Management of Hirschsprung's Disease in Children with Trisomy 21 Donna A. Caniano, MD, Daniel H. Teitelbaum, MD, Stephen J. Qualman, MD, Columbus,Ohio
Thirteen infants and children with trisomy 21 have been treated for Hirschsprung's disease since 1975. Clinical presentation of Hirschsprung's disease included constipation (five); neonatal intestinal obstruction (four); enterocolitis (three); and meconium plug syndrome (one). Additional associated congenital anomalies occurred in 10 patients, of which complex cardiac disease accounted for 25% of the defects. Seven children underwent definitive operation: Duhamel pull-through (four); Soave pull-through (two); and anal myectomy (one). Satisfactory continence occurred in all but one child. Enterocolitis developed in seven patients (54%): two at diagnosis of Hirschsprung's disease; three after colostomy; and two after pull-through. Five children died (38%): one from enterocolitis, two from eardiorespiratory failure after recovery from enterocolitis, and two from end-stage cardiac disease. Children with trisomy 21 can safely undergo definitive operation for Hirschsprung's disease but are at high risk for developing enterocolitis and complications of associated cardiac disease.
lthough trisomy 21 has been considered to occur in A less than 5% of children with Hirschsprung's disease [1], more recent series [2-4] report a 10% to 15% association of these major congenital anomalies. We have previously emphasized that infants with trisomy 21 and Hirschsprung's disease are at increased risk of developing life-threatening enterocolitis with serious morbidity and prolonged hospitalization [5]. However, information about the clinical presentation of Hirschsprung's disease, surgical options, and prognosis in patients with trisomy 21 remains poorly documented. Since 1975, 13 of 80 consecutive children treated for Hirschsprung's disease at our institution have been diagnosed with trisomy 21. This high incidence (16%) provides us with a unique opportunity to comprehensively assess the outcome of contemporary management of these challenging patients. PATIENTS AND METHODS The hospital and office records of all patients with trisomy 21 and Hirschsprung's disease treated at the Children's Hospital, Columbus, Ohio, from 1975 to 1988 were reviewed for age at diagnosis, sex, gestational age, clinical presentation, associated anomalies, chromosomal analysis, level of aganglionosis, operative management, complications, continence, and mortality. The diagnosis of enterocolitis was based on the clinical findings of temperature above 38~ abdominal distention, and fever
[6,71.
Fromthe Divisionof PediatricSurgery(DAC,DHT),the Department ofSurgery(DAC,DHT),and the DepartmentofPathology(SJQ),The OhioStateUniversityCollegeof Medicine,and the Children'sHospital (SJQ), Columbus,Ohio. Supported in part by Grant 75-050 from the Children'sHospital Research Foundation. Requests for reprints shouldbe addressedto DonnaA. Caniano, MD, Departmentof PediatricSurgery,Children'sHospital,700 Children's Drive,Columbus,Ohio43205. Manuscript submittedMay 24, 1989, revisedJuly 20, 1989,and acceptedAugust2, 1989. 402
RESULTS Patients: Eleven male and 2 female patients ranging from 1 day to 8 years of age comprised the study. Prematurity occurred in two infants (15%). Karyotypic analysis demonstrated 47 chromosomes in 12 cases and 46/47 mosaicism in 1. The level of aganglionosis was rectosigmold in 12 children and distal rectum in 1. Ten children (77%) had additional associated congenital anomalies: 9 with one other defect and 1 with the VACTERL syndrome. Anomalies in the nine patients included atrioventrieular canal (four); ventricular septal defect (two); duodenal atresia (one); duodenal stenosis (one); and congenital seizure disorder (one). The child with the VACTERL syndrome had duodenal atresia, atrioventricular canal, unilateral renal dysplasia, limb and vertebralanomalies, and anal atresia with rectoperineal fistula. Clinical presentation: Symptoms of Hirschsprung's disease were variable among the 13 children and included constipation (5, 38%); neonatal intestinal obstruction (4, 31%); enterocolitis (3, 23%); and meconium plug syndrome (1, 8%). The four newborns with intestinal obstruction were between 1 and 3 days of age; barium enema and rectal suction biopsy were diagnostic of
