PROLIFERATIVE RETINOPATHY AS A COMPLICATION OF DYSKERATOSIS CONGENITA John O. Mason III, MD,*† Jacob J. Yunker, MD,*† Peter A. Nixon, MD,*†‡ Rachel S. Vail, COT,† Ekaterina Tsilou, MD,§㛳 Neelam Giri, MD,㛳¶ Blanche P. Alter, MD, MPH㛳¶ Objectives: To describe a patient with dyskeratosis congenita (DC) who developed retinal neovascularization (RNV) and discuss this novel association. Methods: A 10-year-old boy with DC was referred for evaluation of possible retinal vascular disease. He underwent ophthalmologic examination, as well as fluorescein angiography. Results: Fluorescein angiography demonstrated proliferative retinopathy with capillary nonperfusion in the temporal retina of both eyes. The patient underwent further evaluation with an examination with anesthesia and indirect ophthalmoscopic laser photocoagulation to areas of capillary nonperfusion. Conclusion: Although various ocular complications of both acquired aplastic anemia and inherited aplastic anemia due to DC have been previously described, to the authors’ knowledge, this is the first reported case of either disease to exhibit RNV consistent with proliferative retinopathy. Ophthalmologists need to be aware of this potential complication in DC that could threaten vision, to provide prompt laser photocoagulation therapy. RETINAL CASES & BRIEF REPORTS 3:259 –262, 2009
From the *Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama; †Retina Consultants of Alabama, Birmingham, Alabama; the ‡Austin Retina Associates, Austin, Texas; the §Intramural Research Program of the National Eye Institute, Bethesda, Maryland; the 㛳National Eye Institute, Health, Department of Health and Human Services, Bethesda, Maryland; and the ¶Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
involvement of dental, gastrointestinal, skeletal, neurologic, immunologic, ophthalmic, genitourinary, and pulmonary tissues, as well as bone marrow failure (also known as aplastic anemia), myelodysplastic syndrome, leukemia, and head and neck and anogenital carcinomas. Up to 90% of patients with DC develop aplastic anemia. Although many patients do not have aplastic anemia early in childhood, most patients have progression to this diagnosis. The frequency of ophthalmic findings may be as high as 30% to 45%, contributing significant morbidity in terms of both ocular discomfort and potential visual loss.4–7 Specific funduscopic findings, including retinal and vitreous hemorrhages, have been reported in cases of DC7 but may also be found in patients with acquired aplastic anemia without evidence of DC.8 We report an unusual case of DC with aplastic anemia, notable for ophthalmic findings of bilateral retinal neovascularization (RNV), review the ocular findings in acquired aplastic anemia and in inherited DC, and discuss management of this complication.
D
yskeratosis congenita (DC), also known as ZinsserCole-Engman syndrome, is a rare, progressive inherited bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia.1–3 A wide spectrum of clinical manifestations may be seen, including potential
Supported in part by unrestricted departmental grants from Research to Prevent Blindness, Inc. (New York, NY); The Eyesight Foundation of Alabama (Birmingham, AL); and Intramural Research Program of the National Cancer Institute, National Institutes of Health (Rockville, MD). No conflicting relationships exist for any of the material presented in this report. Reprint requests: John O. Mason III, MD, Retina Consultants of Alabama, 700 18th Street South, Suite 707, Birmingham, AL 35233; e-mail: [email protected]
Case Report A 10-year-old boy with Hoyeraal-Hreidarsson variant of DC due to a mutation in the X-linked gene DKC1 (Ala353Val) was referred
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Fig. 2. Color fundus photograph montage demonstrating peripheral retinal neovascularization, seen (A) temporally (arrow) in the right eye and (B) superotemporally and temporally (arrow) in the left eye.
