Hirschsprung's Disease


Although Hirschsprung's disease has been recognized for over 100 years, it is only within the past 3 decades that improved surgical management has been achieved and only within the past few years that an appreciation for the origin of this disease has developed. Over the past few years, significant insight into the etiology of Hirschsprung's disease has taken place. Recent refinements in the surgical techniques for Hirschsprung's disease have occurred. Included in these advances is the performance of the  endorectal pull-through in the newborn period. Others advances in our understanding of Hirschsprung's disease have occurred through detailed studies of patients with Hirschsprung's disease including those with Trisomy 21 syndrome, persistent stooling abnormalities after the pull-through and associated neuronal intestinal dysplasia (NID).

Genetic Deletion in Hirschsprung's Disease
Perhaps one of the most exciting developments in Hirschsprung's disease is the recent attempt at identifying its etiology. Several advances have recently been made in determining the genes associated with Hirschsprung's disease. It has long been appreciated that Hirschsprung's disease may affect more than one family member in 4 to 8% of cases [1] . Martucciello, et al found a deletion in the long arm of chromosome 10 that was associated with Hirschsprung's disease [2]. This child had long segment (total colonic Hirschsprung's disease) and no family history. Last year, further investigation by this group and others narrowed the location of this mutation between 10q11.2 and q21.2 ( Figure 1) [3, 4] .  In the work by Luo, et al the location of the Hirschsrpung's genetic abnormality overlaped the region of the RET proto-oncogene.  The RET proto-oncogene appears to play a major role in the development of the intestinal nervous system and its deletion is also found in patients with the multiple endocrine neoplasia type 2A (MEN 2A) [5] . This may explain why a few patients with Hirschsprung's disease also have MEN 2A [6] .

 

Etiology of Hirschsprung's disease
Several investigators have suggested that the development of Hirschsprung's disease is due to a lack of migrating nerve cells to develop. One study has recently examined neural cell adhesion molecules (NCAM) in Hirschsprung's disease.  Bowel containing ganglion cells (both in control patients and in those with Hirschsprung's disease) had a large amount of NCAM, whereas there was an absence of NCAM in the aganglionic segments [9]. NCAM is believed to be important in nerve cell migration to specific locations during embryogenesis [10] . One might speculate that a loss of NCAM may explain the developmental absence of ganglion cells in Hirschsprung's disease (Figure 2). Another intense area of investigation is the relation of Hirschsprung's disease to nitric oxide production. It has been well recognized for several years that the loss of ganglion cells in Hirschsprung's disease results in a loss of nerves  [11] .

Surgical Therapy
- Primary pull-through
With increasing awareness of Hirschsprung's disease by the pediatric community and easier accessibility to obtain a diagnosis with suction rectal biopsy, the diagnosis of Hirschsprung's disease is being made at a much earlier age [21] . As a result, one of the most significant changes in the management of Hirschsprung's disease is the performance of the pull-through procedure in the newborn period. This approach is in contrast to the previous approach of a colostomy during the newborn period with a subsequent pull-through at 9-12 months of life once the child had attained a weight of approximately 20 pounds [15] .  Initial success with an initial endorectal pull-through was first noted by So, et al in 1980 [17]. Cilley, et al reported on 15 neonates who underwent a one-stage endorectal pull-through [18*]. Ages at the time of surgery ranged from 2 to 52 days (mean 13 days) and no operative complications occurred. The technique is virtually identical to that performed in older children (Figure 3). All operations were performed within 24 hours of diagnosis and as early as 48 hours of age.

The Duhamel procedure is another approach now used in the neonatal period [19] . In this report, a primary Duhamel pull-through was performed in 22 infants whose ages ranged from 14 to 90 days (mean 44 days). Postoperative complications occurred in 18%, including 3 cases of enterocolitis and one case of a retained rectal spur. Kücükaydin, et al reported on their experience with the Swenson procedure in 10 neonates [20].  A primary pull-through was performed in 6 of these 10 infants with no postoperative complications. Unlike the previous two series, however, these operations included performance of a colostomy.

Limited surgery for Hirschsprung's disease
Anal myectomy has been performed as definitive surgery for low-segment Hirschsprung's disease.  A fair number of these patients, however, had persistent constipation requiring enemas and laxatives on a regular basis. Although the authors were satisfied with these results, most surgeons are reluctant to perform an anal myectomy because of the risk of leaving a significant amount of abnormal aganglionic bowel.

 

Stooling abnormalities following surgery
Another difficult area in Hirschsprung's disease is the care of the patient with persistent stooling abnormalities after a pull-through. Occasionally, the surgeon is faced with a child with persistent constipation or recurrent enterocolitis after their pull-through procedure. Because the frequency of these problems is fairly low, little has been written about the management of these children. Rectal biopsy shall be performed in the evaluation of the patient with persistent stooling problems after a pull-through. A diagnostic work-up for such patient is shown above. 

