Late Reactivation of Retinopathy in a Treatment-Naive Female Adult Patient With History of Prematurity and ZNF408 Mutation

Introduction

Retinopathy of prematurity (ROP) is a vasoproliferative disorder affecting neonates that can profoundly interfere with visual development. ROP can manifest after the initial presentation as reactivation or recurrence. Reactivation refers to the appearance of acute features after either partial or complete regression of the original retinopathy but does not necessarily have to be recurrence of type 1 ROP.^1,2 Retinal detachments and exudates can also manifest as late sequelae of ROP.^3,4

The timeline for reactivation of ROP can vary, and much of the literature pertaining to late reactivation of ROP reflects individuals who had previously been treated for ROP, often with bevacizumab.^5–7 Clinically, reactivation occurs in most patients within 2–3 years following the final treatment.^8–12 However, longer intervals have also been reported in the literature.^5–7

While the prevalence of ROP does not seem to differ based on sex, most of the reported cases of later reactivation of ROP in the literature are reported to occur in female patients, despite reports showing that more male neonates are treated for ROP than female neonates.^13,14 There are no reports of genetic testing being performed in these cases. Familial exudative vitreoretinopathy (FEVR) is a rare hereditary disorder that affects the development of the retinal vasculature. ¹⁵ FEVR is a differential diagnosis in premature infants with retinopathy. The association of FEVR with prematurity falls under the proposed term ROPER, and genetic testing helps confirm the diagnosis.^16,17

Herein, we describe the first known case of late occurrence of retinopathy associated with prematurity, which was found to be associated with a genetic variant of unknown significance in the ZNF gene. Reactivation of ROP in this case was limited to the periphery of the retina. The patient had no retinal detachment and good vision at the time of presentation.

Case Report

A 30-year-old woman was referred to our clinic for retinal evaluation. A week prior, the patient had experienced floaters and flashes with blurry vision in the right eye and presented to a local emergency department, where she was seen by a retina specialist. Upon examination, she was found to have scar tissue and neovascularization of the retina. The patient was born prematurely at 26 weeks gestational age, weighing 1 pound 12 ounces. As a neonate, she received follow-up care at a children’s hospital and did not have a recorded diagnosis of ROP. At that time, she was discharged without requiring any ophthalmic treatment. She was lost to follow-up until presentation to our clinic at age 30 years.

At presentation, the patient reported a history of amblyopia of the right eye, and her left eye was patched until the fourth grade. Her medical history was otherwise unremarkable, with no history of diabetes. Her family history was notable for macular degeneration in her paternal grandfather, as well as a significant history of cardiomyopathy and coronary artery disease. Her Snellen best-corrected visual acuity (BCVA) was 20/50 −1 in the right eye and 20/25 +2 in the left eye. Her refractive error was −3.25 to 0.75 × 165° in the right eye and −0.50 to 1.00 × 70° in the left eye. Pressure, pupillary examination findings, visual field measurements, extraocular movements, and slit-lamp examination findings were unremarkable. Fundoscopic evaluation of the right and left eye revealed a clear anterior chamber, normal disc, and flat macula in both eyes.

Temporal avascularity, telangiectatic changes, and pigmentary changes in the temporal peripheral retina were noted in both eyes (Figure 1A). Optical coherence tomography (Spectralis; Heidelberg Engineering) showed hyaloid detachment in the right eye and attached hyaloid in the left eye, with normal foveal contour bilaterally (Figure 1B). Fluorescein angiography revealed 6 clock hours of avascularity in the temporal periphery of both eyes, with temporal leakage and a temporal ridge in the right eye, and a focal leakage inferior temporally in the left eye (Figure 1C).

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Figure 1.

Multimodal imaging findings in the right eye (left panels) and left eye (right panels) of a 30-year-old female patient with late reactivation of treatment-naive retinopathy of prematurity. (A) Color fundus photography demonstrates avascularity, telangiectatic changes, and pigmentary changes in the temporal peripheral retina of both eyes. (B) Optical coherence tomography shows hyaloid detachment in the right eye and attached hyaloid in the left eye. (C) Fluorescein angiography reveals 6 clock hours of avascularity in the temporal periphery of both eyes, 2 clock hours of temporal leakage and a temporal ridge in the right eye, and a focal leakage inferior temporally in the left eye.

The patient underwent genetic saliva testing (performed at Invitae Genetic Testing) to rule out other vitreoretinopathies, specifically FEVR. Sequence analysis and deletion/duplication testing included 22 genes: ATOH7, BEST1, CAPN5, COL11A1*, COL11A2*, COL18A1, COL2A1, COL9A1, COL9A2, COL9A3*, FZD4, KCNJ13, KIF11, LRP5, NDP, NR2E3, P3H2, RCBTB1, RS1, TSPAN12, VCAN, and ZNF408. A heterozygous variant in the ZNF408 gene, c.2137G>A (p.Val713Met), of uncertain significance, was identified in the patient; this mutation is known to be associated with autosomal-dominant FEVR. Genetic testing was conducted on both parents. The same mutation was identified in the father, while the mutation was absent in the mother. Retinal examination of the father revealed normal retinal structure and vasculature. The patient’s only sibling, her sister, declined genetic testing, but retinal examination was unremarkable. The patient was the only individual in the family born prematurely.

