Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Wnt-Spectrum Vitreoretinopathy Masquerading as Congenital Toxoplasmosis

Natalia F. Callaway, MD, MS; Audina M. Berrocal, MD

Abstract

Wnt-spectrum vitreoretinopathies are a group of rare inherited disorders of retinal angiogenesis that include familial exudative vitreoretinopathy/Norrie disease and are most commonly autosomal dominant; however, they can rarely present with other inheritance patterns that are more difficult to diagnose. The authors describe a case of an uncle misdiagnosed as congenital toxoplasmosis for decades and his 2-month-old nephew presenting with bilateral retinal detachments. Genetic analysis revealed an NDP gene mutation in the child and the uncle, as well as heterozygosity of the mother confirming a Wnt-spectrum vitreoretinopathy. This report describes the evaluation, diagnosis, and importance of early laser stabilization of this disorder.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:446–450.]

Abstract

Wnt-spectrum vitreoretinopathies are a group of rare inherited disorders of retinal angiogenesis that include familial exudative vitreoretinopathy/Norrie disease and are most commonly autosomal dominant; however, they can rarely present with other inheritance patterns that are more difficult to diagnose. The authors describe a case of an uncle misdiagnosed as congenital toxoplasmosis for decades and his 2-month-old nephew presenting with bilateral retinal detachments. Genetic analysis revealed an NDP gene mutation in the child and the uncle, as well as heterozygosity of the mother confirming a Wnt-spectrum vitreoretinopathy. This report describes the evaluation, diagnosis, and importance of early laser stabilization of this disorder.

[Ophthalmic Surg Lasers Imaging Retina. 2018;49:446–450.]

Introduction

Wnt-spectrum vitreoretinopathies are a group of rare genetic disorders, including familial exudative vitreoretinopathy (FEVR) and Norrie disease, of retinal angiogenesis where the peripheral retina fails to vascularize resulting in ischemia and neovascularization.1,2 The majority of patients exhibit severe visual impairment as a consequence of progressive complications, including cataracts, macular dragging, retinal detachment, and amblyopia.3–6

FEVR/Norrie was classically described as an autosomal dominant condition,7 but cases have been reported with nearly all modes of inheritance.8 Advances in molecular genetic testing have assisted in the diagnosis and our understanding of pediatric vitreoretinal disorders related to disorders of the Wnt-signaling pathway.

Here, we present a rare case of an uncle misdiagnosed as congenital toxoplasmosis for decades and his 2-month-old nephew presenting with bilateral retinal detachments ultimately diagnosed with a Wnt-spectrum vitreoretinopathy.

Case Report

A 15-year-old male from Cuba presented to the retina clinic in 1976 with count fingers vision in the right eye and hand motion vision in the left eye. There was no family history of genetic disease or blindness. The patient reported stable vision for years prior to presentation. Initial examination demonstrated eccentric fixation, nystagmus, a positive afferent pupillary defect (APD) in the right eye, normal intraocular pressure (IOP), and normal anterior segments. Fundus examination revealed a large macular staphyloma and a preretinal fold with a tractional retinal detachment (TRD) status post-scleral buckle in the right eye (per history had a scleral buckle in Cuba at age 7, no records available) and an extensive TRD in the left eye. The patient had received oral anti-toxoplasmosis therapy in Cuba and was followed with serial retinal examinations that remained stable.

Forty years later, the 2-month-old, full-term male nephew of the first patient was referred to pediatric vitreoretinal clinic for evaluation of retinal folds noted at 6 weeks of age. Family history was significant for the above-mentioned maternal uncle diagnosed with congenital toxoplasmosis.

The child exhibited horizontal nystagmus but no syndromic features. Examination under anesthesia (EUA) revealed normal IOP, an axial length of 17.6 mm in both eyes, and normal anterior segments. Intraoperative photos (Figure 1) and widefield fluorescein angiography (FA) (Figure 2) revealed an avascular peripheral retina with irregular vessels at the vascular/avascular retinal interface in both eyes. TRDs involving the macula with foveal dragging temporally were seen in both eyes, with the left being worse than the right. The patient was promptly treated with laser photocoagulation to the ischemic periphery (Figure 3).

Montage of intraoperative color fundus photos. Right eye (A) with a prominent retinal fold emanating from the optic disc to the temporal peripheral retina, dragging the macula temporally with a tent-like tractional retinal detachment (TRD). Left eye (B) with a more severe retinal fold off the disc with a TRD involving all quadrants of the posterior pole associated with preretinal hemorrhage, dragging of the macula, and retinal fibrosis.

Figure 1.

Montage of intraoperative color fundus photos. Right eye (A) with a prominent retinal fold emanating from the optic disc to the temporal peripheral retina, dragging the macula temporally with a tent-like tractional retinal detachment (TRD). Left eye (B) with a more severe retinal fold off the disc with a TRD involving all quadrants of the posterior pole associated with preretinal hemorrhage, dragging of the macula, and retinal fibrosis.

Intraoperative widefield fluorescein angiography (FA). Right eye (A) with circumferential peripheral avascular retina with irregular vessels at the perfused border. There is a retinal fold with a tractional retinal detachment off the disc with dragging of the macula temporally. The left eye (B) reveals multiple areas of tractional retinal detachment with a large central retinal fold involving the macula. The visible periphery appears avascular with significant blockage by preretinal hemorrhage.

Figure 2.

