- Email: [email protected]
Ocular features of CHARGE syndrome
Ocular features of CHARGE syndrome Karen McMain, BA, OC(C), COMT,a Johane Robitaille, MD, FRSCS,b Isabel Smith, PhD,c Judy Johnson, BEd, MA(Ed),d Ellen Wood, MD, FRCSC,e Francois Tremblay, BSc, PhD,b and Kim Blake, MD, FRCSCf PURPOSE METHODS
RESULTS
CONCLUSIONS
To detail the presence and severity of ocular and cranial nerve abnormalities found in individuals with CHARGE syndrome in a distinct geographic area. Nine individuals with CHARGE syndrome from Maritime Canada identified from a Canadian database were prospectively examined. Structural and sensorial defects associated with functional visual deficits were defined with ophthalmic and neurological evaluation. Consistent with current diagnostic criteria and the literature, colobomas were the major ophthalmic manifestation. These were typically bilateral chorioretinal colobomas involving the optic nerve. All subjects had bilateral severe sensorineural deafness (cranial nerve VIII), and 8 of 9 (89%) had facial nerve (cranial nerve VII) involvement (7 of 9 had unilateral involvement; 1 of 9 had bilateral involvement). Unique to this group of participants were the findings of anisometropia in 8 of the 9 (89%) patients, severe myopic astigmatism in 13 of the 18 eyes (72%), and limited elevation in adduction in 3 of 9 (33%) participants. Associated findings were strabismus, cataracts, microcornea, keratopathy, staphyloma, reduced stereopsis, superior visual field defects, and reduced visual acuity. The presence of coloboma plus another CHARGE feature warrants further investigation, including genetic screening for the CHD7 gene. Early recognition and management of sensory problems (visual, auditory, and vestibular) are crucial to ensure best psychomotor and cognitive development. ( J AAPOS 2008;12:460-465)
C
HARGE syndrome is a multisystem genetic disorder associated with CHD7 gene mutations.1 The CHD7 gene regulates the expression of other genes; therefore, clinical manifestations can be quite variable. Many clinical diagnostic criteria have been used to define the spectrum of anomalies in this syndrome. The earliest anomalies were delineated by Pagon et al,2 who used the mnemonic CHARGE to summarize the 6 cardinal clinical features. With time, 4 anomalies have emerged as key diagnostic indicators that are relatively common in CHARGE syndrome and uncommon in other syndromes: coloboma, choanal atresia, characteristic CHARGE defective ear, and cranial nerve dysfunction.3 Recent evidence suggests that both temporal bone anomalies4,5 and atypical
Author affiliations: aClinical Vision Science, Dalhousie University, Halifax, Nova Scotia, Canada; bDepartment of Ophthalmology and Visual Science, Dalhousie University, Halifax, Nova Scotia, Canada; cDepartment of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada; dAtlantic Provinces Special Education Authority for the Deaf and Visually Impaired, Halifax, Nova Scotia, Canada; e Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; f Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada Submitted May 17, 2007. Revision accepted January 25, 2008. Published online May 2, 2008. Reprint requests: Karen McMain, Eye Care Team, IWK Health Centre, 5850/5980 University Ave., P.O. Box 9700, Halifax, Nova Scotia B3K 6R8, Canada (email: [email protected]). Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2008.02.009
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structure and function of the olfactory nerve and bulb6 may be clinically diagnostic in CHARGE syndrome. Ophthalmologic abnormalities also have been reported in the majority of studies relating to CHARGE syndrome. Russell-Eggitt et al,7 in one of the largest and longest reported studies, found ocular abnormalities in 44 of 50 patients. Of these, 41 (82%) had colobomas, the majority being retinochoroidal colobomas with optic nerve involvement, and 13 (26%) patients had additional iris defect. Two participants had iris colobomas with normal fundi. Other features included microphthalmos in 21 patients, optic nerve hypoplasia in 4, and nystagmus in 12. Twenty-two had facial palsy, of which 4 also had a vertical disorder of eye movement contralateral to facial weakness. Strömland et al8 conducted a review of 21 patients, 12 of whom could not cooperate with full ophthalmologic testing. Their ocular findings were similar to those of Russell-Eggitt et al.7 Detailed ophthalmologic examination is often difficult in the CHARGE syndrome population because of multisensorial deficits and commonly associated autistic behaviors.9,10 This paper is unique, as it reviews in detail the specific eye findings in a geographically defined cohort.
Subjects and Methods Subjects Participants identified by the Canadian Pediatric Surveillance Program and referred to the IWK Health Centre were recruited for participation in a multidisciplinary study of ophthalmic features in CHARGE syndrome. The CPSP is the Canadian na-
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Table 1. Major and minor characteristics of CHARGE syndrome Four major characteristics
Six minor characteristics
Fundus coloboma Choanal atresia Characteristic ear abnormalities Cranial nerve dysfunction
Genital hypoplasia Developmental delay Cardiovascular malformations Growth deficiency Orofacial clefting Tracheoesophageal fistual Distinctive facies
tional epidemiologic surveillance established in 1996 to enhance the collection of data in the study of rare disorders in children. All participants identified by this surveillance program exhibited 2 major and 2 minor CHARGE characteristics, or 3 or 4 major characteristics as defined by Blake et al.3 The major and minor characteristics of CHARGE syndrome are listed in Table 1, and Figure 1 depicts the typical facial features and ear deformities in an individual with CHARGE syndrome. Study inclusion criteria were the diagnosis of CHARGE syndrome and current residence in Maritime Canada.
