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Ocular Findings in CHARGE Syndrome
Ocular Findings in CHARGE Syndrome Six Case Reports and a Review ROBERT J. CHESTLER, MD, THOMAS D. FRANCE, MD
Abstract: CHARGE syndrome is a group of nonrandomly occurring congenital anomalies which may present to the ophthalmologist, because coloboma is one of the major findings. In a series of 54 patients with ocular colobomata, 6 (11 %) were found to meet the criteria for CHARGE syndrome. The mnemonic CHARGE stands for the major features of this syndrome: Qoloboma, .t!eart defects, 8tresia of the choanae, Betarded growth and development, g,enital hypoplasia, and !;ar anomalies and/or hearing loss. No specific etiology is known , but autosomal dominant, autosomal recessive, and X-linked recessive forms have been suggested by familial reports. The authors describe six patients with CHARGE syndrome, including the second reported case occurring in mono zygotic twins. Other syndromes, chromosomal defects, and effects of teratogens may have similar clinical presentations. Though our prevalence may be skewed by our referral setting, the frequency of occurrence of this syndrome is certainly high enough that ophthalmologists should be familiar with it. Evaluation for as sociated defects should be carried out and referral for genetic evaluation un dertaken when appropriate. [Key words: CHARGE, choana! atresia, coloboma, congenital anomalies, ear anomalies, genital hypoplasia, growth retardation, hearing loss, heart defects, mental retardation , monozygotic twins, microphthal mia, retinal detachment.] Ophthalmology 95:1613-1619, 1988
Ocular coloboma is commonly seen as an isolated de fect, but can also be seen in a variety of congenital syn dromes. 1 One which has become recognized over the past decade is the CHARGE syndrome. This syndrome con sists of a specific group of nonrandomly occurring con genital anomalies in patients with normal karyotypes and no other recognized syndrome. It was first described by Pagon and co-workers2 in 1981 and named for its six ma jor features: ~oloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hy poplasia, and ,Ear anomalies and/or hearing loss. Addi tional features have been added as further cases have been described (Table 1). Originally received: April 28, 1988. Revision accepted: July 27, 1988. From the Department of Ophthalmology, University of Wisconsin Hospital and Clinics, Madison. Reprint requests to Thomas D. France, MD, UW CSC, 600 Highland Ave, F4/326, Madison, WI 53792.
It is important for ophthalmologists to be aware of this not uncommon syndrome, because early management of associated defects may be critical. We describe six patients with normal chromosomes and features of this syndrome_ Five of these six patients meet the diagnostic criteria for CHARGE syndrome. The sixth patient is included be cause, though not completely fitting the diagnostic criteria, he has several of the features of CHARGE syndrome and is the monozygotic twin of one of the other five patients.
PATIENTS AND METHODS We reviewed the records of 10,850 patients who had been entered into our database over the last 16 years at the University of Wisconsin Pediatric Ophthalmology Clinic. The 54 cases found, which had some form of col oboma, were reviewed to identify those patients with other congenital anomalies. Six ofthe 54 patients with coloboma were found to have CHARGE syndrome. 1613
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Table 1. Clinical Findings in CHARGE Syndrome Findings .Qoloboma and/or microphthalmos Heart defects Atresia of the choanae Betarded growth and/or development including central nervous system anomalies §enital hypoplasia and/or urinary tract anomalies J;ar malformations and/or combined hearing loss Unilateral Vllth nerve palsy Facial asymmetry Cleft lip/palate Pharyngeal incoordination and/or swallowing problems Short fifth fingers Tracheoesophageal fistula or esophageal atresia
CASE
REPORTS
Case 1. A 16-month-o!d white boy was the product of a term pregnancy which was uncomplicated except for an episode of a viral syndrome at 4 months. Initially, he was noted to have a cleft palate and a grade IV/VI systolic ejection murmur. While in the newborn nursery, he was noted to have bilateral chorio retinal colobomata. At 6 weeks of age, cardiac evaluation showed tetralogy of Fallot with a small atrial septal defect. Genetic evaluation showed general hypotonicity, mild asymmetry of facial features, and skull sutures, and karyotype analysis showed a normal 46XY chromosomal constitution. Brain stem-evoked auditory re sponses showed severe bilateral auditory dysfunction. At 16 months of age, developmental milestones were notably delayed and length had dropped from the 50th percentile at 3 months to below the 5th percentile, while weight remained stable at the 25th percentile. Bilateral cryptorchidism was noted. Results of ophthalmic examination showed horizontal pen dular nystagmus in both eyes. Fixation was not present with the right eye, which was microphthalmic (corneal diameter, 8.5 mm), but was present and maintained with the left. A right exotropia of 25A was present and there was a relative afferent pupillary defect in the right eye. There was no iris coloboma, but bilateral colobomata of the choroid, retina, and optic nerve were noted. The colobomata included the right macula and extended just to the edge of the left macula. Case 2. A 7-year-old white male monozygotic twin was the product of a normal gestation and delivery. He showed normal motor development early, but speech was notably delayed. He had no intelligible speech at 3 years of age. At 7 years of age, he was microcephalic, had left cryptorchi dism, and had a grade 1/VI systolic ejection murmur. Audi ometry showed mild bilateral conductive hearing loss and neu ropsychologic testing showed an intelligence quotient of 68. Analysis of the karyotype showed a normal 46XY chromosomal constitution. At 15 years of age, a grade III/VI systolic ejection murmur was noted. Results of ophthalmic examination at 7 years of age showed a visual acuity of 20/15 in the right eye and 20/20 in the left, orthophoria, and normal motility. An incomplete iris coloboma of the right eye and an iris coloboma which included a small area of lens zonules on the left were noted. The left lens had a small defect inferonasally at the site of the coloboma. The fundi were unremarkable.
