Familial exudative vitreoretinopathy (FEVR) is an inherited disorder characterized by poor development of the retinal vasculature, first described by Criswick and Schepens.1 Peripheral avascularity of the retina is a hallmark of the disease and can lead to neovascularization, vitreous hemorrhage, tractional retinal detachments, exudation, and amblyopia.2 Several genes involved in the Wnt signaling pathway in the retina are associated with the disease, but the most common are the FZD4, LRP5, TSPAN 12, and NDP genes, which are located on chromosomes 11q13–q23, 7q31, and Xp11.3–5
Chromosome 11q has also been associated with Jacobsen syndrome, a rare 11q deletion syndrome. The typical clinical findings of this syndrome include psychomotor retardation, hypertelorism, low set ears, cardiac defects, and abnormalities of the digits.6 However, several authors have reported ophthalmologic manifestations, which include bilateral total retinal detachments and avascularity of the peripheral retina.6,7
The 16p13.11 microdeletion syndrome is another rare entity, with an estimated prevalence at birth of 1:14,000 for carriers of the mutation who have phenotypic features.8 Although a collective phenotype for the 16p13.11 microdeletion has not been established, the syndrome has been associated with autism, developmental delay, epilepsy, and facial dysmorphism.8,9 A few have reported ocular symptoms, including strabismus, congenital cataracts, and nystagmus.9 We present the case of a child with a 16p13.11 microdeletion and an unbalanced t(2;11)(q37;q24) translocation who had retinal findings consistent with FEVR.
A 7-year-old boy with developmental delay, FEVR, intermittent esotropia, nystagmus, pathologic myopia, and amblyopia presented for follow-up evaluation of the retina. The patient initially presented to a pediatric ophthalmologist because his mother had concerns of a possible deviation. He was subsequently referred to the pediatric retina department due to concerning retinal findings of FEVR on funduscopic examination. This led to 360° laser photocoagulation bilaterally.
A referral to the genetics department was made at the time the patient was diagnosed as having FEVR. Basic FEVR panel and testing for facioscapulohumeral syndrome were negative. The geneticist pursued further testing due to developmental delay and cytogenetic testing and oligonucleotide, single nucleotide polymorphism assay from DNA in the peripheral blood were done at 6 years of age. Specifically, SNP microarray and a limited FISH with subtelomere probes for chromosomes 2q and 11q were performed. This revealed a 2.8 Mb 16p13.11 microdeletion, as well as a 10 Mb loss of 11q24.2 and 8.6 Mb gain of 2q37.1. There was no relevant family history. No abnormalities were detected on genetic evaluation and pedigree of the family. The mother had more children, all of whom were genetically normal.
On examination, visual acuity testing was limited to fix and follow in both eyes. Refractive error was −14.00 diopters in the right eye and −10.00 diopters in the left eye. Pupils and red reflex were normal. Horizontal nystagmus was present bilaterally and there was intermittent small to moderate angle esotropia in both eyes.
Slit-lamp examination of the anterior segment was unremarkable in both eyes. Dilated fundus examination showed tilted optic discs, dragging of the macula (left eye > right eye), 360° peripheral retina avascularity with chorioretinal laser scars, and no retinal detachment bilaterally. The left eye also presented with glial elevation temporally. These findings had remained stable since the age of 8 months when fundus photographs and fluorescein angiography were obtained during an examination under anesthesia (Figure 1).
(A and B) Optos ultra-wide–field color imaging (Optos, Inc., Marlborough, MA) showing tilted discs, dragging of the macula and temporal arcades (left eye more than the right eye), and 360° peripheral chorioretinal scars from laser photocoagulation in the right and left eye. (C and D) Optos ultra-wide–field fluorescein angiography highlights peripheral leakage at the vascular/avascular junction (red asterisks) in the right and left eye.
In this case report, we present a patient with ocular findings of FEVR, with a genetic evaluation showing 16p13.11 microdeletion and an unbalanced t(2;11)(q37;q24) translocation leading to 11q deletion syndrome. Chromosome 11q deletion syndrome is associated with several abnormalities in the retina. Sachdeva et al. described a patient with 11q deletion syndrome who presented with strabismus, high myopia, bilateral cataracts, and bilateral retinal detachments.7 Mahjoubi et al. reported the case of a 4-year-old girl with Jacobson syndrome and low vision. The authors hypothesized that the visual abnormalities may be related to mutations in the membrane-frizzled related protein (MFRP) and the C1q And Tumor Necrosis Factor Related Protein 5 (CTRP5) genes.10 MFRP is located on 11q23.3 and is thought to play a role in ocular development, whereas CTRP5 seems to interact with MFRP and has been associated with late-onset retinal degeneration.10
Interestingly, there is a reported case of 11q23 deletion, which was associated with avascularity of peripheral retina and dragging of the retinal vessels similar to what is seen with FEVR.6 This is not surprising because the main gene locus for FEVR, EVR1, is located on chromosome 11q13–q23.4,5 Although our patient's mutation was located on 11q24, because of the close proximity to 11q23 we propose that the t(2;11) translocation contributed to his manifestations of FEVR.