Fig. 1. A, Reticulated hyperpigmentation of skin on the neck. B, Dystrophic changes of the fingernails. C, Oral leukoplakia. Photographs courtesy of Jatin R. Matta and Maria L. Turner (A), Demetrio Domingo (C), and the Department of Photography (B), National Institutes of Health (Bethesda, MD).
for vitreoretinal consultation in December 2005. He had the onset of pancytopenia at 2 years of age and nail dystrophy at 3 years of age. He was diagnosed with DC at 6 years of age because of his physical findings: narrow esophagus requiring multiple dilations, meatal stenosis, epiphora, recurrent tongue ulcers, ataxia, and cerebellar hypoplasia. Recent medical evaluation at the National Institutes of Health (Bethesda, MD) had included ophthalmic screening examination, which identified retinal hemorrhages. Thorough clinical evaluation at the National Institutes of Health revealed the classic clinical triad of DC. Complete blood cell count testing demonstrated a leukocyte count of 3,570/L, absolute neutrophil count of 1,571/L, platelet count of 25,000/L, and hemoglobin and hematocrit of 9.6 g/dL and 26.7%, respectively. The bone marrow was hypocellular for age, with decreased megakaryocytes, and bone marrow chromosomes were normal; these findings are consistent with aplastic anemia. A faint reticulated hyperpigmentation was noted on the arms and legs, with poikiloderma on the back and neck (Fig. 1A). In addition, there was tapering of the fingers with dystrophy of the nails, including erythema and ptery-
gium (Fig. 1B). Examination of the oral cavity showed leukoplakia of the buccal mucosa, as well as erythema of the anterior tongue with linear keratotic striations (Fig. 1C). The patient had intermittent yellow spots in both eyes. At examination, Snellen best-corrected visual acuity was 20/30 in the right eye and 20/20-2 in the left eye. Slit-lamp examination revealed absence of the lacrimal puncta in the upper and lower eyelids, with an otherwise normal anterior segment. Funduscopic examination revealed a normal appearing optic nerve and macula in each eye; however, there was significant RNV temporally in the right eye and superotemporally and temporally in the left eye (Fig. 2). Fluorescein angiography demonstrated vascular leakage at the sites of RNV in both eyes, with large areas of peripheral capillary nonperfusion (Fig. 3). The patient underwent indirect ophthalmoscopic laser photocoagulation during general anesthesia to areas of capillary nonperfusion in both eyes as guided by fluorescein angiography (Fig. 4). He had regression of RNV during follow-up until ⬇8 months, when he was noted to have some new retinal hemorrhages and neovascularization in the temporal periphery of both eyes. He underwent additional laser photocoagulation treatment to these areas, and at the most recent follow-up (11 months since initial presentation), he had maintained stable visual acuity with complete regression of RNV.
RETINOPATHY AND DC
Fig. 3. Fluorescein angiography montage showing proliferative retinopathy with significant capillary nonperfusion peripheral to these areas in each eye (white arrows). Right eye (A) and left eye (B).
Discussion We describe a patient who had aplastic anemia due to DC with bilateral RNV. After a thorough MEDLINE review of the literature, we believe that this is the first report of proliferative retinopathy demonstrated by fluorescein angiography in the setting of either acquired aplastic anemia or DC. Among the ophthalmic complications reported, punctal stenosis with resultant epiphora is the most common manifestation of DC. Funduscopic examination may reveal optic atrophy, arteriosclerosis of the retinal vasculature, retinal hemorrhage, cotton-wool spots, macular edema, anomalous retinal vessels, preretinal fibrosis, hyperpigmented choroid, and choroidal atrophy (Table 1).7 Ocular findings are also commonly seen in patients with a variety of hematologic disorders associated with anemia and/or thrombocytopenia9 and typically manifest
261
Fig. 4. Color fundus photograph montage showing laser photocoagulation treatment to areas of peripheral capillary nonperfusion (arrows). Right eye (A) and left eye (B).