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Case 3. A 7-year-old white boy, the monozygotic twin of case 2, also showed normal motor development but was quite delayed in speech. At 2 years of age, he was noted to have a ventriculoseptal defect. Later he was found to have first degree hypospadias, right cryptorchidism, and syndactyly of the third and fourth toes bi laterally. Neuropsychologic testing at 6 years of age showed an intelligence quotient of 67. Chromosomal analysis showed a normal48XY karyotype. At 7 years ofage, he was microcephalic, and audiologic testing showed a mild bilateral conductive hearing loss. Ophthalmic evaluation at 7 years of age showed a visual acuity of 20/20 in the right eye and 20/15 in the left, orthophoria, normal motility, and normal pupillary reactions. Anterior and posterior segments were unremarkable. There was no evidence of coloboma of the iris or fundus in either eye. Case 4. A 3-month-old white girl was noted shortly after birth to have multiple congenital anomalies (Table 2). Karyotype analysis showed a normal 46XX chromosomal constitution. Results of ophthalmic examination at age 3 months showed central, steady, maintained fixation in the right eye and no fix ation in the left. The left eye was microphthalmic (corneal di ameter, 8.0 mm). There was approximately 45A left esotropia. Inferior colobomata of the iris, retina, and choroid were noted. Results of the most recent ophthalmic examination, at 13 years of age, showed a visual acuity of 20/30 in the right eye and 3/200 in the left. Case 5. A 2-month-old black boy had bilateral microphthal mos (corneal diameter, 7.0 mm). No fixation was present with either eye. An iris coloboma was present in the right eye, with large chorioretinal colobomata involving the optic nerve and macula bilaterally. The left lens had an opacity inferonasally. At 6 months of age, the patient was noted to have pendular nystagmus and would fixate briefly on a penlight. Chromosomal analysis showed a normal 46XY karyotype. Additonal findings are noted in Table 2. The patient died at 1 1/2 years of age. Case 6. A 4-month-old white girl showed no fixation with the right eye, but fixation was steady and maintained with the left eye. There was 50A of right esotropia. There was microphthalmos of the right eye (corneal diameter, 6.0 mm) with a relative afferent pupillary defect and an unreactive pupil. The right eye had a coloboma of the iris inferiorly with a large coloboma of the choroid, retina, and optic nerve. The left fundus was unre markable. Results of the most recent ophthalmic examination at 5 years and 4 months of age showed a visual acuity of light perception with projection in the right eye and 20/30 in the left. Analysis of the karyotype demonstrated a normal 46XX chromosomal constitution. Additional findings are noted in Table 2.
RESULTS Ophthalmic findings are summarized in Table 3. Five of the six patients with CHARGE syndrome presented to the eye clinic because of the ocular abnormalities asso ciated with colobomata. One of the six patients is legally blind and three more have one eye that has a visual acuity of less than 20/200. Microphthalmos, iris defects, cho rioretinal defects, and optic nerve colobomata were pres ent in four cases each, and strabismus in three. Two pa tients had lens abnormalities, one with a lens coloboma
-
Vl
0\
+
Mild hearing loss in both ears
Severe dysfunction in both ears on BEAR, recurrent otitis media
Cleft palate, facial asymme'try
];ar anomalies/ hearing loss
Other CHARGE features
microcephaly*
= 67
Syndactaly 3rd and 4th toes bilaterally
1st degree hypospadias, cryptorchidism Mild hearing loss in both ears
IQ
-
VSD
3 M
Laryngomalacia, left hydronephrosis, pectus excavatum, contracture 3rd fingers, pes planus and calcaneovalgus bilaterally
External ears typical of CHARGE, 16 recurrent otitis media, moderate hearing loss
Developmental delay, microcephaly*
<3rd % weight, height, head circumference at 2 yrs of age
+
4 F
Findings
-
+
Bifid uvula, higharched palate
-
Dysplastic in both ears
<3rd % weight, height, head circumference at 15 mos of age, developmental delay, generalized EEG slowing, microcephaly*
Endocardial cushion defect, PDA, pulmonary stenosis
5 M
Low-set, dysplastic in both ears, moderate mixed hearing loss in the left ear, recurrent otitis media Submucosal cleft palate, short left 5th finger, oligodactaly left foot Mild mandibular and skull asymmetry, hypoplastic nasal cartilage, bilateral simian creases
<3rd % weight, height, head circumference at 5 yrs of age
Mild valvar aortic stenosis, bicuspid aortic valve
+
6 F
ASD = atrial septal defect; VSD = ventriculoseptal defect; PDA = patent ductus arteriosus; EEG = electroencephalogram; CNS = central nervous system; IQ = intelligence quotient; BEAR = brain stem-evoked auditory response. * Head circumference is greater than 3 SO below mean for age.
Other
-
Cryptorchidism
microcephaly*
= 68
Cryptorchidism
fletarded development or CNS abnormalities 2enital hypoplasia IQ
Length < 5th %at age 16 mo
-
Grade Ill/VI systolic ejection murmur
Tetralogy of Fallot, small ASD
+
2 M
1 M
Milestones delayed
8tresia choanae fletarded growth
Case no. Sex Qoloboma .tt.eart defect
Variables
Table 2. Nonocular Findings
m
I
0
)>
m
~
0
::0
0
-< z
en
m
Gl
::0
)>
I
0
•
m
0
z
::0
-n
0
z
)>
::0
m
en -i r
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Table 3. Ocular Findings in Cases 1 to 6 Case No.
2
3 4 5 6
Coloboma
Visual Acuity
Choroid/retina/optic nerve, OU; macula, 00
NCUSNM CUSM
25~
Incomplete iris, 00; iris with lens defect inferonasally, OS None
20/15 20/20
Orthophoric
-2.00 + 1.50 X 85 -1.50 + 1.00 X 90
20/20 20/15 20/30 4/200 NCUSNM NCUSNM
Orthophoric
-1.00 +.50 X 85 -.50+ 1.00 X 95 plano -6.00 + 2.00 X 138
LP 20/30
50~
Iris/choroid/retina/optic nerve, OS Iris, 00; choroid/retina/ optic nerve/macula, OU Iris/choroid/retina/optic nerve, 00
Alignment
45~
Refractive Error
RXT
LET
Orthophoric RET
+1.50 + 1.00 X 150
Other Pendular nystagmus; microphthalmos, 00; anisocoria; afferent pupil defect, 00
Microphthalmos OS Bilateral microphthalmos, pendular nystagmus, inferonasal lens opacity Microphthalmos, 00
OU = both eyes; 00 = right eye; NCUSNM = not central, unsteady, and not maintained; CUSM = central, unsteady, and maintained; RXT = right exotropia; OS = left eye; LET = lett esotropia; LP = light perception; RET = right esotropia.
and one with a peripheral, nonprogressive cataract. Nys tagmus, presumably due to poor vision, was present in two cases.