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Hirschsprung's disease in each case. The three infants with enterocolitis at diagnosis were 6, 11, and 22 days of age, respectively; fever, lethargy, abdominal distention, and diarrhea occurred in each patient. Two of these cases represent a delay in diagnosis. The 11-day-old infant had an abnormal stooling pattern from birth, which was treated by daily suppositories. The 22-day-old patient, with a gestational age of 32 weeks and birth weight of 1,800 g, had persistent abdominal distention and infrequent stools from birth. Barium enema only was utilized for diagnostic evaluation in the cases of enterocolitis. The newborn with meconium plug syndrome underwent a rectal suction biopsy prior to hospital discharge with the finding of aganglionosis. Presence of an associated gastrointestinal anomaly obscured the diagnosis of Hirschsprung's disease in two of the five children with constipation. After repair of duodenal obstruction in the neonatal period, one patient was treated with enemas and laxatives for several years. After an apparently satisfactory perineal anoplasty, the child with the VACTERL syndrome remained constipated and poorly responsive to enemas. Barium enema and rectal suction biopsy were performed in all patients with constipation. Operative management: Twelve children were treated by colostomy at diagnosis: sigmoid (10) and transverse (2). Early postoperative morbidity (Table I) occurred in five patients (42%), all with congenital heart disease: pneumonia (two); congestive heart failure (one); enterocolitis (one); and stomal retraction (one). Two weeks after a sigmoid colostomy performed at 3 days of age, an infant developed fever, abdominal distention, and diarrhea. Toxigenic Escherichia coli was recovered from stool cultures, and the patient responded to antibiotic treatment. The stomal retraction was noted within 3 weeks of colostomy placement in a neonate with enterocolitis at diagnosis; revision of the stoma was required. Late postoperative enterocolitis developed in two infants at 3 and 6 months of age, respectively. Nine children were candidates for definitive operation; however, parental refusal of a pull-through procedure occurred in two cases. Seven patients (54%) underwent a definitive operation: Duhamel pull-through (four); Soave pull-through (two); and anal myectomy (one). No early postoperative complications developed, but late morbidity was experienced by two children (29%). Six months after undergoing a Soave pull-through at another institution, a 3-year-old child was referred to our hospital with refractory enterocolitis. He was found to have a severe anal stricture that was unresponsive to dilatation and required a colostomy. His parents have declined a secondary pull-through operation. The other patient developed a small bowel obstruction 8 months after a Duhamel pull-through and underwent lysis of adhesions. Two years after the pull-through procedure, the same child had a single episode of Cryptosporidium enterocolitis from which he recovered. Continence: The six children who were considered to have adequate definitive operations were available for evaluation from 3 to 7 years after surgery. All patients are
TABLE I
Complications after Colostomy and Pull-Through Procedure Postoperative Complication
Colostomy (n = 12)
Pull-Through (n = 6)
Enterocolitis Sternal retraction Pneumonia Congestive heart failure
3 1 2 1
2 ----
toilet trained, have daytime bowel control, and wear underpants without soiling. Nighttime soiling and lack of spontaneous bowel movements were problematic in each child. Each patient is given a saline enema at least once or twice a week in order to achieve one spontaneous bowel movement daily. Enteroeolitis: One or more episodes of enterocolitis developed in seven patients (54%). Three neonates had enterocolitis at diagnosis of Hirschsprung's disease with recurrent disease following colostomy in one infant. Enterocolitis occurred after colostomy in two additional patients and following a Duhamel pull-through in one child and a Soave pull-through in another. Enterocyte-adherent organisms were documented in tissue specimens and tissue assays in 3 cases: toxigenic E. coli (two) and Cryptosporidium species (one). Mortality: Five children (38%) died. Cardiorespiratory failure from complex heart disease accounted for the deaths of two patients at 6 months and 8 years, respectively. Enterocolitis was the direct cause of death in one infant and was associated with the final illness of two children. A 9-week-old who had undergone a colostomy at 22 days of age for enterocolitis returned in a moribund state. Autopsy confirmed diffuse enterocolitis and perforation of the ascending colon. The other two infants, each with complex