in the form of ocular hemorrhage, usually of the posterior segment. Although aplastic anemia is common in DC, DC is only a rare cause of aplastic anemia, which most often is an acquired condition. Mansour et al8 specifically reported the ocular findings of 18 patients with acquired aplastic anemia (thus presumably none due to DC), along with a review of the literature to include findings for an additional 126 patients. The most common finding was nerve fiber layer or retinal hemorrhage, seen in approximately three fourths of patients (Table 1). There were no cases of RNV. The pathogenesis of DC is due to mutations in components of a ribonucleoprotein complex, which is essential for the elongation and maintenance of chromosome ends or telomeres. All patients with DC have excessively short telomeres, suggesting that the common defective pathway involves telomere maintenance.10 This defect impedes replicating cells from maintaining genetic integrity over time and, thus, tends to affect tissues with a high rate of cell turnover.
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Table 1. Ocular Findings in Dyskeratosis Congenita and Acquired Aplastic Anemia
Ocular Finding(s) Anomalous retinal blood vessels Blepharitis Blue sclerae Cataract Choroidal pigmentary changes Conjunctivitis Corneal erosions or ulcers Cotton-wool spots Ectropion and trichiasis Glaucoma Macular edema Macular hemorrhage Optic atrophy Optic disk edema Orbital/eyelid hematoma Pallor of palpebral conjunctiva Preretinal fibrosis Proliferative retinopathy Punctal stenosis and epiphora Retinal or vitreous hemorrhage Retinal vascular malformation Roth spots Sparse lashes Strabismus
Acquired Dyskeratosis Aplastic Congenita Anemia ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹ Current report ⫹ ⫹ ⫺ ⫺ ⫹ ⫹
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ –
2009
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retinal nonperfusion may minimize future ocular complications and risk of visual loss. Although it would be difficult to determine whether the retinal findings for this patient were due to DC or to aplastic anemia, to our knowledge, this case nevertheless represents the first report of RNV in DC or in aplastic anemia, whether inherited or acquired. We propose that this represents a hitherto unreported additional ophthalmic association with DC and/or aplastic anemia. Key words: aplastic anemia, capillary nonperfusion, dyskeratosis congenita, fluorescein angiography, laser photocoagulation, proliferative retinopathy, retinal neovascularization. References 1.
2.
3.
4. 5.
⫹, present; ⫺, absent.
6.
The clinical manifestation of this may resemble that of a premature aging syndrome.11 At the time of this writing, our patient was undergoing treatment for aplastic anemia with oxymetholone, to which he appeared to be responding. Consideration exists for a future bone marrow transplant from his HLA-identical sibling. In conclusion, we describe a unique case of proliferative retinopathy in a patient with aplastic anemia due to DC, demonstrated with angiographic findings of significant peripheral capillary nonperfusion and RNV. Prompt application of laser photocoagulation to areas of
●
7. 8. 9.
10.
11.
Cole HN, Rauschkolb JC, Toomey J. Dyskeratosis congenita with pigmentation, dystrophia unguis and leukokeratosis oris. Arch Dermatol Syphilol 1930;21:71–95. Engman MF. A unique case of reticular pigmentation of the skin with atrophy. Arch Derm Syphiligraphie 1926;13:685– 687. Zinsser F. Atrophia cutis reticularis cum pigmentatione, dystrophia et leukoplakiaoris. Ikonogr Dermatol 1910;5:219– 223. Drachtman RA, Alter BP. Dyskeratosis congenita. Dermatol Clin 1995;13:33–39. Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Look AT, Ginsburg D, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia, PA: WB Saunders;2003:299–306. Young NS, Alter BP. Aplastic Anemia: Acquired and Inherited. Philadelphia, PA: WB Saunders;1994:325–338. Chambers JK, Salinas CF. Ocular findings in dyskeratosis congenita. Birth Defects 1982;18:167–174. Mansour AM, Salti HI, Han DP, et al. Ocular findings in aplastic anemia. Ophthalmologica 2000;214:399–402. Carraro MC, Rossetti L, Gerli GC. Prevalence of retinopathy in patients with anemia or thrombocytopenia. Eur J Haematol 2001;67:238–244. Alter BP, Baerlocher G, Savage SA, et al. Telomere length measurement by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 2007;110: 1439–1447. Mason PJ, Wilson DB, Bessler M. Dyskeratosis congenita: a disease of dysfunctional telomere maintenance. Current Molecular Medicine 2005;5:159–170.