Given that our patient also had a 2q37 gain mutation and a microdeletion at 16p13.11, it is difficult to determine how these two other mutations affect the retinal findings. The 2q37 gain mutation is rare and there are few case reports.11 Therefore, the phenotype associated with trisomy 2q37 has not been determined and there are no ocular associations in the current literature.11 However, the 16p13.11 microdeletion includes the ABCC6 gene.8 Mutations in the ABCC6 gene are known to cause pseudoxanthoma elasticum, a connective tissue disorder that leads to calcification of elastic fibers in the skin, cardiovascular system, and retina.12 The ocular findings typically associated with this disorder include peau d'orange, angioid streaks, comet lesions, choroidal neovascularization over the macula, chorioretinal atrophy, and optic nerve head drusen.12 Although our patient did not show any findings of pseudoxanthoma elasticum, it is interesting that mutations in this gene have been proven to affect the retina.
Furthermore, gene locus 16p13 presents an interesting association with peripheral avascularity of the retina. The 16p13.11 microdeletion seen in our patient is located near the 16p13.3 microdeletion associated with Rubinstein–Taybi syndrome.13 Specifically, the transcriptional coactivator CREB-binding protein (CREBBP) gene on chromosome 16p13.3 has been shown to be a common cause of Rubinstein–Taybi syndrome.13 Peripheral avascularity of the retina has been reported in a case of Rubinstein–Taybi syndrome.14 Thus, it is possible that mutations located on 16p13 may lead to poor vascular development of the peripheral retina and could have contributed to the retinal abnormalities seen in our patient.
Based on the current report and review of the literature, we recommend a comprehensive ophthalmologic examination for patients with 11q deletion syndrome or 16p13 microdeletions to rule out FEVR-like retinal changes.
- Criswick VG, Schepens CL. Familial exudative vitreoretinopathy. Am J Ophthalmol. 1969;68:578–594. doi:10.1016/0002-9394(69)91237-9 [CrossRef]
- van Nouhuys CE. Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy. Am J Ophthalmol. 1991;111:34–41. doi:10.1016/S0002-9394(14)76893-X [CrossRef]
- Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180–183. doi:10.1038/ng1093-180 [CrossRef]
- 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;74:721–730. doi:10.1086/383202 [CrossRef]
- Poulter JA, Ali M, Gilmour DF, et al. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86:248–253. doi:10.1016/j.ajhg.2010.01.012 [CrossRef]
- Uto H, Shigeto M, Tanaka H, Uchida H, Ohnishi Y, Nishimura M. A case of 11q-syndrome associated with abnormalities of the retinal vessels. Ophthalmologica. 1994;208:233–236. doi:10.1159/000310496 [CrossRef]
- Sachdeva R, Sears JE, Rychwalski PJ. A novel case of bilateral high myopia, cataract, and total retinal detachment associated with interstitial 11q deletion. Ophthalmic Genet. 2010;31:84–88. doi:10.3109/13816811003628833 [CrossRef]
- Tropeano M, Andrieux J, Collier DA. Clinical utility gene card for: 16p13.11 microdeletion syndrome. Eur J Hum Genet. 2014;22(5).
- Ullmann R, Turner G, Kirchhoff M, et al. Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat. 2007;28:674–682. doi:10.1002/humu.20546 [CrossRef]
- Mahjoubi F, Razazian F, Torabi R. A case with 46,XX,del(11) (q23.2) karyotype and poor vision with literature review. Genetic Counseling. 2014;25:277–287.
- Batstone PJ, Simpson S, Bonthron DT, et al. Effective monosomy or trisomy of chromosome band 2q37.3 due to the unbalanced segregation of a 2;11 translocation. Am J Med Genet A. 2003;118A:241–246. doi:10.1002/ajmg.a.10204 [CrossRef]
- Gliem M, Zaeytijd JD, Finger RP, Holz FG, Leroy BP, Charbel Issa P. An update on the ocular phenotype in patients with pseudoxanthoma elasticum. Front Genet. 2013;4:14. doi:10.3389/fgene.2013.00014 [CrossRef]
- Petrij F, Giles RH, Dauwerse HG, et al. Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature. 1995;376:348–351. doi:10.1038/376348a0 [CrossRef]
- Jacobs DJ, Sein J, Berrocal AM, Grajewski AL, Hodapp E. Fluorescein angiography findings in a case of Rubinstein-Taybi syndrome. Clin Ophthalmol. 2012;6:1369–1371. doi:10.2147/OPTH.S31023 [CrossRef]