Severe Familial Exudative Vitreoretinopathy, Congenital Hearing Loss, and Developmental Delay in a Child With Biallelic Variants in <i>FZD4</i>

Ende, Sarah R van der; Meyers, Benjamin S; Capasso, Jenina E.; Sasongko, Mario; Yonekawa, Yoshihiro; Pihlblad, Matthew S.; Huey, Jennifer; Bedoukian, Emma; Krantz, Ian D.; Ngo, Michael Hung; McMaster, Christopher; Levin, Alex V.; Robitaille, Johane

doi:10.1001/jamaophthalmol.2022.2914

Cited by 4 publications

(8 citation statements)

References 14 publications

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“…They suggested that the variants resulted in dramatic loss of Norrin-FZD4 signaling and therefore cause extraocular features. 9 The clinical presentation of the affected individual presented here is isolated, severe FEVR in childhood. This is in line with the findings of Khan et al 8 who describe recessive FEVR without extraocular features.…”

Section: Discussionmentioning

confidence: 86%

“…8 Recently, biallelic FZD4-variants were described as a possible cause of FEVR with extraocular features including hearing loss and developmental delay, because of complete knock-down of the Norrin/Frizzled-4 pathway. 9 This also appears to be the case for hemizygous NDP-variants causing Norrie disease. 10 In addition, heterozygous variants in LRP5 are mainly linked to either FEVR or increased bone density, while biallelic LoF variants cause a syndromic form (OMIM*603506).…”

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confidence: 85%

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Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

Hoem,

Pastore,

Bratland

et al. 2024

Clinical Genetics

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Familial exudative vitreoretinopathy (FEVR) is linked to disruption of the Norrin/Frizzled‐4 signaling pathway, which plays an important role in retinal angiogenesis. Severe or complete knock‐down of proteins in the pathway also causes syndromic forms of the condition. Both heterozygous and biallelic pathogenic variants in the FZD4 gene, encoding the pathway's key protein frizzled‐4, are known to cause FEVR. However, it is not clear what effect different FZD4 variants have, and whether extraocular features should be expected in those with biallelic pathogenic FZD4 variants. Biallelic FZD4 variants were found in a young boy with isolated, severe FEVR. His parents were heterozygous for one variant each and reported normal vision. In‐vitro studies of the two variants, demonstrated that it was the combination of the two which led to severe inhibition of the Norrin/Frizzled‐4 pathway. Our observations demonstrate that biallelic FZD4‐variants are associated with a severe form of FEVR, which does not necessarily include extraocular features. In addition, variants causing severe FEVR in combination, may have no or minimal effect in heterozygous parents as non‐penetrance is also a major feature in dominant FZD4‐FEVR disease. This underscores the importance of genetic testing of individuals and families with FEVR.

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Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 85%

Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

Hoem,

Pastore,

Bratland

et al. 2024

Clinical Genetics

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“…Two cases in our study were progressed very badly, may be due to FZD4 variant. 6 FFA was not helpful to diagnose and treat. Treatment in these cases did not show any response.…”

Section: Discussionmentioning

confidence: 94%

Role of fundus fluorescein angiography in identifying the unexplained visual loss due to macular edema in peripheral retinal diseases

Sultana

2023

IJCEO

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: Aim of our study is to identify the peripheral retinal diseases in patients which is responsible for macular oedema causing visual loss in various age group of patients.: In this retrospective study 30 patients of macular oedema presented to our department between January 2020 to December 2021 were examined in detail. Proper history taking, BCVA, slit lamp examination, fundus examination with indirect ophthalmoscopy, fundus fluorescein angiography (FFA), OCT to quantify macular oedema and documentation done in all cases. Patients were managed with pan retinal photo coagulation, intra vitreal steroids and anti vegf were given to treat macular oedema.: BCVA, fundus examination, FFA and OCT done in all cases, most of the patients showed good outcome with anti vegf, steroid injections and pan retinal photo coagulation, but reoccurrence of macular oedema noted in few cases after one year in cases where the cause of macular edema was not detected even after FFA.: Peripheral examination of fundus is very important to diagnose these conditions, FFA has major role in studying the peripheral retina particularly in conditions where the clinical presentation is not apparent.