From the *Department of Ophthalmology, University of Alabama at Birmingham, Birmingham, Alabama; †Retina Consultants of Alabama, Birmingham, Alabama; the ‡Austin Retina Associates, Austin, Texas; the §Intramural Research Program of the National Eye Institute, Bethesda, Maryland; the 㛳National Eye Institute, Health, Department of Health and Human Services, Bethesda, Maryland; and the ¶Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.
involvement of dental, gastrointestinal, skeletal, neurologic, immunologic, ophthalmic, genitourinary, and pulmonary tissues, as well as bone marrow failure (also known as aplastic anemia), myelodysplastic syndrome, leukemia, and head and neck and anogenital carcinomas. Up to 90% of patients with DC develop aplastic anemia. Although many patients do not have aplastic anemia early in childhood, most patients have progression to this diagnosis. The frequency of ophthalmic findings may be as high as 30% to 45%, contributing significant morbidity in terms of both ocular discomfort and potential visual loss.4–7 Specific funduscopic findings, including retinal and vitreous hemorrhages, have been reported in cases of DC7 but may also be found in patients with acquired aplastic anemia without evidence of DC.8 We report an unusual case of DC with aplastic anemia, notable for ophthalmic findings of bilateral retinal neovascularization (RNV), review the ocular findings in acquired aplastic anemia and in inherited DC, and discuss management of this complication.
D
yskeratosis congenita (DC), also known as ZinsserCole-Engman syndrome, is a rare, progressive inherited bone marrow failure syndrome characterized by the triad of reticulated skin hyperpigmentation, nail dystrophy, and oral leukoplakia.1–3 A wide spectrum of clinical manifestations may be seen, including potential
Supported in part by unrestricted departmental grants from Research to Prevent Blindness, Inc. (New York, NY); The Eyesight Foundation of Alabama (Birmingham, AL); and Intramural Research Program of the National Cancer Institute, National Institutes of Health (Rockville, MD). No conflicting relationships exist for any of the material presented in this report. Reprint requests: John O. Mason III, MD, Retina Consultants of Alabama, 700 18th Street South, Suite 707, Birmingham, AL 35233; e-mail: [email protected]
Case Report A 10-year-old boy with Hoyeraal-Hreidarsson variant of DC due to a mutation in the X-linked gene DKC1 (Ala353Val) was referred
259
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Fig. 2. Color fundus photograph montage demonstrating peripheral retinal neovascularization, seen (A) temporally (arrow) in the right eye and (B) superotemporally and temporally (arrow) in the left eye.
Fig. 1. A, Reticulated hyperpigmentation of skin on the neck. B, Dystrophic changes of the fingernails. C, Oral leukoplakia. Photographs courtesy of Jatin R. Matta and Maria L. Turner (A), Demetrio Domingo (C), and the Department of Photography (B), National Institutes of Health (Bethesda, MD).
