CHARGE and Esophageal
Atresia
By M. Kutiyanawala, R.K.H. Wyse, R.J. Brereton, L. Spitz, E.M. Kiely, D. Drake, and K. Blake London, England 0 CHARGE association was diagnosed in 61 infants, 20 of whom died, mainly during the first 2 years of life. Esophageal atresia and/or tracheoesophageal fistula were present in 10 neonates. Axial skeletal anomalies occurred in 7 of the 10, but none had preaxial limb defects typical of the VATER association. All had major cardiac anomalies, predominantly tetralogy of Fallot. The majority of patients had primary repair of the esophagus. The postoperative course was stormy in all patients, with a high incidence of complications and 70% died. The recognition of features of the CHARGE association is important because it has major prognostic and therapeutic implications. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Esophageal tula; CHARGE association.
atresia; tracheoesophageal
fis-
T
HE ASSOCIATION of colobomata with multiple congenital anomalies was first described by Angelman.’ In 1979, Hittner et al2 described a syndrome of colobomatous microphthalmia associated with heart disease, hearing loss, and mental retardation. Pagon et al3 described 21 patients with the CHARGE association (Coloboma, Heart disease, Atresia choanae, growth and developmental Retardation, Genital hypoplasia, Ear anomalies and deafness). The presence of esophageal atresia (EA) and/or tracheoesophageal fistula (TEF) in patients with the CHARGE association have been observed occasionally and the morbidity and mortality of affected patients have been considerable. We report our experience with 10 patients and endeavour to define the various problems encountered during their management. MATERIALS AND METHODS An attempt was made to identify all infants and children being treated for CHARGE association at this hospital. The computerized records of children with congenital heart defects were analyzed along with those of neonates treated mainly for EA. The records of children attending ophthalmological and plastic surgical clinics were analyzed. Details of the patients were compiled in a data base.
From the Departments of Surgety and Cardiology, The Hospitals for Sick Children and Institute of Child Health, London, England. Date accepted: November 27, 1990. Address reprint requests to R.J. Brerefon, MD, Department of Paediafric Surgery Institute of Child Health, 30 Guilford St, London WC1 IEH, England. Copyright o 1992 by W.B. Saunders Company 0022-3468/92/2705-0005$03.00/0
558
The criteria for diagnosis of CHARGE association required that patients should exhibit at least 4 of the major abnormalities listed by Pagon et aL3 RESULTS
The diagnostic criteria for CHARGE association were met by 61 infants and children (35 boys and 26 girls). EA and/or TEF were discovered in 10 patients, 7 of whom were boys. Complications during pregnancy were common (polyhydramnios [S], fetal distress [2], antepartum hemorrhage [l], pyrexia in third trimester [l], and intrauterine growth retardation [l]). Gestational age varied from 32 to 40 weeks (mean, 37.5) and recorded birth weight ranged from 1.59 to 3.6 kg. Resuscitation at birth, including endotracheal ventilation, was required by 5 of these neonates. One neonate had an H-type fistula divided by a combined cervicothoracic approach, but the other 9 underwent thoracotomy with primary repair in 8. Because of feeding difficulties 5 eventually had a gastrostomy. The anastomosis disrupted in 2 causing tension pneumothorax and there was a stormy postoperative course with severe pulmonary infection in 8. A severe anastomotic stricture developed in one and 2 were ventilator-dependent for several weeks. An additional neonate died at 3 weeks during attempts to reduce dependence on artificial ventilation and another required tracheostomy at the age of 6 weeks. Gastroesophageal reflux was detected in 6 who suffered recurrent attacks of aspiration pneumonia. Antireflux surgery was performed in 2 patients. The 9 patients with EA and the 1 patient with TEF had severe congenital heart disease, predominantly tetralogy of Fallot. A right-sided aortic arch was present in 3 patients. Death occurred in 7 of the 10 patients, 3 as neonates and 4 before the age of 1 year. Uncorrectable congenital heart disease was the cause of death in 3 infants and 1 died elsewhere during attempted balloon dilatation of pulmonary stenosis. Recurrent lung infections caused the death of 2 infants. Posterior choanal atresia or stenosis was present in 7 infants, unilateral in 5 and bilateral in 2 with marked cyanosis at birth. Retinal colobomata were present in 9 infants and 2 had colobomata of the iris. Vision was severely restricted in 4 infants but 2 had useful vision. The solitary long-term survivor has normal eyes.