Methods The study was approved by the Research Ethics Board of the IWK Health Centre and consent obtained according to Canadian Tri-Council guidelines. All examinations were performed at the IWK Health Centre and the Atlantic Special Education Authority for the Hearing and Visually Impaired. The duration of required testing and the age and mental capacity of some of the patients necessitated multiple appointments to complete the study protocol. Study participants wore their full cycloplegic correction for all tests of visual function. Each diagnostic test was repeated on a separate visit if the participant was not cooperative for examination on the first testing to ensure accuracy of data collection. Comprehensive ophthalmologic, orthoptic, and electrodiagnostic evaluations were conducted. Additionally, each participant underwent a neurologic evaluation of cranial function (cranial nerve I through cranial nerve XII) by a pediatric neurologist. A certified instructor for the visually impaired from the Atlantic Provinces Special Education Authority conducted functional vision assessments on each patient. The functional vision assessment was based on observations of the patient in a variety of settings, both indoors and outdoors, including an educational setting. Functional vision testing was conducted independently of comprehensive ophthalmologic examination. This testing was used to complement information available from the comprehensive ophthalmologic examination regarding deficits of visual function due to structural anomalies. Assessment included the ability to find an object or target and fixate long enough to be aware of or recognize it, ability to track objects, accuracy in scanning objects, discrimination of objects, discrimination of details, and identification of patterns using routine testing methods. To describe the severity of findings in this cohort, visual acuity was defined as normal or mildly reduced (6/15 or better in the better eye), impaired (6/18 to 6/48 in the better eye), severely
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FIG 1. Patient (Case 8) demonstrates distinctive CHARGE facies—square face with broad prominent forehead, large eyes, prominent nasal bridge, thick nostrils, and small mouth. His ears are asymmetric and protrude. They are low set, short, wide, and have little or no lobe. A snipped off helix is noted on the left ear. reduced (6/60 to 6/120 in the better eye), or profoundly reduced vision (6/150 or less) in keeping with World Health Organization guidelines.11 Astigmatism was classified as mild (less than 1 D of cylinder), moderate (1-3 D), or severe (⬎3 D). Myopia and hyperopia were considered mild if less than 2 D, moderate if 2-5 D, and severe if greater than 5 D. In this study, anisometropia refers to an interocular difference in refractive error of greater than 2 D, in any meridian.
Results Ten individuals with a diagnosis of CHARGE syndrome were identified in the Canadian Pediatric Surveillance Program and recruited for this study. One identified CHARGE participant declined participation. Therefore, the study comprised 9 patients with CHARGE syndrome (7 male and 2 female), who ranged in age from 2.5 to 25 years (mean 10.1 year). The ocular features, their degree of severity, and cranial nerve dysfunction of individual participants are documented in e-Supplement 1 (available at jaapos.org).
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FIG 2. A 7-year-old patient (Case 4) with a chorioretinal colomboma involving the optic nerve. This patient had no iris involvement of the right eye.
Colobomas were the predominant ocular finding with a frequency of 83% (15/18 eyes). As depicted in Figure 2, typically, we found severe CHARGE chorioretinal colobomas that involved the optic nerve. Of these, 88% (7 of 8) of the participants with colobomas had bilateral involvement. One participant (Case 6) had an iris coloboma in addition to an ipsilateral monocular chorioretinal coloboma, and another (Case 2) had normal fundi. No eyelid colobomas were present. Unilateral microphthalmos was found in one patient (Case 1). The participant with microphthalmos also had manifest jerk nystagmus and bilateral cataracts causing vision loss. We were unable to test the visual acuity in 3 participants (Cases 4, 6, and 9). In 2 cases (Cases 2 and 3), bestcorrected visual acuity was recorded in the normal to mildly reduced range of 6/15 or better in the better eye whereas the remaining participants had best-corrected visual acuity in the impaired vision range of 6/18 or less. Of the participants whose visual acuity could be assessed, none were found to be in the severely or profoundly reduced range in their better eye. Color vision testing was only possible in one participant (Case 2) and found to be normal with American Optical Hardy-Rand-Rittler pseudoisochromatic plates (Richmond Products, San Francisco, CA). Qualitative visual acuity ascertained that, of the 6 participants who could be tested, 83% (5 of 6) did not attend to distant objects, 50% (3 of 6) had difficulty maintaining eye contact, 67% (4 of 6) showed little interest in objects located superiorly, and 33% (2 of 6) had difficulty scanning an object. Figure 3 illustrates the visual-evoked potential (VEP) findings of these participants. Participant age, mental capacity, and hearing loss limited our ability to formally assess patients’ visual fields. Goldmann visual field testing was only possible in only 1 patient (Case 2), and the result was in the normal range because this patient had no chorioretinal coloboma in either eye. Confronta-
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tional visual field testing in 2 additional participants detected superior quadrant field loss. This axonal loss was consistent with VEP results in 2 participants (Cases 5 and 7) who demonstrated no response to pattern stimuli even with large spatial frequency stimuli. All 9 participants had bilateral profound sensorineural hearing loss, with 2 having had cochlear implants. Of the 9, 8 (89%) showed facial paresis, 1 bilateral and 7 unilateral (3 left-sided and 4 right-sided). Consistent with cranial nerve VII paresis and inability to obtain adequate eyelid closure, 3 participants had corneal problems caused by exposure. Two had keratopathy, and one had a corneal scar despite copious lubrication, eyelid surgery (including the use of Gold weights), lateral tarsorrhaphy, and the placement of punctal plugs. Corneal sensation was tested in all study participants and found to be normal. Sense of smell was found to be defective in 2 of 9 participants by informal clinical criteria. Stereopsis testing was possible in 7 participants and was absent in all except one of these (Case 2: no chorioretinal colobomas), who attained 35 arcsec with Frisby testing (Richmond Products, San Francisco, CA). The defective stereopsis was consistent with a high incidence of strabismus in these participants. Strabismus was detected in 7 of 9 (78%) participants: 4 with nonaccommodative infantile esotropia (one of whom also had a vertical deviation); 2 with an exotropia (one of whom had an A pattern), and 1 with an isolated vertical deviation in primary position. A vertical gaze disorder was found in 3 participants (Cases 5, 8, and 9), with a monocular deficiency of upgaze in adduction that is illustrated in Figure 4. This limitation of the inferior oblique was accompanied by overaction of the ipsilateral superior oblique, contralateral yoke superior rectus, and underaction of the contralateral antagonist inferior rectus, indicative of inferior oblique paresis in 2 of the 3 cases. The absence of overaction of the direct antagonist or deviation in primary position in Case 9, suggested the presence of a Brown syndrome. Refractive errors were common and typically consisted of anisometropia and astigmatism. Anisometropia of 2 D or more was found in 89% (8 of 9) of the participants and would have contributed significantly to the potential for amblyopia, if not corrected by spectacles. Astigmatism was present in 78% (14 of 18) of the eyes tested. Severe mixed myopic astigmatism (⬎3 D) accompanied the large chorioretinal colobomas in 78% (14 of 18) of our patients. The remaining participants had moderate compound hyperopic astigmatism at a rate of 17% (3 of 18 eyes) whereas 1 patient had myopia (1-3 D).
