From the Division of Ophthalmology (RUD, NAS, RPK, SER), Maimonides Medical Center, Brooklyn; and the Department of Ophthalmology (NAS, SER), New York Eye and Ear Infirmary, New York, New York.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Norman A. Saffra, MD, Division of Ophthalmology, Maimonides Medical Center, 902 49th Street, Brooklyn, NY 11219.
Coats’ disease is a rare congenital condition that is predominantly unilateral and presents with retinal vascular telangiectasias, intraretinal exudation, and, in advanced stages, non-rhegmatogenous exudative retinal detachment and neovascular glaucoma. The condition appears three times more commonly in boys, with the average age of diagnosis at 10 years, and hence there has been interest regarding an X-linked etiology.1
Interestingly, retinal vascular dysplasia also appears in the X-linked recessive Norrie disease, which is additionally characterized by deafness, retinal detachment, and cataract and corneal opacities. Given both diseases presenting with retinal vascular abnormalities in boys, the etiology of Coats’ disease is suspected to involve norrin, the product of the Norrie disease pseudoglioma (NDP) gene located on chromosome Xp11.4.2
Although a somatic missense mutation in the NDP gene causes Norrie disease, the complete loss of the X-chromosome during meiosis causes the most common form of Turner syndrome. The systemic manifestations of Turner syndrome include short stature, congenital heart defects, and primary ovarian failure, and the common ophthalmic features are amblyopia, strabismus, reduced accommodation, and convergence insufficiency. Apart from the 8% of patients with Turner syndrome with red–green deficiency, retinal manifestations have been described only in case reports.3 To date, there are only two published cases of patients with both Coats’ disease and Turner syndrome, and neither patient was genotyped for the NDP gene.4,5
On another locus, in chromosome 12, the von Willebrand factor gene is believed to cause forms of von Willebrand disease, the most common inherited coagulation disorder. Published von Willebrand disease manifestations in the retina have been limited to three patients with vitreous, retinal, and subretinal hemorrhages.6,7 Another report describes a patient with Turner syndrome and an acquired form of von Willebrand disease in the setting of primary biliary cirrhosis and inflammatory bowel disease.8 We present a patient with Coats’ disease, Turner syndrome, and von Willebrand disease who was genotyped wildtype for the NDP gene.
The patient was born at full term via normal spontaneous vaginal delivery, with no family history of any significant systemic or ocular disease. However, the infant’s webbed neck raised suspicion for Turner syndrome and further evaluation revealed a coarctation of the aorta that required surgery at 9 days of age. Genetics testing karyotyped the infant with the 45X variant of Turner syndrome.
At 3 months of age, the patient developed increased tearing in both eyes and was seen by an ophthalmologist. Examination was significant for epicanthal folds, signs of mild nasolacrimal duct obstruction, full ocular motility, normal pupillary examination, and central steady visual acuity. Alternate cover testing demonstrated intermittent left exotropia at 10 prism diopters at both distance and near fixation. The dilated fundus examination was within normal limits. The cycloplegic refraction was +1.75 + 1.00 × 090 in both eyes. Nasolacrimal massage was initiated.
After 3 months, the left eye was exotropic on nearpoint convergence testing. A review of systems was significant for an episode of bleeding from the ear canal. Hematology work-up was significant for a prolonged partial thromboplastin time of 38 seconds, normal von Willebrand factor mutimer pattern, and factor VIII at 35% of normal, and ristocetin cofactor activity at 34% of normal. All other hematological and coagulation factors were normal. The patient was diagnosed as having von Willebrand disease type 1, with a positive response from an intravenous desmopressin challenge.