Journalof Pediatric Surgery,
Vol 27,
No 5
(May), 1992: pp 558-560
ESOPHAGEAL
ATRESIA AND CHARGE ASSOCIATION
559
Deformities of the external ear were present in 9 infants and 2 of the 3 surviving beyond the age of 1 year had recurrent otitis media with conductive deafness. Sensorineural deafness was present in 4 infants. Of the 6 patients undergoing audiomitory, 2 had mild hearing loss, 2 had moderate hearing loss, and 2 were completely deaf. It was difficult to assess the growth and development in infants subjected to prolonged hospitalisation and numerous operations during the first few months of life but all of those surviving beyond the age of 6 months had some degree of growth retardation. Abnormalities of the axial skeleton, mainly hemivertebrae, were discovered in 7 infants but the preaxial limb deformities characteristic of the VATER association were not detected. All the boys had genital abnormalities. Micropenis was present in 7 and 6 had undescended testis. Renal abnormalities were present in 3 infants, 2 had facial palsy, and 1 had a cleft lip and palate. Chromosomal analysis was performed in 9 patients and the results were apparently normal in 8, whereas 1 had an unbalanced translocation between chromosomes 6 and 8.
DISCUSSION
TEF, gastroesophageal reflux, velopharyngeal incoordination, and facial palsy are important problems in a significant number of patients with features of the CHARGE association.?-‘” Affected infants are said to have a characteristic facial appearance with asymmetry of the face and eyes, malar hypoplasia, and retrognathia, giving the face a flattened and square appearance, with a long philtrum, anteverted nares, or prominant nasal columella.lJJ The external ears are characteristically low-set and lop-shaped or protruding.5 In association with EA, this facial appearance should prompt the surgeon to examine the infant for posterior choanal atresia or stenosis, cardiac anomalies, and microphthalmia or colobomata. In boys, undescended testis or micropenis may be pointers to the diagnosis.“,‘? Clinical suspicion of the CHARGE association should prompt further investigations such as fundoscopy for chorioretinal colobomata, echocardiography, and even computed tomography scanning for structural brain defects and temporal bone anomalies.“J4 Renal ultrasonography should be performed and, if available,
there may be a case for performing visual or auditory evoked responses.” Over half the infants are severely cyanosed at birth and require endotracheal intubation and resuscitation.‘.4,7 Passage of a nasoesophageal tube may be difficult or impossible in the presence of choanal atresia, which occurred in up to 20% of the present patients, so an oroesophageal tube may be necessary. The incidence of CHARGE association in infants with EA is unknown but may be in the region of 3%,‘J although it may be higher because of the high mortality rate of unrecognized affected infants in the first few weeks of life. Postoperative recovery was delayed and associated with major complications such as anastomotic leakage in 20%, gastroesophageal reflux in 60%, and almost universal pulmonary infection. Affected patients may be ventilator dependent for prolonged periods.’ Cardiac anomalies, particularly conotruncal and aortic arch anomalies,” are common in infants with both EA and CHARGE and the presence of a right-sided aortic arch may make access to the esophagus from a right thoracotomy difficult. Cardiac anomalies may be exceedingly complex and, short of heart and lung transplantation, may be uncorrectable in some patients.” A third of the present patients died during the first month and 60% died during the first year of life, whereas the initial survival rate of other infants in Waterston’s group C is now in the region of 70% to 75%.8J5 Only two patients survived beyond the age of 4 years. Whereas most recently treated infants with uncomplicated EA enjoy a virtually normal life,” severe handicaps occurred in both of the long-term survivors with CHARGE association. Short