Trisomy 21
Another group of patients with Hirschsprung's disease that is particularly challenging to manage are those with Trisomy 21 (Down's Syndrome). The association of Trisomy 21 and Hirschsprung's disease has only recently been appreciated [27] . In a study by Quinn, et al, 13% of their patients with Hirschsprung's disease had Trisomy 21 [28] . Interestingly, the outcome of these patients was quite poor. Although a definitive pull-through was performed on 13 of these 17 patients, only one of 13 surviving patients had normal bowel function. Two of the patients had to revert back to a colostomy. These authors suggest that a definitive pull-through in a child with Trisomy 21 requires careful consideration.  These authors' results are somewhat in conflict with another previously published series on patients with Trisomy 21 and Hirschsprung's disease [27] . In this latter series, 6 of 13 patients with Trisomy 21 were deemed to be candidates for a definitive pull-through. Each of these children had a good result with daytime continence although nighttime incontinence did occur.

 

Enterocolitis of Hirschsprung's disease
Another difficult group of patients are those with Hirschsprung's associated enterocolitis (HEC). This entity can be difficult to differentiate from gastroenteritis or a child with an excessively spastic internal  anal sphincter.  An intestinal 'cut-off' sign (loss of rectal air approximately at the top of the pelvis on X-ray).

 

Neuronal Intestinal Dysplasia
Neuronal intestinal dysplasia (NID) is an unusual disorder of the gastrointestinal tract that may be related to Hirschsprung's disease.  Three basic forms of the disease are noted. These are: hyperganglionosis (giant ganglia) in Auerbach's (myenteric muscle) plexus; abnormal ganglia; or a combination of the two. All three of these forms may be seen with Hirschsprung's disease; and each of these may be localized or involve all or most of the intestinal tract. Investigators have noted the occurrence of Hirschsprung's disease in 20-75% of NID cases [26- 27,30] . The significance of NID as seen on pathologic examination As such, some surgeons rely predominately on the clinical presentation of constipation for planning any subsequent surgical intervention.

References

  1. Engum s, Petrites m, Rescorla f, Grosfeld j, Morrison a, Engles D. Familial Hirschsprung's Disease: 20 Cases in 12 Kindreds. J Pediatr Surg 1993;28(10):1286--1290.
  2. Martucciello g, Biocchi m, Dodero p,Lerone m, Cirillo ms, Puliti a, Gimelli g, Romeo g, Jassonni v. Total Colonic Aganglionosis Associated with Intersitial Deletion of the Long Arm of Chromosome 10. Ped Surg Int 1992;7:308--310.
    These investigators made the first association of a case with Hirschsprung's disease with a chromosomal deletion in the long arm of chromosome 10. This was a landmark paper in that it was the first to identify a chromosomal abnomality associated with Hirschsprung's disease
  3. Fewtrell ms, Tam pk, Thomson ah, Fitchett m, Currie j, Huson sm, Mulligan lm. Hirschsprung's Disease Associated with a Deletion of Chromosome 10 (q11.2q21.2): A Further Link with the Neurocristopathies_ J Med Genet 1994;31(4):325--327.
  4. Luo y, Ceccherini i, Pasini b,Matera i, Bicocchi mp. Barone v, Bocciardi r, Kaariainen h, Weber d, Devoto m. Close Linkage with the RET Protooncogene and Boundaries of Deletion Mutations in Autosomal Dominant Hirschsprung Disease. Hum Mol Genet 1993;2(11):1803--1808.
  5. Simpson n, Kidd k, Goodfellow p,McDermid h, Myers s, Kidd jr, Jackson ce, Duncan amv, Farrer la, Brasch k. Assignment of Multiple Endocrine Neoplasia Type 2A to Chromosome 10 by Linkage. Nature 1987;328:528--530.
  6. Decker, ra. Long-term follow-up of a large North American kindred with multiple endocrine neoplasia type 2A. Surgery 1992;112(6):1072--1073.
  7. Kobayashi h, O'Briain ds, Puri p. Lack of Expression of NADPH-Diaphorase and Neural Cell Adhesion Molecule (NCAM) in Colonic Muscle of Patients with Hirschsprung's Disease. J Pediatr Surg 1994;29(2):301--4.
    This study investigated the assoication of nitric oxide and NCAM in patients with Hirschsprung's disease. An absence of NCAM in aganglionic tissue strongly suggests that NCAM is needed for migrating ganglion cells to adhere and develop in the intestine. An local absence of NCAM may explain why ganglion cells fail to develop in that region of the bowel. The lack of nitric oxide appears to be a secondary manifestation due to a lack of ganglion cells and their non-adrenergic, non-cholinergic neurotransmitters.
  8. Tosney k, Watanabe m, Landmesser l. The Distribution of NCAM in the Chick Hind Limb During Azon Outgrowth and Synaptogenesis. Dev Biol 1986;114:437--452.
  9. Furness j, Costa m. Types of Nerves in the Enteric Nervous System. Neuroscience 1980;5:1--20.
  10. Kleinhaus s, Boley s, Sheran m. Hirschsprung's Disease - A Survey of the Members of the Surgical Section of the American Academy of Pediatrics. J Pediatr Surg 1979;12:588--597.
  11. So h, Schwartz d, Becker j, Daum f, Schneider k. Endorectal "Pull-Through" Without Preliminary Colostomy in Neonates with Hirschsprung's Disease. J Pediatr Surg 1980;15:470--471.
  12. Cilley re, Statter mb, Hirschl rb, Coran ag. Definitive Treatment of Hirschsprung's Disease in the Newborn with a One-Stage Procedure. Surgery 1994;115(5):551--6.
    This was an excellent review of 15 patients undergoing a one-stage surgery for Hirschsprung's disease in the neonatal period. Results are excellent and the approach is fairly unique compared to the standard approach of a colostomy in the newborn period followed by a definitive pull-through several months later.
  13. Samuel m, Freeman n. Primary Modified Duhamel Operation for Hirschsprung's Disease in Infants. Pediatr Surg Int 1994;9:61--63.
  14. Kücükaydin m, Okur h, Turan t, Icer m, Zorlu m, Kazez a. Swenson's Operation for Neonatal Hirschsprung's Disease. Eur J Surg 1993;159(9):487--489.
  15. Teitelbaum d, Qualman s, Caniano d. Hirschspurng's Disease: Identification of Risk Factors for Enterocolitis. Ann Surg 1987;207:10--14.
  16. Kimura k, Inomata y, Soper rt. Posterior sagittal rectal Myectomy for Persistent rectal achalasia after the Soave Procedure for Hirschsprung's Disease. J Pediatr Surg 1993;28(9):1200--1201.
  17. Caniano d, Teitelbaum d, Qualman s. Management of Hirschsprung's Disease in Children with Trisomy 21. Am J Surg 1990;159:402--404.
  18. Quinn fm, Surana r, Puri p. The Influence of Trisomy 21 on Outcome in Children with Hirschsprung's Disease. J Pediatr Surg 1994;29(6):781--783.
  19. Briner j, Oswald hw, Hirsig j, Lehner m. Neuronal Intestinal Dysplasia--Clinical and Histochemical Findings and its Association with Hirschsprung's Disease. Z Kinderchir 1986;41(5):282--286.