congenital heart disease, developed enterocolitis at 3 and 6 months of age; both recovered but succumbed during the same hospitalization to cardiac failure and aspiration pneumonia, respectively, COMMENTS The majority of children with Hirschsprung's disease can anticipate a satisfactory outcome [6], but as our series and others [7,8] demonstrate, patients with trisomy 21 have a less certain prognosis. For example, of the 80 cases of Hirschsprung's disease treated at our hospital between 1975 and 1985, the incidence of enterocolitis, postoperative morbidity, and mortality was highest in children with trisomy 21 [5]. Several observations can be made about the clinical course of these patients in order to elucidate the reasons for their high-risk status. First , additional associated anomalies occurred in more than three quarters of the children, of whom 25% had complex congenital heart disease. In contrast, children with Hirschsprung's disease and no chromosomal anomaly have less than a 20% incidence of associated anomalies and virtually no life-threatening defects [1,7]. Second, the diagnosis of Hirschsprung's disease was
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APRIL 1990
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CANIANOET AL
delayed in half of our patients, although an abnormal stooling pattern in the neonates and severe constipation in the infants and children were clearly present by history. A delay in diagnosis may be explained by preoccupation in treating the associated anomalies of infants with trisomy 21, particularly congenital heart disease. In addition, constipation, often attributed to hypotonia or hypothyroidism, is common in children with trisomy 21 [9]. The most serious aspect of the association of trisomy 21 and Hirschsprung's disease concerns enterocolitis. Of the 13 children in our series, enterocolitis caused the death of 1 infant, was associated with the final illnesses of 2 others, and resulted in prolonged hospitalization for 2 patients. Dysfunction of the immune system may underlie the cause of enterocolitis in trisomy 21. In children with trisomy 21, the structure and function of the thymus are abnormal, and there is a qualitative and quantitative deficiency of the T-cell system [10]. Clinically, enterocolitis must be suspected in an infant with trisomy 21 who has abnormal stooling with abdominal distention and should be anticipated in those with Hirschsprung's disease. Pediatricians and parents must be counseled about the signs of enterocolitis, because it may develop after placement of a colostomy or definitive pull-through. Decisions for a pull-through procedure require that each child be managed on an individual basis. Factors to be considered include the patient's overall developmental level, severity of congenital heart disease, and parental desires. O f the seven children who underwent definitive operations, six have satisfactory bowel continence but require regular enemas to alleviate nighttime soiling.
404
Most importantly, these children attend school and are continent of stool during the daytime.
The specialfeatures of Hirschsprung's disease in this group of infants are of particular interest because of the multiple associated malformations and their clinical relevance. REFERENCES 1. Swenson O, Sherman JO, Fisher JH. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8: 587-94. 2. Klein MD, Coran AG, Wesley JR, Drongowski RA. Hirschsprung's disease in the newborn. J Pediatr Surg 1984; 19: 370-4. 3. Polley TZ, Coran AG. Hirschsprung's disease in the newborn. Pediatr Surg Int 1986; 1: 80-3. 4. Harrison MW, Deitz DM, Campbell JR, Campbell TJ. Diagnosis and management of Hirschsprung's disease: a 25-year perspective. Am J Surg 1986; 152: 49-56. 5. Teitelbaum DH, Qualman SJ, Caniano DA. Hirschsprung's disease: identification of risk factors for enterocolitis. Ann Surg 1988; 207: 240-4. 6. Nixon HH. Hirschsprung's disease: progressin management and diagnosis. World J Surg 1985; 9: 189-202. 7. Grosfeld JL, Ballantine TVN, Csicsko JF. A critical evaluation of the Duhamel operation for Hirschsprung's disease. Arch Surg 1978; 113: 454-60. 8. Vane DW, GrosfeldJL. Hirschsprung's disease: experiencewith the Duhamel operationin 195 cases. Pediatr Surg Int 1986; 1: 95-9. 9. Leung AKC, Mui CY, Lau JT. Hirschsprung's disease and mongolism. J Natl Med Assoc 1986; 78: 443-6. 10. Levin S. The immune system and susceptibilityto infectionsin Down's syndrome. In: McCoy EE. Epstein CJ, eds. Ontology and immunology of Down syndrome. New York: Alan R. Liss, 1987: 143-162.
