- Email: [email protected]
CHARGE syndrome with oculomotor nerve palsy
Short Reports CHARGE syndrome with oculomotor nerve palsy Hee Kyung Yang, MD,a,* Byung Yoon Choi, MD,b,* Jae Hyoung Kim, MD,c Ja-Won Koo, MD,b Mun Young Chang, MD,b and Jeong-Min Hwang, MDa CHARGE syndrome is a congenital disorder characterized by coloboma, heart defects, atresia of the choanae, retarded growth, genital hypoplasia, ear anomalies, and/or hearing loss. We report the case of a 2-year-old boy with CHARGE syndrome who presented with left exotropia and elevation deficit since infancy. He had patent ductus arteriosus, small testicles, growth retardation, auricular deformity, left semicircular canal aplasia, and a de novo nonsense mutation (p.Ser705X) of the CHD7 gene. He had a left exotropia of 40 prism diopters, marked limitation of upgaze and mild limitation of downgaze and adduction in the left eye. On upgaze, his left eye adducted but did not elevate. The pupils of both eyes were round and isocoric. Fundus examination revealed optic disk and choroidal colobomas. CHARGE syndrome with oculomotor nerve palsy has not been reported previously.
Case Report
A
2-year-old boy presented at Seoul National University Bundang Hospital with a left exotropia and limited elevation since infancy. He had thick nostrils and a small mouth. His ears were low set and asymmetric, with small lobes. He was born at 40 weeks’ gestation weighing 3.15 kg. He underwent patent ductus arteriosus ligation at the age of 20 days, polydactyly repair of his right toe at 1 year, and bilateral cochlear implantation at 2 years of age. He also had left facial nerve palsy, small testicles, growth and developmental retardation, attention deficit, bilateral microtia, bilateral semicircular canal aplasia, bilateral narrowing of the internal and external auditory canal, absent nerve fiber to cochlea, bilateral cochlear dysplasia, but did not have choanal atresia. This constellation of clinical symptoms and signs indicated typical CHARGE syn-
Author affiliations: Departments of aOphthalmology, bOtorhinolaryngology–Head and Neck Surgery, and cRadiology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Research supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2013R1A1A2010606). * These two authors equally contributed to the work. Submitted April 7, 2015. Revision accepted June 6, 2015. Correspondence: Jeong-Min Hwang, MD, Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumiro, Bundang-gu, Seongnam, Gyeonggi-do 463-707, Korea (email: hjm@snu. ac.kr). J AAPOS 2015;19:555-557. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.06.005
Journal of AAPOS
drome, as suggested by Verloes.1 Subsequent molecular genetic testing involving Sanger sequencing of all 38 exons and both 100 bp of flanking intronic sequences of the CHD7 gene revealed a previously reported pathogenic nonsense mutation (c.2114C.A (p.Ser705X), which would cause truncation of this protein.2 On ophthalmologic examination at two previous university hospitals, he was initially diagnosed first with exotropia and later with double elevator palsy. On his first visit to our institution, he fixed and followed a 5-inch toy with each eye. He showed a left exotropia of 40 prism diopters at distance and near using the Krimsky method. Ductions and versions showed marked limitation of upgaze and mild limitation of downgaze and adduction in the left eye (Figure 1). On upgaze, his left eye adducted but did not elevate. His pupils were round and isocoric in both eyes. Dilated fundus examination revealed optic disk and choroidal colobomas in both eyes (Figure 2). Cycloplegic refraction showed 1.00 diopters (D) in the right eye and 3.50 D in the left eye.
