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injury from button battery, button battery package regulations, systemic complication from button battery, button battery injury in young children. References
FIG 3. Button battery removed under general anesthesia from superonasal fornix. The positive electrode was smooth (A) and the negative electrode, facing the bulbar conjunctiva and sclera, was rough corroded (B).
FIG 4. Mild symblepharon in supero-nasal fornix.
battery.5,6 These include (1) leakage of battery contents, especially alkaline electrolyte; (2) generation of an electric current that hydrolyzes tissue fluid and produces hydroxide ions at battery’s negative pole; and (3) physical pressure on adjacent tissue. In our case, it is likely that battery corrosion led to leakage of alkaline content that caused local tissue damage. This was evident by the high PH of the effected tissues and also by the fact that the battery’s negative electrode facing the bulbar conjunctiva and sclera was corroded. Ocular injury from button batteries is uncommon. Only 3 other case reports have been published.7-9 Clinical features mentioned in 1 report7 suggest that the tissue injury was secondary to blunt trauma; the other 2 cases,8,9 presented with delayed onset of symptoms. Although the exact time of exposure in our case cannot be known for certain, based on the history, it seems that that exposure time was only 3-4 hours. We believe this is the first reported case of such rapid onset of symptoms from exposure to a button battery. Button battery–induced ocular injuries may be severe and require prompt diagnosis and treatment to avoid potential complications such as symblephron formation, scleral thinning, perforation, or limbal stem deficiency. Our case demonstrates how fast injury can occur.
Literature Search The authors searched PubMed and the Athens and University College London (UCL) Library database October 2013 through January 2014 using the following terms: button battery injury, mechanism of button battery injury, ocular
Journal of AAPOS
1. Gomes CC, Sakano E, Lucchezi MC, Porto PR. Button battery as a foreign body in nasal cavities: special aspects. Rhinology 1994;32:98-100. 2. Kavanagh KT, Litovitz T. Miniature battery foreign bodies in auditory and nasal cavities. JAMA 1986;255:1470-72. 3. Huppert J, Griffiths S, Breech L, Hillard P. Vaginal burn injury due to alkaline batteries. J Paediatr Adolesc Gynecol 2009;22:e133-6. 4. National Capital Poison Center. Nonfatal button battery ingestions with severe esophageal or airway injury: 125 cases. http://www. poison.org/battery/severecases. 5. Tanaka J, Yamashita M, Yamashita M, Kajigaya H. Esophageal electrochemical burns due to button type lithium batteries in dogs. Vet Hum Toxicol 1998;40:193-6. 6. Yoshikawa T, Asai S, Takekawa Y, Kida A. Experimental investigation of battery-induced esophageal burn injury in rabbits. Crit Care Med 1997;25:2039-44. 7. Mazer-Amirshahi M, Whitaker N, Kayewilson L, Litovitz T. Severe ocular injury after button battery exposure. J Emerg Med 2013;44:e187-9. 8. Ogasawara M, Goto S, Shiba T, et al. A case of button battery-induced corneal and conjunctive burn injury and experimental findings of local damage [in Japanese]. Nippon Ganka Gakkai zasshi 2011;115:711-17. 9. Ratnarajan G, Calladine D, Bird KJ, Watson SL. Delayed presentation of severe ocular injury from a button battery. BMJ Case Rep 2013. May 2, 2013.
Unusual retinal abnormalities in sisters with tetralogy of Fallot Mario T. Zanolli, MD,a Jenina Capasso, CGC, MS,a Vikas Khetan, MD,a Bego~ na Aristimu~ no, MD,c and Alex V. Levin, MD, MHSca,b Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease and can occur in the setting of chromosomal aberrations or multisystem malformation syndromes. We report unusual focal bilateral retinal defects in sisters with TOF.
