Address correspondence to Luiz Miguel M. Parente, MD, *Clínica de Medicina Materno-Fetal. Av. Othon Gama D"eça 153/703. Florianópolis, SC 88010. Brazil. Ph: 55-482-24-0180; #Dept. of Pediatric Surgery. Hospital Infantil Joana de Gusmão. Florianópolis, SC. Brazil.¶Vanderbilt University, Dept. of Radiology

Synonyms: Hirschsprung"s disease, congenital intestinal aganglionosis¹. When the disease involves the ileum and, less often, the jejunum, it is called the Jirasek-Zuelzer-Wilson syndrome².

Prevalence: M8:F1³. Between 1-2:10,000 births^4,5. A family history is positive in 2.4 to 7.8%^6-11 of the cases, increasing to 21%⁸ when the cecum is involved. An autosomal-recessive form involves the entire bowel^12-14.

Definition: Total absence of ganglion cells in both the submucosal (Meissner"s) and myenteric (Auerbach"s) plexuses of the intestine, leading to functional obstruction proximal to the affected segment. The rectosigmoid colon and rectum are involved in 70 to 80 % of the cases. In the long-segment disease, variable lengths of bowel may be involved, up to aganglionosis of the entire intestine^4,5.

Etiology: Not known. A possible association with hyperthermia during the first trimester of pregnancy has been  reported¹.

Pathogenesis: Interruption of neuroblast migration within the muscle layers of the alimentary tract⁴. Alteration in the enteric neuron"s microenvironment leading to focal neuronal necrosis was suggested by some authors as an alternative hypothesis¹⁵. The normal-sized distal aganglionic intestine lacks effective peristalsis. Functional obstruction of the proximal normal intestine leads to bowel dilation, abdominal wall distention, failure of passing the first meconium stool within the first 24 to 48 hours of life, vomiting, diarrhea and neonatal perforation⁵.

Associated anomalies: Trisomy 21 in 10% of the cases; neurological abnormalities in 5%^5,16. Other reported associations include congenital heart defects (ventricular septal defects, transposition of the great arteries), imperforate anus¹⁶ and hypospadias¹.

Recurrence risk: The risk of recurrence for patient"s siblings or children is 6%¹⁶. In total or near-total intestinal aganglionosis, approximately 50% of the siblings are affected^12,14.

Differential diagnosis: The prenatal diagnosis of aganglionosis of the colon is extremely rare and was previously reported only twice^4,17. Both cases presented with dilated loops of bowel and polyhydramnios. These signs are not specific and the differential diagnosis should include: duodenal, jejunal and ileal atresia; chloride diarrhea and cystic fibrosis.

Prognosis: The mortality rate varies according to the extension of the aganglionic segment. It ranges between 5 and 15%⁵ for patients with the classical form, approximately 40%^11,18 for patients with total aganglionosis of the colon and almost 100%¹⁹ for those with total intestinal aganglionosis.

Management: Patients with aganglionosis of the colon are generally treated with a two-stage surgery. The first stage creates a diverting stoma to relieve the obstruction. The definitive surgery consists of a pull-through procedure, using one of several techniques (Swenson ileorectal anastomoses with total colectomy, Soave ileorectal pull-through²⁰, Martin"s anastomosis²¹, Boley pull-through²², Kimura technique²³), and is usually performed between the ages of 9 and 24 months³.

MESH Hirschsprung-Disease-diagnosis; Hirschsprung-Disease-genetics BDE 0192  MIM 249200  ICD9 751.3  CDC 751.310

Introduction

Aganglionosis of the colon is usually suspected during the neonatal period. In the rare instances where the disease manifested prenatally, the ultrasonographic picture was by no means specific^4,17. Nevertheless, aganglionosis of the colon should be part of the differential diagnosis of every obstetrical ultrasound suggesting proximal intestinal obstruction, because of prognostic implications. We report a case of total aganglionosis of the colon manifesting at 24 weeks of gestational age.