Discussion This study undertook extensive ophthalmological (including electrodiagnostic and orthoptic examination and functional visual testing), in addition to cranial nerve assessment in a distinct group of individuals with CHARGE syndrome from Maritime Canada. These in-depth evalu-
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FIG 3. Visual evoked potential ( VEP) (Case 5): flash responses have normal implicit time (RE: 93 ms; LE 83 ms; significant ocular difference), while responses to patterned stimuli are better in the right eye, showing responses to standard check size of 20 arcmin with the right eye but none with the left. The binocular response is interestingly within normal range both in terms of amplitude and implicit time. The figure arrows indicate the stimulus onset, while the asterisks point to the first positivity measured on the VEP.
FIG 4. 10-year-old patient (Case 5) with limitation of right inferior oblique accompanied by overaction of the superior oblique muscle. Also present is an ipsilateral cranial nerve VII paresis.
ations yielded evidence of more extensive involvement in all areas of visual function and ocular structural anomalies than had been reported previously. Although numerous ocular abnormalities were found within this population, is this result because more ocular abnormalities are present or because they were studied more carefully? The association of the CHD7 gene mutation would suggest a predilection for ocular abnormalities. Mutation of the Chd7 gene produced organ abnormalities affected by CHARGE syndrome including the eye, olfactory epithelium, inner ear, and vascular system.12,13
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We found that this Eastern Canadian population of CHARGE syndrome participants typically had bilateral asymmetric chorioretinal colobomas as a major ophthalmic finding. The prevalence of 83% was comparable with those of other major studies of ophthalmic findings in CHARGE syndrome: Russell-Eggitt et al7 (86%), Tellier et al14 (79%), and Störmland et al15 (90%). CHARGE colobomas typically involve the choroid, retina, and optic nerve. Iris colobomas may have been reported less commonly and have been under-reported in studies that did not include a detailed ophthalmologic examination. Chester and France’s review16 of 54 clinic patients presenting with colobomas found that 11% met the major criteria for CHARGE syndrome. The frequent occurrence of this syndrome in patients with chorioretinal colobomas7,14-20 suggests that ophthalmologists should evaluate a patient for associated CHARGE defects (and refer for genetic evaluation when appropriate), particularly if the participant presents with either an additional major clinical criterion of CHARGE syndrome or a number of minor features (see Table 1). Typical CHARGE syndrome colobomas will produce a field defect in the upper quadrant and are associated with significant refractive errors, microphthalmos, microcornea, and vision loss. Optic disk colobomas vary greatly in presentation. Central visual acuity may be poor if the macula is involved. If a large coloboma does not involve the fovea, central vision is usually adequate. Formal visual field testing is difficult in this population because of their hearing loss and common autistic-like behaviors.9,10,21-24
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Only 1 of our 9 participants could perform a Goldmann visual field test, and only 4 had successful confrontational visual field testing. Educators of the visually impaired and deaf find that these children have difficulty attending to distant objects or to objects located superiorly and have difficulty scanning objects. Those patients have difficulty maintaining eye contact as a function of their visual impairments or possibly because of an additional autistic-spectrum disorder. It is also noteworthy that individuals with autism may display atypical gaze behaviors that should not be assumed to reflect poor visual acuity or other sensory limitations. This is an important consideration especially when acuity can be assessed only by examining fixation patterns. Davenport et al25 reported on 2 participants who were visually inattentive until their hearing impairment was addressed. A complication of typical CHARGE colobomas is retinal detachment7,17,23 Guirgis and Luder26 reported a choroidal neovascular membrane associated with optic nerve coloboma that developed in a 21-month-old boy with CHARGE syndrome, posing a risk for serous retinal detachment. None of our participants developed a retina detachment. Nevertheless, it is advisable to follow these patients routinely with dilated fundus examination to reduce the risk of vision loss from retinal detachment. Blake et al17 reported one case of eyelid colobomas, which had not been previously reported in CHARGE syndrome. None of the participants in our series had an eyelid coloboma but, one of the participants did have an atypical iris coloboma, a feature also, infrequently reported, in CHARGE syndrome.7,8,14 This atypical coloboma was accompanied by an ipsilateral, monocular chorioretinal coloboma: the typical CHARGE disk colobomas are bilateral. For CHARGE syndrome patients who have atypical eyelid and iris colobomas related to cranial nerve VII dysfunction, photophobia might be a profound symptom. Anisometropia and severe compound myopic astigmatism were common, in keeping with their bilateral asymmetric chorioretinal colobomas. This population of CHARGE participants presents a challenge to examine. Because of the presence of concurrent development delay, hearing loss, and ocular abnormalities, repeat refractions are indicated to ensure accuracy of correction. Vision loss from unilateral or bilateral amblyopia may occur if spectacle correction is not instituted. Additional amblyopia therapy may also be required. Strabismus is a frequent feature in this population and results in a lack of stereopsis. Visual field loss and reduced acuity in this population make adequate compensation problematic. Balance problems have been extensively reported in CHARGE syndrome. These are in part related to vestibular dysfunction but can be exacerbated by visual field defects, reduced acuity, and lack of depth perception.7 Russell-Eggitt et al7 reported 4 cases of a vertical eye movement disorder associated with facial palsy and deficiency of upgaze, particularly in adduction, of the eye contralateral to the facial nerve weakness. We also detected 3
