Familial exudative vitreoretinopathy (FEVR) is a hereditary disorder resulting from aberrations of retinal vascularization.1 It is classically bilateral with characteristic findings of peripheral nonperfusion, neovascularization, and tractional retinal detachment.1 The phenotype is variable and ranges in severity from being asymptomatic to complete blindness.1 Inheritance in FEVR is most commonly autosomal dominant, and associated features of high penetrance and variable expressivity are typical.1 Autosomal dominant FEVR results from mutations of the FZD4, LRP5, and TSPAN12 genes, whereas x-linked FEVR is caused by mutations of the NDP gene.1 Homozygous mutations of LRP5 are uncommon and result in autosomal recessive FEVR and, in some instances, osteoporosis pseudoglioma syndrome (OPPG), a rare condition characterized by juvenile-onset low bone density and congenital blindness.2,3
Persistent fetal vasculature, previously termed persistent hyperplastic primary vitreous, is an idiopathic unilateral persistence of fetal vasculature with no obvious genetic cause. It classically appears as a retrolental fibrovascular tissue connecting the posterior lens capsule and the optic disc in a microphthalmic eye and often shares clinical features with FEVR such as tractional retinal detachment, retrolental fibrovascular tissue, retinal folds, and cataract.4 The lack of a significant family history, unilateral ocular involvement, normal retinal vascularization in the fellow eye, and genetic testing can distinguish cases of persistent fetal vasculature from FEVR.4,5 We present novel mutations of LRP5 and TSPAN12 that resulted in the diagnosis of FEVR in the spectrum of OPPG in a case initially presumed to be persistent fetal vasculature.
A 6-month-old male infant was referred for evaluation of possible bilateral retinoblastoma. The patient was born full term at 39 weeks with a birth weight of 3,100 g. He had an uncomplicated prenatal and postnatal course, family history was unremarkable for ocular disease, and he had no siblings.
On initial ocular examination in March 2008, visual acuity was no fix-and-follow in both eyes. Corneal diameter was 11 mm in both eyes and intraocular pressure was 18 mm Hg in the right eye and 21 mm Hg in the left eye. Anterior segment examination revealed persistent tunica vasculosa lentis with deep anterior chamber in both eyes (Figures 1A–1B). On fundus examination, there was total tractional retinal detachment in both eyes with peripheral exudation in the right eye and subretinal hemorrhage in the left eye (Figures 1C–1D). Fluorescein angiography showed mild late leakage from tunica vasculosa lentis and diffuse leakage from fibrovascular membranes overlying the retina in both eyes. There was no intraocular mass on ultrasonography in both eyes and axial lengths were 19 mm in both eyes. The differential diagnosis included FEVR and persistent fetal vasculature. Funduscopic examination results of both parents were normal. Genetic testing was advised but declined, so the child was observed conservatively.
Simultaneous mutations of LRP5 and TSPAN12 in familial exudative vitreoretinopathy. (A–B) Persistent tunica vasculosa lentis was seen on anterior segment fluorescein angiography in the (A) right and (B) left eyes associated with late leakage. (C–D) Dilated fundus examination of both eyes showed total tractional pseudogliomatous retinal detachment with temporal and anterior retinal dragging toward the lens mimicking persistent hyperplastic primary vitreous. In addition, (C) peripheral exudation can be appreciated superiorly in the right eye and (D) subretinal hemorrhage inferiorly in the left eye.
At 10 months of age, the child demonstrated horizontal nystagmus, iris neovascularization, and posterior subcapsular cataract in both eyes. Fundus examination revealed bilateral total tractional retinal detachment with preretinal fibrovascular membrane causing anterior and temporal dragging toward the posterior lens capsule. A high clinical suspicion for FEVR prompted fluorescein angiography of both parents; the mother showed mild temporal dragging and the father had an unremarkable angiogram (Figure 2). Genetic testing was again advised and agreed to by both parents.
Fundus photographs and fluorescein angiography of parents. (A–B) Montage fundus photographs of the father were unremarkable and (C–D) fluorescein angiography did not reveal nonperfusion, neovascularization, dragging, or vascular anomalies. (E–F) Montage fundus photographs and (G–H) fluorescein angiography of the mother showed mild temporal dragging in both eyes without nonperfusion.