Author affiliations: aOcular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania; b Thomas Jefferson University, Philadelphia; c360 St. Charles Way, York, Pennsylvania Funded in part by the Foerderer Fund (AVL), the Robison D. Harley, MD Endowed Chair in Pediatric Ophthalmology and Ocular Genetics (AVL), the Joseph F. Bradway, Sr. Endowed Research Scholar Fund, and the Alcon Ocular Genetics Fellowship (MTZ). The funding organizations had no role in the design or conduct of this research. Submitted April 24, 2014. Revision accepted July 5, 2014. Published online October 24, 2014. Correspondence: Alex V. Levin, MD, MHSc, Chief, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Suite 1210, 840 Walnut Street, Philadelphia, PA 191075109 (email: [email protected]). J AAPOS 2014;18:601-604. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.07.163
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Volume 18 Number 6 / December 2014
Case 1
A
10-year-old girl with a history of repaired tetralogy of Fallot (TOF). was referred to Wills Eye Hospital for assessment of a retinal abnormality found on routine eye examination after failed school vision screening. She had not required blood transfusions and was born with cleft lip and palateShe had a history of right anisometropic amblyopia and congenital right superior oblique palsy diagnosed and treated by another physician with glasses and patching from 4 years of age. Best-corrected Snellen acuity was 20/40 right eye ( 3.00 D) and 20/20 left eye (plano). Ishihara color plates, pupillary responses, slit-lamp examination, and intraocular pressures on applanation tonometry were normal. Dilated retinal examination showed a tiny focal atrophic defect in each macula, with focal pigmentary alteration on the lesion border in the right eye. The vitreous examination was normal. Optical coherence tomography (OCT) showed geometric, sharp-edged defects without vitreous traction (Figure 1). The findings were confirmed as nonartifactual through repeat scanning and correlation between the OCT findings and the clinical abnormalities geographically. Fundus autofluorescence and full-field electroretinogram were normal.
FIG 1. Case 1 right eye fundus photograph (A) and OCT (B). There is a tiny focal atrophic retinal defect in the macula (black arrow), with a corresponding geometric, sharp-edged defect in the retina on OCT, without evidence of overlying vitreous traction. C, choroid; ELM, external limiting membrane, GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS/OS, inner segment/outer segment junction; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.
Case 2 This 7-year-old girl, the sister of case 1, is the result of a dizygotic twin gestation with a male twin who does not have TOF and has no ocular abnormalities. She had mildly cyanotic TOF. She had anemia not requiring blood transfusion. TOF was repaired when she was 18 days of age. Further heart surgery was performed twice. At 2 years of age she was diagnosed with left anisometropic amblyopia, which was treated with glasses and patching by another physician. She also had retinal abnormalities noted on routine examination. Best-corrected Snellen visual acuity was 20/60 in the right eye ( 5.50 D) and 20/25 in the left eye (plano 10.25 143 ). Eye movements were full, and there was strabismus. Ishihara color plates, pupillary responses, and slit-lamp examination were normal. Dilated retinal examination showed tiny macular retinal defects in both eyes, with mild retinal pigmentary epithelium changes. Vitreous examination was normal except for a right free-floating nonpigmented vitreous cyst. OCT revealed geometric, sharp-edged defects without overlying vitreous traction (Figure 2). Fundus autofluorescence was normal. Electroretinogram was not performed, in view of her age and abilities. Parental ophthalmological examinations, including OCT, were normal. The patients’ mother had previously had a normal echocardiogram. The pedigree is otherwise unremarkable (Figure 3). Oligo-single nucleotide polymorphism chromosomal assay (Affymetrix CytoScan HD) showed an approximate 519 kb gain at 12q24.31 in both girls. The mother has the same copy number variation as her daughters.
FIG 2. Fundus photograph (A) and OCT (B) of the left eye of case 2. There are multiple macular retinal defects (black arrows), with corresponding geometric, sharp-edged defect in the retina on OCT, shown for the largest lesion, without evidence of overlying vitreous traction. The vertical dark line in the middle of the fundus picture is the fixation device. C, choroid; ELM, external limiting membrane, GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS/OS, inner segment/outer segment junction; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.
Discussion TOF is the most common cyanotic congenital heart disease.1 Approximately 20% of cases occur in the setting of chromosomal aberrations or multisystem malformation syndromes.2 For TOF, del22q11.2 is the most frequently related genetic anomaly.3 Multiple additional loci have been mapped for TOF, including 8q23.1, 18q11.2, 19p13.11, and 20p12.2. Family studies indicate a significant complex genetic component to the disease.4 Mutations in NKX2-5 gene at 5q35 were reported in 4% of nonsyndromic TOF patients and demonstrate a dominant pattern with variable penetrance.1,5 Our patients showed retinal defects, which, to our knowledge, have not been previously described in patients with TOF. Although the lesion could be the result of congenital developmental abnormalities of the retina,
Journal of AAPOS
Volume 18 Number 6 / December 2014
FIG 3. Unremarkable pedigree, with the exception of affected sisters with tetralogy of Fallot. COD, cause of death; m/o, months old; p, unknown gender pregnancy.