for vitreoretinal consultation in December 2005. He had the onset of pancytopenia at 2 years of age and nail dystrophy at 3 years of age. He was diagnosed with DC at 6 years of age because of his physical findings: narrow esophagus requiring multiple dilations, meatal stenosis, epiphora, recurrent tongue ulcers, ataxia, and cerebellar hypoplasia. Recent medical evaluation at the National Institutes of Health (Bethesda, MD) had included ophthalmic screening examination, which identified retinal hemorrhages. Thorough clinical evaluation at the National Institutes of Health revealed the classic clinical triad of DC. Complete blood cell count testing demonstrated a leukocyte count of 3,570/L, absolute neutrophil count of 1,571/L, platelet count of 25,000/L, and hemoglobin and hematocrit of 9.6 g/dL and 26.7%, respectively. The bone marrow was hypocellular for age, with decreased megakaryocytes, and bone marrow chromosomes were normal; these findings are consistent with aplastic anemia. A faint reticulated hyperpigmentation was noted on the arms and legs, with poikiloderma on the back and neck (Fig. 1A). In addition, there was tapering of the fingers with dystrophy of the nails, including erythema and ptery-
gium (Fig. 1B). Examination of the oral cavity showed leukoplakia of the buccal mucosa, as well as erythema of the anterior tongue with linear keratotic striations (Fig. 1C). The patient had intermittent yellow spots in both eyes. At examination, Snellen best-corrected visual acuity was 20/30 in the right eye and 20/20-2 in the left eye. Slit-lamp examination revealed absence of the lacrimal puncta in the upper and lower eyelids, with an otherwise normal anterior segment. Funduscopic examination revealed a normal appearing optic nerve and macula in each eye; however, there was significant RNV temporally in the right eye and superotemporally and temporally in the left eye (Fig. 2). Fluorescein angiography demonstrated vascular leakage at the sites of RNV in both eyes, with large areas of peripheral capillary nonperfusion (Fig. 3). The patient underwent indirect ophthalmoscopic laser photocoagulation during general anesthesia to areas of capillary nonperfusion in both eyes as guided by fluorescein angiography (Fig. 4). He had regression of RNV during follow-up until ⬇8 months, when he was noted to have some new retinal hemorrhages and neovascularization in the temporal periphery of both eyes. He underwent additional laser photocoagulation treatment to these areas, and at the most recent follow-up (11 months since initial presentation), he had maintained stable visual acuity with complete regression of RNV.
RETINOPATHY AND DC
Fig. 3. Fluorescein angiography montage showing proliferative retinopathy with significant capillary nonperfusion peripheral to these areas in each eye (white arrows). Right eye (A) and left eye (B).
Discussion We describe a patient who had aplastic anemia due to DC with bilateral RNV. After a thorough MEDLINE review of the literature, we believe that this is the first report of proliferative retinopathy demonstrated by fluorescein angiography in the setting of either acquired aplastic anemia or DC. Among the ophthalmic complications reported, punctal stenosis with resultant epiphora is the most common manifestation of DC. Funduscopic examination may reveal optic atrophy, arteriosclerosis of the retinal vasculature, retinal hemorrhage, cotton-wool spots, macular edema, anomalous retinal vessels, preretinal fibrosis, hyperpigmented choroid, and choroidal atrophy (Table 1).7 Ocular findings are also commonly seen in patients with a variety of hematologic disorders associated with anemia and/or thrombocytopenia9 and typically manifest
261
Fig. 4. Color fundus photograph montage showing laser photocoagulation treatment to areas of peripheral capillary nonperfusion (arrows). Right eye (A) and left eye (B).
in the form of ocular hemorrhage, usually of the posterior segment. Although aplastic anemia is common in DC, DC is only a rare cause of aplastic anemia, which most often is an acquired condition. Mansour et al8 specifically reported the ocular findings of 18 patients with acquired aplastic anemia (thus presumably none due to DC), along with a review of the literature to include findings for an additional 126 patients. The most common finding was nerve fiber layer or retinal hemorrhage, seen in approximately three fourths of patients (Table 1). There were no cases of RNV. The pathogenesis of DC is due to mutations in components of a ribonucleoprotein complex, which is essential for the elongation and maintenance of chromosome ends or telomeres. All patients with DC have excessively short telomeres, suggesting that the common defective pathway involves telomere maintenance.10 This defect impedes replicating cells from maintaining genetic integrity over time and, thus, tends to affect tissues with a high rate of cell turnover.