Discussion CHARGE syndrome (OMIM 214800) is a congenital disease characterized by coloboma, heart defects, atresia of the choanae, retarded growth, genital hypoplasia, ear anomalies, and/or hearing loss.1 Cranial nerve palsies (most commonly affecting the facial, vestibulocochlear, glossopharyngeal, and vagus nerves) have been frequently reported with CHARGE syndrome3; oculomotor nerve involvement has not been previously reported. Although the most common ophthalmic sign of CHARGE syndrome is coloboma,1 ocular motility can also be affected. McMain and colleagues4 described 3 patients with “vertical gaze disorder” with a monocular deficiency of upgaze. They suggested inferior oblique paresis in 2 patients, and Brown syndrome in another. These 3 patients may represent partial oculomotor nerve palsy, as in our patient. Our patient showed 5 characteristic findings of CHARGE syndrome: (1) coloboma of the eye, (2) heart defects, (3) retardation of growth and development, (4) genital abnormalities, and (5) ear abnormalities.1 In addition, he showed polydactyly as well as oculomotor and facial nerve palsies. There was no choanal atresia. A single heterozygous CHD7 mutation that mostly arises in de novo in approximately 60% to 70% of patients with CHARGE syndrome was identified.3 Genetic analysis of the CHD7 gene contribute tremendously to the diagnosis of CHARGE syndrome and is therefore necessary for the correct diagnosis of this syndrome, especially for atypical cases. Ophthalmologic findings associated with CHARGE syndrome include coloboma, microphthalmos, microcornea, ptosis, persistent fetal vasculature, nystagmus, cataract, optic nerve hypoplasia, refractive errors and strabismus.4 Our patient showed coloboma, anisomyopia, and exotropia caused by partial congenital
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Volume 19 Number 6 / December 2015
FIG 1. Ocular versions show a marked limitation of upgaze, mild limitation of downgaze and a very small limitation of adduction in the left eye. On upgaze, his left eye adducted instead of elevating.
FIG 2. Fundus photography showing optic disk and choroidal colobomas in right eye (A) and left eye (B).
oculomotor nerve palsy. Aberrant innervation of adduction on upgaze was present. His eyelid and pupils were not affected. Song and colleagues5 reported that missense mutations of CHD7 had milder symptoms as compared with other CHARGE patients carrying truncation mutations of CHD7 in Koreans. The additional ophthalmologic finding of oculomotor nerve palsy in our patient, carrying a nonsense truncation mutation of CHD7, may reflect the previously proposed genotype– phenotype correlation.6 Conditions that cause congenital elevation deficiency include monocular elevation deficiency, congenital oculomotor nerve palsy, Brown syndrome, inferior oblique palsy, superior oblique overaction, variant of Duane retraction syndrome, contralateral inferior rectus aplasia, adherence syndrome, congenital ocular fibrosis syndrome, and blow-out fracture.6-10 Our patient showed elevation deficit in both adduction and abduction, unlike inferior oblique palsy or Brown syndrome. He did not show superior oblique overaction. He denied any history of facial trauma as well as ocular surgery. He did not show ptosis as in patients with congenital ocular fibrosis
syndrome or myasthenia gravis. He did not show any characteristic findings of Duane retraction syndrome, such as fissure narrowing with adduction, upshoot or downshoot, and abduction was full in both eyes. A previous case series of congenital oculomotor nerve palsy showed that 2 of 3 patients with congenital oculomotor nerve palsy presented with an elevation deficit.6 Detection of an adduction deficit is easily missed in Asian children, because the skin folds cover the medial canthal area; similarly, depression deficit can be covered by the lower eyelid. Thus, an elevation deficit is much more easily recognized than adduction or depression deficit, which explains why our patient was previously misdiagnosed with monocular elevation deficiency. The present case report highlights the fact that a patient with CHARGE syndrome may show exotropia associated with partial oculomotor nerve palsy. Congenital oculomotor nerve palsy could be discordant among branches and may not be accompanied by ptosis or anisocoria and may thus be misdiagnosed as primary exotropia or monocular elevation deficiency (formerly called double elevator palsy).
Journal of AAPOS
Volume 19 Number 6 / December 2015
Matalia et al
557
Literature Search MEDLINE was searched on January 25, 2015, without language or date restriction, for the following terms: CHARGE, oculomotor nerve palsy, and third nerve palsy. References 1. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A 2005;133:306-8. 2. Zentner GE, Layman WS, Martin DM, Scacheri PC. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A 2010;52:674-86. 3. Blake KD, Hartshorne TS, Lawand C, Dailor AN, Thelin JW. Cranial nerve manifestations in CHARGE syndrome. Am J Med Genet A 2008;146:585-92. 4. McMain K, Blake K, Smith I, et al. Ocular features of CHARGE syndrome. J AAPOS 2008;12:460-65. 5. Song MH, Cho HJ, Lee HK, et al. CHD7 mutational analysis and clinical considerations for auditory rehabilitation in deaf patients with CHARGE syndrome. PLoS One 2011;6: e24511. 6. Kim JH, Hwang JM. Magnetic resonance imaging in three patients with congenital oculomotor nerve palsy. Br J Ophthalmol 2009;93: 1266-7. 7. Kim JH, Hwang JM. Congenital monocular elevation deficiency. Ophthalmology 2009;116:580-84. 8. Kee C, Cha DM, Ahn J, Hwang JM. Myasthenia mimicking monocular elevation deficiency. J Child Neurol 2013;28:108-10. 9. Kim JH, Hwang JM, Hwang YS, Kim KJ, Chae J. Childhood ocular myasthenia gravis. Ophthalmology 2003;110:1458-62. 10. Kim JH, Hwang JM. Simulated Brown syndrome in the contralateral eye in superior oblique palsy. Neurol Sci 2013;34:107-9.