somewhat similar macular lesions have been reported in vitreoretinal traction, including idiopathic macular hole and lamellar hole. Our patients did not show evidence of vitreoretinal traction by clinical examination or on OCT. Focal posterior vitreous detachment and secondary traction are rare in young children. Blunt trauma can also cause similar lesions, but our patients had no history of injury. Case 2 has a free-floating vitreous cyst, but this finding has not been associated previously with TOF, traction, ischemia, or proliferative retinopathy. Vitreous cysts may be congenital or associated with factors not relevant in this child including parasitic infection, tumors, trauma, high myopia, inflammation and retinitis pigmentosa. Goel and colleagues6 reported bilateral proliferative retinopathy in a patient with TOF and cardiac shunt surgery. The patient also had polycythemia. Genetic testing was not done. The authors suggest that their findings are secondary to ischemia. Tsai and colleagues reported a 17-year-old male with TOF and central retinal artery occlusion who had foveal cystic cavities without traction.7 Other findings reported in patients with cyanotic heart disease include retinal vascular tortuosity, retinal hemorrhages, disk edema, central retinal vein,8,9 and artery occlusions.7 A cross sectional study showed a high correlation between cyanotic heart disease, including TOF, and ocular findings.8 To our knowledge, there are no reported duplications at 12q24.31 similar to those in our patients. No ophthalmic abnormalities have been reported from this genetic abnormality, although only one case specifically notes an ocular examination.10 This locus has, however, been associated with TOF2 but has not been associated with retinal abnormalities. The region contains several genes, including ACADS, HNF1, CABP1 and ZFOC1. Neither ACADS nor HNF1 have been associated with retinal disease, and both are not expressed in ocular or heart tissues. Mutations in ACADS result in autosomal recessive deficiency of short chain Acyl-CoA dehydrogenase, with no reported ocular manifestations. Retinal dystrophy has been described in long chain 3-hydroxy-
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acyl-coA dehydrogenase deficiency. CABP1 is expressed in brain neural tissue and retina but not in the heart. It is involved in signal transduction, cell contraction, secretion and cell proliferation. Its role in retina development is unknown. ZFOC1 is also expressed in the retina. To our knowledge, there are no reports of CABP1- or ZFOC1related eye disease. The absence of systemic features in our patients attributable to the copy number variation, a gene within the region likely to cause the retinal findings and affected maternal disease despite the presence of the same copy number variation lead us to conclude that the dup12q24.31 is not likely related to the ocular abnormalities seen in our patients. Both of our patients had moderate myopia. Although myopia is associated with a 3- to 4-fold increased risk of posterior vitreous detachment, our patients have a normal vitreoretinal interface clinically and by OCT. A locus has been described for familial high myopia at 12q21-23, but this has not been associated with myopic degeneration. Our patients also had the same retinal abnormalities in their plano fellow eye. Therefore, we do not believe that myopia explains the ocular findings. The unusual retinal defects in the sisters presented here are not satisfactorily explained by clinical history, ophthalmological testing, or genetic findings. We cannot rule out a role of microischemic retinal injury during their earlier periods of cyanotic disease. Although we do not believe the duplication on chromosome 12 is in of itself causative, sequencing of those genes with retinal expression in that region could be revealing. Whole exome or genome sequencing may indicate a gene that could explain the combination of findings or the retinal disease as being unrelated to the TOF. Although we acknowledge that the findings reported here in may be chance association, the presence of both the cardiac defect and rare retinal manifestations in sisters makes the chance of coinheritance remote. The retinal findings in our patients are somewhat subtle. Careful retinal examination and OCT of patients with TOF or perhaps other forms of cyanotic retinal disease might show these abnormalities to be more widespread.
Literature Search Medline/PubMed, Google Scholar, and UCSC Genome Browser were searched using the following terms: tetralogy of Fallot, congenital cyanotic heart disease, retinopathy, and retinal abnormalities. The reference lists of retrieved articles were searched to identify other useful publications. References 1. Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with Tetralogy of Fallot. Circulation 2001;104:2565-8. 2. Cordell HJ, Topf A, Mamasoula C, et al. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot. Hum Mol Genet 2013;22:1473-81. 3. Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet 2000; 9:2421-6.