Case report

A G₃P₂ patient was referred for further evaluation at 24 weeks" gestation because of massive polyhydramnios. Her past medical history was unremarkable.

Ultrasound demonstrated a singleton pregnancy and confirmed the polyhydramnios. In addition, we found multiple small cystic images (up to 7 mm in diameter) filling the abdominal cavity of the fetus. Peristalsis was present; therefore, we concluded that the images represented bowel. The diagnostic impression was that of intestinal obstruction.

The patient complained of abdominal cramps, and a therapeutic amniocentesis was performed, obtaining 800 ml of clear amniotic fluid. The patient was discharged home on oral tocolysis with terbutaline and oriented to return for follow-up in one week.

On the next visit, the loops of bowel were massively dilated (fig. 1) and the fluid had reaccumulated. Several therapeutic amniocenteses throughout gestation were necessary in order to relieve the abdominal pain and prevent premature labor. These were performed on a weekly basis, sometimes requiring the drainage of up to 2,300 ml of amniotic fluid in a single tap. Fetal well-being was concomitantly evaluated with the fetal biophysical profile.

At 35 weeks, the patient complained of diminished fetal movements. Fetal biophysical profile demonstrated a hypotonic fetus, no fetal and breathing movements, and a non-reactive non-stress test over a 30-minute period, even after sonic stimulation. A cesarean section was performed, delivering a 3,100 gram male fetus, with Apgar scores of 1, 3 and 7 at 1, 5 and 10 minutes, respectively.

Figure 1: Several views through the fetal abdomen, demonstrating the dilated loops of bowel and polyhydramnios in aganglionosis of the colon.

Postnatal course

At the neonatal intensive care unit, the neonate passed a highly mucoid, meconium-tinted stool. The abdomen was very distended; the bowel contour and peristalsis could be observed through the abdominal wall. A nasogastric tube was placed. The abdominal x-ray showed multiple distended loops of small bowel and calcifications in the left lower quadrant (fig. 2).

Figure 2: Plain x-ray of the fetal abdomen demonstrating multiple dilated loops of small bowel and calcifications in the left lower quadrant.

A rectal digital examination demonstrated bolus emission of a highly mucoid stool. The immediate neonatal period was complicated by metabolic acidosis and elevated leukocyte counts. A barium enema, performed 5 days after birth, demonstrated normal caliber colon with no evidence of a transition zone (fig. 3). Reflux was noted into the ileum. Given these findings, the diagnosis of colonic aganglionosis was considered. Multiple biopsies obtained during laparotomy confirmed aganglionosis up to the distal portion of the ileum. A diverting ileostomy was performed.

Figure 3: Barium enema demonstrating colon of normal caliber and reflux of contrast into the ileum. No transition zone is identified. 

Total parenteral nutrition was initiated. However, massive loss of fluid through the ileostomy began, leading to dehydration and, again, metabolic acidosis.  Biochemical analysis of the intestinal fluid  (Na=124mEq/ml; K=12mEq/ml; Cl=96mEq/ml; HCO₃=50mEq/ml; osmolarity=268; protein concentration=8g/dl) ruled out the hypothesis of chloride diarrhea. A complete screening for inborn metabolic errors, TORCH  infections and thyroid function proved normal. Fifteen days after surgery the neonate developed sepsis, convulsions, and increased the loss of fluid  through the ileostomy. Despite all diagnostic and therapeutic measures, the baby became unstable, dying one month later of sepsis.

Discussion

This is, to our knowledge, the third case of aganglionosis of the colon visualized prenatally by ultrasound (Table 1)^4,17. Another article reports an unsuccessful attempt to diagnose aganglionosis of the colon using amniography, ultrasound and amniotic fluid disaccharidase analyses, in a patient with three affected first- and second-degree relatives²⁴.