THE AMERICAN JOURNAL OF SURGERY VOLUME 159 APRIL 1990
Thirteen infants and children with trisomy 21 have been treated for Hirschsprung's disease since 1975. Clinical presentation of Hirschsprung's disease included constipation (five); neonatal intestinal obstruction (four); enterocolitis (three); and meconium plug syndrome (one). Additional associated congenital anomalies occurred in 10 patients, of which complex cardiac disease accounted for 25% of the defects. Seven children underwent definitive operation: Duhamel pull-through (four); Soave pull-through (two); and anal myectomy (one). Satisfactory continence occurred in all but one child. Enterocolitis developed in seven patients (54%): two at diagnosis of Hirschsprung's disease; three after colostomy; and two after pull-through. Five children died (38%): one from enterocolitis, two from eardiorespiratory failure after recovery from enterocolitis, and two from end-stage cardiac disease. Children with trisomy 21 can safely undergo definitive operation for Hirschsprung's disease but are at high risk for developing enterocolitis and complications of associated cardiac disease.
lthough trisomy 21 has been considered to occur in A less than 5% of children with Hirschsprung's disease [1], more recent series [2-4] report a 10% to 15% association of these major congenital anomalies. We have previously emphasized that infants with trisomy 21 and Hirschsprung's disease are at increased risk of developing life-threatening enterocolitis with serious morbidity and prolonged hospitalization [5]. However, information about the clinical presentation of Hirschsprung's disease, surgical options, and prognosis in patients with trisomy 21 remains poorly documented. Since 1975, 13 of 80 consecutive children treated for Hirschsprung's disease at our institution have been diagnosed with trisomy 21. This high incidence (16%) provides us with a unique opportunity to comprehensively assess the outcome of contemporary management of these challenging patients. PATIENTS AND METHODS The hospital and office records of all patients with trisomy 21 and Hirschsprung's disease treated at the Children's Hospital, Columbus, Ohio, from 1975 to 1988 were reviewed for age at diagnosis, sex, gestational age, clinical presentation, associated anomalies, chromosomal analysis, level of aganglionosis, operative management, complications, continence, and mortality. The diagnosis of enterocolitis was based on the clinical findings of temperature above 38~ abdominal distention, and fever
[6,71.
Fromthe Divisionof PediatricSurgery(DAC,DHT),the Department ofSurgery(DAC,DHT),and the DepartmentofPathology(SJQ),The OhioStateUniversityCollegeof Medicine,and the Children'sHospital (SJQ), Columbus,Ohio. Supported in part by Grant 75-050 from the Children'sHospital Research Foundation. Requests for reprints shouldbe addressedto DonnaA. Caniano, MD, Departmentof PediatricSurgery,Children'sHospital,700 Children's Drive,Columbus,Ohio43205. Manuscript submittedMay 24, 1989, revisedJuly 20, 1989,and acceptedAugust2, 1989. 402
RESULTS Patients: Eleven male and 2 female patients ranging from 1 day to 8 years of age comprised the study. Prematurity occurred in two infants (15%). Karyotypic analysis demonstrated 47 chromosomes in 12 cases and 46/47 mosaicism in 1. The level of aganglionosis was rectosigmold in 12 children and distal rectum in 1. Ten children (77%) had additional associated congenital anomalies: 9 with one other defect and 1 with the VACTERL syndrome. Anomalies in the nine patients included atrioventrieular canal (four); ventricular septal defect (two); duodenal atresia (one); duodenal stenosis (one); and congenital seizure disorder (one). The child with the VACTERL syndrome had duodenal atresia, atrioventricular canal, unilateral renal dysplasia, limb and vertebralanomalies, and anal atresia with rectoperineal fistula. Clinical presentation: Symptoms of Hirschsprung's disease were variable among the 13 children and included constipation (5, 38%); neonatal intestinal obstruction (4, 31%); enterocolitis (3, 23%); and meconium plug syndrome (1, 8%). The four newborns with intestinal obstruction were between 1 and 3 days of age; barium enema and rectal suction biopsy were diagnostic of
THE AMERICAN JOURNAL OF SURGERY VOLUME159 APRIL 1990
HIRSCHSPRUNG'S DISEASE AND TRISOMY 21
