Ophthalmic Surgery, Lasers and Imaging Retina

Case Report 

Adult Coats' Disease, Dubin-Johnson Syndrome, and the Search for Targeted Therapies

Omar Moinuddin, BS; Edward H. Wood, MD; Kimberly A. Drenser, MD, PhD

Abstract

Coats' disease is nonhereditary retinal vascular disorder characterized by telangiectatic retinal vessels with prominent aneurysmal changes and exudation. A conclusive etiology has not yet been determined. In this retrospective case report and literature review, a 64-year-old male with Dubin-Johnson syndrome presented with unilateral retinal vascular changes and exudation consistent with a diagnosis of adult Coats' disease. The authors conclude that patients with Dubin-Johnson syndrome carry mutations in a multidrug resistance associated protein (MRP). MRPs are also expressed in the retina, retinal pigment epithelium, and vascular endothelium, where they export toxins and metabolites, and may serve as a therapeutic target.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:318–321.]

Abstract

Coats' disease is nonhereditary retinal vascular disorder characterized by telangiectatic retinal vessels with prominent aneurysmal changes and exudation. A conclusive etiology has not yet been determined. In this retrospective case report and literature review, a 64-year-old male with Dubin-Johnson syndrome presented with unilateral retinal vascular changes and exudation consistent with a diagnosis of adult Coats' disease. The authors conclude that patients with Dubin-Johnson syndrome carry mutations in a multidrug resistance associated protein (MRP). MRPs are also expressed in the retina, retinal pigment epithelium, and vascular endothelium, where they export toxins and metabolites, and may serve as a therapeutic target.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:318–321.]

Introduction

Coats' disease is a nonhereditary retinal vascular disorder most commonly occurring unilaterally in young males characterized by telangiectatic retinal vessels with prominent aneurysmal changes and exudation. Children with Coats' disease typically require no systemic workup in the absence of other notable systemic disease (such as fascioscapulohumeral muscular dystrophy,1 Senior-Løken syndrome,2 Turner syndrome,3 and others).

Adult patients with this constellation of ocular findings should be considered as having either (a) systemic vascular diseases such as hypertension, diabetes, and hypercholesterolemia; (b) a Coats'-like response to another primary ophthalmic disease such as inflammation, infection, retinal degeneration, vascular tumor, and post-radiation therapy; (c) idiopathic juxtafoveal macular telangiectasia (when predominantly posterior); or (d) adult Coats' disease without other ocular or systemic disease.4 As opposed to Coats' disease in children, adults more commonly exhibit localized retinal exudation, hemorrhage around macroaneurysms when present, and a slower rate of disease progression.5

To date, the pathogenesis of Coats' disease remains unclear. Associating Coats' disease with subtle systemic disease may promote further understanding and the development of new therapies for Coats' disease.

Case Report

A 64-year-old male presented to our clinic for an “imperfection” noted in his right eye during routine ophthalmic screening with widefield fundus photography. His past medical history was significant only for Dubin-Johnson syndrome, a rare inherited hepatic enzyme defect. He had no visual symptoms, and aside from having intermittent episodes of jaundice related to his hepatic disease, he was in good health. Upon presentation, his best-corrected visual acuity (BCVA) was 20/20 in both eyes, and the anterior segment examination was unremarkable. The posterior segment examination in the right eye was significant for microaneurysmal vascular changes with intraretinal exudation and pigmentary changes in the inferior-temporal far periphery (Figure 1a). The posterior segment in the left eye was unremarkable (Figure 1b). Multi-modal imaging was performed, including fundus photography (Figures 1a and 1b), fluorescein angiography (FA) (Figures 1c and 1d), optical coherence tomography (OCT) (Figures 1e and 1f), and OCT angiography (OCTA) (Figures 1g and 1h). FA in the right eye (Figures 1c and 1d) showed hypofluorescence consistent with peripheral capillary nonperfusion and hyperfluorescence consistent with microaneurysmal leakage in the temporal far periphery. OCT (Figures 1e and 1f) and OCTA (Figures 1g and 1h) were unremarkable in both eyes. He was treated with ablative laser therapy to the avascular retina and aneurysms (Figures 2a–2c), with resultant improvement in exudation and stability to date.

Multimodal ophthalmic imaging upon presentation showing microaneurysmal vascular changes and exudation on fundus photography (a), with peripheral capillary nonperfusion and aneurysms on fluorescein angiography (FA) (c, d), but a normal optical coherence tomography (OCT) (f) and OCT angiography (h–k) in the right eye. Fundus photography (b), FA (e), and OCT (g) were unremarkable in the left eye.

Figure 1.