Since the large intestine absorbs most of the ingested water, distal bowel obstruction during prenatal life, as a rule, should not be accompanied by an increase in the amount of amniotic fluid. Fetuses with multiple dilated loops of bowel and polyhydramnios are more likely to have obstruction of the small intestine.  Aganglio­no­sis of the colon  is, classically, a diagnosis of the neonatal period, with the symptoms beginning usually after the first 24 hours of life. The present report documents the earliest manifestation of aganglionosis of the colon, in the 24^th week of gestation.

Table 1: Prenatal cases of aganglionosis of the colon. Review of the literature.

Embryology

Neuroblasts migrate between the layers of the developing alimentary tract during the 5^th to 12^th week of gestation to form the submucous and myenteric plexuses of Meissner and Auerbach. By the 7^th week they populate the small intestine and, by the 12^th week, the rectum²⁴.

Etiology

The etiology of aganglionosis of the colon is not known. Lipson reported a statistically significant incidence of hyperthermia during the first trimester of pregnancy in 40 cases of aganglionosis of the colon¹.

Pathogenesis

The most accepted mechanism of aganglionosis of the colon is the interruption of neuroblast migration within the muscle layers of the alimentary tract, between the 5^th and the 12^th week of development¹. Alteration in the enteric neuron"s microenvironment leading to focal neuronal necrosis was suggested by some authors as an alternative hypothesis¹⁵.

Whatever the mechanism, the normal-sized distal aganglionic intestine lacks effective peristalsis, leading to functional obstruction of the proximal normal intestine. This functional obstruction is followed by bowel dilation, abdominal wall distension, failure of passing the first meconium stool usually within the first 24 to 48 hours of life, vomiting, diarrhea and intestinal perforation⁵.

The mechanisms leading to the early manifestations during the prenatal period are not completely understood.

Diagnosis

The diagnosis of aganglionosis of the colon is, classically, a neonatal one. Ninety-four percent of the affected neonates fail to pass the first meconium stool within the first 24 to 48 hours of life. Since the prognosis is directly related to the early diagnosis and therapy, individuals must undergo a thorough evaluation as soon as the anomaly is suspected.

The two diagnostic modalities used to confirm the diagnosis are barium enema and rectal biopsy. Barium enema demonstrates the nondistended aganglionic bowel and a transition zone extending through the distended normal bowel in 90% of cases. Rectal biopsy is the modality of choice for most surgeons, yelding a diagnostic accuracy of at least 95%⁵.

The prenatal diagnosis of aganglionosis of the colon is the exception rather than the rule. In all cases reported in the literature, including the present one (Table 1), the sonographic picture was characterized by multiple dilated loops of bowel and polyhydramnios.

Table 2: Management of total colon aganglionosis

Differential diagnosis

The signs mentioned above are not specific for aganglionosis of the colon and may be found prenatally in the following disorders:

Duodenal atresia

Duodenal atresia is the most common type of congenital small-bowel obstruction. Associated anomalies include congenital heart disease, esophageal atresia, imperforate anus, small bowel atresias, biliary atresias, renal and vertebral anomalies. Approximately 25 to 30% of patients with duodenal atresia have trisomy 21. Duodenal atresia is classically identified prenatally by the association of the "double-bubble†sign and polyhydramnios. The double-bubble corresponds to the distended stomach and proximal duodenum²⁵.

Jejunal and ileal atresia

Jejunal and ileal atresias usually occur after an in utero vascular accident. The sonographic picture is that of several dilated loops of bowel, with strong peristaltic movements. Polyhydramnios is frequently observed  as the level of obstruction becomes higher^25,26. Close follow-up is recommended since intestinal perforation can occur. In this case, fetal ascites and sonographic changes related to meconium peritonitis may be observed.  For a detailed discussion, please refer to pages 7511-1-4.