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cases of vertical deficiency in elevation and adduction: 2 with overaction of the direct antagonist (superior oblique), suggesting an isolated inferior oblique paresis, and 1 without direct antagonist overaction, indicative of Brown syndrome. No relationship to the side of the facial muscle paresis was detected. Weaver et al27 reported a case of bilateral Marcus Gunn jaw-winking in one with CHARGE syndrome patient. Interestingly, an association also exists among Marcus Gunn jaw-winking dysinnervation, CHARGE, and Kabuki syndrome ( both Kabuki and CHARGE syndrome share phenotypic features); congenital fibrosis of the extraocular muscles; and another monocular elevation deficiency (also known as double elevator palsy).28,29 Facial and auditory nerve miswiring has also been reported in CHARGE syndrome and was found in one participant (Case 5) in our study.30 Congenital aberrant innervation may support a primary neural pathology underlying the vertical deviations noted in our study participants. All of our patients were deaf. Deafness in CHARGE syndrome is speculated to arise from congenital defects of the ossicular chain, “dysplasia” of the bony labyrinth, eustantian tube dysfunction, and high frequency sensorineural loss.21,26,30 Clinical neurological testing was conducted because detailed cranial magnetic resonance imaging was unavailable. Recent magnetic resonance imaging data from Europe revealed anomalies of olfactory tracts and bulbs in 100% of CHARGE syndrome patients, varying from moderate hypoplasia to complete aplasia.6 Using a recently validated olfactory test—the French Biolfa test— Chalouhi et al6 found olfactory deficiency in CHARGE patients. Those authors suggested that cranial nerve I anomalies should be considered a major criterion for the diagnosis of CHARGE syndrome. We did not have access to this olfactory test when our assessments were conducted. Although our participants were found to have normal corneal sensation, multiple cranial involvement occurs frequently in CHARGE and CNV-1 function should be tested. Lack of corneal sensation caused by trigeminal nerve paresis, either presenting exclusively or combined with inadequate lid closure due to facial nerve paresis may result in patients with CHARGE syndrome developing corneal abrasions and/or exposure keratopathy. Corneal abrasions/exposure keratopathy compound the developmental dysfunction as the result of colobomas. Ocular problems, which are common in our cohort of patients with CHARGE syndrome, included asymmetric bilateral chorioretinal colobomas involving the optic nerve, anisometropia, severe myopic astigmatism, strabismus, corneal exposure, microphthalmia, and reduced visual acuity. Cranial nerve involvement identified in this study included cranial nerves II, III, VII, and VIII. The presence of a fundus coloboma plus another CHARGE feature warrants further investigation, including genetic testing.
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References 1. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, et al. Mutations in a new member of the chromodomain gene family cause CHARGE Syndrome. Nat Genet 2004; 36:955-7. 2. Pagon RA, Graham JM Jr., Zonana J, Yong SL. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 1981;99:223-7. 3. Blake KD, Davenport SL, Hall BD, Hefner MA, Pagon RA, Williams MS, et al. CHARGE association: An update and review for the primary pediatrician. Clin Pediatr (Phila) 1998;37:159-73. 4. Amiel J, Attiee-Bitach T, Marianowski R, Cormier-Daire V, Abadie V, Bonnet D, et al. Temporal bone anomaly proposed as a major criteria for diagnosis of CHARGE Syndrome. Am J Med Genet 2001;99:124-7. 5. Verloes A. Updated diagnostic criteria for CHARGE Syndrome: A proposal. Am J Med Genet 2005;133A:306-8. 6. Chalouhi D, Faulcon P, LeBihan C, Hertz-Pannier L, Bonfils P, Abadie V. Olfactory evaluation in children: Application to the CHARGE Syndrome. Pediatrics 2005;116:81-8. 7. Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK. The eye in the CHARGE association. Br J Ophthalmol 1990;74:421-6. 8. Strömland K, Sjögreen L, Johansson M, Ekman Joelsson BM, Miller M, Danielsson S, et al. CHARGE association in Sweden: Malformations and functional deficits. Am J Med Genet 2005;133A:331-9. 9. Smith IM, Nichols SL, Issekutz K, Blake K. Behavioral profiles and symptoms of autism in CHARGE syndrome: Preliminary epidemiological data. Am J Med Genet 2004;133A:248-56. 10. Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism with ophthalmologic malformations: The plot thickens. Trans Am Ophthalmol Soc 2004;102:107-20. 11. World Health Organization. Magnitude and causes of visual impairment. Available from http://www.who.int/mediacentre/factsheets/ fs282/en/. 12. Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP. Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Human Mol Genet 2005;14:3463-76. 13. Faulkner-Jones BE, Godinho LN, Reese BE, Pasquini GF, Ruefli A, Tan SS. Cloning and expression of mouse Cadehein-7, a type-II cadeherin isolated from the developing eye. Mol Cell Neurosci 1999;14:1-16. 14. Tellier AL, Cormier-Daire V, Abadie V, Amiel J, Sigaudy S, Bonnet D, et al. CHARGE syndrome: Report of 47 cases and review. Am J Med Genet 1998;76:402-9.
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15. Strömland K, Sjögreen L, Johansson M, Ekman Joelsson BM, Miller M, Danielsson S, et al. CHARGE association in Sweden: Malformations and functional deficits. Am J Med Genet 2005;133A:331-9. 16. Chester RJ, France TD. Ocular findings in CHARGE syndrome. Six case reports and review. Ophthalmology 1988;95:1613-9. 17. Blake KD, Russell-Eggitt IM, Morgan DW, Ratcliffe JM, Wyse RK. Who’s in CHARGE? Multidisciplinary management of patients with CHARGE association. Arch Dis Child 1990;65:217-23. 18. Feigel B, Urlesberger B, Anderhuber W, Haas A. Cataract as an additional sign in CHARGE syndrome. J Pediatr Ophthal Strab 2000;37:111-3. 19. Hsueh KF, Yang CS, Lu JH, Hsu WM. Clinical characteristics of CHARGE syndrome. J Chin Med Assoc 2004;67:542-6. 20. Berk AT, Yaman A, Saatci AO. Ocular and systemic findings associated with optic disc colobomas. J Pediatric Ophthalmol Strabismus 2003;40:272-8. 21. Lauger K, Cornelius N, Keedy W. Behavioral features of CHARGE syndrome: Parents’ perspectives of three children with CHARGE syndrome. Am J Med Genet 2005;133A:291-9. 22. Hartshorne TS, Grialou TL, Parker KR. Autistic-like behavior in CHARGE syndrome. Am J Med Genet 2004;133A:257-61. 23. Fernell E, Olsson VA, Karlgren-Leitner C, Norlin B, Hagberg B, Gillberg C. Autistic disorders in children with CHARGE association. Dev Med Child Neurol 1999;41:270-2. 24. Olsen TW, Summers CG, Knobloch WH. Predicting visual acuity in children with colobomas involving the optic nerve. J Pediatr Ophthal Strabismus 1996;33:47-51. 25. Davenport SL, Hefner MA, Mitchell JA. The spectrum of clinical features in CHARGE syndrome. Clinical Genet 1986;29:298-310. 26. Guirgis MF, Lueder GT. Choroidal neovascular membrane associated with optic nerve coloboma in a patient with CHARGE association. Am J Ophthalmol 2003;135:919-20. 27. Weaver GR, Seaton AD, Jewett T. Bilateral Marcus Gunn ( Jawwinking) phenomenon occurring with CHARGE. J Ped Ophthal Strabismus 1997;34:308-9. 28. Emmert-Buck LT, Preslan MW, Kathuria SS. Jaw-winking ptosis in a patient with Kabuki syndrome J Pediatr Ophthalmol Strabismus 2004;41:369-72. 29. Wright KW, Liu GY, Murphree AL, Brown BZ, Edelman PM. Double elevator palsy, ptosis and jaw winking. Am Orthopt J 1989; 39:143-9. 30. Bauer PW, Wippold FJ II, Goldin J, Lusk RP. Cochlear implantation in children with CHARGE association. Arch Otolaryngol Head Neck Surg 2002;128:1013-7.