Intraoperative widefield fluorescein angiography (FA). Right eye (A) with circumferential peripheral avascular retina with irregular vessels at the perfused border. There is a retinal fold with a tractional retinal detachment off the disc with dragging of the macula temporally. The left eye (B) reveals multiple areas of tractional retinal detachment with a large central retinal fold involving the macula. The visible periphery appears avascular with significant blockage by preretinal hemorrhage.

Montage of intraoperative color fundus photos. After successful treatment with laser photocoagulation to the ischemic periphery in the right (A) and left (B) eyes.

Figure 3.

Montage of intraoperative color fundus photos. After successful treatment with laser photocoagulation to the ischemic periphery in the right (A) and left (B) eyes.

Widefield FA of available family members exhibited normal vasculature in the father and a straightening of the vasculature in the mother and sister. The maternal uncle was brought to the pediatric vitreoretinal clinic and found to have a chronic TRD with a similar retinal fold emanating from the optic disc in the right eye (Figure 4) and a complete funnel retinal detachment in the left.

Widefield fundus photograph of uncle. Right eye demonstrates diffuse chorioretinal atrophy and a tractional retinal detachment off the nerve involving the macula. The view to the periphery is limited.

Figure 4.

Widefield fundus photograph of uncle. Right eye demonstrates diffuse chorioretinal atrophy and a tractional retinal detachment off the nerve involving the macula. The view to the periphery is limited.

The patient and willing family members (mom, uncle) underwent genetic testing for FEVR/Norrie genes (NDP, FZD4, LRP5, TSPAN12, and ZNF408) at Casey Eye Institute Molecular Diagnostics Laboratory. The analysis confirmed that the patient was positive for the NDP exon 3 missense mutation (c.362G>T) associated with Wnt-spectrum vitreoretinopathies that include Norrie disease and X-linked FEVR. Linkage analysis verified carrier status for the mother and hemizygous mutation in the uncle for the same gene confirming X-linked inheritance.

Discussion

Here, we present an unusual case of misdiagnosed congenital toxoplasmosis later found to be a familial X-linked Wnt-spectrum vitreoretinopathy. The maternal uncle presented at age 7 in Cuba with bilateral TRDs diagnosed with congenital toxoplasmosis and followed for 40 years with this diagnosis. It was not until advancements in genetic testing and the presentation of his 2-month-old nephew that the diagnosis of an NDP mutation consistent with Wnt-spectrum vitreoretinopathy that includes X-linked FEVR and Norrie disorders was established.

The clinical appearance of the fundus during EUA, with a bilaterally avascular peripheral retina and TRDs with retinal folds, strongly suggested an inherited process and a family history of a blind maternal uncle carrying a diagnosis of toxoplasmosis prompted genetic testing. The differential included Norrie's disease, incontinentia pigmenti, Warburg syndrome, bilateral persistent fetal vasculature, and FEVR. These conditions are difficult to distinguish solely with clinical examination and recent advances in genetic testing assist in more conclusive diagnosis.

Wnt-spectrum vitreoretinopathies are a rare group of genetic diseases caused by dysregulated retinal vascular development.1–3 Aberrant angiogenesis gives rise to an avascular and ischemic peripheral retina that releases vascular endothelial growth factor-A, promoting neovascularization and precipitating the secondary complications of the disorder including retinal fibrosis, detachments, and folds that ultimately lead to vision loss.4–6 Classically, FEVR is inherited in an autosomal dominant pattern; however, other inheritance patterns, including X-linked FEVR and Norrie as seen in this case, have been reported.8–10 The condition is a genetically heterogeneous disease ranging from asymptomatic peripheral retinal changes (as seen in mom) to profound vision loss. Even among patients with the same genetic mutation, expressivity can be decidedly variable with marked differences between family members and asymmetry between the eyes, as demonstrated in this family.11,12

FEVR, Norrie disease, and other vitreoretinopathies have been associated with mutations in the Wnt-signaling pathway, which is thought to have a critical role in developmental biology and specifically retinal angiogenesis.13 Thus, these entities may actually represent a spectrum of disorders affecting various components of the Wnt pathway termed Wnt-spectrum vitreoretinopathies or NDP-related retinopathies.14 In our case genetic testing confirmed a mutation in the NDP gene. The pedigree demonstrated a mother who was a carrier and an uncle who was heterozygous for the same mutation thus, an X-linked pattern of inheritance was confirmed. Family members were informed of the condition and offered examination and genetic counseling. One case series reported poorer visual outcomes among X-linked cases than the autosomal dominant variant suggesting more frequent examinations may be appropriate in this family.15

As with all pediatric vitreoretinal disorders, early identification and treatment with thermal laser therapy, cataract extraction or pars plana vitrectomy can optimize vision potential for these children.16–18 This case report alerts us to rethink long-standing diagnoses in the presence of new clinical findings among family members with the aid of genetic testing.

Advanced classification and study of this rare condition may not only improve our understanding of molecular retinal angiogenesis pathways critical in a variety of retinal disease, but it may also facilitate the development of treatment strategies that preserve or restore vision in the future.

References

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Authors

From Bascom Palmer Eye Institute, Miami.

The authors report no relevant financial disclosures.

This study was supported by the NIH Center Core Grant P30EY014801 and a Research to Prevent Blindness Unrestricted Grant to Bascom Palmer Eye Institute.

Address correspondence to Audina M. Berrocal, MD, Professor of Clinical Ophthalmology, University of Miami Bascom Palmer Eye Institute, 900 NW 17th Street, Miami, FL 33136; email: aberrocal@med.miami.edu.

Received: August 22, 2017
Accepted: January 22, 2018

10.3928/23258160-20180601-10

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