Familial exudative vitreoretinopathy (FEVR) is a rare inherited disorder of retinal angiogenesis, characterized by failure of peripheral retinal vascularization with non-perfusion, retinal traction, vitreous fibrosis, and loss of vision. This condition is genetically heterogeneous and can exhibit autosomal dominant, autosomal recessive, or X-linked inheritance. The clinical appearance can be remarkably asymmetric and considerable phenotypic variability can be observed, even within a family. The most severely affected patients are often blind during infancy, whereas those with mild disease have limited peripheral non-perfusion and preserved visual acuity.
The diagnosis of FEVR is primarily based on clinical features of bilateral peripheral retinal nonperfusion with retinal traction, most apparent on fluorescein angiography of the retina. Other retinal findings can include falciform retinal fold, retinal or vitreoretinal fibrosis, and vitreoretinal neovascularization.1 Family history of the disease could exist but the clinical severity can vary even within families.
Five genes have been identified that potentially lead to clinical features of FEVR, including Norrie disease protein (NDP) (NM_000266.3; MIM 300658), Frizzled 4 (FZD4) (NM_012193.3; MIM 604579), low density lipoprotein receptor-related protein 5 (LRP5) (NM_002335.2; MIM 603506), tetraspanin12 (TSPAN12) (NM_012338.3; MIM 613138), and zinc finger protein 408 (ZNF408).1 The association of an LRP5 mutation with FEVR was initially identified in 2004,2 and since then 49 unique mutations3 associated with both autosomal dominant1,2 and recessive inheritance4 have been described. We describe a novel missense change in the LRP5 gene in a child and father with FEVR.
Approval from the Wills Eye Hospital Institutional Review Board was obtained for this report. A 20-month-old boy was found to display xanthocoria in the right eye, with eventual exotropia (Figure 1A). Visual acuity was minimal fix and follow in the right eye and fix and follow in the left eye. Intraocular pressures were 18 mm Hg in both eyes. There was no iris or lens abnormality.
(A) Right xanthocoria and slight exotropia is noted. (B) Fundus photograph of the right eye showing extensive exudative retinopathy and shallow retinal detachment. (C) Fundus photograph of the left eye appeared normal. (D) Fluoroscein angiography montage of the right eye demonstrating prominent peripheral non-perfusion with telangiectatic vessels in the temporal region and with retinal staining from subretinal fluid. (E) Fluoroscein angiography of the left eye showing normally perfused macular region, but in the periphery there was mild vascular looping and non-perfusion.
Funduscopically, the right eye demonstrated extensive exudative maculopathy with shallow retinal detachment and peripheral telengiectatic retinal vessels extending temporally (Figure 1B). The left fundus appeared clinically normal (Figure 1C). Fluorescein angiography of the right eye revealed temporal retinal dragging, extensive peripheral retinal non-perfusion, and telangiectatic vessels (Figure 1D). Fluorescein angiography of the left eye showed minimal peripheral non-perfusion and vascular looping without dragging, telangiectasia, or leakage (Figure 1E).
Based on the bilateral, asymmetric features of exudative retinopathy, FEVR was suspected. Fundus examination and fluorescein angiography of the parents revealed normal findings in the mother and subtle evidence of FEVR with hyperacute branching and slight retinal vascular traction without leakage in the father. The patient was successfully treated with retinal cryotherapy and laser photocoagulation to areas of non-perfusion, leading to the resolution of exudative retinopathy. The left eye was observed. At 31 months of follow-up, the eyes remained stable.
The patient was genetically evaluated for four known FEVR genes: NDP, FZD4, LRP5, and TSPAN12. The patient showed no clinical or genetic features of fascioscapulohumeral muscular dystrophy. Genomic DNA samples were extracted from the peripheral blood and amplified by polymerase chain reaction for analysis. Bidirectional sequence was obtained for the coding regions and intron-exon boundaries of the NDP, FZD4, LRP5, and TSPAN12 genes and DNA sequence were analyzed and compared to published reference sequences (NM_000266.3;MIM 300658, NM_012193.3; MIM 604579, NM_002335.2; MIM 603506, NM_012338.3; MIM 613138). These methods are expected to be more than 99% sensitive for detecting sequencing mutations.
Results revealed that the child was negative for NDP, FZD4, and TSPAN12 mutations. The child was heterozygous for a c.2234 C>T nucleotide substitution in exon 10 of the LRP5 gene, resulting in a replacement of alanine codon (GCG) with a valine codon (GTG) at amino-acid position 745 (p.A745V). There was no other mutation in the rest of the LRP5 gene. The mother demonstrated no mutations in NDP, FZD4, LRP5, or TSPAN12, whereas the father was found to have the p.A745V missense change and mild retinal anomalies of FEVR. LRP5-associated osteoporosis was negative for this child and such testing was advised for the father.
Familial exudative vitreoretinopathy is an inherited, potentially blinding disorder of the retinal vascular system. This condition is inherited as an autosomal dominant trait in the majority of cases and can manifest with markedly different phenotypes, even among patients from the same family or between the two eyes of an affected individual.3 In some cases, FEVR is an autosomal recessive5 or X-linked disorder.6 Mutations in FZD4,7LRP5,7 and TSPAN128 generally cause an autosomal dominant form, although mutations in LRP59 can also cause autosomal recessive disease, whereas mutations in NDP6 cause X-linked forms of FEVR.
The LRP5 gene consists of 23 exons and encodes a 1,615–amino acid protein. The specific function of LRP5 remains unknown, but mutations in this gene can also cause a degenerative disorder in bone density, termed osteoporosis-pseudoglioma syndrome.10 In the current case, the patient demonstrated classic FEVR and was heterozygous for a novel LRP5 A745V missense change. This has not been reported previously as a disease causing mutation or as a benign polymorphism.
The NHLBI ESP Exome Variant Server reports that A745V was observed in 14 of 8,600 alleles from individuals of European background, indicating that it could be a rare benign variant in this population. The A745V amino acid substitution is conservative because both alanine and valine are neutral and non-polar residues. However, most in silico models predict that the A745V missense change would be a deleterious change. There is a nearby mutation in LRP5 (R752G) that has been associated with FEVR.11 The pathogenic role of A745V is further supported by the family history in this case because it was also observed in the subclinically affected father.
Genetic evaluation of patients with FEVR can lead to detection of a related mutation in 25% to 33% of cases. The literature reveals mutation in the LRP5 gene in 12% to 18% of patients,7,9TSPAN12 in 8% to 12% of patients with autosomal dominant FEVR,8,12,13FZD4 in 4% to 20% of patients with autosomal dominant FEVR,9,14 and NDP in approximately 13% of male patients with this disorder.15 Therefore, it is evident that there is a large percentage of patients with FEVR in whom the pathogenic genetic variants remain unidentified. Furthermore, mutations in the genes currently known to be associated with most cases of FEVR indicate incomplete knowledge of the causes of this disorder. Although FEVR is a rare disease, genetic investigation of the disease is of considerable importance for families and can also help to provide insight into the disease mechanism and an appreciation of basic biological processes in the anatomic and angiogenic development of the retina.
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