title: Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy.
abstract: Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors: M
authors: M
authors: Kvarnung
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet Science Park, Stockholm, Sweden.
authors: F
authors: F
authors: Taylan
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.|Science for Life Laboratory, Karolinska Institutet Science Park, Stockholm, Sweden.
authors: D
authors: D
authors: Nilsson
authors: Department of Paediatrics, Astrid Lindgren Childrens Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors: M
authors: M
authors: Albåge
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors: M
authors: M
authors: Nordenskjöld
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors: B M
authors: BM
authors: Anderlid
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors: A
authors: A
authors: Nordgren
authors: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
authors: E
authors: E
authors: Syk Lundberg
mesh_terms: D000483:Alleles; D001921:Brain; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D006832:Hydranencephaly / Q000175:diagnosis* / Q000235:genetics*; D006849:Hydrocephalus / Q000175:diagnosis* / Q000235:genetics*; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011991:Receptors, Virus / Q000235:genetics*; D035781:Siblings; D013577:Syndrome; D014652:Vascular Diseases / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C553450:FLVCR2 protein, human; D026901:Membrane Transport Proteins; D011991:Receptors, Virus
keywords: FLVCR2; Fowler; hydranencephaly; intellectual disability; syndrome; whole-exome sequencing