Hirschsprung's disease in each case. The three infants with enterocolitis at diagnosis were 6, 11, and 22 days of age, respectively; fever, lethargy, abdominal distention, and diarrhea occurred in each patient. Two of these cases represent a delay in diagnosis. The 11-day-old infant had an abnormal stooling pattern from birth, which was treated by daily suppositories. The 22-day-old patient, with a gestational age of 32 weeks and birth weight of 1,800 g, had persistent abdominal distention and infrequent stools from birth. Barium enema only was utilized for diagnostic evaluation in the cases of enterocolitis. The newborn with meconium plug syndrome underwent a rectal suction biopsy prior to hospital discharge with the finding of aganglionosis. Presence of an associated gastrointestinal anomaly obscured the diagnosis of Hirschsprung's disease in two of the five children with constipation. After repair of duodenal obstruction in the neonatal period, one patient was treated with enemas and laxatives for several years. After an apparently satisfactory perineal anoplasty, the child with the VACTERL syndrome remained constipated and poorly responsive to enemas. Barium enema and rectal suction biopsy were performed in all patients with constipation. Operative management: Twelve children were treated by colostomy at diagnosis: sigmoid (10) and transverse (2). Early postoperative morbidity (Table I) occurred in five patients (42%), all with congenital heart disease: pneumonia (two); congestive heart failure (one); enterocolitis (one); and stomal retraction (one). Two weeks after a sigmoid colostomy performed at 3 days of age, an infant developed fever, abdominal distention, and diarrhea. Toxigenic Escherichia coli was recovered from stool cultures, and the patient responded to antibiotic treatment. The stomal retraction was noted within 3 weeks of colostomy placement in a neonate with enterocolitis at diagnosis; revision of the stoma was required. Late postoperative enterocolitis developed in two infants at 3 and 6 months of age, respectively. Nine children were candidates for definitive operation; however, parental refusal of a pull-through procedure occurred in two cases. Seven patients (54%) underwent a definitive operation: Duhamel pull-through (four); Soave pull-through (two); and anal myectomy (one). No early postoperative complications developed, but late morbidity was experienced by two children (29%). Six months after undergoing a Soave pull-through at another institution, a 3-year-old child was referred to our hospital with refractory enterocolitis. He was found to have a severe anal stricture that was unresponsive to dilatation and required a colostomy. His parents have declined a secondary pull-through operation. The other patient developed a small bowel obstruction 8 months after a Duhamel pull-through and underwent lysis of adhesions. Two years after the pull-through procedure, the same child had a single episode of Cryptosporidium enterocolitis from which he recovered. Continence: The six children who were considered to have adequate definitive operations were available for evaluation from 3 to 7 years after surgery. All patients are
TABLE I
Complications after Colostomy and Pull-Through Procedure Postoperative Complication
Colostomy (n = 12)
Pull-Through (n = 6)
Enterocolitis Sternal retraction Pneumonia Congestive heart failure
3 1 2 1
2 ----
toilet trained, have daytime bowel control, and wear underpants without soiling. Nighttime soiling and lack of spontaneous bowel movements were problematic in each child. Each patient is given a saline enema at least once or twice a week in order to achieve one spontaneous bowel movement daily. Enteroeolitis: One or more episodes of enterocolitis developed in seven patients (54%). Three neonates had enterocolitis at diagnosis of Hirschsprung's disease with recurrent disease following colostomy in one infant. Enterocolitis occurred after colostomy in two additional patients and following a Duhamel pull-through in one child and a Soave pull-through in another. Enterocyte-adherent organisms were documented in tissue specimens and tissue assays in 3 cases: toxigenic E. coli (two) and Cryptosporidium species (one). Mortality: Five children (38%) died. Cardiorespiratory failure from complex heart disease accounted for the deaths of two patients at 6 months and 8 years, respectively. Enterocolitis was the direct cause of death in one infant and was associated with the final illness of two children. A 9-week-old who had undergone a colostomy at 22 days of age for enterocolitis returned in a moribund state. Autopsy confirmed diffuse enterocolitis and perforation of the ascending colon. The other two infants, each with complex congenital heart disease, developed enterocolitis at 3 