Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Familial Exudative Vitreoretinopathy With Neurodevelopmental Delay and Hypoplasia of the Corpus Callosum

Giulia M. Amorelli, MD; Costanza Barresi, MD; Marco H. Ji, MD; Lorenzo Orazi, MD; Fernando Molle, MD; Domenico Lepore, MD

Abstract

A 2-year-old child was referred to the authors' pediatric retina service for bilateral retinal folds, strabismus, and psychomotor retardation, as well as marked thinning of the corpus callosum. Family history was unremarkable and genetic testing revealed a previously undescribed mutation in the LRP5 gene. Widefield fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were used to image the retinal fundus. The authors' case suggests a correlation between LRP5 and neurological development, since its variants may lead to a syndromic condition characterized by FEVR-like abnormalities along with neurodevelopmental delay and hypoplasia of the corpus callosum.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:588–591.]

Abstract

A 2-year-old child was referred to the authors' pediatric retina service for bilateral retinal folds, strabismus, and psychomotor retardation, as well as marked thinning of the corpus callosum. Family history was unremarkable and genetic testing revealed a previously undescribed mutation in the LRP5 gene. Widefield fundus photography, fluorescein angiography, and spectral-domain optical coherence tomography were used to image the retinal fundus. The authors' case suggests a correlation between LRP5 and neurological development, since its variants may lead to a syndromic condition characterized by FEVR-like abnormalities along with neurodevelopmental delay and hypoplasia of the corpus callosum.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:588–591.]

Introduction

Familial exudative vitreoretinopathy (FEVR) is a hereditary retinal vascular disorder characterized by peripheral retinal abnormalities, such as avascular areas, neovascularization, epiretinal membranes (ERMs), tractional retinal detachment (TRD) and congenital falciform folds.1,2 All these features can be found to a different extent in a wide range of pediatric retinal vascular conditions,3 including retinopathy of prematurity, persistent hyperplastic primary vitreous, Norrie disease, incontinentia pigmenti, and congenital toxoplasmosis.4–6 Examination with indirect ophthalmoscopy and fluorescein angiography (FA), combined with genetic testing, are fundamental in the diagnostic framework. Genetic testing of mutations of genes involved in the Wnt signaling pathway (FZD4, NDP, TSPAN12, and LRP5)7–10 supports the diagnosis in less than half of patients, suggesting a broader spectrum of mutations is still unknown.11,12 Herein, we report the case of a 2-year-old boy presenting with bilateral retinal folds and neurodevelopmental delay, later confirmed to have a genetic mutation suggestive of FEVR.

Case Report

A 2-year-old boy was referred for nystagmus to the pediatric retina service at “Agostino Gemelli” University Hospital, Rome, Italy. Previous examination at another hospital at 7 months of age reported presence of nystagmus, hypopigmented fundus, rigid retinal folds extending from the optic nerve to the retinal periphery with optic nerve distortion, and macular involvement. The child also presented psychomotor retardation, and magnetic resonance imaging (MRI) showed thinning of the corpus callosum. Genetic testing revealed compound heterozygosity of the paternal segregated variant c.2123C>T (p. Ser708Leu) and of the maternally segregated variant c.4622C>G (p.Thr1541Arg) in the LRP5 gene, which is associated with type IV FEVR. Family history was negative for neurological abnormalities, developmental delay, and retinal diseases. The clinical examination revealed the presence of horizontal nystagmus with a vertical component and compensatory head posture, divergent strabismus with abnormal ocular motility and absent stereopsis. Binocular visual acuity was 0.9 logMAR using Teller Acuity Cards. The baby was examined with hand-held spectral-domain optical coherence tomography (SD-OCT) Envisu 2300 (Bioptigen Incorporated, Durham, NC) and widefield fundus photography and FA using RetCam III (Natus Medical Incorporated, Pleasanton, CA) under general anesthesia. Digital retinal imaging revealed bilateral folds in both eyes, which ran temporally from the optic disc ending in the mid-retinal periphery with a circumferential fibrotic structure in both eyes (Figures 1A and 1B). FA showed good filling of the choriocapillaris and large circumferential peripheral avascular areas. Both eyes presented retinal folds with stretched vessels inside. Vascular shunts, relevant leakage, and abnormal branching were evident above and outside the folds in the extreme retinal periphery (Figures 1C and 1D). SD-OCT scans showed glial tissue thickening, elevation, and distortion of all retinal layers drawn into the folds, schisis of the peripapillary retina, and absent foveal depression (Figures 1E and 1F). Because of the relatively stable clinical picture, a wait-and-see strategy was applied with a strict functional and structural follow-up.