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4. Burn J, Brennan P, Little J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998;351:311-16. 5. McElhinney DB, Geiger E, Blinder J, et al. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 2003;42:1650-55. 6. Goel N, Kumar V, Seth A, Ghosh B. Proliferative retinopathy in a child with congenital cyanotic heart disease. J AAPOS 2010;14:455-6. 7. Tsai FF, Spindle J, Lazzaro EC, Olumba KC. Central retinal artery occlusion in a patient with tetralogy of Fallot. J AAPOS 2013;17:621-2. 8. Mansour AM, Bitar FF, Traboulsi EI, et al. Ocular pathology in congenital heart disease. Eye 2004;19:29-34. 9. VanderVeen DK, Pasquale LR, Fulton AB. Central retinal vein occlusion in a young child with cyanotic heart disease. Arch Ophthalmol 1997;115:1077. 10. Qiao Y, Tyson C, Hrynchak M, et al. Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Clinical Genetics 2012;83:145-54.
An unusual case of coats disease associated with Takayasu arteritis Pok Chien Tan, MB ChB, and Benjamin Chong-Ming Chang, FRCOphth A 3-year-old Malay boy with strabismus in the left eye was found to have Coats disease in the same eye and underlying Takayasu arteritis. Coats disease is usually idiopathic but can be associated with systemic and ocular conditions. To our knowledge, this is the first reported case of Coats disease associated with Takayasu arteritis.
Case Report
A
3-year-old Malay boy presented at Khoo Teck Puat Hospital, Singapore, with left eye strabismus of 2 months’ duration. He had no significant medical or family history. On examination, his best-corrected visual acuity was 20/25 in the right eye and counting fingers in the left eye. Orthoptic assessment was consistent with a left sensory exotropia. Anterior segment examination was unremarkable. Dilated fundus examination of the left eye revealed the presence of extensive yellow exudates and edema at the posterior pole, with telangiectatic vessels and fusiform dilation of retinal arterioles (Figure 1). The fundus of the right eye appeared normal. A diagnosis of
Author affiliations: Ophthalmology and Visual Science Department, Khoo Teck Puat Hospital, Singapore, KK Women’s and Children’s Hospital, Singapore Submitted April 16, 2014. Revision accepted July 6, 2014. Published online November 12, 2014. Correspondence: Pok Chien Tan, MB ChB, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828 (email: [email protected], [email protected]). J AAPOS 2014;18:604-605. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.07.164
Volume 18 Number 6 / December 2014
FIG 1. Fundus photograph of the right eye (A) and left eye (B), which shows extensive yellow exudates and edema at the posterior pole with telangiectatic vessels and fusiform dilation of retinal arterioles.
Coats disease was made and diode laser photocoagulation to the telangiectatic vessels of the left eye was performed under general anesthesia. Intraoperatively the patient was found to have severe hypertension that necessitated intensive-care monitoring and control of blood pressure. Magnetic resonance angiography (MRA) renal vessels and magnetic resonance imaging (MRI) of the thorax were subsequently performed. The investigations revealed bilateral renal artery stenosis and tapered narrowing of the prerenal abdominal aorta distal to the origin of the mesenteric artery with periaortic soft tissue, which were consistent with Takayasu arteritis. Blood investigations showed raised inflammatory markers (erythrocyte sedimentation rate of 101 mm/hr and C-reactive protein of 21.6 mg/L) and elevated serum renin and aldosterone. Other tests, including full blood count, renal panel, thyroid function test, liver function test, TB T-spot test, chest X-ray and autoimmune workup were unremarkable. The patient responded well to oral prednisolone, methotrexate, and antihypertensive medications and was discharged after 18 days of in-patient care. On follow-up, progressive resolution of most of the exudates and retinal edema was noted with a return to normal retinal vessel caliber at 9 months postoperatively (Figure 2). Best-corrected visual acuity at that time was 20/200 in the left eye.
Discussion To our knowledge, this is the first case showing an association of Coats disease with Takayasu arteritis. Coats disease is unilateral in most cases and classically presents with yellow lipid-rich subretinal and intraretinal exudates and abnormalities in the retinal vessels, including telangiectasia, aneurysmal dilatations, and vascular tortuosity,1 as in our case. In later stages, the exudates can progress to a total retinal detachment.2 Untreated, the disease can lead to neovascular glaucoma and phthisis bulbi in advanced stages.1 The incidental finding of severe hypertension intraoperatively gave rise to a suspicion of the underlying Takayasu arteritis. Takayasu arteritis is characterized by attenuation of the aorta and its branches, as a result of autoimmune inflammation of the arteries,3 which was corroborated by
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injury from button battery, button battery package regulations, systemic complication from button battery, button battery injury in young children. References
FIG 3. Button battery removed under general anesthesia from superonasal fornix. The positive electrode was smooth (A) and the negative electrode, facing the bulbar conjunctiva and sclera, was rough corroded (B).