RESULTS
CONCLUSIONS
To detail the presence and severity of ocular and cranial nerve abnormalities found in individuals with CHARGE syndrome in a distinct geographic area. Nine individuals with CHARGE syndrome from Maritime Canada identified from a Canadian database were prospectively examined. Structural and sensorial defects associated with functional visual deficits were defined with ophthalmic and neurological evaluation. Consistent with current diagnostic criteria and the literature, colobomas were the major ophthalmic manifestation. These were typically bilateral chorioretinal colobomas involving the optic nerve. All subjects had bilateral severe sensorineural deafness (cranial nerve VIII), and 8 of 9 (89%) had facial nerve (cranial nerve VII) involvement (7 of 9 had unilateral involvement; 1 of 9 had bilateral involvement). Unique to this group of participants were the findings of anisometropia in 8 of the 9 (89%) patients, severe myopic astigmatism in 13 of the 18 eyes (72%), and limited elevation in adduction in 3 of 9 (33%) participants. Associated findings were strabismus, cataracts, microcornea, keratopathy, staphyloma, reduced stereopsis, superior visual field defects, and reduced visual acuity. The presence of coloboma plus another CHARGE feature warrants further investigation, including genetic screening for the CHD7 gene. Early recognition and management of sensory problems (visual, auditory, and vestibular) are crucial to ensure best psychomotor and cognitive development. ( J AAPOS 2008;12:460-465)
C
HARGE syndrome is a multisystem genetic disorder associated with CHD7 gene mutations.1 The CHD7 gene regulates the expression of other genes; therefore, clinical manifestations can be quite variable. Many clinical diagnostic criteria have been used to define the spectrum of anomalies in this syndrome. The earliest anomalies were delineated by Pagon et al,2 who used the mnemonic CHARGE to summarize the 6 cardinal clinical features. With time, 4 anomalies have emerged as key diagnostic indicators that are relatively common in CHARGE syndrome and uncommon in other syndromes: coloboma, choanal atresia, characteristic CHARGE defective ear, and cranial nerve dysfunction.3 Recent evidence suggests that both temporal bone anomalies4,5 and atypical
Author affiliations: aClinical Vision Science, Dalhousie University, Halifax, Nova Scotia, Canada; bDepartment of Ophthalmology and Visual Science, Dalhousie University, Halifax, Nova Scotia, Canada; cDepartment of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada; dAtlantic Provinces Special Education Authority for the Deaf and Visually Impaired, Halifax, Nova Scotia, Canada; e Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; f Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada Submitted May 17, 2007. Revision accepted January 25, 2008. Published online May 2, 2008. Reprint requests: Karen McMain, Eye Care Team, IWK Health Centre, 5850/5980 University Ave., P.O. Box 9700, Halifax, Nova Scotia B3K 6R8, Canada (email: [email protected]). Copyright © 2008 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2008/$35.00 ⫹ 0 doi:10.1016/j.jaapos.2008.02.009
460
structure and function of the olfactory nerve and bulb6 may be clinically diagnostic in CHARGE syndrome. Ophthalmologic abnormalities also have been reported in the majority of studies relating to CHARGE syndrome. Russell-Eggitt et al,7 in one of the largest and longest reported studies, found ocular abnormalities in 44 of 50 patients. Of these, 41 (82%) had colobomas, the majority being retinochoroidal colobomas with optic nerve involvement, and 13 (26%) patients had additional iris defect. Two participants had iris colobomas with normal fundi. Other features included microphthalmos in 21 patients, optic nerve hypoplasia in 4, and nystagmus in 12. Twenty-two had facial palsy, of which 4 also had a vertical disorder of eye movement contralateral to facial weakness. Strömland et al8 conducted a review of 21 patients, 12 of whom could not cooperate with full ophthalmologic testing. Their ocular findings were similar to those of Russell-Eggitt et al.7 Detailed ophthalmologic examination is often difficult in the CHARGE syndrome population because of multisensorial deficits and commonly associated autistic behaviors.9,10 This paper is unique, as it reviews in detail the specific eye findings in a geographically defined cohort.
Subjects and Methods Subjects Participants identified by the Canadian Pediatric Surveillance Program and referred to the IWK Health Centre were recruited for participation in a multidisciplinary study of ophthalmic features in CHARGE syndrome. The CPSP is the Canadian na-
Journal of AAPOS
Volume 12 Number 5 / October 2008
McMain et al
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Table 1. Major and minor characteristics of CHARGE syndrome Four major characteristics
Six minor characteristics
Fundus coloboma Choanal atresia Characteristic ear abnormalities Cranial nerve dysfunction
Genital hypoplasia Developmental delay Cardiovascular malformations Growth deficiency Orofacial clefting Tracheoesophageal fistual Distinctive facies
tional epidemiologic surveillance established in 1996 to enhance the collection of data in the study of rare disorders in children. All participants identified by this surveillance program exhibited 2 major and 2 minor CHARGE characteristics, or 3 or 4 major characteristics as defined by Blake et al.3 The major and minor characteristics of CHARGE syndrome are listed in Table 1, and Figure 1 depicts the typical facial features and ear deformities in an individual with CHARGE syndrome. Study inclusion criteria were the diagnosis of CHARGE syndrome and current residence in Maritime Canada.