DISCUSSION Ocular colobomata were found to be present in 54 of 10,850 (0.05%) patients followed at the University of Wisconsin Pediatric Eye Clinic. Six (11%) ofthese patients were believed to exhibit findings typical of CHARGE syndrome. In view of the significant systemic abnormal ities associated with CHARGE and the possibility that patients with colobomata may have CHARGE, all patients with an ocular coloboma should be carefully evaluated for the presence of this condition. The mnemonic CHARGE was first suggested in 1981 by Pagon and co-workers2 for the strikingly similar pattern of associated anomalies they reported in 21 patients with normal karyotypes. Hittner and co-workers3 and Hall4 had previously reported 10 and 17 cases, respectively, which displayed a similar constellation of anomalies with normal chromosomes. In fact, in retrospect, several other authors had described small series of patients, some of whom showed many of these same nonrandomly occur ring anomalies. 5- 12 The six findings responsible for the name are Colo boma, Heart defects, Atresia of the choanae, Ret~ded growth and development, Genital hypoplasia, -and ~ar anomalies and/or hearing loss. Over the years, these cat egories have been better defined, and other associated anomalies have been added (Table 1). Typical colobomata are those that arise from failure of 1616
the embryologic fissure of the optic cup to close. Normal closure occurs between the fifth and sixth weeks of ges tation, and proceeds proximally and distally from the midpoint of the fissure. 1•3 Failure of closure can lead to defects of the optic nerve, sclera, choroid, retina, ciliary body, and/or iris inferiorly (Figs 1, 2). Any location other than inferior would constitute an atypical coloboma and is not consistent with this mechanism of formation. Mi crophthalmos is not unusual in association with colo bomatous defects, where globe size can range from normal to clinical anophthalmos. 13 Visual function is variable, but usually good acuity is preserved unless the macula or optic nerve are involved. In patients with CHARGE syndrome, colobomata are usually bilateral and somewhat asymmetric, but often are only unilateral. 3•7 •8 All varieties oftypical coloboma have been reported, 14 including clinical anophthalmos. 2 •10 The congenital heart defects seen in these patients are varied; the most common being atrial and ventricular septal defects, tetralogy of Fallot, patent ductus arteriosus, and pulmonary stenosis. 2•7 • 15 Unilateral or bilateral atresia of the choanae is an in frequently occurring developmental anomaly caused by membranous and/or bony obstruction of the posterior nasal choanae. Though Pagon and co-workers2 and Hall4 reported a high frequency of this defect, our series and others have had few or no patients with this finding. 14• 15 This discrepancy reflects the bias ofascertainment in those studies which used choana! atresia as a criterion for se lection, and thus shows a greater number of patients with this defect. Choana! stenosis has also been reported in CHARGE 14 and may occur more frequently than reported because of the inability to easily examine this structure. Mental retardation is a common finding, though vari
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Fig 2. Typical inferior iris coloboma.
Fig 1. Large inferior chorioretinal coloboma including optic nerve and macula.
able; ranging from profound to mild. Individuals living independently and functioning well with low-normal in telligence have been reported. 14 ·16 Retarded growth is another common feature. Pagan and co-workers 2 found only 2 of 20 patients at less than the tenth percentile for birth weight, but, in most, growth dropped below the third percentile during the first 6 months of life. Genital hypoplasia is most commonly manifested as microphallus, cryptorchidism, and/or hypospadias.2.7 This criterion for selection has included primarily male pa tients, but Davenport and co-workers 14 report two female patients with labial hypoplasia. 14 Hypogonadotropic hy pogonadism also has been reported. 2• 14 A variety ofexternal ear malformations can be seen, 2•3• 17 but Davenport and co-workers 18 describe a specific set of external ear features which they believe are distinctive enough to make a presumptive diagnosis of CHARGE syndrome. Case 4 in our series shows the most striking of these features: a triangular-shaped concha (Fig 3). Thelin and associates 19 also describe a characteristic wedge-shaped audiogram secondary to progressive, mixed conductive, and sensorineural hearing loss, though others have described a primarily sensorineural hearing loss. 2 Degree of hearing loss ranged from mild to profound. Additional associated malformations include unilateral Vllth nerve palsy/-4·15 facial asymmetry, 2• 14 cleft pal ate,2·4·7· 14 congenital pharyngeal incoordination and/or swallowing problems, 2·3 short fifth fingers and polysyn dactaly,4·14·15 tracheoesophageal fistula or esophageal atresia, 2.4· 10 and urinary tract abnormalities. 3•10·14
Fig 3. Left ear of case 4. Notice the triangular-shaped concha. The ear is short and wide.
The original criteria for the diagnosis of CHARGE as sociation, as outlined by Pagan and co-workers, 2 included those patients with coloboma or choana! atresia, or both, and a total of at least four of the seven features designated by the acronym (they counted retarded growth and re tarded development as two separate features). According to these criteria, five of our six patients may be designated as having CHARGE syndrome. Case 3, despite having four separate features of CHARGE syndrome, does not fit these criteria because of the absence ofboth coloboma and choana! atresia. He is of interest, though, because he is the monozygotic twin of case 2 who does fit the criteria. We believe he represents variable expression of the syn drome, as in other familial cases reported in the literature, in which not all affected family members necessarily con formed to the strict diagnostic criteria. 20 There has been only one other case of CHARGE syndrome occurring in monozygotic twins reported in the literature. Levin and co-workers,21 in 1973, described a set of monozygotic twins with congenital heart disease who in retrospect fit the criteria for CHARGE syndrome. 1617