 

Suggested readings authored by the University of Michigan, Section of Pediatric Surgery

1.  van Leeuwen, K, Geiger, JD, Coran, AG, Barnett, J, Teitelbaum, DH: Stooling and manometric findings in Hirschsprung’s disease: Perineal vs. abdominal approaches. J Pediatr Surg 37(9):1321-1325, 2002.

2.  Teitelbaum, DH, Cilley, R, Sherman, NJ, Bliss, D, Uitvlugt, ND, Renaud, EJ, Kiristioglu, I, Bengstom, T, Coran, AG: A decade experience with the primary pull-through for Hirschsprung’s disease in the newborn period: A multi-center analysis of outcomes. Ann Surg 232(3):372-380, 2000.

3.  Coran, AG, Teitelbaum, DH: Recent advances in the management of Hirschsprung’s disease. Am J Surg 180:382-387, 2000.

4.  van Leeuwen, K, Teitelbaum, DH, Elhalaby, EA, Coran, AG: The long-term follow-up of redo-pullthrough procedures for Hirschsprung’s disease. J Pediatr Surg 35(6):829-834, 2000.

5.  Teitelbaum DH, Drongowski R, Chamberlain JN, Coran AG: Long-term stooling patterns in infants undergoing a primary endorectal pullthrough (ERPT) for Hirschsprung’s disease. J Pediatr Surg 32(7):1049-1053, 1997.

6.  Elhalaby EA, Teitelbaum DH, Coran AG, Heidelberger, KP: Enterocolitis Associated with Hirschsprung’s Disease: A Clinical Histopathologic Correlative Study. J Pediatr Surgery 30(7):1023-1027, 1995.

7.  Elhalaby EA, Coran AG, Blane CE, Hirschl RB, Teitelbaum DH: Enterocolitis Associated with Hirschsprung’s Disease: A Clinical-Radiological Characterization Based on 168 Patients. J Pediatr Surg 30(1):76-83, 1995.

8.  Elhalaby E, Coran AG, Blane C, Hirschl RB, Teitelbaum, DH: Enterocolitis Associated with Hirschsprung's Disease: A Clinical-Radiological Characterization Based on 168 Patients. J Ped Surg 30:76-83, 1995.

9.  Cilley RE, Statter MB, Hirschl RB, Coran AG: Definitive Treatment of Hirschsprung's Disease in the Newborn With a One-Stage Procedure. Surgery 115(5):551-556, 1994.

 

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