Abstract
Purpose:
This report discusses a patient with Leber congenital amaurosis who presented with severe bilateral Coats-like reaction and 3 novel sequence variants in 2 different genes.
Methods:
The patient underwent complete ophthalmic and retinal evaluations including fluorescein angiography and optical coherence tomography as well as genetic studies. She was treated with intravitreal injection of intravitreal bevacizumab and laser photocoagulation.
Results:
Genetic analysis of the patient identified 2 novel sequence variants in the CEP290 (centrosomal protein 290) gene and another novel sequence variant in the RPGRIP1 (RPGR interacting protein 1) gene.
Conclusions:
The clinical presentation of Coats-like reaction in Leber congenital amaurosis can be associated with sequence variants in certain genes. The presence of multiple gene sequence variants in this patient may have contributed to the severity of disease.
Keywords: Coats-like reaction, genetic study, Leber congenital amaurosis, novel sequence variant
Introduction
Leber congenital amaurosis (LCA) is a group of genetically and phenotypically heterogeneous inherited retinal dystrophies. Originally described by Leber in 1869, 1 it is characterized by profound infantile vision loss or impairment, sensory nystagmus, poor pupillary light responses, and absent or abnormal electrical signals on electroretinogram. LCA is a rare retinal dystrophy but accounts for 5% or more of all inherited retinal dystrophies and approximately 20% of legally blind children worldwide. 1,2 We present an unusual case of LCA with Coats-like response and 3 novel sequence variants in 2 different genes.
Methods
Case Report
A 26-year-old Brazilian woman with a medical history significant for LCA, renal failure, renal transplant, papillary thyroid carcinoma, and non-Hodgkin lymphoma initially presented to the clinic with a 1-month history of increasing cloudy vision in her left eye. The patient denied any ocular pain but stated that she was no longer able to identify objects with her left eye. Her examination was significant for a visual acuity of hand motion in the right eye and light perception in the left eye, pendular nystagmus, and pupils nonreactive to light bilaterally. Funduscopic examination revealed bilateral vessel attenuation, retinal pigment epithelial changes, exudation, and retinal detachments in the inferior peripheral retina, all of which were worse in the left eye. Findings were consistent with Coats-like response in the context of LCA.
Results
At a 3-month follow-up visit, visual acuity and previous fundoscopic findings remained stable, and the patient began receiving a series of off-label intravitreal bevacizumab (Avastin, Genentech Inc, San Francisco, CA) injections. During this time, the patient’s vision improved to hand motion in both eyes. To better control the bilateral Coats-like exudative vasculopathy, the patient received laser photocoagulation combined with intravitreal Avastin injections for 1 year from initial presentation. Fundoscopic examination of both eyes during the procedure showed bilateral vessel attenuation, retinal pigment epithelial changes, exudation, and retinal detachments. Fluorescein angiography revealed areas of peripheral and mostly inferior leakage in both eyes (Figure 1).
Figure 1.
Optic disc pallor, vessel attenuation, and pigmentary changes are consistent with advanced Leber congenital amaurosis. Extensive retinal exudates and serous retinal detachment are evident in the inferior retina of both eyes. (Left: right eye; top right: left eye.) Fluorescein angiography (bottom right) shows the leakage from the abnormal vessels in the inferior retina.
On optical coherence tomography, the patient displayed outer retinal degeneration bilaterally. Genetic analysis of the patient identified 2 novel sequence variants in the CEP290 (centrosomal protein 290) gene: p. Leu805Pro: c.2414T>C (predicted to be damaging by a PolyPhen-2 score of 0.999 out of 1.0) and c.1189+1G>A (splice site sequence variant). Additionally, another novel sequence variant was identified in the RPGRIP1 (RPGR interacting protein 1) gene: p. Arg890Tcr: c.2668C>T (nonsense sequence variant).
Conclusions
To date, 23 causal genes of LCA have been identified, many of which are inherited in an autosomal recessive pattern. 1 Together, they account for approximately 70% of all patients with LCA. 2 However, LCA’s genetic heterogeneity encumbers the genetic diagnosis of patients. Genotyping LCA patients is important because it both confirms the diagnosis on a molecular level and helps determine each patient’s prognosis. As gene therapy treatments are developed, genotyping LCA patients will become even more imperative. Despite advances, genetic testing remains potentially costly and time-consuming. Correlations between genotypes and phenotypes in LCA patients exist and can potentially guide physicians to a potential genotype even before genetic testing is performed. 3 Therefore, establishing genotype-phenotype associations can aid physicians in predicting a potential genotype based on detailed eye examinations.
Coats-like disease is an unusual presentation of LCA that has been associated with the CRB1 (crumbs cell polarity complex component 1) gene 4 but rarely associated with the CEP290 gene, and only with the c.2991+1655A>G sequence variant of that gene. 5 CEP290 encodes for a centrosomal protein that localizes to the connecting cilium of photoreceptors. 6 RPGRIP1 encodes for a protein that interacts with retinitis pigmentosa GTPase at the connecting cilia between the inner and outer segments of photoreceptor cells. 6 Certain sequence variants, such as nonsense, frameshift, canonical splice site, initiation codon, and exon deletion sequence variants, can often be assumed to disrupt gene function by altering transcription and resulting in a decrease or lack of the gene product. 7
In our unique case of LCA, the patient presented with bilateral Coats-like disease, and genetic testing revealed novel sequence variants in the CEP290 and RPGRIP1 genes. The presence of sequence variants in 2 different causal genes of LCA may have contributed to the severity of disease. This case provides additional evidence that the presentation of Coats-like disease in LCA may be associated with the CEP290 or the RPGRIP1 genes and aids in the establishment of genotype-phenotype associations and medical management that can help maintain stability.
Footnotes
Ethical Approval: Not applicable.
Statement of Informed Consent: Not applicable.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
ORCID iD: Mehdi Tavakoli, MD 
https://orcid.org/0000-0002-4828-2313
Audina M. Berrocal, MD
https://orcid.org/0000-0002-2446-2184
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