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The specific etiology for CHARGE syndrome remains unknown. Warburg 15 suggests the syndrome is caused by a derangement in migration of neural crest cells and cau dad presumptive mesodermal cells between the fifth and sixth weeks of gestation. The majority of recorded cases have been sporadic, though autosomal dominant, auto somal recessive, and X-linked recessive inheritance have been suggested by some familial cases. 2 •3•20•22 •23 Therefore, it may reflect a common phenotypic pathway for various genetic defects (genetic heterogeneity). Coloboma has been reported as a finding in abnor malities (trisomy and partial deletion or duplication) of chromosomes 4, 11, 13, 18, and 22. 1 But patients with complete or partial trisomy of chromosome 13 may also have other features in common with patients with CHARGE syndrome. 24•25 The Cat's Eye syndrome, which is caused by a dupli cation of the q 11 region of chromosome 22, shows similar features. 26 It is characterized by coloboma and an imper forate anus, but most patients also have multiple other CHARGE-like malformations, including urinary, cardiac, genital, and ear anomalies. 24•27 - 29 Coloboma and other CHARGE-like findings have also been reported in patients with long-arm deletions ofchro mosome 11. 30•31 In reviewing our cases of coloboma, we came across such a patient who phenotypically met the clinical criteria for CHARGE syndrome, but showed a deletion of the long arm of chromosome 11. Because of phenotypic similarities, chromosomal analysis is required in any CHARGE syndrome suspect. The VACTERL association consists ofY:ertebral, ~nal, ~ardiac, Iracheal, £sophageal, Renal, and _Limb anom alies with similarities to CHARGE syndrome, also in pa tients with normal chromosomesY Some investigators believe these two may be different expressions on a con tinuum of a single embryologic defect. 15 CHARGE syndrome anomalies also can be seen in thalidomide embryopathy, which, in addition to causing phocomelia, can cause a variety of other abnormalities, including ocular coloboma, heart disease, choanal atresia, facial palsy, ear anomalies, and hearing loss. 33 In reviewing our cases of ocular coloboma, we were somewhat surprised at the frequency of occurrence of CHARGE syndrome ( 11%). Even though this high prev alence may be skewed by our referral population, this syndrome is common enough that ophthalmologists should be aware ofit, since early identification and therapy for nonocular problems such as heart defects and hearing loss may be critical. Patients with ocular coloboma should be evaluated for other, perhaps silent, abnormalities, whether or not other obvious anomalies are present. In addition to surgical correction of various malformations and early training for the hearing impaired, newer hor monal therapies may be helpful in growth delay and gen ital hypoplasia. Nutritional supplementation may be re quired in cases of swallowing difficulties and/or cleft pal ate. Since the recurrence risk to normal parents is probably slightly higher than that of the general population, 2 and
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since some cases may be clearly heritable, evaluation by a medical geneticist and genetic counseling is advised. Long-term ophthalmic follow-up is necessary, because retinal detachment can occur as a complication of cho rioretinal coloboma. 34
REFERENCES 1. Pagon RA. Ocular coloboma. Surv Ophthalmol 1981; 25:223-36. 2. Pagon RA, Graham JM Jr, Zonana J, Yong S-L. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 1981; 99:223-7. 3. Hittner HM, Hirsch NJ, Kreh GM, Rudolph AJ. Colobomatous mi crophthalmia, heart disease, hearing loss, and mental retardation a syndrome. J Pediatr Ophthalmol Strabismus 1979; 16:122-8. 4. Hall BD. Choanal atresia and associated multiple anomalies. J Pediatr 1979; 95:395-8. 5. Angelman H. Syndrome of coloboma with multiple congenital abnor malities in infancy. Br Med J 1961; 1:1212-4. 6. Edwards JH, Young RB, Finlay HVL. Coloboma with multiple congenital anomalies [Letter). Br Med J 1961; 2:586-7. 7. HoCK, Kaufman RL, Podos SM. Ocular colobomata, cardiac defect, and other anomalies: a study of seven cases including two sibs. J Med Genet 1975; 12:289-93. 8. James PML, Karseras AG, Wybar KC. Systemic associations of uveal coloboma. Br J Ophthalmol1974; 58:917-21. 9. Lillquist K, Warburg M, Andersen SR. Hagerstrand I. Colobomata of the iris, ciliary body and choroid in an infant with oesophago-tracheal fistula and congenital heart defects: an unknown malformation com plex. Acta Paediatr Scand 1980; 69:427-30. 10. Sassani JW, Yanoff M. Anophthalmos in an infant with multiple con genital anomalies. Am J Ophthalmol1977; 83:43-8. 11. Say B, Berry J, Barber N. The Stickler syndrome (hereditary arthro ophthalmopathy). Clin Genet 1977; 12:179-82. 12. Stool SE, Kemper Bl. Choanal atresia and/or cardiac disease. Pediatrics 1968; 42:525-8. 13. Goldberg MF, McKusick VA. X-linked colobomatous microphthalmos and other congenital anomalies: a disorder resembling Lenz's dys morphogenetic syndrome. Am J Ophthalmol 1971; 71:1128-33. 14. Davenport SLH, Hefner MA, Mitchell JA. The spectrum of clinical features in CHARGE syndrome. Clin Genet 1986; 29:298-310. 15. Warburg M. Ocular coloboma and multiple congenital anomalies: the CHARGE association. Ophthalmic Paediatr Genet 1983; 2:189-99. 16. Goldson E, Smith AC, Stewart JM. The CHARGE association: How well can they do? Am J Dis Child 1986; 140:918-21. 17. Dobrowski JM, Grundfast KM, Rosenbaum KN, Zajtchuk JT. Otorhin olaryngic manifestations of CHARGE association. Otolaryngol Head Neck Surg 1985; 93:798-803. 18. Davenport SLH, Hefner MA, Thelin JW. CHARGE Syndrome. Part I. External ear anomalies. lnt J Pediatr Otorhinolaryngol1986; 12:137 43. 19. Thelin JW, Mitchell JA, Hefner MA, Davenport SLH. CHARGE Syn drome. Part II. Hearing loss. lnt J Pediatr Otorhinolaryngol1986; 12: 145-63. 20. Mitchell JA, Giangiacomo J, Hefner MA, et al. Dominant CHARGE association. Ophthalmic Paediatr Genet 1985; 6:31-6. 21. Levin DL, Muster AJ, Newfeld EA, Paul MH. Concordant aortic arch anomalies in monozygotic twins. J Pediatr 1973; 83:459-61. 22. Awrich PO, Flannery DB, Robertson L, Mamunes P. CHARGE asso ciation anomalies in siblings. Am J Hum Genet 1982; 34(Suppi):80A.
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23. Abruzzo MA, Erickson RP. A new syndrome of cleft palate associated with coloboma, hypospadias, deafness, short stature, and radial syn ostosis. J Med Genet 1977; 14:76-80.
29.
24. Lewandowski RC Jr, Yunis JJ. New chromosomal syndromes. Am J Dis Child 1975; 129:515-29.
30.
25. Noel B, Quack B, Rethore MO. Partial deletions and trisomies of chro mosome 13; mapping of bands associated with particular malfor mations. Clin Genet 1976; 9:593-602.
31.
partial trisomy of G chromosome. Arch Ophthalmol 1973; 90:287 91. Schachenmann G, Schmid W, Fraccaro M, et al. Chromosomes in coloboma and anal atresia. Lancet 1965; 2:290. Schinzel A, Auf der Maur P, Moser H. Partial deletion of long arm of chromosome 11 [del(11)(q23)]: Jacobsen syndrome: two new cases and review of the clinical findings. J Med Genet 1977; 14:438-44. Lee ML, Sciarra LJ. Partial monosomy of the long arm of chromosome 11 in a severely affected child. Ann Genet 1981; 24:51-3. Temtamy SA, Miller JD. Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 1974; 85:345-9. Smithells RW. Defects and disabilities of thalidomide children. Br Med
26. McDermid HE, Duncan AMV, Brasch KR, et al. Characterization of the supernumerary chromosome in cat eye syndrome. Science 1986; 232:646-8.
32.
27. Bolinger MK, Soukup SW. Cat eye syndrome: partial trisomy 22 due to translocation in the mother. Am J Dis Child 1977; 131:893-7.
J 1973: 1:269-72. 34. Wang K, Hilton GF. Retinal detachment associated with coloboma of the choroid. Trans Am Ophthalmol Soc 1985; 83:49-62.
28. Petersen RA. Schmid-Fraccaro syndrome ("eat's eye" syndrome):
33.