Methods The study was approved by the Research Ethics Board of the IWK Health Centre and consent obtained according to Canadian Tri-Council guidelines. All examinations were performed at the IWK Health Centre and the Atlantic Special Education Authority for the Hearing and Visually Impaired. The duration of required testing and the age and mental capacity of some of the patients necessitated multiple appointments to complete the study protocol. Study participants wore their full cycloplegic correction for all tests of visual function. Each diagnostic test was repeated on a separate visit if the participant was not cooperative for examination on the first testing to ensure accuracy of data collection. Comprehensive ophthalmologic, orthoptic, and electrodiagnostic evaluations were conducted. Additionally, each participant underwent a neurologic evaluation of cranial function (cranial nerve I through cranial nerve XII) by a pediatric neurologist. A certified instructor for the visually impaired from the Atlantic Provinces Special Education Authority conducted functional vision assessments on each patient. The functional vision assessment was based on observations of the patient in a variety of settings, both indoors and outdoors, including an educational setting. Functional vision testing was conducted independently of comprehensive ophthalmologic examination. This testing was used to complement information available from the comprehensive ophthalmologic examination regarding deficits of visual function due to structural anomalies. Assessment included the ability to find an object or target and fixate long enough to be aware of or recognize it, ability to track objects, accuracy in scanning objects, discrimination of objects, discrimination of details, and identification of patterns using routine testing methods. To describe the severity of findings in this cohort, visual acuity was defined as normal or mildly reduced (6/15 or better in the better eye), impaired (6/18 to 6/48 in the better eye), severely
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FIG 1. Patient (Case 8) demonstrates distinctive CHARGE facies—square face with broad prominent forehead, large eyes, prominent nasal bridge, thick nostrils, and small mouth. His ears are asymmetric and protrude. They are low set, short, wide, and have little or no lobe. A snipped off helix is noted on the left ear. reduced (6/60 to 6/120 in the better eye), or profoundly reduced vision (6/150 or less) in keeping with World Health Organization guidelines.11 Astigmatism was classified as mild (less than 1 D of cylinder), moderate (1-3 D), or severe (⬎3 D). Myopia and hyperopia were considered mild if less than 2 D, moderate if 2-5 D, and severe if greater than 5 D. In this study, anisometropia refers to an interocular difference in refractive error of greater than 2 D, in any meridian.
Results Ten individuals with a diagnosis of CHARGE syndrome were identified in the Canadian Pediatric Surveillance Program and recruited for this study. One identified CHARGE participant declined participation. Therefore, the study comprised 9 patients with CHARGE syndrome (7 male and 2 female), who ranged in age from 2.5 to 25 years (mean 10.1 year). The ocular features, their degree of severity, and cranial nerve dysfunction of individual participants are documented in e-Supplement 1 (available at jaapos.org).
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FIG 2. A 7-year-old patient (Case 4) with a chorioretinal colomboma involving the optic nerve. This patient had no iris involvement of the right eye.
Colobomas were the predominant ocular finding with a frequency of 83% (15/18 eyes). As depicted in Figure 2, typically, we found severe CHARGE chorioretinal colobomas that involved the optic nerve. Of these, 88% (7 of 8) of the participants with colobomas had bilateral involvement. One participant (Case 6) had an iris coloboma in addition to an ipsilateral monocular chorioretinal coloboma, and another (Case 2) had normal fundi. No eyelid colobomas were present. Unilateral microphthalmos was found in one patient (Case 1). The participant with microphthalmos also had manifest jerk nystagmus and bilateral cataracts causing vision loss. We were unable to test the visual acuity in 3 participants (Cases 4, 6, and 9). In 2 cases (Cases 2 and 3), bestcorrected visual acuity was recorded in the normal to mildly reduced range of 6/15 or better in the better eye whereas the remaining participants had best-corrected visual acuity in the impaired vision range of 6/18 or less. Of the participants whose visual acuity could be assessed, none were found to be in the severely or profoundly reduced range in their better eye. Color vision testing was only possible in one participant (Case 2) and found to be normal with American Optical Hardy-Rand-Rittler pseudoisochromatic plates (Richmond Products, San Francisco, CA). Qualitative visual acuity ascertained that, of the 6 participants who could be tested, 83% (5 of 6) did not attend to distant objects, 50% (3 of 6) had difficulty maintaining eye contact, 67% (4 of 6) showed little interest in objects located superiorly, and 33% (2 of 6) had difficulty scanning an object. Figure 3 illustrates the visual-evoked potential (VEP) findings of these participants. Participant age, mental capacity, and hearing loss limited our ability to formally assess patients’ visual fields. Goldmann visual field testing was only possible in only 1 patient (Case 2), and the result was in the normal range because this patient had no chorioretinal coloboma in either eye. Confronta-
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tional visual field testing in 2 additional participants detected superior quadrant field loss. This axonal loss was consistent with VEP results in 2 participants (Cases 5 and 7) who demonstrated no response to pattern stimuli even with large spatial frequency stimuli. All 9 participants had bilateral profound sensorineural hearing loss, with 2 having had cochlear implants. Of the 9, 8 (89%) showed facial paresis, 1 bilateral and 7 unilateral (3 left-sided and 4 right-sided). Consistent with cranial nerve VII paresis and inability to obtain adequate eyelid closure, 3 participants had corneal problems caused by exposure. Two had keratopathy, and one had a corneal scar despite copious lubrication, eyelid surgery (including the use of Gold weights), lateral tarsorrhaphy, and the placement of punctal plugs. Corneal sensation was tested in all study participants and found to be normal. Sense of smell was found to be defective in 2 of 9 participants by informal clinical criteria. Stereopsis testing was possible in 7 participants and was absent in all except one of these (Case 2: no chorioretinal colobomas), who attained 35 arcsec with Frisby testing (Richmond Products, San Francisco, CA). The defective stereopsis was consistent with a high incidence of strabismus in these participants. Strabismus was detected in 7 of 9 (78%) participants: 4 with nonaccommodative infantile esotropia (one of whom also had a vertical deviation); 2 with an exotropia (one of whom had an A pattern), and 1 with an isolated vertical deviation in primary position. A vertical gaze disorder was found in 3 participants (Cases 5, 8, and 9), with a monocular deficiency of upgaze in adduction that is illustrated in Figure 4. This limitation of the inferior oblique was accompanied by overaction of the ipsilateral superior oblique, contralateral yoke superior rectus, and underaction of the contralateral antagonist inferior rectus, indicative of inferior oblique paresis in 2 of the 3 cases. The absence of overaction of the direct antagonist or deviation in primary position in Case 9, suggested the presence of a Brown syndrome. Refractive errors were common and typically consisted of anisometropia and astigmatism. Anisometropia of 2 D or more was found in 89% (8 of 9) of the participants and would have contributed significantly to the potential for amblyopia, if not corrected by spectacles. Astigmatism was present in 78% (14 of 18) of the eyes tested. Severe mixed myopic astigmatism (⬎3 D) accompanied the large chorioretinal colobomas in 78% (14 of 18) of our patients. The remaining participants had moderate compound hyperopic astigmatism at a rate of 17% (3 of 18 eyes) whereas 1 patient had myopia (1-3 D).