At 19 months of age, follow-up examination revealed an unchanged exotropia, but a new retinal finding of perifoveal exudate was noted in the left eye. Examination under anesthesia revealed yellow exudate that threatened the macula with subretinal fluid extending from the posterior pole through the entire temporal periphery associated with multiple telangiectatic vessels. A diagnosis of Coats’ disease stage 2B was made, and the patient underwent laser photocoagulation (Fig. 1). Despite laser treatment, 4 months later the patient progressed to Coats’ disease stage 3B with complete exudative retinal detachment, displacing the macula, and telangiectatic vessels present temporally, inferotemporally, and supertemporally. Cryotherapy and laser photocoagulation were applied to the telangiectatic vessels with stabilization of her disease.
Figure. RetCam II (clarity Medical Systems, Inc., Pleasanton, CA) Image of the Patient’s Left Eye, Demonstrating Telangiectatic Vessels Temporally with Laser Photocoagulation Marks.
A peripheral blood sample was sent to the University of Iowa’s Carver Nonprofit Genetic Testing Laboratory, which revealed a normal coding sequence for the NDP gene.
The association of Turner syndrome, Coats’ disease, and von Willebrand disease has not been previously reported. Turner syndrome is clearly genetic in origin, whereas Coats’ disease is not a classically inherited retinal disorder. However, there has been increasing evidence of the role of the NDP gene in retinal vasculogenesis and a possible role in Coats’ disease.9,10 Black et al. described a woman with Coats’ disease and her son who had Norrie disease, both of whom carried a somatic missense mutation on the NDP gene. The authors also demonstrated both normal and mutant NDP genes in the retinal tissue of 1 of 9 enucleated eyes from males with Coats’ disease.2
Black et al. proposed that Coats’ disease is a mosaic phenotype, with possible contribution from either partial escape X-inactivation or an additional somatic mutation in the other NDP allele, in a segment of the developing retina. Because our patient only carried one X-chromosome that was wildtype for the NDP gene, we provide more evidence for the escape X-inactivation hypothesis of Coats’ disease.
Because the von Willebrand factor gene is located on chromosome 12 and has no known linkage or association with the X chromosome, it is more likely that our patient’s von Willebrand disease may simply be a diagnostic coincidence with Turner syndrome.
- Shields JA, Shields CL. Review: coats disease: the 2001 LuEsther T. Mertz lecture. Retina. 2002;22:80–91. doi:10.1097/00006982-200202000-00014 [CrossRef]
- 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;8:2031–2035. doi:10.1093/hmg/8.11.2031 [CrossRef]
- Denniston AK, Butler L. Ophthalmic features of Turner’s syndrome. Eye. 2004;18:680–684. doi:10.1038/sj.eye.6701323 [CrossRef]
- Cameron JD, Yanoff M, Frayer WC. Coats’ disease and Turner’s syndrome. Am J Ophthalmol. 1974;78:852–854.
- 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;243:1291–1293. doi:10.1007/s00417-005-1194-x [CrossRef]
- Herrmann WA, Lohmann CP, Demmler-Hackenberg M, Gabel VP. Von Willebrand’s disease type I as a cause for subvitreal, retinal and subretinal haemorrhages. Graefes Arch Clin Exp Ophthalmol. 2005;243:383–385. doi:10.1007/s00417-004-0999-3 [CrossRef]
- Shiono T, Abe S, Watabe T, et al. Vitreous, retinal and subretinal hemorrhages associated with von Willebrand’s syndrome. Graefes Arch Clin Exp Ophthalmol. 1992;230:496–497. doi:10.1007/BF00175940 [CrossRef]
- Sokol L, Stueben ET, Jaikishen JP, Lamarche MB. Turner syndrome associated with acquired von Willebrand disease, primary biliary cirrhosis, and inflammatory bowel disease. Am J Hematol. 2002;70:257–259. doi:10.1002/ajh.10120 [CrossRef]
- Berger W, Meindl A, van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet. 1992;1:199–203. doi:10.1038/ng0692-199 [CrossRef]
- Ruether K, van de Pol D, Jaissle G, Berger W, Tornow RP, Zrenner E. Retinoschisis like alterations in the mouse eye caused by gene targeting of the Norrie disease gene. Invest Ophthalmol Vis Sci. 1997;38:710–718.