stature is one of the major manifestations of the CHARGE syndrome5,1h,” and occurred in all of the present patients surviving the first year of life. Substantial hearing loss is almost universal and severely restricted vision is common.13.1xDisorders of the central nervous system, agenesis of the corpus callosum, cerebellar hypoplasia, microcephaly, and arrhinencephalia frequently occur. “).lJSevere mental retardation is common and occurred in all but one of the longer-term survivors. Before embarking on treatment of the esophagus, full evaluation of these infants is necessary and some parents may elect for their infant not to receive aggressive treatment.‘]
REFERENCES I. Angelman tal abnormalities 2. Hittner
H: Syndrome of coloboma with multiple in infancy. Br Med J 1:1212-1214, 1961 HM,
Hirsch
NJ, Kreh
GM,
congeni-
et al: Colobomatous
microphthalmia, heart disease. hearing tion-A syndrome. J Pediatr Opthalmol 3. Pagon RA. Graham
JM. Zonana
loss, and mental retarda16:122-128, 1979 J. et al: Coloboma,
congeni-
560
tal heart disease, and choanal atresia with multiple anomalies, CHARGE association. .I Pediatr 99:223-227, 1981 4. Koletzko B, Majewski F: Congenital anomalies in patients with choanal atresia: CHARGE association. Eur J Pediatr 142:271275,1984 5. Davenport SLH, Hefner MA, Mitchell JA: The spectrum of clinical features in CHARGE syndrome. Clin Genet 29:298-310, 1986 6. Lillquist K, Warburg M, Andersen SRY, et al: Colobomata of the iris, ciliary body and choroid in an infant with oesophagotracheal fistula and congenital heart defects. An unknown malformation complex. Acta Paediatr Stand 69:427-430.1980 7. Valente A, Brereton RJ: Esophageal atresia and the CHARGE association. Pediatr Surg Int 2:93-94, 1987 8. Chittmittrapap S, Spitz L, Kiely EM, et al: Oesophageal atresia and associated anomalies. Arch Dis Child 64:364-368, 1984 9. Lin AE, Chin AJ, Devine W, et al: The pattern of cardiovascular malformation in the CHARGE association. Am J Dis Child 141:1010-1013,1987 10. Peters H, Pontz BF: Klinisches bild und verlauf von kindern mit CHARGE association. Monatsschr Kinderheilkd 136:690-693, 1988
KUTIYANAWALA
ET AL
11. Blake KD, Russell-Eggitt IM, Morgan DW, et al: Who’s in charge? Multidisciplinary management of patients with the CHARGE association. Arch Dis Child 65:217-223,199O 12. Oley CA, Baraitser M, Grant DB: A reappraisal of the CHARGE association. J Med Genet 25:147-156,1988 13. Chestler RJ, France TD: Ocular findings in CHARGE syndrome: Six case reports and a review. Ophthalmology 95:16131619,1988 14. Curatolo P, Libutti G, Brinchi V: Infantile spasms and the CHARGE association. Dev Med Child Neurol2.5:367-369, 1983 15. Spitz L, Kiely E, Brereton RJ: Esophageal atresia: Five years experience with 148 cases. J Pediatr Surg 22:103-108,1987 16. Goldson E, Smith AC, Stewart JM: The CHARGE association. How well can they do? Am J Dis Child 140:918-921,1986 17. August GP, Rosenbaum KN, Friendly D, et al: Hypopituatarism and the CHARGE association. J Pediatr 103:424-425,1983 18. Thelin JW, Mitchell JA, Hefner MA, et al: CHARGE syndrome: Part II. Hearing loss. J Pediatr Otolaryngol 12:145-163, 1986
Atresia
By M. Kutiyanawala, R.K.H. Wyse, R.J. Brereton, L. Spitz, E.M. Kiely, D. Drake, and K. Blake London, England 0 CHARGE association was diagnosed in 61 infants, 20 of whom died, mainly during the first 2 years of life. Esophageal atresia and/or tracheoesophageal fistula were present in 10 neonates. Axial skeletal anomalies occurred in 7 of the 10, but none had preaxial limb defects typical of the VATER association. All had major cardiac anomalies, predominantly tetralogy of Fallot. The majority of patients had primary repair of the esophagus. The postoperative course was stormy in all patients, with a high incidence of complications and 70% died. The recognition of features of the CHARGE association is important because it has major prognostic and therapeutic implications. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Esophageal tula; CHARGE association.