Genetic testing of the patient revealed two novel heterozygous mutations in LRP5 involving c.1678T>G at the cDNA level or p.Trp560Gly (W560G) at the protein level that was maternally inherited, and a separate, distinct mutation at c.3871G>T at the cDNA level or p.Asp1291Tyr (D1291Y) at the protein level that was paternally inherited. Both missense mutations in LRP5 were not previously reported as disease-causing mutations or benign polymorphisms. The W560G amino acid substitution is semi-conservative with a neutral and nonpolar residue (Trp) being replaced by a much smaller residue with the same properties (Gly). The position at which this substitution occurs is highly conserved within a YWTD spacer repeat domain. Other missense mutations in nearby condons (T552M, R570W, R570Q) have been reported in association with OPPG and autosomal recessive FEVR, respectively.6–8 In addition, another maternally inherited (heterozygous) novel mutation in TSPAN12 at c.307A>G at the cDNA level or (I103V) at the protein level was detected. The I103V missense change has also not been published or reported as benign polymorphisms. Its associated amino acid substitution is conservative with a neutral and nonpolar residue (Ile) being replaced by another residue (Val) with similar properties. The residue at which this substitution occurs is evolutionarily conserved and other missense mutations (L101H and C105R) have been reported in nearby codons in association with autosomal dominant FEVR.9,10 Genetic analyses for FZD4 and NDP were negative in the patient and both parents. Genetic testing for FZD4, LRP5, and TSPAN12 was performed by GeneDx (Gaithersburg, MD), whereas testing for NDP gene mutations was done at the Neurogenetics DNA Diagnostic Laboratory of Massachusetts General Hospital (Boston, MA). To determine genotypic-phenotypic correlation and inheritance pattern, familial linkage analysis and examination of all family members was recommended, but the family declined.
Although physical examination revealed generalized joint hypermobility, an initial bone mineral dual energy x-ray absorptiometry (DEXA) scan conducted in 2013 was normal. However, a repeat DEXA scan 1 year later revealed reduced lumbar spine bone mineral density for age with decreased lumbar bone mineral content (10.55 g), bone mineral density (0.34 g/cm2), and Z score (−3.52), confirming osteoporosis and our diagnosis of FEVR in the spectrum of OPPG. Initial full body x-ray was normal. Genetic counseling and observation were recommended due to poor visual prognosis secondary to chronic tractional retinal detachment and nystagmus and continued monitoring for bone density loss was emphasized.
The Wnt signaling pathway is a complex signaling cascade involved in retinal vascularization.1 In the canonical pathway, proper signal activation requires the interaction of Frizzled (FZD) protein and low-density lipoprotein (LRP), which function as the pathway's receptor and co-receptor, respectively.1 Genetic abnormalities of FZD4, LRP5, and less frequently NDP and TSPAN12 result in FEVR, a disease characterized by incomplete retinal vascularization.1 In 2002, Robitaille et al. confirmed the genetic etiology of FEVR when they found autosomal dominant mutations of FZD4 in families with known FEVR.11 The important interaction of LRP5 with FZD4 in the Wnt pathway led to consideration of LRP5 as a candidate gene in FEVR, and Toomes et al. confirmed LRP5 to be a cause of autosomal dominant FEVR.4 Jiao et al. later found homozygous mutations in LRP5 in three consanguineous families with FEVR and established an autosomal recessive pattern of inheritance.8 In addition, homozygous mutations of LRP5 can also lead to OPPG, a condition that is characterized by severe early-onset osteoporosis and congenital blindness secondary to microphthalmia, bilateral pseudogliomatous retinal detachment, cataract, and glaucoma.3,6–8
Children often present with severe fractures from minimal trauma, short stature, hypotonia, and joint hyperextensibility.3,6–8 Although OPPG is often an autosomal recessive disease, obligate carriers with heterozygous mutations also have reduced bone mass.2 In a report by Gong et al. analyzing LRP5 mutations causing OPPG in 28 families, those with homozygous mutations had a mean DEXA Z-score of −4.7, whereas obligate carriers (heterozygotes) had a mean Z-score of −1.4 compared to a Z-score of 1.0 for normal non-carriers.2 Although our patient harbored two distinct heterozygous mutations in LRP5 inherited separately from each parent of a nonconsanguineous marriage (compound heterozygote), he still exhibited features of OPPG with a Z-score comparable with patients carrying autosomal recessive LRP5 mutations (3.52 vs 4.7).2
Compound heterozygosity is a phenomenon wherein two distinct heterogeneous recessive alleles for the same gene are present in a single individual. Mutations in these recessive alleles cause severe disease in a homozygous state and less severe manifestations through heterozygous inheritance. However, the presence of abnormal and separate maternally and paternally inherited alleles, albeit in different loci, in a compound heterozygote produces a phenotype similar to individuals with homozygous mutations. Cheung et al. reported two novel missense mutations in a single family of a nonconsanguineous marriage wherein three of four children had features of OPPG.12 Genetic testing in this family showed two distinct heterozygous mutations of LRP5 in each parent, whereas the affected children were compound heterozygotes carrying preserved LRP5 mutations from each parent.12
Our patient presented with joint hyperextensibility, osteoporosis, and pseudogliomatous retinal detachments in both eyes and was suspected to have OPPG. Although the patient's DEXA scan was initially normal, as this case demonstrates, osteoporosis can develop at a later date.3 The early onset of severe and progressive vision loss in our case is a feature of OPPG and autosomal recessive FEVR.6–8 Furthermore, development of osteoporosis suggests that this patient's condition arose secondary to homozygous mutations of LRP5. However, the patient's genetic analysis clearly disputes this method of inheritance. Familial linkage analysis and examination of family members would have clarified the inheritance pattern of the three novel mutations (two LRP5 and one TSPAN12) from his parents and explain which mutation is mainly responsible for his phenotype, but the family did not agree to further testing. Nevertheless, speculations can be made from known facts about OPPG and the different disease-causing mutations in FEVR.