Isolated posterior capsular split limited by Weiger’s ligament after blunt ocular trauma in a child mimicking posterior lenticonus Jyoti Matalia, DNB, Nirupama Kasturi, MS, Hemant Anaspure, MS, Bhujang K. Shetty, MS, and Himanshu Matalia, MS A 9-year-old boy presented with a posterior capsular split in the lens following a blunt ocular injury. This split was probably limited by the margins of the Weiger’s ligament with opacification of the anterior vitreous face along the patellar fossa producing an appearance of posterior lenticonus.
Author affiliations: Narayana Nethralaya, Bangalore, Karnataka, India Submitted February 27, 2015. Revision accepted May 12, 2015. Correspondence: Dr. Jyoti Matalia, DNB, Department of Pediatric Ophthalmology and Strabismus, Narayana Nethralaya-2, Narayana Health City, 258/A, Bommasandra, Hosur road, Bangalore-560099, India (email: [email protected]). J AAPOS 2015;19:557-558. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.05.022
Journal of AAPOS
FIG 1. Slit-lamp photograph. A, Diffuse illumination showing clear lens with posterior capsular split and opacification along the margins of the split (arrow) and the anterior vitreous face. B, Retroillumination showing the extent of the posterior capsular split.
Case Report
A
9-year-old boy presented at the Pediatric Ophthalmology Department of Narayana Nethralaya 2, Bangalore, India, with the history of injury to the right eye with a cricket ball 4 weeks earlier. On examination, visual acuity was 20/100 in the right eye and 20/20 in the left eye. Slit-lamp biomicroscopy of the right eye showed a clear cornea and iris sphincter tear at 9 o’clock, with traumatic mydriasis. The anterior chamber was deep and quiet. The lens showed an oval posterior capsular split of approximately 7–8 mm in width restricted to the center (Figure 1). The posterior capsule showed features of concentric opacification around the split, with early opacification of the anterior vitreous face just behind the patellar fossa, giving the appearance of a posterior lenticonus on oblique slit-lamp examination (Figure 2A). Intraocular pressure was 23 mm Hg in the right eye and 16 mm Hg in the left eye; there were signs of angle recession on
Case Report
A
2-year-old boy presented at Seoul National University Bundang Hospital with a left exotropia and limited elevation since infancy. He had thick nostrils and a small mouth. His ears were low set and asymmetric, with small lobes. He was born at 40 weeks’ gestation weighing 3.15 kg. He underwent patent ductus arteriosus ligation at the age of 20 days, polydactyly repair of his right toe at 1 year, and bilateral cochlear implantation at 2 years of age. He also had left facial nerve palsy, small testicles, growth and developmental retardation, attention deficit, bilateral microtia, bilateral semicircular canal aplasia, bilateral narrowing of the internal and external auditory canal, absent nerve fiber to cochlea, bilateral cochlear dysplasia, but did not have choanal atresia. This constellation of clinical symptoms and signs indicated typical CHARGE syn-
Author affiliations: Departments of aOphthalmology, bOtorhinolaryngology–Head and Neck Surgery, and cRadiology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Korea Research supported by Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science and Technology (2013R1A1A2010606). * These two authors equally contributed to the work. Submitted April 7, 2015. Revision accepted June 6, 2015. Correspondence: Jeong-Min Hwang, MD, Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 166, Gumiro, Bundang-gu, Seongnam, Gyeonggi-do 463-707, Korea (email: hjm@snu. ac.kr). J AAPOS 2015;19:555-557. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.06.005
Journal of AAPOS
drome, as suggested by Verloes.1 Subsequent molecular genetic testing involving Sanger sequencing of all 38 exons and both 100 bp of flanking intronic sequences of the CHD7 gene revealed a previously reported pathogenic nonsense mutation (c.2114C.A (p.Ser705X), which would cause truncation of this protein.2 On ophthalmologic examination at two previous university hospitals, he was initially diagnosed first with exotropia and later with double elevator palsy. On his first visit to our institution, he fixed and followed a 5-inch toy with each eye. He showed a left exotropia of 40 prism diopters at distance and near using the Krimsky method. Ductions and versions showed marked limitation of upgaze and mild limitation of downgaze and adduction in the left eye (Figure 1). On upgaze, his left eye adducted but did not elevate. His pupils were round and isocoric in both eyes. Dilated fundus examination revealed optic disk and choroidal colobomas in both eyes (Figure 2). Cycloplegic refraction showed 1.00 diopters (D) in the right eye and 3.50 D in the left eye.
