Fowler Syndrome Presenting as a Dandy-Walker Malformation: A Second Case Report

Al-Adnani, Mudher; Kiho, Liina; Scheimberg, Irene

doi:10.2350/07-09-0348.1

Cited by 9 publications

(10 citation statements)

References 17 publications

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“…No vascular lesions were seen in any other organ. All of these abnormalities we report in F1 have been previously documented in the published FS cases [Al-Adnani et al, 2009;Castro-Gago et al, 2001;Fowler et al, 1972;Halder et al, 2003;Harper et al, 1983;Ibrahim et al, 2007;Usta et al, 2005;Witters et al, 2002]. Moreover, parents of F1 had lost a fetus with a phenotype of Fowler syndrome at 24 weeks of gestation 1…”

Section: Methodssupporting

confidence: 75%

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing

et al. 2010

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Protein coding genes constitute approximately 1% of the human genome but harbor 85% of the mutations with large effects on disease-related traits. Therefore, efficient strategies for selectively sequencing complete coding regions (i.e., ''whole exome'') have the potential to contribute our understanding of human diseases. We used a method for whole-exome sequencing coupling Agilent whole-exome capture to the Illumina DNA-sequencing platform, and investigated two unrelated fetuses from nonconsanguineous families with Fowler Syndrome (FS), a stereotyped phenotype lethal disease. We report novel germline mutations in feline leukemia virus subgroup C cellular-receptor-family member 2, FLVCR2, which has recently been shown to cause FS. Using this technology, we identified three types of genetic abnormalities: point-mutations, insertionsdeletions, and intronic splice-site changes (first pathogenic report using this technology), in the fetuses who both were compound heterozygotes for the disease. Although revealing a high level of allelic heterogeneity and mutational spectrum in FS, this study further illustrates the successful application of whole-exome sequencing to uncover genetic defects in rare Mendelian disorders. Of importance, we show that we can identify genes underlying rare, monogenic and recessive diseases using a limited number of patients (n 5 2), in the absence of shared genetic heritage and in the presence of allelic heterogeneity. Hum Mutat 31:918-923,

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Section: Methodssupporting

confidence: 75%

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing

et al. 2010

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“…This could only be confirmed at autopsy in one, and it is possible that this was a consequence of secondary disruption, rather than failure of development. Other cases have been reported with antenatally diagnosed Dandy–Walker malformation, confirmed on autopsy [Al‐Adnani et al, 2009]. Hydrocephaly/hydranencephaly in Fowler syndrome appears to be a consequence of destruction of brain tissue, rather than obstruction to the flow of cerebrospinal fluid.…”

Section: Discussionmentioning

confidence: 89%

“…Fowler syndrome is a rare lethal condition, with only 20 cases from 11 families reported so far [Fowler et al, 1972; Harper and Hockey, 1983; Norman and McGillivray, 1988; Harding et al, 1995; Castro‐Gago et al, 2001; Laurichesse‐Delmas et al, 2002; Witters et al, 2002; Halder et al, 2003; Usta et al, 2005; Ibrahim et al, 2007; Al‐Adnani et al, 2009]. All 14 of the cases presented here were identified by the presence of glomeruloid cerebral vascular proliferation, the characteristic finding in Fowler syndrome.…”

Section: Discussionmentioning

confidence: 99%

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

Williams

Patel

Fallet-Bianco

et al. 2009

American J of Med Genetics Pt A

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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.

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“…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 . There are indications of a correlation between presence of arthtrogryphosis and the anatomical extent of the histopathological findings with a less severe phenotype for fetuses with vascular proliferation limited to the brain, not extending into the spinal cord .…”

Section: Discussionmentioning

confidence: 99%

“…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). Recently, mutations in the gene FLVCR2 (feline leukemia virus subgroup C cellular receptor family, member 2) were identified as being causative of the disorder (13,14).…”

mentioning

confidence: 99%

Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy

et al. 2015

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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.

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Fowler Syndrome Presenting as a Dandy-Walker Malformation: A Second Case Report

Cited by 9 publications

References 17 publications

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing

Unexpected allelic heterogeneity and spectrum of mutations in Fowler syndrome revealed by next-generation exome sequencing

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

Mutations in FLVCR2 associated with Fowler syndrome and survival beyond infancy

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