(A, B) Bilateral retinal folds extending from the optic nerve to the temporal retinal periphery ending with a circumferential fibrous structure. (C, D) Fluorescein angiograms with large avascular areas beyond the folds and relevant leakage above and outside the folds. Spectral-domain optical coherence tomography scans (E, F) with raised retinal layers drawn into the folds, schisis of the peripapillary retina, and fibrous tissue above the folds.

Figure 1.

(A, B) Bilateral retinal folds extending from the optic nerve to the temporal retinal periphery ending with a circumferential fibrous structure. (C, D) Fluorescein angiograms with large avascular areas beyond the folds and relevant leakage above and outside the folds. Spectral-domain optical coherence tomography scans (E, F) with raised retinal layers drawn into the folds, schisis of the peripapillary retina, and fibrous tissue above the folds.

Discussion

The diagnosis of FEVR can be challenging when patients come to our attention very late with leukocoria, nystagmus, or vision loss, especially in case of negative family history. Retinal folds are a typical but often misinterpreted finding of FEVR. An accurate evaluation of the main characteristics of the folds is pivotal, using a combination of digital retinal photography and OCT in suspected cases to achieve a differential diagnosis. The presence of bilateral symmetric retinal lesions associated with severe delay in psychomotor development and a thinning of the corpus callosum suggested a syndromic clinical picture. To date, several genetic mutations causing 30% to 50% of FEVR cases have been reported,13 including those involving FZD4 (MIM: 604579, dominant), LRP5 (MIM: 603506, dominant and recessive), NDP (MIM: 300658, X-linked), TSPAN12 (MIM: 613138, dominant), KIF11 (MIM: 004523, dominant), and ZNF408 (MIM: 616454, dominant) genes, which play a critical role in retinal angiogenesis.14,15 Lately, more genes have been found to be associated with FEVR, such as RCBTB1 (MIM: 607867)16 and EVR3 on chromosome 11p12-13 (MIM: 605750).17 Mutations in the FZD4 gene have been shown to contribute to autosomal dominant FEVR; TSPAN12 and LRP5 mutations are believed to be inherited as dominant or recessive traits,11,18 whereas mutations in the NDP gene have been found in X-linked FEVR.19,20 Our patient was found to be affected by a compound heterozygosity for two previously unknown sporadic mutations in the LRP5 gene. Neither variants have been described in the literature, and their clinical significance is still unknown. Wnt signaling plays a relevant role in the pathophysiology of several mental disorders including schizophrenia, bipolar disorder, and autism spectrum disorder, confirming how its disruption can lead to both neurological and behavioral phenotypes.21–23 The LRP5 gene is well known to be involved in the regulation of bone mass and its mutations are linked to osteoporosis, pseudoglioma, sclerosteosis, or idiopathic osteoporosis.24,25 Studies conducted recently in zebrafish show that LRP5 gene plays a crucial role in cranial neural crest cells migration and morphogenesis of the cranial skeleton.26 To date, literature still does not report associations between LRP5 gene abnormalities and thinning of corpus callosum. Our case suggests a link between LRP5 and neurological development, since its variants may lead to a syndromic condition characterized by FEVR-like abnormalities along with psychomotor retardation and hypoplasia of the corpus callosum. Therefore, the presence of folds or vascular retinal abnormalities in a child should always elicit a comprehensive systemic and genetic work-up to identify further associations with psychomotor disabilities, microcephaly, hearing loss or osteopenia.27–31