Discussion CHARGE syndrome (OMIM 214800) is a congenital disease characterized by coloboma, heart defects, atresia of the choanae, retarded growth, genital hypoplasia, ear anomalies, and/or hearing loss.1 Cranial nerve palsies (most commonly affecting the facial, vestibulocochlear, glossopharyngeal, and vagus nerves) have been frequently reported with CHARGE syndrome3; oculomotor nerve involvement has not been previously reported. Although the most common ophthalmic sign of CHARGE syndrome is coloboma,1 ocular motility can also be affected. McMain and colleagues4 described 3 patients with “vertical gaze disorder” with a monocular deficiency of upgaze. They suggested inferior oblique paresis in 2 patients, and Brown syndrome in another. These 3 patients may represent partial oculomotor nerve palsy, as in our patient. Our patient showed 5 characteristic findings of CHARGE syndrome: (1) coloboma of the eye, (2) heart defects, (3) retardation of growth and development, (4) genital abnormalities, and (5) ear abnormalities.1 In addition, he showed polydactyly as well as oculomotor and facial nerve palsies. There was no choanal atresia. A single heterozygous CHD7 mutation that mostly arises in de novo in approximately 60% to 70% of patients with CHARGE syndrome was identified.3 Genetic analysis of the CHD7 gene contribute tremendously to the diagnosis of CHARGE syndrome and is therefore necessary for the correct diagnosis of this syndrome, especially for atypical cases. Ophthalmologic findings associated with CHARGE syndrome include coloboma, microphthalmos, microcornea, ptosis, persistent fetal vasculature, nystagmus, cataract, optic nerve hypoplasia, refractive errors and strabismus.4 Our patient showed coloboma, anisomyopia, and exotropia caused by partial congenital
555
556
Yang et al
Volume 19 Number 6 / December 2015
FIG 1. Ocular versions show a marked limitation of upgaze, mild limitation of downgaze and a very small limitation of adduction in the left eye. On upgaze, his left eye adducted instead of elevating.
FIG 2. Fundus photography showing optic disk and choroidal colobomas in right eye (A) and left eye (B).
oculomotor nerve palsy. Aberrant innervation of adduction on upgaze was present. His eyelid and pupils were not affected. Song and colleagues5 reported that missense mutations of CHD7 had milder symptoms as compared with other CHARGE patients carrying truncation mutations of CHD7 in Koreans. The additional ophthalmologic finding of oculomotor nerve palsy in our patient, carrying a nonsense truncation mutation of CHD7, may reflect the previously proposed genotype– phenotype correlation.6 Conditions that cause congenital elevation deficiency include monocular elevation deficiency, congenital oculomotor nerve palsy, Brown syndrome, inferior oblique palsy, superior oblique overaction, variant of Duane retraction syndrome, contralateral inferior rectus aplasia, adherence syndrome, congenital ocular fibrosis syndrome, and blow-out fracture.6-10 Our patient showed elevation deficit in both adduction and abduction, unlike inferior oblique palsy or Brown syndrome. He did not show superior oblique overaction. He denied any history of facial trauma as well as ocular surgery. He did not show ptosis as in patients with congenital ocular fibrosis
syndrome or myasthenia gravis. He did not show any characteristic findings of Duane retraction syndrome, such as fissure narrowing with adduction, upshoot or downshoot, and abduction was full in both eyes. A previous case series of congenital oculomotor nerve palsy showed that 2 of 3 patients with congenital oculomotor nerve palsy presented with an elevation deficit.6 Detection of an adduction deficit is easily missed in Asian children, because the skin folds cover the medial canthal area; similarly, depression deficit can be covered by the lower eyelid. Thus, an elevation deficit is much more easily recognized than adduction or depression deficit, which explains why our patient was previously misdiagnosed with monocular elevation deficiency. The present case report highlights the fact that a patient with CHARGE syndrome may show exotropia associated with partial oculomotor nerve palsy. Congenital oculomotor nerve palsy could be discordant among branches and may not be accompanied by ptosis or anisocoria and may thus be misdiagnosed as primary exotropia or monocular elevation deficiency (formerly called double elevator palsy).