FIG 4. Mild symblepharon in supero-nasal fornix.
battery.5,6 These include (1) leakage of battery contents, especially alkaline electrolyte; (2) generation of an electric current that hydrolyzes tissue fluid and produces hydroxide ions at battery’s negative pole; and (3) physical pressure on adjacent tissue. In our case, it is likely that battery corrosion led to leakage of alkaline content that caused local tissue damage. This was evident by the high PH of the effected tissues and also by the fact that the battery’s negative electrode facing the bulbar conjunctiva and sclera was corroded. Ocular injury from button batteries is uncommon. Only 3 other case reports have been published.7-9 Clinical features mentioned in 1 report7 suggest that the tissue injury was secondary to blunt trauma; the other 2 cases,8,9 presented with delayed onset of symptoms. Although the exact time of exposure in our case cannot be known for certain, based on the history, it seems that that exposure time was only 3-4 hours. We believe this is the first reported case of such rapid onset of symptoms from exposure to a button battery. Button battery–induced ocular injuries may be severe and require prompt diagnosis and treatment to avoid potential complications such as symblephron formation, scleral thinning, perforation, or limbal stem deficiency. Our case demonstrates how fast injury can occur.
Literature Search The authors searched PubMed and the Athens and University College London (UCL) Library database October 2013 through January 2014 using the following terms: button battery injury, mechanism of button battery injury, ocular
Journal of AAPOS
1. Gomes CC, Sakano E, Lucchezi MC, Porto PR. Button battery as a foreign body in nasal cavities: special aspects. Rhinology 1994;32:98-100. 2. Kavanagh KT, Litovitz T. Miniature battery foreign bodies in auditory and nasal cavities. JAMA 1986;255:1470-72. 3. Huppert J, Griffiths S, Breech L, Hillard P. Vaginal burn injury due to alkaline batteries. J Paediatr Adolesc Gynecol 2009;22:e133-6. 4. National Capital Poison Center. Nonfatal button battery ingestions with severe esophageal or airway injury: 125 cases. http://www. poison.org/battery/severecases. 5. Tanaka J, Yamashita M, Yamashita M, Kajigaya H. Esophageal electrochemical burns due to button type lithium batteries in dogs. Vet Hum Toxicol 1998;40:193-6. 6. Yoshikawa T, Asai S, Takekawa Y, Kida A. Experimental investigation of battery-induced esophageal burn injury in rabbits. Crit Care Med 1997;25:2039-44. 7. Mazer-Amirshahi M, Whitaker N, Kayewilson L, Litovitz T. Severe ocular injury after button battery exposure. J Emerg Med 2013;44:e187-9. 8. Ogasawara M, Goto S, Shiba T, et al. A case of button battery-induced corneal and conjunctive burn injury and experimental findings of local damage [in Japanese]. Nippon Ganka Gakkai zasshi 2011;115:711-17. 9. Ratnarajan G, Calladine D, Bird KJ, Watson SL. Delayed presentation of severe ocular injury from a button battery. BMJ Case Rep 2013. May 2, 2013.
Unusual retinal abnormalities in sisters with tetralogy of Fallot Mario T. Zanolli, MD,a Jenina Capasso, CGC, MS,a Vikas Khetan, MD,a Bego~ na Aristimu~ no, MD,c and Alex V. Levin, MD, MHSca,b Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease and can occur in the setting of chromosomal aberrations or multisystem malformation syndromes. We report unusual focal bilateral retinal defects in sisters with TOF.
Author affiliations: aOcular Genetics, Wills Eye Hospital, Philadelphia, Pennsylvania; b Thomas Jefferson University, Philadelphia; c360 St. Charles Way, York, Pennsylvania Funded in part by the Foerderer Fund (AVL), the Robison D. Harley, MD Endowed Chair in Pediatric Ophthalmology and Ocular Genetics (AVL), the Joseph F. Bradway, Sr. Endowed Research Scholar Fund, and the Alcon Ocular Genetics Fellowship (MTZ). The funding organizations had no role in the design or conduct of this research. Submitted April 24, 2014. Revision accepted July 5, 2014. Published online October 24, 2014. Correspondence: Alex V. Levin, MD, MHSc, Chief, Pediatric Ophthalmology and Ocular Genetics, Wills Eye Hospital, Suite 1210, 840 Walnut Street, Philadelphia, PA 191075109 (email: [email protected]). J AAPOS 2014;18:601-604. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.07.163
602
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Volume 18 Number 6 / December 2014
Case 1
A
10-year-old girl with a history of repaired tetralogy of Fallot (TOF). was referred to Wills Eye Hospital for assessment of a retinal abnormality found on routine eye examination after failed school vision screening. She had not required blood transfusions and was born with cleft lip and palateShe had a history of right anisometropic amblyopia and congenital right superior oblique palsy diagnosed and treated by another physician with glasses and patching from 4 years of age. Best-corrected Snellen acuity was 20/40 right eye ( 3.00 D) and 20/20 left eye (plano). Ishihara color plates, pupillary responses, slit-lamp examination, and intraocular pressures on applanation tonometry were normal. Dilated retinal examination showed a tiny focal atrophic defect in each macula, with focal pigmentary alteration on the lesion border in the right eye. The vitreous examination was normal. Optical coherence tomography (OCT) showed geometric, sharp-edged defects without vitreous traction (Figure 1). The findings were confirmed as nonartifactual through repeat scanning and correlation between the OCT findings and the clinical abnormalities geographically. Fundus autofluorescence and full-field electroretinogram were normal.