Multimodal ophthalmic imaging upon presentation showing microaneurysmal vascular changes and exudation on fundus photography (a), with peripheral capillary nonperfusion and aneurysms on fluorescein angiography (FA) (c, d), but a normal optical coherence tomography (OCT) (f) and OCT angiography (h–k) in the right eye. Fundus photography (b), FA (e), and OCT (g) were unremarkable in the left eye.

Multimodal ophthalmic imaging upon follow-up showing improved exudation and aneurysmal changes in the bed of ablative laser therapy on fundus photography (a) and fluorescein angiography (b, c).

Figure 2.

Multimodal ophthalmic imaging upon follow-up showing improved exudation and aneurysmal changes in the bed of ablative laser therapy on fundus photography (a) and fluorescein angiography (b, c).

Discussion

To date, a conclusive common pathogenesis for Coats' disease is yet to be determined. Several have posited perivascular lymphocyte infiltration within inner retinal vascular beds,6 a chronically dysfunctional blood-retinal barrier,7 mutations within the NDP gene on chromosome Xp11.289 implicating primarily abnormal retinal vasculogenesis, increased expression of vascular endothelial growth factor or other similar growth factors,10 and others. Children manifesting the Coats' phenotype earlier likely carry a higher burden of disease than adults who are able to maintain microvascular homeostasis until later in life.

To the best of our knowledge, Coats' disease has not previously been documented in a patient with Dubin-Johnson Syndrome. Dubin-Johnson Syndrome is a rare autosomal recessive disorder caused by a mutation in the ATP-binding-cassette domain of the cMOAT gene on chromosome 10, which encodes for multidrug resistance associated protein 2 (MRP2) — a transporter that mediates the removal of bilirubin from hepatocytes into bile.11 Hallmark findings include fluctuating conjugated hyperbilirubinemia and bilirubinuria in an otherwise asymptomatic patient, persistent low-grade jaundice under physiological stress, and a darkly pigmented liver. As serum bilirubin concentrations rise, the high affinity of elastin fibers to bilirubin elucidates the classic yellowing of the overlying conjunctival membranes in patients with this and other disorders of the liver.12

Although most highly expressed in the liver for the excretion of bilirubin, MRP2, a member of the ATP binding cassette transporter superfamily, is expressed in numerous tissues including the retina, the retinal pigment epithelium (RPE), and retinal capillary endothelium.13 As a family, multidrug resistance associated proteins (MRPs) contribute to the regulation of cellular metabolism and survival by continuously exporting toxins, organic anions, and active metabolites in an energy dependent manner, hence limiting the exposure of the cell to its potentially harmful substrates. Therefore, it can be posited that insufficiency of this transport protein in Dubin-Johnson Syndrome can result in impairment of the retinal capillary endothelium and/or RPE, which may contribute to the peripheral retinal findings in a manner similar to Coats' Disease.12,14 Furthermore, MRP2 expression appears to be regulated by sex hormones, with decreased expression in the presence of testosterone and increased in the presence of estrogen,15 thereby implicating a predisposition to more MRP abnormalities in males. Despite being autosomal recessive, males do appear to be affected with Dubin-Johnson syndrome at a higher rate than females.16 Although hypothetical in association with this case, MRPs may represent a novel target for treating Coats' disease and retinal exudation at large.

This case also illustrates the increased incidence of asymptomatic peripheral retinal findings prompting vitreoretinal referral based on widefield retinal imaging. To this end, it is worth noting that not all peripheral retinal findings on widefield imaging are pathologic. Shah et al.17 evaluated 58 eyes of patients with epiretinal membranes or choroidal nevi without any other ocular pathology serving as surrogates for “normal” eyes and found that one or more peripheral angiographic and/or funduscopic anomalies were noted in all patients. In order of decreasing prevalence, these findings included absence of capillary refill (98.28%), ground glass hypofluorescence (87.93%), terminal networks (77.59%), right angle vessels (70.69%), vessels crossing the horizontal raphe (44.83%), microaneurysms (41.38%), and drusen (34.48%). Although the microaneurysmal changes noted in our patient with Dubin-Johnson Syndrome may be attributed to the use of widefield retinal imaging in otherwise normal eyes as suggested by Shah, the findings of inferior-temporal vascular dilatations with progressive intraretinal exudation on follow-up exam prompted appropriate evaluation and subsequent treatment.

