Coats Plus Syndrome and Mutation of the TERT Gene: A Case Report

Coats Plus Syndrome and Mutation of the TERT Gene: A Case Report Typhaine Grenet1,2, Caroline Kannengiesser3,4,5, Raphael Borie3, 5, 6, 7, Audrey Giocanti-Aurégan2 1Centre d’imagerie et de Laser, 11 rue Antoine Bourdelle, Paris, France 2Ophthalmology department, Avicenne hospital, Paris 13 University, APHP, Bobigny, France 3Université Paris Diderot, Paris, France 4Laboratoire de Génétique, APHP, Hôpital Bichat, Paris, France 5Service de Pneumologie A, Centre de Compétence des Maladies Pulmonaires Rares, Paris, France 6DHU FIRE, Hôpital Bichat, APHP, Paris, France 7INSERM, Unité 1152, Paris, France


Case Report
A 35-year-old man was referred for blurred vision in his right eye (RE).
Visual acuity was 20/40 in the RE and 20/20 in the left eye (LE). The slit lamp examination was unremarkable. Intraocular pressure was normal in both eyes. The fundus examination revealed hard exudates and hemorrhages at the right posterior pole ( Figure  1A) and bilateral temporal peripheral vascularization rarefaction (Figure 1 A, B). Optical coherence tomography (OCT) of the RE revealed a voluminous macular edema (Figure 2A, B), and OCT of the LE was normal ( Figure 2C). Fluorescein angiography ( Figure 3A-D) showed bilateral retinal ischemia of the temporal periphery with bilateral capillaropathy and telangiectasia in the temporal periphery. In the RE ( Figure 3A, B), telangiectasia were also observed at the posterior pole, responsible for fluorescein leakage in the late frames ( Figure 3B). A bilateral hyperfluorescence of the optic disc was also seen ( Figure 3B, D). OCT angiography confirmed the presence of telangiectasia dilation in the right fovea, responsible for macular edema ( The patient had long personal medical history since he had early hair greying since the age of 13, he underwent a liver transplant 8 months ago for liver fibrosis, and he also had pancytopenia and idiopathic lung fibrosis (IPF). His father died 3 years ago of IPF. A diagnosis of telomeropathy responsible for these systemic failures    was suspected in this family with familial IPF, liver disease and bone marrow failure, A molecular exploration was performed on the DNA of the father. A germline heterozygous missense variation was identified in exon 6 of TERT: c.2225G>A, p.Arg742His Our patient was also carrier of this variation confirming a telomeropathy transmitted in an autosomic dominant manner. The missense variation of TERT was interpreted as pathogenous (class 5) due to its rare frequency, the in silico analysis predicting a deleterious effect, co segregation of the variation with the phenotype and the identification of this variation in another independent family (our unpublished data, C Kannengiesser and the publication recently in another patient with IPF 1 .) Based on bilateral Coats-like lesions associated with systemic involvement, we suggested the diagnosis of Coats Plus syndrome (CPS) due to the TERT gene pathogenous variation.

Discussion
CPS also referred to as cerebro-retinal microangiopathy with calcifications and cysts (CRMCC) 2,3 is a genetic disease that was described in 1988 by Tolmie et al 4 . The prevalence of CPS is less than 1 case for 1 billion. It has been first described in association with CTC1 (conserved telomere maintenance component 1) bi-allelic mutations. This gene encodes a protein participating to the maintenance of the integrity of the telomeres, the TTAGGG repeated sequences at the ends of the chromosomes. The transmission is autosomal recessive. The ophthalmologic lesions described were similar to Coats disease, an idiopathic disorder characterized by an abnormal development of retinal vessels (telangiectasia) with progressive exudation leading potentially to exudative retinal detachment, although they were bilateral. The ophthalmic involvement is bilateral in CPS while only 25% 5,6 to 62% 7 of cases of classical Coats disease show a bilateral involvement. Another difference is that in CPS, a systemic involvement is associated, unlike in Coats disease. The two main ophthalmologic complications of Coats disease and CPS are retinal neovascularization and exudation.
CPS has also been associated to another telomeropathy due to a TERC deletion 8 . Mammalian telomeres are maintained by an enzyme referred to as telomerase, a complex that includes a RNA template (hTERC), a reverse transcriptase subunit (hTERT) 'coded by' TERC and TERT, and various other proteins. This enzyme prevents a progressive telomere shortening 8 . Critical telomere shortening results in a proliferative defect in hematopoietic stem cells leading to bone marrow failure syndrome 9 .
The exact pathophysiological mechanism underlying Coats disease is unknown, while we know that CPS is part of the spectrum of telomeropathies. Several patients with CPS have been shown to have shortened telomeres, suggesting that telomere dysfunction could play a role in CPS pathogeny 10 .
The case described by Peene et al. 8 supported this assumption and they have suggested that the presence of bone marrow failure and telomere dysfunction in patients with CPS could strongly support a relationship between the disruption of telomere homeostasis and the ocular pathology and that the TERC gene deletion could be etiologically associated with exudative retinopathy.
Our case is the first description of CPS associated with a TERT gene mutation. This could be due to the fact that our patient had a particularly severe form of telomeropathy with lung fibrosis 11 and that he had visual symptoms only due to the presence of the right macular edema. It could be assumed that in the presence of extra central exudation, the patient would have remained visually asymptomatic.
Regarding ophthalmological treatment, exudations are usually treated with photocoagulation of the telangiectasia vessels responsible for the exudation 5,6 . In our case, photocoagulation was not an option given the central location of the telangiectasia dilation responsible for edema. It has thus been decided to treat the RE with anti-VEGF injections.
In conclusion, in a young patient with bilateral Coatslike lesions associated with systemic liver and lung failures due to a TERT mutation, we described a case of CPS. Ophthalmological examination should be carried out in telomeropathy individuals.