Micro-ophthalmos, posterior lenticonus, persistent fetal vasculature, and coloboma (MPPC) is a rare syndrome previously reported in a series of eight patients.1 MPPC eyes have been treated with lensectomy and vitrectomy, with improvement of visual acuity in some cases. There is no known genetic mutation associated with MPPC, but the syndrome shares phenotypic similarities with animal model knockouts of Wnt-pathway genes.2
Herein, we present a case of 6-week-old girl with MPPC in the right eye and morning glory disc anomaly and falciform retinal folds the left eye. The child has no other systemic abnormalities and no family history of blindness or congenital eye abnormalities. She was born full-term via uncomplicated vaginal delivery, received prenatal vitamins, and had a normal prenatal screening. Exome sequencing was performed and revealed a mutation in the ZNF408 gene, a previously unreported variation of undetermined significance (VUS). To our knowledge, this is the first report of a genetic mutation associated with MPPC.
A 6-week-old girl presented with a micro-opthalmic right eye (Figure 1A). She had no other medical history and was born at 39 weeks gestational age via uncomplicated vaginal delivery. Ophthalmic exam was significant for a corneal diameter of 6.0 mm in the right eye and 9.0 mm in the left eye. Anterior segment exam of the right eye revealed a significantly elongated lens with a vascularized stalk adherent to the posterior lens capsule (Figure 1B). Posterior segment exam on the right was significant for an inferonasal coloboma involving the optic nerve (Figure 1E). The fundus exam of the left eye was significant for a morning glory disc anomaly with inferotemporal and superotemporal radial retinal folds (Figures 1C and 1D). Fluorescein angiography demonstrated decreased perfusion in the peripheral retina in both eyes (Figures 1F and 1G). In addition, an anomalous vessel crossed the macula in the left eye (Figure 1G). No subretinal fluid was present in either eye. An MRI was performed and demonstrated the conical shape of the elongated lens in the right eye with the attached stalk (Figures 2A and 2B). A cystic cavity was present in the left orbit (Figure 2C). Targeted genetic sequencing of the genes Pax6 and Fz5 revealed no abnormalities. In an effort to identify a potential causative mutation, whole-exome sequencing (WES) was performed and revealed a VUS, c.1471A>G (p.T491A) in ZNF408. No other known mutations were identified.
(A) External photograph demonstrating microcornea of the right eye. (B) Anterior tip of the vascularized stalk in the right eye. (C) Fundus photo of the left eye, with inferotemporal and superotemporal radial folds. (D) Higher magnification photo of the morning glory disc anemology in the left eye. (E) Fundus photo of the right eye, demonstrating and inferonasal coloboma involving the optic nerve. (F) Fluorescein angiogram of the right eye showing anomalous vascular arcade with reduced vascular density. (G) Fluorescein angiogram of the left eye showing inferotemporal retinal fold, anomalous vessel crossing the macula, and avascular temporal periphery.
(A) T2 weighted sagittal section through the right eye showing small globe, large conical shaped lens with attached stalk. (B) T2 weighed sagittal section through the left eye showing a retrobulbar cyst. (C) Coronal section showing the conical shaped lens in the right eye and retrobulbar cyst in the left eye.
MPPC is a rare congenital eye disorder associated with poor but variable visual outcomes, and the underlying molecular genetics remain unknown. No genomic alterations have been associated with MPPC. We present a case of a 6-week-old girl with MPPC who was found on WES to have a VUS in the transcription ZNF408 but no other known pathogenic mutations. To our knowledge, this is the first report of a genetic mutation associated with MPPC. ZNF408 is a zinc-finger transcription factor highly expressed in the human retina,3 with strong expression in many retinal cell types, including photoreceptors, some neuronal subtypes, and blood vessels.4 Zinc-finger transcription factors are proteins that bind DNA and other proteins, and whose function is directly linked to the amino acid structure of their zinc finger domains.5 Genetic mutations in ZNF408 are associated with eye diseases. The missense heterozygous mutation H455Y has been associated with familial exudative vitreoretinopathy (FEVR) in a large Dutch pedigree,3 and the missense homozygous mutation R541C or a two-base pair deletion has been associated with retinitis pigmentosa 72 (RP72) in two unrelated Spanish families.4 In animal models, knocking down expression of ZNF408 in zebrafish led to reduced retinal vascularization during development.3 In the patient reported here, the mutation is T491A, which is a nonconservative mutation likely to have detrimental effects on protein function.
Our results suggest the possibility that MPPC is a Wnt-signaling pathway phenotype. This is based on three lines of evidence. First, ZNF408 is associated with FEVR, and mutations in the Wnt-pathway genes FZD4, LRP5, TSPAN12, and NDP account for up to 50% of all cases of FEVR.6–8 Secondly, knocking out ZNF408 in zebrafish leads to persistent fetal vasculature and poor retinal vascularization.3 Finally, mouse model knockouts of Wnt-pathway genes produce similar phenotypes to those observed in MPPC. Specifically, FZ5 defects result in persistent fetal vasculature, coloboma, micro-ophthalmos, and lenticonus.2 It is likely that MPPC and FEVR are distinct diseases that both originate from Wnt-pathway dysfunction. Animal studies have shown that knockouts of Wnt-pathway genes produce overlapping but nonidentical phenotypes.
We cannot completely exclude the possibility that other genomic variants responsible for this patient's presentation are not covered by the WES in this study. However, the identification of the VUS in ZNF408, combined with the known association between ZNF408 and FEVR, and vascular abnormalities in animal models, strongly implicate ZNF408 in this case of MPPC. Confirmation of Wnt pathway mutations in MPPC awaits WES of additional patients.
- Ranchod TM, Quiram PA, Hathaway N, Ho LY, Glasgow BJ, Trese MT. Microcornea, posterior megalolenticonus, persistent fetal vasculature, and coloboma: A new syndrome. Ophthalmology. 2010;117(9):1843–1847. doi:10.1016/j.ophtha.2009.12.045 [CrossRef]
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- 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]
- Avila-Fernandez A, Perez-Carro R, Corton M, et al. Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations. Hum Mol Genet. 2015;24(14):4037–4048. doi:10.1093/hmg/ddv140 [CrossRef]
- Pavletich NP, Pabo CO. Crystal structure of a five-finger GLI-DNA complex: New perspectives on zinc fingers. Science. 1993;261(5129):1701–1707. doi:10.1126/science.8378770 [CrossRef]
- Boonstra FN, van Nouhuys CE, Schuil J, et al. Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2009;50(9):4379–4385. doi:10.1167/iovs.08-3320 [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]