Discussion This study undertook extensive ophthalmological (including electrodiagnostic and orthoptic examination and functional visual testing), in addition to cranial nerve assessment in a distinct group of individuals with CHARGE syndrome from Maritime Canada. These in-depth evalu-
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FIG 3. Visual evoked potential ( VEP) (Case 5): flash responses have normal implicit time (RE: 93 ms; LE 83 ms; significant ocular difference), while responses to patterned stimuli are better in the right eye, showing responses to standard check size of 20 arcmin with the right eye but none with the left. The binocular response is interestingly within normal range both in terms of amplitude and implicit time. The figure arrows indicate the stimulus onset, while the asterisks point to the first positivity measured on the VEP.
FIG 4. 10-year-old patient (Case 5) with limitation of right inferior oblique accompanied by overaction of the superior oblique muscle. Also present is an ipsilateral cranial nerve VII paresis.
ations yielded evidence of more extensive involvement in all areas of visual function and ocular structural anomalies than had been reported previously. Although numerous ocular abnormalities were found within this population, is this result because more ocular abnormalities are present or because they were studied more carefully? The association of the CHD7 gene mutation would suggest a predilection for ocular abnormalities. Mutation of the Chd7 gene produced organ abnormalities affected by CHARGE syndrome including the eye, olfactory epithelium, inner ear, and vascular system.12,13
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We found that this Eastern Canadian population of CHARGE syndrome participants typically had bilateral asymmetric chorioretinal colobomas as a major ophthalmic finding. The prevalence of 83% was comparable with those of other major studies of ophthalmic findings in CHARGE syndrome: Russell-Eggitt et al7 (86%), Tellier et al14 (79%), and Störmland et al15 (90%). CHARGE colobomas typically involve the choroid, retina, and optic nerve. Iris colobomas may have been reported less commonly and have been under-reported in studies that did not include a detailed ophthalmologic examination. Chester and France’s review16 of 54 clinic patients presenting with colobomas found that 11% met the major criteria for CHARGE syndrome. The frequent occurrence of this syndrome in patients with chorioretinal colobomas7,14-20 suggests that ophthalmologists should evaluate a patient for associated CHARGE defects (and refer for genetic evaluation when appropriate), particularly if the participant presents with either an additional major clinical criterion of CHARGE syndrome or a number of minor features (see Table 1). Typical CHARGE syndrome colobomas will produce a field defect in the upper quadrant and are associated with significant refractive errors, microphthalmos, microcornea, and vision loss. Optic disk colobomas vary greatly in presentation. Central visual acuity may be poor if the macula is involved. If a large coloboma does not involve the fovea, central vision is usually adequate. Formal visual field testing is difficult in this population because of their hearing loss and common autistic-like behaviors.9,10,21-24
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Only 1 of our 9 participants could perform a Goldmann visual field test, and only 4 had successful confrontational visual field testing. Educators of the visually impaired and deaf find that these children have difficulty attending to distant objects or to objects located superiorly and have difficulty scanning objects. Those patients have difficulty maintaining eye contact as a function of their visual impairments or possibly because of an additional autistic-spectrum disorder. It is also noteworthy that individuals with autism may display atypical gaze behaviors that should not be assumed to reflect poor visual acuity or other sensory limitations. This is an important consideration especially when acuity can be assessed only by examining fixation patterns. Davenport et al25 reported on 2 participants who were visually inattentive until their hearing impairment was addressed. A complication of typical CHARGE colobomas is retinal detachment7,17,23 Guirgis and Luder26 reported a choroidal neovascular membrane associated with optic nerve coloboma that developed in a 21-month-old boy with CHARGE syndrome, posing a risk for serous retinal detachment. None of our participants developed a retina detachment. Nevertheless, it is advisable to follow these patients routinely with dilated fundus examination to reduce the risk of vision loss from retinal detachment. Blake et al17 reported one case of eyelid colobomas, which had not been previously reported in CHARGE syndrome. None of the participants in our series had an eyelid coloboma but, one of the participants did have an atypical iris coloboma, a feature also, infrequently reported, in CHARGE syndrome.7,8,14 This atypical coloboma was accompanied by an ipsilateral, monocular chorioretinal coloboma: the typical CHARGE disk colobomas are bilateral. For CHARGE syndrome patients who have atypical eyelid and iris colobomas related to cranial nerve VII dysfunction, photophobia might be a profound symptom. Anisometropia and severe compound myopic astigmatism were common, in keeping with their bilateral asymmetric chorioretinal colobomas. This population of CHARGE participants presents a challenge to examine. Because of the presence of concurrent development delay, hearing loss, and ocular abnormalities, repeat refractions are indicated to ensure accuracy of correction. Vision loss from unilateral or bilateral amblyopia may occur if spectacle correction is not instituted. Additional amblyopia therapy may also be required. Strabismus is a frequent feature in this population and results in a lack of stereopsis. Visual field loss and reduced acuity in this population make adequate compensation problematic. Balance problems have been extensively reported in CHARGE syndrome. These are in part related to vestibular dysfunction but can be exacerbated by visual field defects, reduced acuity, and lack of depth perception.7 Russell-Eggitt et al7 reported 4 cases of a vertical eye movement disorder associated with facial palsy and deficiency of upgaze, particularly in adduction, of the eye contralateral to the facial nerve weakness. We also detected 3