References

  1. Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68(4):578–594. doi:10.1016/0002-9394(69)91237-9 [CrossRef]. Internet. PMID:5394449
  2. Iwata A, Kusaka S, Ishimaru M, Kondo H, Kuniyoshi K. Early vitrectomy to reverse macular dragging in a one-month-old boy with familial exudative vitreoretinopathy. Am J Ophthalmol Case Rep. 2019;15:100493. doi:10.1016/j.ajoc.2019.100493 [CrossRef]. Internet. PMID:31294129
  3. Nishimura M, Yamana T, Sugino M, et al. Falciform retinal fold as sign of familial exudative vitreoretinopathy. Jpn J Ophthalmol. 1983;27(1):40–53. https://pubmed.ncbi.nlm.nih.gov/6855020/. Internet. PMID:6855020
  4. Brady-McCreery KM, Hussein MAW, Paysse EA. Congenital toxoplasmosis with unusual retinal findings. Arch Ophthalmol. 2003;121(8):1200–1201. PMID: doi:10.1001/archopht.121.8.1200 [CrossRef]12912703
  5. Goldberg MF. Persistent fetal vasculature (PFV): an integrated interpretation of signs and symptoms associated with persistent hyperplastic primary vitreous (PHPV). LIV Edward Jackson Memorial Lecture. Am J Ophthalmol. 1997;124(5):587–626. doi:10.1016/S0002-9394(14)70899-2 [CrossRef]. Internet. PMID:9372715
  6. Nishina S, Suzuki Y, Yokoi T, Kobayashi Y, Noda E, Azuma N. Clinical features of congenital retinal folds. Am J Ophthalmol. 2012;153(1):81–7.e1. doi:10.1016/j.ajo.2011.06.002 [CrossRef]. Internet. PMID:
  7. Kashani AH, Brown KT, Chang E, Drenser KA, Capone A, Trese MT. Diversity of retinal vascular anomalies in patients with familial exudative vitreoretinopathy. Ophthalmology. 2014;121(11):2220–2227. doi:10.1016/j.ophtha.2014.05.029 [CrossRef]. Internet. PMID:25005911
  8. Salvo J, Lyubasyuk V, Xu M, et al. Next-generation sequencing and novel variant determination in a cohort of 92 familial exudative vitreoretinopathy patients. Invest Ophthalmol Vis Sci. 2015;56(3):1937–1946. PMID: doi:10.1167/iovs.14-16065 [CrossRef]25711638
  9. Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. 2007;22(4):211–217. PMID: doi:10.1080/08820530701745124 [CrossRef]18097984
  10. Amorelli GM, Ji MH, Orazi L, Molle F, Lepore D. Familial exudative retinopathy TSPAN12 positive presenting as bilateral retinal stalks: late structural and functional findings. Am J Ophthalmol Case Rep. 2019;15:100480. doi:10.1016/j.ajoc.2019.100480 [CrossRef]. Internet. PMID:
  11. Seo SH, Yu YS, Park SW, et al. Molecular characterization of FZD4, LRP5, and TSPAN12 in familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2015;56(9):5143–5151. PMID: doi:10.1167/iovs.14-15680 [CrossRef]26244290
  12. Rao FQ, Cai XB, Cheng FF, et al. Mutations in LRP5, FZD4, TSPAN12, NDP, ZNF408, or KIF11 Genes Account for 38.7% of Chinese Patients With Familial Exudative Vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017;58(5):2623–2629. doi:10.1167/iovs.16-21324 [CrossRef] PMID:28494495
  13. Tang M, Sun L, Hu A, et al. Mutation spectrum of the LRP5, NDP, and TSPAN12 genes in Chinese patients with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2017;58(13):5949–5957. PMID: doi:10.1167/iovs.17-22577 [CrossRef]29181528
  14. Zhu X, Sun K, Huang L, et al. Identification of novel mutations in the FZD4 and NDP genes in patients with familial exudative vitreoretinopathy in South India. Genet Test Mol Biomarkers. 2020;24(2):92–98. PMID: doi:10.1089/gtmb.2019.0212 [CrossRef]31999491
  15. Chen C, Sun L, Li S, et al. The spectrum of genetic mutations in patients with asymptomatic mild familial exudative vitreoretinopathy. Exp Eye Res. 2020;192:107941. doi:10.1016/j.exer.2020.107941 [CrossRef]. Internet. PMID:31987760
  16. Wu JH, Liu JH, Ko YC, et al. Haploinsufficiency of RCBTB1 is associated with Coats disease and familial exudative vitreoretinopathy. Hum Mol Genet. 2016;25(8):1637–1647. PMID: doi:10.1093/hmg/ddw041 [CrossRef]26908610
  17. Bamashmus MA, Downey LM, Inglehearn CF, Gupta SR, Mansfield DC. Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree. Br J Ophthalmol. 2000;84(4):358–363. PMID: doi:10.1136/bjo.84.4.358 [CrossRef]10729291