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Table 1. Ocular Findings in Dyskeratosis Congenita and Acquired Aplastic Anemia
Ocular Finding(s) Anomalous retinal blood vessels Blepharitis Blue sclerae Cataract Choroidal pigmentary changes Conjunctivitis Corneal erosions or ulcers Cotton-wool spots Ectropion and trichiasis Glaucoma Macular edema Macular hemorrhage Optic atrophy Optic disk edema Orbital/eyelid hematoma Pallor of palpebral conjunctiva Preretinal fibrosis Proliferative retinopathy Punctal stenosis and epiphora Retinal or vitreous hemorrhage Retinal vascular malformation Roth spots Sparse lashes Strabismus
Acquired Dyskeratosis Aplastic Congenita Anemia ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹ Current report ⫹ ⫹ ⫺ ⫺ ⫹ ⫹
⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫺ ⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹ ⫹ ⫺ –
2009
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retinal nonperfusion may minimize future ocular complications and risk of visual loss. Although it would be difficult to determine whether the retinal findings for this patient were due to DC or to aplastic anemia, to our knowledge, this case nevertheless represents the first report of RNV in DC or in aplastic anemia, whether inherited or acquired. We propose that this represents a hitherto unreported additional ophthalmic association with DC and/or aplastic anemia. Key words: aplastic anemia, capillary nonperfusion, dyskeratosis congenita, fluorescein angiography, laser photocoagulation, proliferative retinopathy, retinal neovascularization. References 1.
2.
3.
4. 5.
⫹, present; ⫺, absent.
6.
The clinical manifestation of this may resemble that of a premature aging syndrome.11 At the time of this writing, our patient was undergoing treatment for aplastic anemia with oxymetholone, to which he appeared to be responding. Consideration exists for a future bone marrow transplant from his HLA-identical sibling. In conclusion, we describe a unique case of proliferative retinopathy in a patient with aplastic anemia due to DC, demonstrated with angiographic findings of significant peripheral capillary nonperfusion and RNV. Prompt application of laser photocoagulation to areas of
●
7. 8. 9.
10.
11.
Cole HN, Rauschkolb JC, Toomey J. Dyskeratosis congenita with pigmentation, dystrophia unguis and leukokeratosis oris. Arch Dermatol Syphilol 1930;21:71–95. Engman MF. A unique case of reticular pigmentation of the skin with atrophy. Arch Derm Syphiligraphie 1926;13:685– 687. Zinsser F. Atrophia cutis reticularis cum pigmentatione, dystrophia et leukoplakiaoris. Ikonogr Dermatol 1910;5:219– 223. Drachtman RA, Alter BP. Dyskeratosis congenita. Dermatol Clin 1995;13:33–39. Alter BP. Inherited bone marrow failure syndromes. In: Nathan DG, Orkin SH, Look AT, Ginsburg D, eds. Nathan and Oski’s Hematology of Infancy and Childhood. 6th ed. Philadelphia, PA: WB Saunders;2003:299–306. Young NS, Alter BP. Aplastic Anemia: Acquired and Inherited. Philadelphia, PA: WB Saunders;1994:325–338. Chambers JK, Salinas CF. Ocular findings in dyskeratosis congenita. Birth Defects 1982;18:167–174. Mansour AM, Salti HI, Han DP, et al. Ocular findings in aplastic anemia. Ophthalmologica 2000;214:399–402. Carraro MC, Rossetti L, Gerli GC. Prevalence of retinopathy in patients with anemia or thrombocytopenia. Eur J Haematol 2001;67:238–244. Alter BP, Baerlocher G, Savage SA, et al. Telomere length measurement by flow fluorescence in situ hybridization identifies patients with dyskeratosis congenita. Blood 2007;110: 1439–1447. Mason PJ, Wilson DB, Bessler M. Dyskeratosis congenita: a disease of dysfunctional telomere maintenance. Current Molecular Medicine 2005;5:159–170.