FIG 1. Case 1 right eye fundus photograph (A) and OCT (B). There is a tiny focal atrophic retinal defect in the macula (black arrow), with a corresponding geometric, sharp-edged defect in the retina on OCT, without evidence of overlying vitreous traction. C, choroid; ELM, external limiting membrane, GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS/OS, inner segment/outer segment junction; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.
Case 2 This 7-year-old girl, the sister of case 1, is the result of a dizygotic twin gestation with a male twin who does not have TOF and has no ocular abnormalities. She had mildly cyanotic TOF. She had anemia not requiring blood transfusion. TOF was repaired when she was 18 days of age. Further heart surgery was performed twice. At 2 years of age she was diagnosed with left anisometropic amblyopia, which was treated with glasses and patching by another physician. She also had retinal abnormalities noted on routine examination. Best-corrected Snellen visual acuity was 20/60 in the right eye ( 5.50 D) and 20/25 in the left eye (plano 10.25 143 ). Eye movements were full, and there was strabismus. Ishihara color plates, pupillary responses, and slit-lamp examination were normal. Dilated retinal examination showed tiny macular retinal defects in both eyes, with mild retinal pigmentary epithelium changes. Vitreous examination was normal except for a right free-floating nonpigmented vitreous cyst. OCT revealed geometric, sharp-edged defects without overlying vitreous traction (Figure 2). Fundus autofluorescence was normal. Electroretinogram was not performed, in view of her age and abilities. Parental ophthalmological examinations, including OCT, were normal. The patients’ mother had previously had a normal echocardiogram. The pedigree is otherwise unremarkable (Figure 3). Oligo-single nucleotide polymorphism chromosomal assay (Affymetrix CytoScan HD) showed an approximate 519 kb gain at 12q24.31 in both girls. The mother has the same copy number variation as her daughters.
FIG 2. Fundus photograph (A) and OCT (B) of the left eye of case 2. There are multiple macular retinal defects (black arrows), with corresponding geometric, sharp-edged defect in the retina on OCT, shown for the largest lesion, without evidence of overlying vitreous traction. The vertical dark line in the middle of the fundus picture is the fixation device. C, choroid; ELM, external limiting membrane, GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS/OS, inner segment/outer segment junction; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; RPE, retinal pigment epithelium.
Discussion TOF is the most common cyanotic congenital heart disease.1 Approximately 20% of cases occur in the setting of chromosomal aberrations or multisystem malformation syndromes.2 For TOF, del22q11.2 is the most frequently related genetic anomaly.3 Multiple additional loci have been mapped for TOF, including 8q23.1, 18q11.2, 19p13.11, and 20p12.2. Family studies indicate a significant complex genetic component to the disease.4 Mutations in NKX2-5 gene at 5q35 were reported in 4% of nonsyndromic TOF patients and demonstrate a dominant pattern with variable penetrance.1,5 Our patients showed retinal defects, which, to our knowledge, have not been previously described in patients with TOF. Although the lesion could be the result of congenital developmental abnormalities of the retina,
Journal of AAPOS
Volume 18 Number 6 / December 2014
FIG 3. Unremarkable pedigree, with the exception of affected sisters with tetralogy of Fallot. COD, cause of death; m/o, months old; p, unknown gender pregnancy.
