Familial exudative vitreoretinopathy (FEVR) is a rare hereditary ocular disorder characterized by incomplete or abnormal development of peripheral retinal vasculature. Although the most common form of inheritance is autosomal dominant, FEVR is also observed with autosomal recessive and X-linked inheritance. Approximately 50% of FEVR cases have been linked to five genes: NDP, LRP5, FZD4, ZNF408, and TSPAN12.1–4 These genes are associated with the wingless-related integration site (Wnt) signaling pathway, a critical pathway for the development of retinal vasculature. A pathogenic variant in any one of these genes may disrupt normal retinal vasculogenesis. Furthermore, the type and number of pathogenic variants may influence the severity of disease and a patient's clinical course. Genetic analysis in patients with FEVR assists with diagnosis, prognosis, and genetic counselling for patients and their family members. In this report, we identify a novel pathogenic variant in the NDP gene not previously described in the literature.
A 3-year-old male presented to the Pediatric Retina service after his left eye began “drifting outwards” 3 months prior. He was born at 38 weeks gestation after an uncomplicated pregnancy. His medical history was otherwise non-contributory. Family history was notable for an early retinal detachment in his maternal uncle at age 18.
His distance visual acuity was 20/40 in the right eye and 20/50 in the left eye (OS). At near, his vision was 20/20 in both eyes (OU). Pupils were normal, he had full range of ocular movements OU, and his anterior segment exam was normal. Dilated fundus exam was notable for an irregular nerve margin, peripheral whitening, and temporal dragging of the retina OS. Fluorescein angiography (FA) revealed peripheral avascularity with small vessel leakage and neovascularization OU (Figure 1). Therefore, the patient was treated with laser photocoagulation in the areas of nonperfusion (Figure 2). His mother's dilated fundus examination was remarkable for straightening of the temporal vessels and an anomalous vitreous insertion OS. The mother's FA also showed peripheral avascularity and leakage OU (Figure 3). His maternal grandmother also had peripheral avascularity and trace leakage OU on FA. The patient's sister had a normal exam and FA. His maternal aunt did not undergo examination.
Color fundus images and late-phase fluorescein angiography of the proband before treatment. (A) Right eye: Color fundus image showing a relatively normal posterior pole. (B) Left eye: Color fundus image showing straightening of the retinal vasculature and temporal drag of the nerve and macula structures. (C) Right eye: Fluorescein angiography with an avascular nonperfused temporal retina and leakage. (D) Left eye: Fluorescein angiography with an avascular temporal retina and leakage.
Color fundus images and late-phase fluorescein angiography (FA) of the proband after treatment. (A) Right eye: Color fundus image now with peripheral laser scars. (B) Left eye: Color fundus image with peripheral laser scars. (C) Right eye: FA with peripheral laser scars and inferior leakage. (D) Left eye: FA with peripheral laser scars.
Color fundus images and late phase fluorescein angiography of the probands mother. (A) Right eye: Normal-appearing fundus. (B) Left eye: Evidence of vascular straightening. (C) Right eye: Peripheral leakage and nonperfusion. (D) Left eye: Peripheral leakage and nonperfusion.
Peripheral blood was collected from the patient, his siblings, his maternal uncle, his maternal aunt, and his maternal grandmother. All samples were sent to Baylor Genetics (Houston, TX) and Molecular Vision Laboratory (Portland, OR). Next-generation sequencing of a panel of 19 genes known to be associated with peripheral vascular agenesis was performed on each sample. His mother did not undergo genetic testing. Genetic analysis revealed a novel variant in the NDP gene on chromosome X, c.118A>G. The patient and his maternal uncle were both hemizygous for this variant, the grandmother was heterozygous, and both sisters were homozygous wild-type (Figure 4). This pathogenic variant is predicted to cause a substitution of methionine with valine at the fortieth amino acid of the protein (M40V). A diagnosis of X-linked FEVR was made.
Family pedigree: NDP gene on chromosome X, c.118A>G, M40V.