Chloride diarrhea

Congenital chloride diarrhea is an autosomal recessive disorder characterized by absence of the chloride-bicarbonate ion-exchange pump in the distal ileum and colon. Disturbed active transport of substances in the intestines leads to in utero diarrhea, high amniotic fluid bilirubin and alpha-fetoprotein, and polyhydramnios. When the disease manifests in utero, the sonographic picture is the same as for jejunal or ileal obstruction (see above)^27,28. The neonatal period is characterized by profuse watery diarrhea, with a high chloride concentration in the stools (normal values for newborns: Na⁺=128-148 mEq/l; K⁺=5-7 mEq/l; Cl^-=93-112 mEq/l; Na⁺ + K⁺  Cl^-)²⁹. Dehydration, hypochloremia, hypokalemia, hyponatremic metabolic alkalosis and secondary hyperaldosteronism follow the diarrhea. Therapeutic measures, including the vigorous replacement of fluids and electrolytes, should begin promptly in the neonatal period, in order to avoid retarded physical and psychomotor growth, hypermineralization of the skeleton and severe damage to the kidneys²⁷.

Cystic fibrosis

Cystic fibrosis is an autosomal-recessive disorder involving the dysfunction of all exocrine glands. Abnormal mucous secretion makes the meconium abnormally thick and tenacious, causing a form of obstruction known as meconium ileus. The meconium tends to impact in the distal ileum with a normal jejunum and an empty colon. Polyhydramnios is a frequent associated finding^25,29. For a detailed discussion, please refer to pages 2770-1-4.

Anorectal malformations

Anorectal malformations include a spectrum of anomalies that have in common abnormalities of hindgut termination: imperforate anus, anal agenesis, anorectal agenesis and rectal atresia. They are associated with a high incidence of other anomalies. The most common are the VACTERL syndrome (vertebral, anal, cardiovascular, tracheoesophageal, renal, radial and limb malformations), the caudal regression syndrome and also other complex abnormalities of cloacal development²⁵ (cloacal dysgenesis and cloacal exstrophy^30,31). In some cases, ultrasound will reveal a dilated fetal colon. Since the obstruction is low, polyhydramnios is not expected. Caution should be exercised in making this diagnosis since the normal colon can be quite prominent late in pregnancy. The presence of a dilated V- or U-shaped segment of bowel in the fetal pelvis or lower abdomen is quite suggestive of the malformation³².

Associated anomalies

Associated anomalies include trisomy 21 in 10% of the cases; neurological abnormalities in 5%^5,16. Other reported associations include congenital heart defects (ventricular septal defects, transposition of the great arteries), imperforate anus in 3% of the cases¹⁶ and hypospadias¹.

Recurrence risk

The risk of recurrence for patient"s siblings or children is 6%¹⁶. In total or near-total intestinal aganglionosis, approximately 50% of the siblings are affected^12,14.

Prognosis

The mortality rate for affected infants with the classical form of aganglionosis of the colon is approximately 5 to 15%⁵.

Table 2 compares the experience of multiple centers in the management of total aganglionosis of the colon. Major complications include enterocolitis, heavy fluid and electrolyte loss from the proximal stoma after enterostomy, and sepsis. Overall, the mortality rate is approximately 40%^11,18 for the largest series.

Total intestinal aganglionosis has been considered uniformly fatal. A preliminary report by Ziegler et al.¹⁹ described an operative technique, called long segment small bowel myectomyotomy, which permitted the survival of a neonate with near-total small bowel aganglionosis, supporting ever-increasing amounts of enteral nutrition. 

Management

Patients with aganglionosis of the colon are generally treated with a two-stage surgery. The first stage creates a diverting stoma to relieve the obstruction. The identification of the transition zone between normal and compromised bowel is essential and should be done by frozen section histo­patho­logy³.

The definitive surgery consists of a pull-through procedure using one of several techniques (Swenson ileorectal anastomoses with total colectomy, Soave ileorectal pull-through²⁰, Martin"s anastomosis²¹, Boley pull-through²², Kimura technique²³). Surgery is performed between the ages of 9 and 24 months³.

References

1. Lipson A: Hirschsprung disease in the offspring of mothers exposed to hyperthermia during pregnancy. Am J Med Genet 29:117-24, 1988.

