaging showed diffuse polymicrogyria, with calcifications, cortical and subcortical atrophy, and ventriculomegaly. There was no history of consanguinity, neither a family history of similar disorders. Since gestational and perinatal data were unremarkable for congenital infections, whole exome sequencing (WES) was requested. WES showed compound heterozygous pathogenic missense variants in FLVCR2 (chr14:75.633.650 A>G and chr14:75.634.909 G> C, p. Tyr325Cys and c.1021–1G>C). This variant is related to proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome – Fowler Syndrome.

Discussion: Fowler syndrome is a rare, autosomal recessive, usually prenatally lethal disorder. The mechanism by which mutations in FLVCR2 cause this syndrome is not well defined, however, the encoded protein may play a role in the development of brain vascular endothelial cells, as variants at this locus have been associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome. Hydranencephaly, a distinctive vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications might be present. Few cases survive until young adulthood, all young cases described had intracranial calcifications, although an association between the variants of FLVCR2 and severity of clinical presentation has not been found yet.

Final comments: Fowler syndrome is a rare condition, mainly prenatally lethal or occurring in infancy. It is important to consider Fowler syndrome in patients with gross ventriculomegaly, cortical malformations, and cerebral calcifications on brain imaging. Genetic testing allows the diagnostic of this condition, and hereafter will allow the delineation of the genotype-phenotype relationship.

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Artikel online veröffentlicht:
18. September 2023