somewhat similar macular lesions have been reported in vitreoretinal traction, including idiopathic macular hole and lamellar hole. Our patients did not show evidence of vitreoretinal traction by clinical examination or on OCT. Focal posterior vitreous detachment and secondary traction are rare in young children. Blunt trauma can also cause similar lesions, but our patients had no history of injury. Case 2 has a free-floating vitreous cyst, but this finding has not been associated previously with TOF, traction, ischemia, or proliferative retinopathy. Vitreous cysts may be congenital or associated with factors not relevant in this child including parasitic infection, tumors, trauma, high myopia, inflammation and retinitis pigmentosa. Goel and colleagues6 reported bilateral proliferative retinopathy in a patient with TOF and cardiac shunt surgery. The patient also had polycythemia. Genetic testing was not done. The authors suggest that their findings are secondary to ischemia. Tsai and colleagues reported a 17-year-old male with TOF and central retinal artery occlusion who had foveal cystic cavities without traction.7 Other findings reported in patients with cyanotic heart disease include retinal vascular tortuosity, retinal hemorrhages, disk edema, central retinal vein,8,9 and artery occlusions.7 A cross sectional study showed a high correlation between cyanotic heart disease, including TOF, and ocular findings.8 To our knowledge, there are no reported duplications at 12q24.31 similar to those in our patients. No ophthalmic abnormalities have been reported from this genetic abnormality, although only one case specifically notes an ocular examination.10 This locus has, however, been associated with TOF2 but has not been associated with retinal abnormalities. The region contains several genes, including ACADS, HNF1, CABP1 and ZFOC1. Neither ACADS nor HNF1 have been associated with retinal disease, and both are not expressed in ocular or heart tissues. Mutations in ACADS result in autosomal recessive deficiency of short chain Acyl-CoA dehydrogenase, with no reported ocular manifestations. Retinal dystrophy has been described in long chain 3-hydroxy-
Journal of AAPOS
Zanolli et al
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acyl-coA dehydrogenase deficiency. CABP1 is expressed in brain neural tissue and retina but not in the heart. It is involved in signal transduction, cell contraction, secretion and cell proliferation. Its role in retina development is unknown. ZFOC1 is also expressed in the retina. To our knowledge, there are no reports of CABP1- or ZFOC1related eye disease. The absence of systemic features in our patients attributable to the copy number variation, a gene within the region likely to cause the retinal findings and affected maternal disease despite the presence of the same copy number variation lead us to conclude that the dup12q24.31 is not likely related to the ocular abnormalities seen in our patients. Both of our patients had moderate myopia. Although myopia is associated with a 3- to 4-fold increased risk of posterior vitreous detachment, our patients have a normal vitreoretinal interface clinically and by OCT. A locus has been described for familial high myopia at 12q21-23, but this has not been associated with myopic degeneration. Our patients also had the same retinal abnormalities in their plano fellow eye. Therefore, we do not believe that myopia explains the ocular findings. The unusual retinal defects in the sisters presented here are not satisfactorily explained by clinical history, ophthalmological testing, or genetic findings. We cannot rule out a role of microischemic retinal injury during their earlier periods of cyanotic disease. Although we do not believe the duplication on chromosome 12 is in of itself causative, sequencing of those genes with retinal expression in that region could be revealing. Whole exome or genome sequencing may indicate a gene that could explain the combination of findings or the retinal disease as being unrelated to the TOF. Although we acknowledge that the findings reported here in may be chance association, the presence of both the cardiac defect and rare retinal manifestations in sisters makes the chance of coinheritance remote. The retinal findings in our patients are somewhat subtle. Careful retinal examination and OCT of patients with TOF or perhaps other forms of cyanotic retinal disease might show these abnormalities to be more widespread.
Literature Search Medline/PubMed, Google Scholar, and UCSC Genome Browser were searched using the following terms: tetralogy of Fallot, congenital cyanotic heart disease, retinopathy, and retinal abnormalities. The reference lists of retrieved articles were searched to identify other useful publications. References 1. Goldmuntz E, Geiger E, Benson DW. NKX2.5 mutations in patients with Tetralogy of Fallot. Circulation 2001;104:2565-8. 2. Cordell HJ, Topf A, Mamasoula C, et al. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot. Hum Mol Genet 2013;22:1473-81. 3. Scambler PJ. The 22q11 deletion syndromes. Hum Mol Genet 2000; 9:2421-6.