References

  1. Gurwin EB, Fitzsimons RB, Sehmi KS, Bird AC. Retinal telangiectasis in facioscapulohumeral muscular dystrophy with deafness. Arch Ophthalmol. 1985;103(11):1695–1700. doi:10.1001/archopht.1985.01050110089033 [CrossRef]
  2. Schuman JS, Lieberman KV, Friedman AH, Berger M, Schoeneman MJ. Senior-Loken syndrome (familial renal-retinal dystrophy) and Coats' disease. Am J Ophthalmol. 1985;100(6):822–827. doi:10.1016/S0002-9394(14)73374-4 [CrossRef]
  3. Beby F, Roche O, Burillon C, Denis P. Coats' disease and bilateral cataract in a child with Turner syndrome: A case report. Graefes Arch Clin Exp Ophthalmol. 2005;243(12):1291–1293. doi:10.1007/s00417-005-1194-x [CrossRef]
  4. Grosso A, Pellegrini M, Cereda MG, Panico C, Staurenghi G, Sigler EJ. Pearls and pitfalls in diagnosis and management of coats disease. Retina. 2015;35(4):614–623. doi:10.1097/IAE.0000000000000485 [CrossRef]
  5. Smithen LM, Brown GC, Brucker AJ, Yannuzzi LA, Klais CM, Spaide RF. Coats' disease diagnosed in adulthood. Ophthalmology. 2005;112(6):1072–1078. doi:10.1016/j.ophtha.2004.12.038 [CrossRef]
  6. Reese AB. Telangiectasis of the retina and Coats' disease. Am J Ophthalmol. 1956;42(1):1–8. doi:10.1016/0002-9394(56)90002-2 [CrossRef]
  7. Tarkkanen A, Laatikainen L. Coat's disease: Clinical, angiographic, histopathological findings and clinical management. Br J Ophthalmol. 1983;67(11):766–776. doi:10.1136/bjo.67.11.766 [CrossRef]
  8. Desai RU, Saffra NA, Krishna RP, Rosenberg SE. Coats' disease, Turner syndrome, and Von Willebrand disease in a patient with wildtype Norrie disease pseudoglioma. J Pediatr Ophthalmol Strabismus. 2011;48Online:e1–3. doi:10.3928/01913913-20100318-01 [CrossRef]. Epub 2010 May 21.
  9. Black GC, Perveen R, Bonshek R, et al. Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: A role for norrin in retinal angiogenesis. Hum Mol Genet. 1999;8(11):2031–2035. doi:10.1093/hmg/8.11.2031 [CrossRef]
  10. Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103(11):1820–1828. doi:10.1016/S0161-6420(96)30420-X [CrossRef]
  11. Toh S, Wada M, Uchiumi T, et al. Genomic structure of the canalicular multispecific organic anion–transporter gene (MRP2/cMOAT) and mutations in the ATP-binding–cassette region in Dubin-Johnson syndrome. Am J Hum Genet. 1999;64(3):739–746. doi:10.1086/302292 [CrossRef]
  12. Kuiper JJ. Conjunctival icterus. Ann Intern Med. 2001;134(4):345–346. doi:10.7326/0003-4819-134-4-200102200-00029 [CrossRef]
  13. Pelis RM, Shahidullah M, Ghosh S, Coca-Prados M, Wright SH, Delamere NA. Localization of multidrug resistance-associated protein 2 in the nonpigmented ciliary epithelium of the eye. J Pharmacol Exp Ther. 2009;329(2):479–485. doi:10.1124/jpet.108.149625 [CrossRef]
  14. Hosoya K-I, Makihara A, Tsujikawa Y, et al. Roles of inner blood-retinal barrier organic anion transporter 3 in the vitreous/retina-to-blood efflux transport of p-aminohippuric acid, benzylpenicillin, and 6-mercaptopurine. J Pharmacol Exp Ther. 2009;329(1):87–93. doi:10.1124/jpet.108.146381 [CrossRef]
  15. Simon FR, Iwahashi M, Hu L-J, et al. Hormonal regulation of hepatic multidrug resistance-associated protein 2 (Abcc2) primarily involves the pattern of growth hormone secretion. Am J Physiol Gastrointest Liver Physiol. 2006;290(4):G595–G608. doi:10.1152/ajpgi.00240.2005 [CrossRef]
  16. Bissonnette B, Luginbuehl I, Marciniak B, Dalens B. Syndromes: Rapid Recognition and Perioperative Implications. New York, NY: McGraw-Hill; 2006.
  17. Shah AR, Abbey AM, Yonekawa Y, et al. Widefield fluorescein angiography in patients without peripheral disease: A Study of Normal Peripheral Findings. Retina. 2016;36(6):1087–1092. doi:10.1097/IAE.0000000000000878 [CrossRef]
Authors

From Oakland University William Beaumont School of Medicine, Rochester, Michigan (OM, KAD); and Associated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan (EHW, KAD).

The authors report no relevant financial disclosures.

Address correspondence to Kimberly A. Drenser, MD, PhD, Associated Retinal Consultants, William Beaumont Hospital, Neuroscience Center, 3555 W. 13 Mile Road, Suite LL-20, Royal Oak, MI 48073; email: kdrenser@arcpc.net.

Received: June 13, 2018
Accepted: November 05, 2018

10.3928/23258160-20190503-10

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