atresia; tracheoesophageal
fis-
T
HE ASSOCIATION of colobomata with multiple congenital anomalies was first described by Angelman.’ In 1979, Hittner et al2 described a syndrome of colobomatous microphthalmia associated with heart disease, hearing loss, and mental retardation. Pagon et al3 described 21 patients with the CHARGE association (Coloboma, Heart disease, Atresia choanae, growth and developmental Retardation, Genital hypoplasia, Ear anomalies and deafness). The presence of esophageal atresia (EA) and/or tracheoesophageal fistula (TEF) in patients with the CHARGE association have been observed occasionally and the morbidity and mortality of affected patients have been considerable. We report our experience with 10 patients and endeavour to define the various problems encountered during their management. MATERIALS AND METHODS An attempt was made to identify all infants and children being treated for CHARGE association at this hospital. The computerized records of children with congenital heart defects were analyzed along with those of neonates treated mainly for EA. The records of children attending ophthalmological and plastic surgical clinics were analyzed. Details of the patients were compiled in a data base.
From the Departments of Surgety and Cardiology, The Hospitals for Sick Children and Institute of Child Health, London, England. Date accepted: November 27, 1990. Address reprint requests to R.J. Brerefon, MD, Department of Paediafric Surgery Institute of Child Health, 30 Guilford St, London WC1 IEH, England. Copyright o 1992 by W.B. Saunders Company 0022-3468/92/2705-0005$03.00/0
558
The criteria for diagnosis of CHARGE association required that patients should exhibit at least 4 of the major abnormalities listed by Pagon et aL3 RESULTS
The diagnostic criteria for CHARGE association were met by 61 infants and children (35 boys and 26 girls). EA and/or TEF were discovered in 10 patients, 7 of whom were boys. Complications during pregnancy were common (polyhydramnios [S], fetal distress [2], antepartum hemorrhage [l], pyrexia in third trimester [l], and intrauterine growth retardation [l]). Gestational age varied from 32 to 40 weeks (mean, 37.5) and recorded birth weight ranged from 1.59 to 3.6 kg. Resuscitation at birth, including endotracheal ventilation, was required by 5 of these neonates. One neonate had an H-type fistula divided by a combined cervicothoracic approach, but the other 9 underwent thoracotomy with primary repair in 8. Because of feeding difficulties 5 eventually had a gastrostomy. The anastomosis disrupted in 2 causing tension pneumothorax and there was a stormy postoperative course with severe pulmonary infection in 8. A severe anastomotic stricture developed in one and 2 were ventilator-dependent for several weeks. An additional neonate died at 3 weeks during attempts to reduce dependence on artificial ventilation and another required tracheostomy at the age of 6 weeks. Gastroesophageal reflux was detected in 6 who suffered recurrent attacks of aspiration pneumonia. Antireflux surgery was performed in 2 patients. The 9 patients with EA and the 1 patient with TEF had severe congenital heart disease, predominantly tetralogy of Fallot. A right-sided aortic arch was present in 3 patients. Death occurred in 7 of the 10 patients, 3 as neonates and 4 before the age of 1 year. Uncorrectable congenital heart disease was the cause of death in 3 infants and 1 died elsewhere during attempted balloon dilatation of pulmonary stenosis. Recurrent lung infections caused the death of 2 infants. Posterior choanal atresia or stenosis was present in 7 infants, unilateral in 5 and bilateral in 2 with marked cyanosis at birth. Retinal colobomata were present in 9 infants and 2 had colobomata of the iris. Vision was severely restricted in 4 infants but 2 had useful vision. The solitary long-term survivor has normal eyes.