2. Senyüz OF, Büyükünal ND, Erdogan E, et al: Extensive intestinal aganglionosis. J Pediatr Surg 24:453-6, 1989.

3. Dykes EH, Guiney EJ: Total colonic aganglionosis. J Pediatr Gastr Nutr 8:129-32, 1989.

4. Vermesh M, Mayden KL, Confino E, et al: Prenatal sonographic diagnosis of Hirschsprung"s disease. J Ultrasound Med 5:37-9, 1986.

5. Blisard KS, Kleinman R: Hirschsprung"s disease: a clinical and pathologic overview. Hum Pathol 17:1189-91, 1986.

6. Bodian M, Carter CO: A familial study of Hirschsprung"s disease. Ann Hum Genet 26:261-77, 1963.

7. Gordon H, Torrington M, Lown JH, Cynes S: A genetical study of Hirschsprung"s disease. Afr Med J 40:720-1, 1966.

8. Kleinhaus S, Baley SJ, Sheran M, et al: Hirschsprung"s disease - a survey of the members of the surgical section of the American Academy of Pediatrics. J Pediatr Surg 14:588-97, 1979.

9. Leenders E, Sieber WK, Gindany Br, et al: Aganglionic megacolon in infancy. Surg Gynaecol Obstet 131:424-30, 1970.

10. Passarge E: The genetics of Hirschsprung"s disease. Evidence for heterogeneous etiology and a study of 63 families. N Engl J Med 276:138-143, 1967.

11. Ikeda K, Goto S: Diagnosis and treatment of Hirschsprung"s disease in Japan. An analysis of 1628 patients. Ann Surg 99:400-405, 1984.

12. Caniano DA, Ormsbee HSIII, Polito W, et al: Total intestinal aganglionosis. J Pediatr Surg 20:456-60, 1985.

13. Costil J: Forme familiale d"aganglionose totale avec absence de fibres nerveuses. Arch Fr Pediatr 40:781-83, 1983.

14. Mackinnon AE, Choen SJ: Total intestinal aganglionosis. Arch Dis Child 52:898-900, 1977.

15. Tam PKH, Lister J: Development profile of neuron-specific enolase in human gut and its implications in Hirschsprung"s disease. Gastroenterology 90:1901, 1986.

16. Buyse ML. Birth Defects Encyclopedia. Blackwell Scientific Publications, Cambridge, 1990, pp. 427-8.

17. Wrobleski D, Wesselhoeft C: Ultrasonic diagnosis of prenatal intestinal obstruction. J Pediatr Surg 14:598-600, 1979.

18. N-Fékété C, Ricour C, Martelli H, et al: Total colonic aganglionosis (with or without ileal involvement): a review of 27 cases. J Pediatr Surg 21:251-4, 1986.

19. Ziegler MM, Ross AJ III, Bishop HC. Total intestinal aganglionosis: a new technique for prolonged survival. J Pediatr Surg 22(1):82-3, 1987.

20. Soave F: A new surgical technique for treatment of Hirschsprung"s disease. Surgery 56:1007-14, 1964.

21. Martin LW: Surgical management of total colonic aganglionosis. Ann Surg 176:343-6, 1972.

22. Boley SJ: A new operative approach to total aganglionosis of the colon. Surg Gynecol Obstet 159:481-4, 1984.

23. Kimura K, Nishijima E, Muraji T, et al: A new surgical approach to extensive aganglionosis. J Pediatr Surg 16:840-3, 1981.

24. Jarmas AL, Weaver DD, Padilla LM, et al: Hirschsprung disease: etiologic implications of unsuccessful prenatal diagnosis. Am J Med Genet 16;163-7, 1983.

25. Jeanty P. Sonographic depiction of fetal neck and chest abnormalities. In: Fleischer AC, Romero R, Manning, et al. The Principles and Practice of Ultrasonography in Obstetrics and Gyneco