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Abstract: CHARGE syndrome is a group of nonrandomly occurring congenital anomalies which may present to the ophthalmologist, because coloboma is one of the major findings. In a series of 54 patients with ocular colobomata, 6 (11 %) were found to meet the criteria for CHARGE syndrome. The mnemonic CHARGE stands for the major features of this syndrome: Qoloboma, .t!eart defects, 8tresia of the choanae, Betarded growth and development, g,enital hypoplasia, and !;ar anomalies and/or hearing loss. No specific etiology is known , but autosomal dominant, autosomal recessive, and X-linked recessive forms have been suggested by familial reports. The authors describe six patients with CHARGE syndrome, including the second reported case occurring in mono zygotic twins. Other syndromes, chromosomal defects, and effects of teratogens may have similar clinical presentations. Though our prevalence may be skewed by our referral setting, the frequency of occurrence of this syndrome is certainly high enough that ophthalmologists should be familiar with it. Evaluation for as sociated defects should be carried out and referral for genetic evaluation un dertaken when appropriate. [Key words: CHARGE, choana! atresia, coloboma, congenital anomalies, ear anomalies, genital hypoplasia, growth retardation, hearing loss, heart defects, mental retardation , monozygotic twins, microphthal mia, retinal detachment.] Ophthalmology 95:1613-1619, 1988
Ocular coloboma is commonly seen as an isolated de fect, but can also be seen in a variety of congenital syn dromes. 1 One which has become recognized over the past decade is the CHARGE syndrome. This syndrome con sists of a specific group of nonrandomly occurring con genital anomalies in patients with normal karyotypes and no other recognized syndrome. It was first described by Pagon and co-workers2 in 1981 and named for its six ma jor features: ~oloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital hy poplasia, and ,Ear anomalies and/or hearing loss. Addi tional features have been added as further cases have been described (Table 1). Originally received: April 28, 1988. Revision accepted: July 27, 1988. From the Department of Ophthalmology, University of Wisconsin Hospital and Clinics, Madison. Reprint requests to Thomas D. France, MD, UW CSC, 600 Highland Ave, F4/326, Madison, WI 53792.
It is important for ophthalmologists to be aware of this not uncommon syndrome, because early management of associated defects may be critical. We describe six patients with normal chromosomes and features of this syndrome_ Five of these six patients meet the diagnostic criteria for CHARGE syndrome. The sixth patient is included be cause, though not completely fitting the diagnostic criteria, he has several of the features of CHARGE syndrome and is the monozygotic twin of one of the other five patients.
PATIENTS AND METHODS We reviewed the records of 10,850 patients who had been entered into our database over the last 16 years at the University of Wisconsin Pediatric Ophthalmology Clinic. The 54 cases found, which had some form of col oboma, were reviewed to identify those patients with other congenital anomalies. Six ofthe 54 patients with coloboma were found to have CHARGE syndrome. 1613
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Table 1. Clinical Findings in CHARGE Syndrome Findings .Qoloboma and/or microphthalmos Heart defects Atresia of the choanae Betarded growth and/or development including central nervous system anomalies §enital hypoplasia and/or urinary tract anomalies J;ar malformations and/or combined hearing loss Unilateral Vllth nerve palsy Facial asymmetry Cleft lip/palate Pharyngeal incoordination and/or swallowing problems Short fifth fingers Tracheoesophageal fistula or esophageal atresia
CASE
REPORTS
Case 1. A 16-month-o!d white boy was the product of a term pregnancy which was uncomplicated except for an episode of a viral syndrome at 4 months. Initially, he was noted to have a cleft palate and a grade IV/VI systolic ejection murmur. While in the newborn nursery, he was noted to have bilateral chorio retinal colobomata. At 6 weeks of age, cardiac evaluation showed tetralogy of Fallot with a small atrial septal defect. Genetic evaluation showed general hypotonicity, mild asymmetry of facial features, and skull sutures, and karyotype analysis showed a normal 46XY chromosomal constitution. Brain stem-evoked auditory re sponses showed severe bilateral auditory dysfunction. At 16 months of age, developmental milestones were notably delayed and length had dropped from the 50th percentile at 3 months to below the 5th percentile, while weight remained stable at the 25th percentile. Bilateral cryptorchidism was noted. Results of ophthalmic examination showed horizontal pen dular nystagmus in both eyes. Fixation was not present with the right eye, which was microphthalmic (corneal diameter, 8.5 mm), but was present and maintained with the left. A right exotropia of 25A was present and there was a relative afferent pupillary defect in the right eye. There was no iris coloboma, but bilateral colobomata of the choroid, retina, and optic nerve were noted. The colobomata included the right macula and extended just to the edge of the left macula. Case 2. A 7-year-old white male monozygotic twin was the product of a normal gestation and delivery. He showed normal motor development early, but speech was notably delayed. He had no intelligible speech at 3 years of age. At 7 years of age, he was microcephalic, had left cryptorchi dism, and had a grade 1/VI systolic ejection murmur. Audi ometry showed mild bilateral conductive hearing loss and neu ropsychologic testing showed an intelligence quotient of 68. Analysis of the karyotype showed a normal 46XY chromosomal constitution. At 15 years of age, a grade III/VI systolic ejection murmur was noted. Results of ophthalmic examination at 7 years of age showed a visual acuity of 20/15 in the right eye and 20/20 in the left, orthophoria, and normal motility. An incomplete iris coloboma of the right eye and an iris coloboma which included a small area of lens zonules on the left were noted. The left lens had a small defect inferonasally at the site of the coloboma. The fundi were unremarkable.