  18. Poulter JA, Ali M, Gilmour DF, et al. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86(2):248–253. doi:10.1016/j.ajhg.2010.01.012 [CrossRef]. Internet. PMID:20159112
  19. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreo-retinopathy. Nat Genet. 1993;5(2):180–183. doi:10.1038/ng1093-180 [CrossRef] Internet. PMID:8252044
  20. Shastry BS, Hejtmancik JF, Trese MT. Identification of novel missense mutations in the Norrie disease gene associated with one X-linked and four sporadic cases of familial exudative vitreoretinopathy. Hum Mutat. 1997;9(5):396–401. PMID: doi:10.1002/(SICI)1098-1004(1997)9:5<396::AID-HUMU3>3.0.CO;2-2 [CrossRef]9143917
  21. Mulligan KA, Cheyette BNR. Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry. Mol Neuropsychiatry. 2017;2(4):219–246. PMID: doi:10.1159/000453266 [CrossRef]28277568
  22. Grünblatt E, Nemoda Z, Werling AM, et al. The involvement of the canonical Wnt-signaling receptor LRP5 and LRP6 gene variants with ADHD and sexual dimorphism: association study and meta-analysis. Am J Med Genet B Neuropsychiatr Genet. 2019;180(6):365–376. PMID: doi:10.1002/ajmg.b.32695 [CrossRef]
  23. Kumar S, Reynolds K, Ji Y, Gu R, Rai S, Zhou CJ. Impaired neuro-developmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J Neurodev Disord. 2019;11(1):10. doi:10.1186/s11689-019-9268-y [CrossRef] PMID:31202261
  24. Williams BO. LRP5: from bedside to bench to bone. Bone. 2017;102:26–30. doi:10.1016/j.bone.2017.03.044 [CrossRef]. Internet. PMID:28341377
  25. Hartikka H, Mäkitie O, Männikkö M, et al. Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children. J Bone Miner Res. 2005;20(5):783–789. PMID: doi:10.1359/JBMR.050101 [CrossRef]15824851
  26. Willems B, Tao S, Yu T, Huysseune A, Witten PE, Winkler C. The Wnt co-receptor Lrp5 is required for cranial neural crest cell migration in zebrafish. PLoS One. 2015;10(6):e0131768. doi:10.1371/journal.pone.0131768 [CrossRef] PMID:26121341
  27. Toomes C, Bottomley HM, Jackson RM, et al. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004;74(4):721–730. PMID: doi:10.1086/383202 [CrossRef]15024691
  28. Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat. 2005;26(2):104–112. PMID: doi:10.1002/humu.20191 [CrossRef]15981244
  29. Robitaille JM, Gillett RM, LeBlanc MA, et al. Phenotypic overlap between familial exudative vitreoretinopathy and microcephaly, lymph-edema, and chorioretinal dysplasia caused by KIF11 mutations. JAMA Ophthalmol. 2014;132(12):1393–1399. PMID: doi:10.1001/jamaophthalmol.2014.2814 [CrossRef]25124931
  30. Coussa RG, Zhao Y, DeBenedictis MJ, Babiuch A, Sears J, Traboulsi EI. Novel mutation in CTNNB1 causes familial exudative vitreoretinopathy (FEVR) and microcephaly: case report and review of the literature. Ophthalmic Genet. 2020;41(1):63–68. doi:10.1080/13816810.2020.1723118 [CrossRef]. Internet. PMID:32039639
  31. Hull S, Arno G, Ostergaard P, et al. Clinical and Molecular Characterization of Familial Exudative Vitreoretinopathy Associated With Microcephaly. Am J Ophthalmol. 2019;207:87–98. doi:10.1016/j.ajo.2019.05.001 [CrossRef]. Internet. PMID:31077665
Authors

From Institute of Ophthalmology, Università Cattolica del Sacro Cuore, Rome, Italy (GMA, CB, FM, DL); Byers Eye Institute, Horngren Family Vitreo-retinal Center, Department of Ophthalmology, Stanford University School of Medicine, Palo Alto, California (MHJ); the Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York (MHJ); Italian National Center of Services and Research for Prevention of Blindness and Rehabilitation of the Visually Impaired, Rome, Italy (LO); and Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy (FM, DL).

The authors report no relevant financial disclosures.

Address correspondence to Marco H. Ji, MD, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl., New York, NY 10029; email: marcoji@stanford.edu.

Received: July 03, 2020
Accepted: July 09, 2020

10.3928/23258160-20201005-07

Sign up to receive

Journal E-contents