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cases of vertical deficiency in elevation and adduction: 2 with overaction of the direct antagonist (superior oblique), suggesting an isolated inferior oblique paresis, and 1 without direct antagonist overaction, indicative of Brown syndrome. No relationship to the side of the facial muscle paresis was detected. Weaver et al27 reported a case of bilateral Marcus Gunn jaw-winking in one with CHARGE syndrome patient. Interestingly, an association also exists among Marcus Gunn jaw-winking dysinnervation, CHARGE, and Kabuki syndrome ( both Kabuki and CHARGE syndrome share phenotypic features); congenital fibrosis of the extraocular muscles; and another monocular elevation deficiency (also known as double elevator palsy).28,29 Facial and auditory nerve miswiring has also been reported in CHARGE syndrome and was found in one participant (Case 5) in our study.30 Congenital aberrant innervation may support a primary neural pathology underlying the vertical deviations noted in our study participants. All of our patients were deaf. Deafness in CHARGE syndrome is speculated to arise from congenital defects of the ossicular chain, “dysplasia” of the bony labyrinth, eustantian tube dysfunction, and high frequency sensorineural loss.21,26,30 Clinical neurological testing was conducted because detailed cranial magnetic resonance imaging was unavailable. Recent magnetic resonance imaging data from Europe revealed anomalies of olfactory tracts and bulbs in 100% of CHARGE syndrome patients, varying from moderate hypoplasia to complete aplasia.6 Using a recently validated olfactory test—the French Biolfa test— Chalouhi et al6 found olfactory deficiency in CHARGE patients. Those authors suggested that cranial nerve I anomalies should be considered a major criterion for the diagnosis of CHARGE syndrome. We did not have access to this olfactory test when our assessments were conducted. Although our participants were found to have normal corneal sensation, multiple cranial involvement occurs frequently in CHARGE and CNV-1 function should be tested. Lack of corneal sensation caused by trigeminal nerve paresis, either presenting exclusively or combined with inadequate lid closure due to facial nerve paresis may result in patients with CHARGE syndrome developing corneal abrasions and/or exposure keratopathy. Corneal abrasions/exposure keratopathy compound the developmental dysfunction as the result of colobomas. Ocular problems, which are common in our cohort of patients with CHARGE syndrome, included asymmetric bilateral chorioretinal colobomas involving the optic nerve, anisometropia, severe myopic astigmatism, strabismus, corneal exposure, microphthalmia, and reduced visual acuity. Cranial nerve involvement identified in this study included cranial nerves II, III, VII, and VIII. The presence of a fundus coloboma plus another CHARGE feature warrants further investigation, including genetic testing.
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References 1. Vissers LE, van Ravenswaaij CM, Admiraal R, Hurst JA, de Vries BB, Janssen IM, et al. Mutations in a new member of the chromodomain gene family cause CHARGE Syndrome. Nat Genet 2004; 36:955-7. 2. Pagon RA, Graham JM Jr., Zonana J, Yong SL. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 1981;99:223-7. 3. Blake KD, Davenport SL, Hall BD, Hefner MA, Pagon RA, Williams MS, et al. CHARGE association: An update and review for the primary pediatrician. Clin Pediatr (Phila) 1998;37:159-73. 4. Amiel J, Attiee-Bitach T, Marianowski R, Cormier-Daire V, Abadie V, Bonnet D, et al. Temporal bone anomaly proposed as a major criteria for diagnosis of CHARGE Syndrome. Am J Med Genet 2001;99:124-7. 5. Verloes A. Updated diagnostic criteria for CHARGE Syndrome: A proposal. Am J Med Genet 2005;133A:306-8. 6. Chalouhi D, Faulcon P, LeBihan C, Hertz-Pannier L, Bonfils P, Abadie V. Olfactory evaluation in children: Application to the CHARGE Syndrome. Pediatrics 2005;116:81-8. 7. Russell-Eggitt IM, Blake KD, Taylor DS, Wyse RK. The eye in the CHARGE association. Br J Ophthalmol 1990;74:421-6. 8. Strömland K, Sjögreen L, Johansson M, Ekman Joelsson BM, Miller M, Danielsson S, et al. CHARGE association in Sweden: Malformations and functional deficits. Am J Med Genet 2005;133A:331-9. 9. Smith IM, Nichols SL, Issekutz K, Blake K. Behavioral profiles and symptoms of autism in CHARGE syndrome: Preliminary epidemiological data. Am J Med Genet 2004;133A:248-56. 10. Miller MT, Strömland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism with ophthalmologic malformations: The plot thickens. Trans Am Ophthalmol Soc 2004;102:107-20. 11. World Health Organization. Magnitude and causes of visual impairment. Available from http://www.who.int/mediacentre/factsheets/ fs282/en/. 12. Bosman EA, Penn AC, Ambrose JC, Kettleborough R, Stemple DL, Steel KP. Multiple mutations in mouse Chd7 provide models for CHARGE syndrome. Human Mol Genet 2005;14:3463-76. 13. Faulkner-Jones BE, Godinho LN, Reese BE, Pasquini GF, Ruefli A, Tan SS. Cloning and expression of mouse Cadehein-7, a type-II cadeherin isolated from the developing eye. Mol Cell Neurosci 1999;14:1-16. 14. Tellier AL, Cormier-Daire V, Abadie V, Amiel J, Sigaudy S, Bonnet D, et al. CHARGE syndrome: Report of 47 cases and review. Am J Med Genet 1998;76:402-9.
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