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Case 3. A 7-year-old white boy, the monozygotic twin of case 2, also showed normal motor development but was quite delayed in speech. At 2 years of age, he was noted to have a ventriculoseptal defect. Later he was found to have first degree hypospadias, right cryptorchidism, and syndactyly of the third and fourth toes bi laterally. Neuropsychologic testing at 6 years of age showed an intelligence quotient of 67. Chromosomal analysis showed a normal48XY karyotype. At 7 years ofage, he was microcephalic, and audiologic testing showed a mild bilateral conductive hearing loss. Ophthalmic evaluation at 7 years of age showed a visual acuity of 20/20 in the right eye and 20/15 in the left, orthophoria, normal motility, and normal pupillary reactions. Anterior and posterior segments were unremarkable. There was no evidence of coloboma of the iris or fundus in either eye. Case 4. A 3-month-old white girl was noted shortly after birth to have multiple congenital anomalies (Table 2). Karyotype analysis showed a normal 46XX chromosomal constitution. Results of ophthalmic examination at age 3 months showed central, steady, maintained fixation in the right eye and no fix ation in the left. The left eye was microphthalmic (corneal di ameter, 8.0 mm). There was approximately 45A left esotropia. Inferior colobomata of the iris, retina, and choroid were noted. Results of the most recent ophthalmic examination, at 13 years of age, showed a visual acuity of 20/30 in the right eye and 3/200 in the left. Case 5. A 2-month-old black boy had bilateral microphthal mos (corneal diameter, 7.0 mm). No fixation was present with either eye. An iris coloboma was present in the right eye, with large chorioretinal colobomata involving the optic nerve and macula bilaterally. The left lens had an opacity inferonasally. At 6 months of age, the patient was noted to have pendular nystagmus and would fixate briefly on a penlight. Chromosomal analysis showed a normal 46XY karyotype. Additonal findings are noted in Table 2. The patient died at 1 1/2 years of age. Case 6. A 4-month-old white girl showed no fixation with the right eye, but fixation was steady and maintained with the left eye. There was 50A of right esotropia. There was microphthalmos of the right eye (corneal diameter, 6.0 mm) with a relative afferent pupillary defect and an unreactive pupil. The right eye had a coloboma of the iris inferiorly with a large coloboma of the choroid, retina, and optic nerve. The left fundus was unre markable. Results of the most recent ophthalmic examination at 5 years and 4 months of age showed a visual acuity of light perception with projection in the right eye and 20/30 in the left. Analysis of the karyotype demonstrated a normal 46XX chromosomal constitution. Additional findings are noted in Table 2.
RESULTS Ophthalmic findings are summarized in Table 3. Five of the six patients with CHARGE syndrome presented to the eye clinic because of the ocular abnormalities asso ciated with colobomata. One of the six patients is legally blind and three more have one eye that has a visual acuity of less than 20/200. Microphthalmos, iris defects, cho rioretinal defects, and optic nerve colobomata were pres ent in four cases each, and strabismus in three. Two pa tients had lens abnormalities, one with a lens coloboma
-
Vl
0\
+
Mild hearing loss in both ears
Severe dysfunction in both ears on BEAR, recurrent otitis media
Cleft palate, facial asymme'try
];ar anomalies/ hearing loss
Other CHARGE features
microcephaly*
= 67
Syndactaly 3rd and 4th toes bilaterally
1st degree hypospadias, cryptorchidism Mild hearing loss in both ears
IQ
-
VSD
3 M
Laryngomalacia, left hydronephrosis, pectus excavatum, contracture 3rd fingers, pes planus and calcaneovalgus bilaterally
External ears typical of CHARGE, 16 recurrent otitis media, moderate hearing loss
Developmental delay, microcephaly*
<3rd % weight, height, head circumference at 2 yrs of age
+
4 F
Findings
-
+
Bifid uvula, higharched palate
-
Dysplastic in both ears
<3rd % weight, height, head circumference at 15 mos of age, developmental delay, generalized EEG slowing, microcephaly*
Endocardial cushion defect, PDA, pulmonary stenosis
5 M
Low-set, dysplastic in both ears, moderate mixed hearing loss in the left ear, recurrent otitis media Submucosal cleft palate, short left 5th finger, oligodactaly left foot Mild mandibular and skull asymmetry, hypoplastic nasal cartilage, bilateral simian creases
<3rd % weight, height, head circumference at 5 yrs of age
Mild valvar aortic stenosis, bicuspid aortic valve
+
6 F
ASD = atrial septal defect; VSD = ventriculoseptal defect; PDA = patent ductus arteriosus; EEG = electroencephalogram; CNS = central nervous system; IQ = intelligence quotient; BEAR = brain stem-evoked auditory response. * Head circumference is greater than 3 SO below mean for age.
Other
-
Cryptorchidism
microcephaly*
= 68
Cryptorchidism
fletarded development or CNS abnormalities 2enital hypoplasia IQ
Length < 5th %at age 16 mo
-
Grade Ill/VI systolic ejection murmur
Tetralogy of Fallot, small ASD
+
2 M
1 M
Milestones delayed
8tresia choanae fletarded growth
Case no. Sex Qoloboma .tt.eart defect
Variables
Table 2. Nonocular Findings
m
I
0
)>
m
~
0
::0
0
-< z
en
m
Gl
::0
)>
I
0
•
m
0
z
::0
-n
0
z
)>
::0
m
en -i r
OPHTHALMOLOGY
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Table 3. Ocular Findings in Cases 1 to 6 Case No.
2
3 4 5 6
Coloboma
Visual Acuity
Choroid/retina/optic nerve, OU; macula, 00
NCUSNM CUSM
25~
Incomplete iris, 00; iris with lens defect inferonasally, OS None
20/15 20/20
Orthophoric
-2.00 + 1.50 X 85 -1.50 + 1.00 X 90
20/20 20/15 20/30 4/200 NCUSNM NCUSNM
Orthophoric
-1.00 +.50 X 85 -.50+ 1.00 X 95 plano -6.00 + 2.00 X 138
LP 20/30
50~
Iris/choroid/retina/optic nerve, OS Iris, 00; choroid/retina/ optic nerve/macula, OU Iris/choroid/retina/optic nerve, 00
Alignment
45~
Refractive Error
RXT
LET
Orthophoric RET
+1.50 + 1.00 X 150
Other Pendular nystagmus; microphthalmos, 00; anisocoria; afferent pupil defect, 00
Microphthalmos OS Bilateral microphthalmos, pendular nystagmus, inferonasal lens opacity Microphthalmos, 00
OU = both eyes; 00 = right eye; NCUSNM = not central, unsteady, and not maintained; CUSM = central, unsteady, and maintained; RXT = right exotropia; OS = left eye; LET = lett esotropia; LP = light perception; RET = right esotropia.
and one with a peripheral, nonprogressive cataract. Nys tagmus, presumably due to poor vision, was present in two cases.