Our patient clinically presented with features of advanced FEVR at an early age and juvenile osteoporosis; hence, it is evident that compound heterozygosity for LRP5 genetic mutations played a role in his phenotype.12 The question is whether the TSPAN12 mutation is an expressed genotype that contributed to his ocular findings. The first family ever reported carrying disease-causing mutations in TSPAN12 showed autosomal dominant inheritance of FEVR.9,13 More extensive TSPAN12 screening in the same family later led to identification of homozygous mutations in the most severely affected members compared to mild manifestations in heterozygous members.14 Because the patient was born from a nonconsanguineous marriage, there was paternal absence of TSPAN12 mutation, and the patient was heterozygous for the maternally inherited TSPAN12 mutation, we can speculate that the early severe manifestation of FEVR in this setting does not support TSPAN12 as the only disease-causing mutation in our case. However, it is possible that simultaneous mutations of different genetic loci, such as LRP5 and TSPAN12 in our patient, led to a more severe phenotype as described previously by Qin et al.15
We present a case of bilateral total tractional retinal detachment with normal standard fluorescein angiography of both parents leading to an initial diagnosis of bilateral persistent fetal vasculature. The correct diagnosis was made after repeat wide-field angiography detected mild nonperfusion and peripheral dragging in the mother, prompting genetic testing and diagnosis of FEVR caused by compound heterozygous mutations in LRP5 and heterozygous mutations in TSPAN12. The presence of juvenile osteoporosis suggests the diagnosis of FEVR occurs in the spectrum of OPPG. This case illustrates the intricacies and difficulties in establishing a correct diagnosis with clinical examination alone and the role of genetic testing and wide-field angiography, especially when parental disease is mild. It also demonstrates the genotype-phenotype variability in FEVR and the role of familial linkage analysis to establish mode of inheritance. However, it should be emphasized that the diagnosis of FEVR is usually clinical, with genetic testing used for confirmation. This is important because a significant number of causative mutations related to FEVR are still unknown.
- Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. 2007;22:211–217. doi:10.1080/08820530701745124 [CrossRef]
- Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–523. doi:10.1016/S0092-8674(01)00571-2 [CrossRef]
- Lee DH, Wenkert D, Whyte MP, Trese MT, Cruz OA. Congenital blindness and osteoporosis-pseudoglioma syndrome. J AAPOS. 2003;7:75–77. doi:10.1016/S1091-8531(03)00051-X [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]
- Shastry BS. Persistent hyperplastic primary vitreous: congenital malformation of the eye. Clin Experiment Ophthalmol. 2009;37:884–890. doi:10.1111/j.1442-9071.2009.02150.x [CrossRef]
- Narumi S, Numakura C, Shiihara T, et al. Various types of LRP5 mutations in four patients with osteoporosis-pseudoglioma syndrome: identification of a 7.2-kb microdeletion using oligonucleotide tiling microarray. Am J Med Genet A. 2010;152A:133–140. doi:10.1002/ajmg.a.33177 [CrossRef]
- Ai M, Heeger S, Bartels CF, Schelling DKOsteoporosis-Pseudoglioma Collaborative Group. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77:741–753. doi:10.1086/497706 [CrossRef]
- Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum Genet. 2004;75:878–884. doi:10.1086/425080 [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]
- Yang H, Xiao X, Li S, Mai G, Zhang Q. Novel TSPAN12 mutations in patients with familial exudative vitreoretinopathy and their associated phenotypes. Mol Vis. 2011;17:1128–1135.
- Robitaille J, MacDonald ML, Kaykas A, et al. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32:326–330. doi:10.1038/ng957 [CrossRef]
- Cheung WMW, Jin LY, Smith DK, et al. A family with osteoporosis due to compound heterozygosity of two novel mutations in the LRP5 gene. Bone. 2006;39:470–476. doi:10.1016/j.bone.2006.02.069 [CrossRef]
- Nikopoulos K, Gilissen C, Hoischen A, et al. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86:240–247. doi:10.1016/j.ajhg.2009.12.016 [CrossRef]
- Poulter JA, Davidson AE, Ali M, et al. Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR). Invest Ophthalmol Vis Sci. 2012;53:2873–2879. doi:10.1167/iovs.11-8629 [CrossRef]
- 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;26:104–112. doi:10.1002/humu.20191 [CrossRef]