After a young boy presented with strabismus, we identified a novel pathogenic variant of the NDP gene in a family with FEVR. As in other disorders of retinal vascularization like retinopathy of prematurity (ROP), peripheral avascularity is the defining feature of FEVR. Patients with Wnt-signaling pathogenic variants may have history of prematurity, and sometimes, this can contribute to complex ROP phenotypes, so widefield FA is useful for screening family members.10 Though affected individuals can be asymptomatic, neovascularization at the border of the avascular retina can lead to bleeding, fibrosis, traction, and additional complications. Retinal detachments, as seen in the patient's uncle, can be tractional, rhegmatogenous, or serous and occur in 21% to 64% of cases.5
Though FEVR is commonly inherited in an autosomal dominant manner, pathogenic variants in NDP are known to confer an X-linked form of the disease, the inheritance pattern seen in this family. The NPD gene encodes the Norrin protein, which binds to a receptor complex of the Wnt pathway.6 This signaling cascade has been shown to be important in the development and maintenance of the vasculature of the retina. Pathogenic variants that alter the conformation of the NPD protein disrupt its ability to act as a ligand for the Wnt receptor complex, resulting in abnormal retinal vasculogenesis.7 Disulfide bonds may be particularly important for mediating Norrin-Wnt complex interactions, and pathogenic variants that disrupt these bonds may create more profound disease.8
Some studies suggest that, compared to the other four genes known to cause FEVR, pathogenic variants in the NDP gene confer more severe phenotypes. More than 80-point pathogenic variants, translocations, inversions, and deletions have been described in the NPD gene with a variety of resulting diseases.9 In addition to FEVR, NPD pathogenic variants have also been associated with Norrie disease, Coats disease,9 and retinopathy of prematurity.10–12 Berger and Ropers suggested that more impactful NPD pathogenic variants, such as deletions and truncations, diminish NPD protein function significantly and, therefore, cause Norrie disease. Conversely, milder missense pathogenic variants can cause either FEVR or Norrie disease.9
However, even identical pathogenic variants can result in different phenotypic severities, as the family discussed in this case demonstrated. The proband showed extensive vascular straightening and proliferative disease on FA, illustrated in Figure 1. Despite the same genetic pathogenic variant, examination of his mother revealed less-extensive disease, and his uncle did not develop complications until a later age. This variety is likely due to either X chromosome mosaicism in the retina or skewed X chromosome inactivation in the mother and the absence of this in the male patients.13
The variability seen within families is also seen within individuals. In FEVR, it is well-documented that one eye may be severely affected, whereas the fellow eye is asymptomatic.5 Given this wide spectrum of disease, it is likely that environmental factors and molecular modifiers play a significant role in phenotypic expression. Nevertheless, no studies have isolated significant environmental factors or molecular modifiers in NPD pathogenic variants.
Through the evaluation of a young boy and his family, we have identified a novel pathogenic variant in the NPD gene that leads to X-linked FEVR. The precise relationship between genotype and phenotype in this disease remains ambiguous, and it is important to continue to investigate the molecular basis FEVR. Ultimately, fully characterizing the genetic changes involved will enable more accurate diagnoses, prognoses, and genetic counseling for patients and their families.
- Collin RW, Nikopoulos K, Dona M, et al. ZNF408 is mutated in familial exudative vitreoretinopathy and is crucial for the development of zebrafish retinal vasculature. Proc Natl Acad Sci U S A. 2013;110(24):9856–9861. doi:10.1073/pnas.1220864110 [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(2):240–247. doi:10.1016/j.ajhg.2009.12.016 [CrossRef]
- 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]
- Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat. 2010;31(6):656–666. doi:10.1002/humu.21250 [CrossRef]
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- MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: Components mechanisms, and diseases. Dev Cell. 2009;17(1):9–26. doi:10.1016/j.devcel.2009.06.016 [CrossRef]
- Xu Q, Wang Y, Dabdoub A, et al. Vascular development in the retina and inner ear: Control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116(6):883–895. doi:10.1016/S0092-8674(04)00216-8 [CrossRef]
- Berger W, Ropers HH. Norrie disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. McGraw Hill: New York; 2001;5977–5985.
- Black GC, Perveen R, Bonshek R, et al. Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet. 1999;8(11):2031–2035. doi:10.1093/hmg/8.11.2031 [CrossRef]
- Shastry BS, Pendergast SD, Hartzer MK, Liu X, Trese MT. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol. 1997;115(5):651–655. doi:10.1001/archopht.1997.01100150653015 [CrossRef]
- Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis. 2005;11:501–508.
- Rao F, Cai X, Cheng F, 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]
- Shastry BS, Hiraoka M, Trese DC, et al. Norrie disease and exudative vitreoretinopathy in families with affected female carriers. Eur J Ophthalmol. 1999;9(3):238–242. doi:10.1177/112067219900900312 [CrossRef]