DISCUSSION Ocular colobomata were found to be present in 54 of 10,850 (0.05%) patients followed at the University of Wisconsin Pediatric Eye Clinic. Six (11%) ofthese patients were believed to exhibit findings typical of CHARGE syndrome. In view of the significant systemic abnormal ities associated with CHARGE and the possibility that patients with colobomata may have CHARGE, all patients with an ocular coloboma should be carefully evaluated for the presence of this condition. The mnemonic CHARGE was first suggested in 1981 by Pagon and co-workers2 for the strikingly similar pattern of associated anomalies they reported in 21 patients with normal karyotypes. Hittner and co-workers3 and Hall4 had previously reported 10 and 17 cases, respectively, which displayed a similar constellation of anomalies with normal chromosomes. In fact, in retrospect, several other authors had described small series of patients, some of whom showed many of these same nonrandomly occur ring anomalies. 5- 12 The six findings responsible for the name are Colo boma, Heart defects, Atresia of the choanae, Ret~ded growth and development, Genital hypoplasia, -and ~ar anomalies and/or hearing loss. Over the years, these cat egories have been better defined, and other associated anomalies have been added (Table 1). Typical colobomata are those that arise from failure of 1616
the embryologic fissure of the optic cup to close. Normal closure occurs between the fifth and sixth weeks of ges tation, and proceeds proximally and distally from the midpoint of the fissure. 1•3 Failure of closure can lead to defects of the optic nerve, sclera, choroid, retina, ciliary body, and/or iris inferiorly (Figs 1, 2). Any location other than inferior would constitute an atypical coloboma and is not consistent with this mechanism of formation. Mi crophthalmos is not unusual in association with colo bomatous defects, where globe size can range from normal to clinical anophthalmos. 13 Visual function is variable, but usually good acuity is preserved unless the macula or optic nerve are involved. In patients with CHARGE syndrome, colobomata are usually bilateral and somewhat asymmetric, but often are only unilateral. 3•7 •8 All varieties oftypical coloboma have been reported, 14 including clinical anophthalmos. 2 •10 The congenital heart defects seen in these patients are varied; the most common being atrial and ventricular septal defects, tetralogy of Fallot, patent ductus arteriosus, and pulmonary stenosis. 2•7 • 15 Unilateral or bilateral atresia of the choanae is an in frequently occurring developmental anomaly caused by membranous and/or bony obstruction of the posterior nasal choanae. Though Pagon and co-workers2 and Hall4 reported a high frequency of this defect, our series and others have had few or no patients with this finding. 14• 15 This discrepancy reflects the bias ofascertainment in those studies which used choana! atresia as a criterion for se lection, and thus shows a greater number of patients with this defect. Choana! stenosis has also been reported in CHARGE 14 and may occur more frequently than reported because of the inability to easily examine this structure. Mental retardation is a common finding, though vari
CHESTLER AND FRANCE
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CHARGE SYNDROME
Fig 2. Typical inferior iris coloboma.
Fig 1. Large inferior chorioretinal coloboma including optic nerve and macula.
able; ranging from profound to mild. Individuals living independently and functioning well with low-normal in telligence have been reported. 14 ·16 Retarded growth is another common feature. Pagan and co-workers 2 found only 2 of 20 patients at less than the tenth percentile for birth weight, but, in most, growth dropped below the third percentile during the first 6 months of life. Genital hypoplasia is most commonly manifested as microphallus, cryptorchidism, and/or hypospadias.2.7 This criterion for selection has included primarily male pa tients, but Davenport and co-workers 14 report two female patients with labial hypoplasia. 14 Hypogonadotropic hy pogonadism also has been reported. 2• 14 A variety ofexternal ear malformations can be seen, 2•3• 17 but Davenport and co-workers 18 describe a specific set of external ear features which they believe are distinctive enough to make a presumptive diagnosis of CHARGE syndrome. Case 4 in our series shows the most striking of these features: a triangular-shaped concha (Fig 3). Thelin and associates 19 also describe a characteristic wedge-shaped audiogram secondary to progressive, mixed conductive, and sensorineural hearing loss, though others have described a primarily sensorineural hearing loss. 2 Degree of hearing loss ranged from mild to profound. Additional associated malformations include unilateral Vllth nerve palsy/-4·15 facial asymmetry, 2• 14 cleft pal ate,2·4·7· 14 congenital pharyngeal incoordination and/or swallowing problems, 2·3 short fifth fingers and polysyn dactaly,4·14·15 tracheoesophageal fistula or esophageal atresia, 2.4· 10 and urinary tract abnormalities. 3•10·14
Fig 3. Left ear of case 4. Notice the triangular-shaped concha. The ear is short and wide.
The original criteria for the diagnosis of CHARGE as sociation, as outlined by Pagan and co-workers, 2 included those patients with coloboma or choana! atresia, or both, and a total of at least four of the seven features designated by the acronym (they counted retarded growth and re tarded development as two separate features). According to these criteria, five of our six patients may be designated as having CHARGE syndrome. Case 3, despite having four separate features of CHARGE syndrome, does not fit these criteria because of the absence ofboth coloboma and choana! atresia. He is of interest, though, because he is the monozygotic twin of case 2 who does fit the criteria. We believe he represents variable expression of the syn drome, as in other familial cases reported in the literature, in which not all affected family members necessarily con formed to the strict diagnostic criteria. 20 There has been only one other case of CHARGE syndrome occurring in monozygotic twins reported in the literature. Levin and co-workers,21 in 1973, described a set of monozygotic twins with congenital heart disease who in retrospect fit the criteria for CHARGE syndrome. 1617
OPHTHALMOLOGY
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DECEMBER 1988