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4. Burn J, Brennan P, Little J, et al. Recurrence risks in offspring of adults with major heart defects: results from first cohort of British collaborative study. Lancet 1998;351:311-16. 5. McElhinney DB, Geiger E, Blinder J, et al. NKX2.5 mutations in patients with congenital heart disease. J Am Coll Cardiol 2003;42:1650-55. 6. Goel N, Kumar V, Seth A, Ghosh B. Proliferative retinopathy in a child with congenital cyanotic heart disease. J AAPOS 2010;14:455-6. 7. Tsai FF, Spindle J, Lazzaro EC, Olumba KC. Central retinal artery occlusion in a patient with tetralogy of Fallot. J AAPOS 2013;17:621-2. 8. Mansour AM, Bitar FF, Traboulsi EI, et al. Ocular pathology in congenital heart disease. Eye 2004;19:29-34. 9. VanderVeen DK, Pasquale LR, Fulton AB. Central retinal vein occlusion in a young child with cyanotic heart disease. Arch Ophthalmol 1997;115:1077. 10. Qiao Y, Tyson C, Hrynchak M, et al. Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability. Clinical Genetics 2012;83:145-54.
An unusual case of coats disease associated with Takayasu arteritis Pok Chien Tan, MB ChB, and Benjamin Chong-Ming Chang, FRCOphth A 3-year-old Malay boy with strabismus in the left eye was found to have Coats disease in the same eye and underlying Takayasu arteritis. Coats disease is usually idiopathic but can be associated with systemic and ocular conditions. To our knowledge, this is the first reported case of Coats disease associated with Takayasu arteritis.
Case Report
A
3-year-old Malay boy presented at Khoo Teck Puat Hospital, Singapore, with left eye strabismus of 2 months’ duration. He had no significant medical or family history. On examination, his best-corrected visual acuity was 20/25 in the right eye and counting fingers in the left eye. Orthoptic assessment was consistent with a left sensory exotropia. Anterior segment examination was unremarkable. Dilated fundus examination of the left eye revealed the presence of extensive yellow exudates and edema at the posterior pole, with telangiectatic vessels and fusiform dilation of retinal arterioles (Figure 1). The fundus of the right eye appeared normal. A diagnosis of
Author affiliations: Ophthalmology and Visual Science Department, Khoo Teck Puat Hospital, Singapore, KK Women’s and Children’s Hospital, Singapore Submitted April 16, 2014. Revision accepted July 6, 2014. Published online November 12, 2014. Correspondence: Pok Chien Tan, MB ChB, Khoo Teck Puat Hospital, 90 Yishun Central, Singapore 768828 (email: [email protected], [email protected]). J AAPOS 2014;18:604-605. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.07.164
Volume 18 Number 6 / December 2014
FIG 1. Fundus photograph of the right eye (A) and left eye (B), which shows extensive yellow exudates and edema at the posterior pole with telangiectatic vessels and fusiform dilation of retinal arterioles.
Coats disease was made and diode laser photocoagulation to the telangiectatic vessels of the left eye was performed under general anesthesia. Intraoperatively the patient was found to have severe hypertension that necessitated intensive-care monitoring and control of blood pressure. Magnetic resonance angiography (MRA) renal vessels and magnetic resonance imaging (MRI) of the thorax were subsequently performed. The investigations revealed bilateral renal artery stenosis and tapered narrowing of the prerenal abdominal aorta distal to the origin of the mesenteric artery with periaortic soft tissue, which were consistent with Takayasu arteritis. Blood investigations showed raised inflammatory markers (erythrocyte sedimentation rate of 101 mm/hr and C-reactive protein of 21.6 mg/L) and elevated serum renin and aldosterone. Other tests, including full blood count, renal panel, thyroid function test, liver function test, TB T-spot test, chest X-ray and autoimmune workup were unremarkable. The patient responded well to oral prednisolone, methotrexate, and antihypertensive medications and was discharged after 18 days of in-patient care. On follow-up, progressive resolution of most of the exudates and retinal edema was noted with a return to normal retinal vessel caliber at 9 months postoperatively (Figure 2). Best-corrected visual acuity at that time was 20/200 in the left eye.
Discussion To our knowledge, this is the first case showing an association of Coats disease with Takayasu arteritis. Coats disease is unilateral in most cases and classically presents with yellow lipid-rich subretinal and intraretinal exudates and abnormalities in the retinal vessels, including telangiectasia, aneurysmal dilatations, and vascular tortuosity,1 as in our case. In later stages, the exudates can progress to a total retinal detachment.2 Untreated, the disease can lead to neovascular glaucoma and phthisis bulbi in advanced stages.1 The incidental finding of severe hypertension intraoperatively gave rise to a suspicion of the underlying Takayasu arteritis. Takayasu arteritis is characterized by attenuation of the aorta and its branches, as a result of autoimmune inflammation of the arteries,3 which was corroborated by
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