Treatment consisted of panretinal photocoagulation (PRP) laser therapy, which was guided by the clinical findings. PRP therapy was administered 3 times to the right eye, followed by 4 sessions of PRP administered to the left eye, due to disease progression in that eye. At 8 months’ follow-up after initial presentation, her vision improved in the right eye to a Snellen BCVA of 20/25 and remained stable in the left eye (Snellen BCVA 20/25). There was a mild vitreous hemorrhage that developed in the area of the leaking blood vessels in the right eye, which improved over time. Additionally, there was some improvement in the focal leakage identified on fluorescein angiography.

Conclusions

We present a rare case of adult recurrence of retinopathy in a treatment-naive female patient born at 26 weeks gestational age whose initial screening showed no ROP. The late reactivation of ROP in this case was associated with a mutation in the ZNF408 gene known to be linked to FEVR. This case is unique because the clinical and imaging findings were limited to the periphery of the retina, retinal detachment was absent, and the patient maintained good vision.

Uner et al reported 2 cases of late reactivation of ROP in treatment-naive subjects. The patients in that report experienced reactivation in their 40s and significant decline in their visual acuity, despite treatment with intravitreal bevacizumab and/or vitrectomy. The aggressive course of the ROP in those cases may be indicative of the involvement of FEVR. However, no genetic testing was performed. ¹² Brown et al described late reactivation of ROP in 11 patients between the ages of 29 years and 39 years who presented with exudative retinopathy on ocular exam and who had evidence of a retinal detachment. ⁶ Many of those patients underwent surgical treatment for the retinal detachment, but the authors concluded that the natural history of the disease is uncertain. Another study, by Tasman, describes an amalgam of pediatric and adult patients with a retinal detachment associated with ROP. ¹⁸ However, no genetic testing was performed in that cohort.

In our case, genetic testing revealed that the patient had a single variant of unknown significance in the ZNF408 gene, which was also present in the father. Although classified as a variant of uncertain significance, meaning that the available evidence is currently insufficient to determine the role of this variant in the disease, the combination of the genetic results and clinical findings—focal avascularity in the temporal periphery with focal leakage in both eyes, and a temporal ridge in the right eye—suggests a potential pathogenic role of this variant. Mutations within the ZNF408 gene have been associated with autosomal-dominant FEVR and have been described in patients with concomitant ROP. One case report documented a novel pathogenic variant of the ZNF408 gene that contributed to both FEVR and ROP in a 10-month-old premature boy. ¹⁶ The concurrence of FEVR and ROP has been termed ROPER, which often presents atypically with possibly more severe phenotypes.^19,20 Furthermore, a systematic review characterizing genotype associations with FEVR found that pathogenic variants of ZNF408 occurred in 1.6% of cases. ²¹ Mutations in the ZNF408 gene have also been identified as potentially damaging, according to the PolyPhen-2 score, and disease-causing, with presumable pathogenic mechanisms reflecting loss of protein function. ²² Thus, while ZNF408 pathogenic variants have not been implicated in all cases of ROPER, this variant appears to have a significant role in the development of many concomitant cases of FEVR and ROP, resulting in atypical and possibly more severe phenotypes. All the prior reported cases of potential ROPER presented in patients during childhood. This case is unique in that the reactivation of ROP was seen in a patient at age 30 years.

It is unknown if the patient’s retina vascularized in the neonatal period. Mild ROP may have been missed or the retina may have never fully vascularized, especially because the patient, who was born prematurely at gestational age 26 weeks, was considered at high risk of avascularity. Without retinal imaging by fluorescein angiography, the extent of peripheral avascularity may be underestimated.^23,24 At a certain age after premature birth, usually between postconceptual ages 55 weeks and 60 weeks, the clinical examination of the peripheral retina becomes challenging and remains a challenge for many years. ²⁵ Additionally, not all centers have adequate resources to allow for inspections of the patient’s retina under anesthesia. Our patient was followed up with eye patching until age 4 years, without identification of the avascularity. In cases with avascular retina associated with prematurity, with or without treatment, prophylactic treatment of the persistent avascular retina could be considered to prevent late recurrence and compensatory neovascularization.

Some of the cited cases may be associated with occult FEVR. There is increasing evidence that there is an overlap with ROP, with premature patients with retinopathy being found to have genetic mutations associated with FEVR. ²⁰ Although our case had a mutation associated with FEVR, her retinal features, as assessed by ophthalmic examination and imaging, were less consistent with those of FEVR. Specifically, there was no significant exudation, traction, or vessel straightening. Moreover, the area of avascular retina was not just temporal, but rather circumferential. There was no significant pruning in the periphery. Nevertheless, although the literature fails to offer valuable insights regarding the key factors predicting who will experience reactivation of retinopathy, those who present a component of both FEVR and ROP are likely at higher risk of reactivation.

Our patient was treated with laser in the right eye, followed by laser in the left eye a few months later. While there is the option to administer laser photocoagulation in both eyes concurrently, it is possible that epiretinal membrane formation, crunch, and retinal detachments can occur post–laser therapy.^26–28 Therefore, a decision was made to proceed with laser treatment for 1 eye at a time, to mitigate these risks, since the patient had good vision in both eyes. Visual stability was successfully maintained following the procedure in the right eye, with fluorescein angiography showing no signs of leakage in that eye.

In conclusion, this report describes a case of adult-onset retinopathy in a patient who was born prematurely at 26 weeks gestational age. Genetic testing revealed a variant in the ZNF408 gene, suggesting a possible concomitant FEVR diagnosis, likely resulting in a higher risk of reactivation of retinopathy in this patient. There is a need for long-term ophthalmologic follow-up for premature neonates who are under 30 weeks gestational age. Genetic testing should be considered in those with late reactivation of retinopathy associated with prematurity.