and 6 months of age; both recovered but succumbed during the same hospitalization to cardiac failure and aspiration pneumonia, respectively, COMMENTS The majority of children with Hirschsprung's disease can anticipate a satisfactory outcome [6], but as our series and others [7,8] demonstrate, patients with trisomy 21 have a less certain prognosis. For example, of the 80 cases of Hirschsprung's disease treated at our hospital between 1975 and 1985, the incidence of enterocolitis, postoperative morbidity, and mortality was highest in children with trisomy 21 [5]. Several observations can be made about the clinical course of these patients in order to elucidate the reasons for their high-risk status. First , additional associated anomalies occurred in more than three quarters of the children, of whom 25% had complex congenital heart disease. In contrast, children with Hirschsprung's disease and no chromosomal anomaly have less than a 20% incidence of associated anomalies and virtually no life-threatening defects [1,7]. Second, the diagnosis of Hirschsprung's disease was
THE A M E R I C A N J O U R N A L O F S U R G E R Y
VOLUME 159
APRIL 1990
403
CANIANOET AL
delayed in half of our patients, although an abnormal stooling pattern in the neonates and severe constipation in the infants and children were clearly present by history. A delay in diagnosis may be explained by preoccupation in treating the associated anomalies of infants with trisomy 21, particularly congenital heart disease. In addition, constipation, often attributed to hypotonia or hypothyroidism, is common in children with trisomy 21 [9]. The most serious aspect of the association of trisomy 21 and Hirschsprung's disease concerns enterocolitis. Of the 13 children in our series, enterocolitis caused the death of 1 infant, was associated with the final illnesses of 2 others, and resulted in prolonged hospitalization for 2 patients. Dysfunction of the immune system may underlie the cause of enterocolitis in trisomy 21. In children with trisomy 21, the structure and function of the thymus are abnormal, and there is a qualitative and quantitative deficiency of the T-cell system [10]. Clinically, enterocolitis must be suspected in an infant with trisomy 21 who has abnormal stooling with abdominal distention and should be anticipated in those with Hirschsprung's disease. Pediatricians and parents must be counseled about the signs of enterocolitis, because it may develop after placement of a colostomy or definitive pull-through. Decisions for a pull-through procedure require that each child be managed on an individual basis. Factors to be considered include the patient's overall developmental level, severity of congenital heart disease, and parental desires. O f the seven children who underwent definitive operations, six have satisfactory bowel continence but require regular enemas to alleviate nighttime soiling.
404
Most importantly, these children attend school and are continent of stool during the daytime.
The specialfeatures of Hirschsprung's disease in this group of infants are of particular interest because of the multiple associated malformations and their clinical relevance. REFERENCES 1. Swenson O, Sherman JO, Fisher JH. Diagnosis of congenital megacolon: an analysis of 501 patients. J Pediatr Surg 1973; 8: 587-94. 2. Klein MD, Coran AG, Wesley JR, Drongowski RA. Hirschsprung's disease in the newborn. J Pediatr Surg 1984; 19: 370-4. 3. Polley TZ, Coran AG. Hirschsprung's disease in the newborn. Pediatr Surg Int 1986; 1: 80-3. 4. Harrison MW, Deitz DM, Campbell JR, Campbell TJ. Diagnosis and management of Hirschsprung's disease: a 25-year perspective. Am J Surg 1986; 152: 49-56. 5. Teitelbaum DH, Qualman SJ, Caniano DA. Hirschsprung's disease: identification of risk factors for enterocolitis. Ann Surg 1988; 207: 240-4. 6. Nixon HH. Hirschsprung's disease: progressin management and diagnosis. World J Surg 1985; 9: 189-202. 7. Grosfeld JL, Ballantine TVN, Csicsko JF. A critical evaluation of the Duhamel operation for Hirschsprung's disease. Arch Surg 1978; 113: 454-60. 8. Vane DW, GrosfeldJL. Hirschsprung's disease: experiencewith the Duhamel operationin 195 cases. Pediatr Surg Int 1986; 1: 95-9. 9. Leung AKC, Mui CY, Lau JT. Hirschsprung's disease and mongolism. J Natl Med Assoc 1986; 78: 443-6. 10. Levin S. The immune system and susceptibilityto infectionsin Down's syndrome. In: McCoy EE. Epstein CJ, eds. Ontology and immunology of Down syndrome. New York: Alan R. Liss, 1987: 143-162.
THE AMERICAN JOURNAL OF SURGERY VOLUME 159 APRIL 1990