The specific etiology for CHARGE syndrome remains unknown. Warburg 15 suggests the syndrome is caused by a derangement in migration of neural crest cells and cau dad presumptive mesodermal cells between the fifth and sixth weeks of gestation. The majority of recorded cases have been sporadic, though autosomal dominant, auto somal recessive, and X-linked recessive inheritance have been suggested by some familial cases. 2 •3•20•22 •23 Therefore, it may reflect a common phenotypic pathway for various genetic defects (genetic heterogeneity). Coloboma has been reported as a finding in abnor malities (trisomy and partial deletion or duplication) of chromosomes 4, 11, 13, 18, and 22. 1 But patients with complete or partial trisomy of chromosome 13 may also have other features in common with patients with CHARGE syndrome. 24•25 The Cat's Eye syndrome, which is caused by a dupli cation of the q 11 region of chromosome 22, shows similar features. 26 It is characterized by coloboma and an imper forate anus, but most patients also have multiple other CHARGE-like malformations, including urinary, cardiac, genital, and ear anomalies. 24•27 - 29 Coloboma and other CHARGE-like findings have also been reported in patients with long-arm deletions ofchro mosome 11. 30•31 In reviewing our cases of coloboma, we came across such a patient who phenotypically met the clinical criteria for CHARGE syndrome, but showed a deletion of the long arm of chromosome 11. Because of phenotypic similarities, chromosomal analysis is required in any CHARGE syndrome suspect. The VACTERL association consists ofY:ertebral, ~nal, ~ardiac, Iracheal, £sophageal, Renal, and _Limb anom alies with similarities to CHARGE syndrome, also in pa tients with normal chromosomesY Some investigators believe these two may be different expressions on a con tinuum of a single embryologic defect. 15 CHARGE syndrome anomalies also can be seen in thalidomide embryopathy, which, in addition to causing phocomelia, can cause a variety of other abnormalities, including ocular coloboma, heart disease, choanal atresia, facial palsy, ear anomalies, and hearing loss. 33 In reviewing our cases of ocular coloboma, we were somewhat surprised at the frequency of occurrence of CHARGE syndrome ( 11%). Even though this high prev alence may be skewed by our referral population, this syndrome is common enough that ophthalmologists should be aware ofit, since early identification and therapy for nonocular problems such as heart defects and hearing loss may be critical. Patients with ocular coloboma should be evaluated for other, perhaps silent, abnormalities, whether or not other obvious anomalies are present. In addition to surgical correction of various malformations and early training for the hearing impaired, newer hor monal therapies may be helpful in growth delay and gen ital hypoplasia. Nutritional supplementation may be re quired in cases of swallowing difficulties and/or cleft pal ate. Since the recurrence risk to normal parents is probably slightly higher than that of the general population, 2 and
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since some cases may be clearly heritable, evaluation by a medical geneticist and genetic counseling is advised. Long-term ophthalmic follow-up is necessary, because retinal detachment can occur as a complication of cho rioretinal coloboma. 34
REFERENCES 1. Pagon RA. Ocular coloboma. Surv Ophthalmol 1981; 25:223-36. 2. Pagon RA, Graham JM Jr, Zonana J, Yong S-L. Coloboma, congenital heart disease, and choanal atresia with multiple anomalies: CHARGE association. J Pediatr 1981; 99:223-7. 3. Hittner HM, Hirsch NJ, Kreh GM, Rudolph AJ. Colobomatous mi crophthalmia, heart disease, hearing loss, and mental retardation a syndrome. J Pediatr Ophthalmol Strabismus 1979; 16:122-8. 4. Hall BD. Choanal atresia and associated multiple anomalies. J Pediatr 1979; 95:395-8. 5. Angelman H. Syndrome of coloboma with multiple congenital abnor malities in infancy. Br Med J 1961; 1:1212-4. 6. Edwards JH, Young RB, Finlay HVL. Coloboma with multiple congenital anomalies [Letter). Br Med J 1961; 2:586-7. 7. HoCK, Kaufman RL, Podos SM. Ocular colobomata, cardiac defect, and other anomalies: a study of seven cases including two sibs. J Med Genet 1975; 12:289-93. 8. James PML, Karseras AG, Wybar KC. Systemic associations of uveal coloboma. Br J Ophthalmol1974; 58:917-21. 9. Lillquist K, Warburg M, Andersen SR. Hagerstrand I. Colobomata of the iris, ciliary body and choroid in an infant with oesophago-tracheal fistula and congenital heart defects: an unknown malformation com plex. Acta Paediatr Scand 1980; 69:427-30. 10. Sassani JW, Yanoff M. Anophthalmos in an infant with multiple con genital anomalies. Am J Ophthalmol1977; 83:43-8. 11. Say B, Berry J, Barber N. The Stickler syndrome (hereditary arthro ophthalmopathy). Clin Genet 1977; 12:179-82. 12. Stool SE, Kemper Bl. Choanal atresia and/or cardiac disease. Pediatrics 1968; 42:525-8. 13. Goldberg MF, McKusick VA. X-linked colobomatous microphthalmos and other congenital anomalies: a disorder resembling Lenz's dys morphogenetic syndrome. Am J Ophthalmol 1971; 71:1128-33. 14. Davenport SLH, Hefner MA, Mitchell JA. The spectrum of clinical features in CHARGE syndrome. Clin Genet 1986; 29:298-310. 15. Warburg M. Ocular coloboma and multiple congenital anomalies: the CHARGE association. Ophthalmic Paediatr Genet 1983; 2:189-99. 16. Goldson E, Smith AC, Stewart JM. The CHARGE association: How well can they do? Am J Dis Child 1986; 140:918-21. 17. Dobrowski JM, Grundfast KM, Rosenbaum KN, Zajtchuk JT. Otorhin olaryngic manifestations of CHARGE association. Otolaryngol Head Neck Surg 1985; 93:798-803. 18. Davenport SLH, Hefner MA, Thelin JW. CHARGE Syndrome. Part I. External ear anomalies. lnt J Pediatr Otorhinolaryngol1986; 12:137 43. 19. Thelin JW, Mitchell JA, Hefner MA, Davenport SLH. CHARGE Syn drome. Part II. Hearing loss. lnt J Pediatr Otorhinolaryngol1986; 12: 145-63. 20. Mitchell JA, Giangiacomo J, Hefner MA, et al. Dominant CHARGE association. Ophthalmic Paediatr Genet 1985; 6:31-6. 21. Levin DL, Muster AJ, Newfeld EA, Paul MH. Concordant aortic arch anomalies in monozygotic twins. J Pediatr 1973; 83:459-61. 22. Awrich PO, Flannery DB, Robertson L, Mamunes P. CHARGE asso ciation anomalies in siblings. Am J Hum Genet 1982; 34(Suppi):80A.
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23. Abruzzo MA, Erickson RP. A new syndrome of cleft palate associated with coloboma, hypospadias, deafness, short stature, and radial syn ostosis. J Med Genet 1977; 14:76-80.
29.
24. Lewandowski RC Jr, Yunis JJ. New chromosomal syndromes. Am J Dis Child 1975; 129:515-29.
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25. Noel B, Quack B, Rethore MO. Partial deletions and trisomies of chro mosome 13; mapping of bands associated with particular malfor mations. Clin Genet 1976; 9:593-602.
31.
partial trisomy of G chromosome. Arch Ophthalmol 1973; 90:287 91. Schachenmann G, Schmid W, Fraccaro M, et al. Chromosomes in coloboma and anal atresia. Lancet 1965; 2:290. Schinzel A, Auf der Maur P, Moser H. Partial deletion of long arm of chromosome 11 [del(11)(q23)]: Jacobsen syndrome: two new cases and review of the clinical findings. J Med Genet 1977; 14:438-44. Lee ML, Sciarra LJ. Partial monosomy of the long arm of chromosome 11 in a severely affected child. Ann Genet 1981; 24:51-3. Temtamy SA, Miller JD. Extending the scope of the VATER association: definition of the VATER syndrome. J Pediatr 1974; 85:345-9. Smithells RW. Defects and disabilities of thalidomide children. Br Med
26. McDermid HE, Duncan AMV, Brasch KR, et al. Characterization of the supernumerary chromosome in cat eye syndrome. Science 1986; 232:646-8.
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27. Bolinger MK, Soukup SW. Cat eye syndrome: partial trisomy 22 due to translocation in the mother. Am J Dis Child 1977; 131:893-7.
J 1973: 1:269-72. 34. Wang K, Hilton GF. Retinal detachment associated with coloboma of the choroid. Trans Am Ophthalmol Soc 1985; 83:49-62.
28. Petersen RA. Schmid-Fraccaro syndrome ("eat's eye" syndrome):
33.
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