Journal of AAPOS
Volume 19 Number 6 / December 2015
Matalia et al
557
Literature Search MEDLINE was searched on January 25, 2015, without language or date restriction, for the following terms: CHARGE, oculomotor nerve palsy, and third nerve palsy. References 1. Verloes A. Updated diagnostic criteria for CHARGE syndrome: a proposal. Am J Med Genet A 2005;133:306-8. 2. Zentner GE, Layman WS, Martin DM, Scacheri PC. Molecular and phenotypic aspects of CHD7 mutation in CHARGE syndrome. Am J Med Genet A 2010;52:674-86. 3. Blake KD, Hartshorne TS, Lawand C, Dailor AN, Thelin JW. Cranial nerve manifestations in CHARGE syndrome. Am J Med Genet A 2008;146:585-92. 4. McMain K, Blake K, Smith I, et al. Ocular features of CHARGE syndrome. J AAPOS 2008;12:460-65. 5. Song MH, Cho HJ, Lee HK, et al. CHD7 mutational analysis and clinical considerations for auditory rehabilitation in deaf patients with CHARGE syndrome. PLoS One 2011;6: e24511. 6. Kim JH, Hwang JM. Magnetic resonance imaging in three patients with congenital oculomotor nerve palsy. Br J Ophthalmol 2009;93: 1266-7. 7. Kim JH, Hwang JM. Congenital monocular elevation deficiency. Ophthalmology 2009;116:580-84. 8. Kee C, Cha DM, Ahn J, Hwang JM. Myasthenia mimicking monocular elevation deficiency. J Child Neurol 2013;28:108-10. 9. Kim JH, Hwang JM, Hwang YS, Kim KJ, Chae J. Childhood ocular myasthenia gravis. Ophthalmology 2003;110:1458-62. 10. Kim JH, Hwang JM. Simulated Brown syndrome in the contralateral eye in superior oblique palsy. Neurol Sci 2013;34:107-9.
Isolated posterior capsular split limited by Weiger’s ligament after blunt ocular trauma in a child mimicking posterior lenticonus Jyoti Matalia, DNB, Nirupama Kasturi, MS, Hemant Anaspure, MS, Bhujang K. Shetty, MS, and Himanshu Matalia, MS A 9-year-old boy presented with a posterior capsular split in the lens following a blunt ocular injury. This split was probably limited by the margins of the Weiger’s ligament with opacification of the anterior vitreous face along the patellar fossa producing an appearance of posterior lenticonus.
Author affiliations: Narayana Nethralaya, Bangalore, Karnataka, India Submitted February 27, 2015. Revision accepted May 12, 2015. Correspondence: Dr. Jyoti Matalia, DNB, Department of Pediatric Ophthalmology and Strabismus, Narayana Nethralaya-2, Narayana Health City, 258/A, Bommasandra, Hosur road, Bangalore-560099, India (email: [email protected]). J AAPOS 2015;19:557-558. Copyright Ó 2015 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2015.05.022
Journal of AAPOS
FIG 1. Slit-lamp photograph. A, Diffuse illumination showing clear lens with posterior capsular split and opacification along the margins of the split (arrow) and the anterior vitreous face. B, Retroillumination showing the extent of the posterior capsular split.
Case Report
A
9-year-old boy presented at the Pediatric Ophthalmology Department of Narayana Nethralaya 2, Bangalore, India, with the history of injury to the right eye with a cricket ball 4 weeks earlier. On examination, visual acuity was 20/100 in the right eye and 20/20 in the left eye. Slit-lamp biomicroscopy of the right eye showed a clear cornea and iris sphincter tear at 9 o’clock, with traumatic mydriasis. The anterior chamber was deep and quiet. The lens showed an oval posterior capsular split of approximately 7–8 mm in width restricted to the center (Figure 1). The posterior capsule showed features of concentric opacification around the split, with early opacification of the anterior vitreous face just behind the patellar fossa, giving the appearance of a posterior lenticonus on oblique slit-lamp examination (Figure 2A). Intraocular pressure was 23 mm Hg in the right eye and 16 mm Hg in the left eye; there were signs of angle recession on