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“…[ 32 ] reported that most eyes of 13 probands with two disease-causing variants had stage 4 (38.46%) or stage 5 (26.92%) disease. A case series detected a heterozygous biallelic variant in FZD4 leading to hearing deficits and developmental delays [ 19 ]. In LRP5 variants, a higher incidence of severe phenotype was observed in patients with biallelic variants compared to those with monoallelic variants [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Catenin beta 1 ( CTNNB1 ) is also an uncommon cause of microcephaly [ 18 ]. Frizzled-4 ( FZD4 ) variants can result in hearing deficits and developmental delays [ 19 ]. Current research indicates that only around 40–50% of cases of FEVR harbour identifiable genetic variants [ 20–22 ], while the relationship between the genotype and clinical manifestations is complex, which are responsible for the challenges in early clinical diagnosis and effective treatment.…”

Section: Introductionmentioning

confidence: 99%

Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy

et al. 2022

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Objective To explore the clinical manifestations and search for the variants of six related genes ( LRP5 , FZD4 , TSPAN12 , NDP , KIF11 and ZNF408 ) in Chinese patients with familial exudative vitreoretinopathy (FEVR), and investigate the correlation between the genetic variants and the clinical characteristics. Patients and methods Clinical data, including the retinal artery angle, acquired from wide-field fundus imaging, structural and microvascular features of the retina obtained from optical coherence tomography (OCT) and OCT angiography (OCTA) were collected from 33 pedigrees. Furthermore, mutation screening was performed. Variants filtering, bioinformatics analysis and Sanger sequencing were conducted to verify the variants. Results Twenty-one variants were successfully detected in 16 of 33 families, of which 10 variants were newly identified. The proportion of variants in LRP5 , FZD4 , TSPAN12 , NDP and KIF11 was 38.1% (8/21), 33.3% (7/21), 19.1% (4/21), 4.8% (1/21) and 4.8% (1/21), respectively. Three new variants were considered to be pathogenic or likely pathogenic. The FEVR group tended to exhibit a smaller retinal artery angle, higher incidence of foveal hypoplasia and lower vascular density compared to the control group. Patients who harboured variants of FZD4 exhibited greater severity of FEVR than those with LRP5 variants. However, those who harboured LRP5 variants tended to possess lower foveal vascular density. Conclusions Six known pathogenic genes were screened in 33 pedigrees with FEVR in our study, which revealed 10 novel variants. These findings enrich the clinical features and mutation spectrum in Chinese patients with FEVR, revealing the genotype-phenotype relationship, and contributing to the diagnosis and treatment of the disease. Key messages We identified 21 variants in 5 genes ( LRP5, FZD4, TSPAN12, NDP and KIF11) associated with FEVR, 10 of which are novel (three were pathogenic or likely pathogenic). The proportion of variants was the highest for the LRP5 gene. FZD4 variants may be responsible for greater FEVR severity than LRP5 variants.

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Severe Familial Exudative Vitreoretinopathy, Congenital Hearing Loss, and Developmental Delay in a Child With Biallelic Variants in FZD4

Abstract: This case series investigates if variants in the FZD4 gene are associated with familial exudative vitreoretinopathy (FEVR) with extraocular features.

Cited by 4 publications

References 14 publications

Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

Severe isolated exudative vitreoretinopathy caused by biallelic FZD4 variants

Role of fundus fluorescein angiography in identifying the unexplained visual loss due to macular edema in peripheral retinal diseases

Clinical characteristics and mutation spectrum in 33 Chinese families with familial exudative vitreoretinopathy

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