Journalof Pediatric Surgery,
Vol 27,
No 5
(May), 1992: pp 558-560
ESOPHAGEAL
ATRESIA AND CHARGE ASSOCIATION
559
Deformities of the external ear were present in 9 infants and 2 of the 3 surviving beyond the age of 1 year had recurrent otitis media with conductive deafness. Sensorineural deafness was present in 4 infants. Of the 6 patients undergoing audiomitory, 2 had mild hearing loss, 2 had moderate hearing loss, and 2 were completely deaf. It was difficult to assess the growth and development in infants subjected to prolonged hospitalisation and numerous operations during the first few months of life but all of those surviving beyond the age of 6 months had some degree of growth retardation. Abnormalities of the axial skeleton, mainly hemivertebrae, were discovered in 7 infants but the preaxial limb deformities characteristic of the VATER association were not detected. All the boys had genital abnormalities. Micropenis was present in 7 and 6 had undescended testis. Renal abnormalities were present in 3 infants, 2 had facial palsy, and 1 had a cleft lip and palate. Chromosomal analysis was performed in 9 patients and the results were apparently normal in 8, whereas 1 had an unbalanced translocation between chromosomes 6 and 8.
DISCUSSION
TEF, gastroesophageal reflux, velopharyngeal incoordination, and facial palsy are important problems in a significant number of patients with features of the CHARGE association.?-‘” Affected infants are said to have a characteristic facial appearance with asymmetry of the face and eyes, malar hypoplasia, and retrognathia, giving the face a flattened and square appearance, with a long philtrum, anteverted nares, or prominant nasal columella.lJJ The external ears are characteristically low-set and lop-shaped or protruding.5 In association with EA, this facial appearance should prompt the surgeon to examine the infant for posterior choanal atresia or stenosis, cardiac anomalies, and microphthalmia or colobomata. In boys, undescended testis or micropenis may be pointers to the diagnosis.“,‘? Clinical suspicion of the CHARGE association should prompt further investigations such as fundoscopy for chorioretinal colobomata, echocardiography, and even computed tomography scanning for structural brain defects and temporal bone anomalies.“J4 Renal ultrasonography should be performed and, if available,
there may be a case for performing visual or auditory evoked responses.” Over half the infants are severely cyanosed at birth and require endotracheal intubation and resuscitation.‘.4,7 Passage of a nasoesophageal tube may be difficult or impossible in the presence of choanal atresia, which occurred in up to 20% of the present patients, so an oroesophageal tube may be necessary. The incidence of CHARGE association in infants with EA is unknown but may be in the region of 3%,‘J although it may be higher because of the high mortality rate of unrecognized affected infants in the first few weeks of life. Postoperative recovery was delayed and associated with major complications such as anastomotic leakage in 20%, gastroesophageal reflux in 60%, and almost universal pulmonary infection. Affected patients may be ventilator dependent for prolonged periods.’ Cardiac anomalies, particularly conotruncal and aortic arch anomalies,” are common in infants with both EA and CHARGE and the presence of a right-sided aortic arch may make access to the esophagus from a right thoracotomy difficult. Cardiac anomalies may be exceedingly complex and, short of heart and lung transplantation, may be uncorrectable in some patients.” A third of the present patients died during the first month and 60% died during the first year of life, whereas the initial survival rate of other infants in Waterston’s group C is now in the region of 70% to 75%.8J5 Only two patients survived beyond the age of 4 years. Whereas most recently treated infants with uncomplicated EA enjoy a virtually normal life,” severe handicaps occurred in both of the long-term survivors with CHARGE association. Short stature is one of the major manifestations of the CHARGE syndrome5,1h,” and occurred in all of the present patients surviving the first year of life. Substantial hearing loss is almost universal and severely restricted vision is common.13.1xDisorders of the central nervous system, agenesis of the corpus callosum, cerebellar hypoplasia, microcephaly, and arrhinencephalia frequently occur. “).lJSevere mental retardation is common and occurred in all but one of the longer-term survivors. Before embarking on treatment of the esophagus, full evaluation of these infants is necessary and some parents may elect for their infant not to receive aggressive treatment.‘]
REFERENCES I. Angelman tal abnormalities 2. Hittner
H: Syndrome of coloboma with multiple in infancy. Br Med J 1:1212-1214, 1961 HM,
Hirsch
NJ, Kreh
GM,
congeni-
et al: Colobomatous
microphthalmia, heart disease. hearing tion-A syndrome. J Pediatr Opthalmol 3. Pagon RA. Graham
JM. Zonana
loss, and mental retarda16:122-128, 1979 J. et al: Coloboma,
congeni-
560
tal heart disease, and choanal atresia with multiple anomalies, CHARGE association. .I Pediatr 99:223-227, 1981 4. Koletzko B, Majewski F: Congenital anomalies in patients with choanal atresia: CHARGE association. Eur J Pediatr 142:271275,1984 5. Davenport SLH, Hefner MA, Mitchell JA: The spectrum of clinical features in CHARGE syndrome. Clin Genet 29:298-310, 1986 6. Lillquist K, Warburg M, Andersen SRY, et al: Colobomata of the iris, ciliary body and choroid in an infant with oesophagotracheal fistula and congenital heart defects. An unknown malformation complex. Acta Paediatr Stand 69:427-430.1980 7. Valente A, Brereton RJ: Esophageal atresia and the CHARGE association. Pediatr Surg Int 2:93-94, 1987 8. Chittmittrapap S, Spitz L, Kiely EM, et al: Oesophageal atresia and associated anomalies. Arch Dis Child 64:364-368, 1984 9. Lin AE, Chin AJ, Devine W, et al: The pattern of cardiovascular malformation in the CHARGE association. Am J Dis Child 141:1010-1013,1987 10. Peters H, Pontz BF: Klinisches bild und verlauf von kindern mit CHARGE association. Monatsschr Kinderheilkd 136:690-693, 1988
KUTIYANAWALA
ET AL
11. Blake KD, Russell-Eggitt IM, Morgan DW, et al: Who’s in charge? Multidisciplinary management of patients with the CHARGE association. Arch Dis Child 65:217-223,199O 12. Oley CA, Baraitser M, Grant DB: A reappraisal of the CHARGE association. J Med Genet 25:147-156,1988 13. Chestler RJ, France TD: Ocular findings in CHARGE syndrome: Six case reports and a review. Ophthalmology 95:16131619,1988 14. Curatolo P, Libutti G, Brinchi V: Infantile spasms and the CHARGE association. Dev Med Child Neurol2.5:367-369, 1983 15. Spitz L, Kiely E, Brereton RJ: Esophageal atresia: Five years experience with 148 cases. J Pediatr Surg 22:103-108,1987 16. Goldson E, Smith AC, Stewart JM: The CHARGE association. How well can they do? Am J Dis Child 140:918-921,1986 17. August GP, Rosenbaum KN, Friendly D, et al: Hypopituatarism and the CHARGE association. J Pediatr 103:424-425,1983 18. Thelin JW, Mitchell JA, Hefner MA, et al: CHARGE syndrome: Part II. Hearing loss. J Pediatr Otolaryngol 12:145-163, 1986
