Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital disorder of intestinal motility affecting approximately 1 in 5,000 live births, with a 4:1 male predominance. No single underlying cause has been identified, with both sporadic and familial cases reported. Most often HSCR is an isolated finding, but 20% of cases are associated with a chromosomal abnormality or with other congenital anomalies of the cardiac, genitourinary, gastrointestinal, and/or nervous systems. Also, a variety of syndromes pose an increased risk of HSCR, including Down syndrome, multiple endocrine neoplasia type IIA, and congenital hypoventilation syndrome, among others. Most cases are linked to the RET receptor tyrosine kinase locus, and others to loci such as SEMA1 and NRG1. Nonmendelian inheritance operates, with the cumulative risk of disease proportional to the number of single nucleotide polymorphisms.The characteristic lack of enteric ganglia in myenteric and submucosal plexuses arises from a defect in neural crest cell migration during fetal development between the 5th and 12th weeks of gestation. The variable length of aganglionic bowel depends on the timing of the interrupted cell migration; the earlier it happens, the longer the affected segment of bowel. HSCR is categorized by how much bowel is aganglionic: HSCR commonly presents in the neonatal period, with 40% of patients symptomatic by 6 months of age. The neonate typically presents with passage of meconium delayed more than 48 hours after birth, abdominal distention, feeding intolerance, and/or bilious emesis. Highly suggestive physical examination findings include an empty rectal vault with explosive foul-smelling stool after rectal stimulation—the so-called squirt sign. In 5% of neonatal cases, bowel perforation is the presenting issue. Beyond early infancy, and the shorter the aganglionic segment, the clinical presentation is usually that of chronic constipation with fecal soiling that is often poorly responsive to laxative therapy. Other findings that support the diagnosis of HSCR include emesis, abdominal pain and/or distention, recurrent fecal impactions, and growth disturbances. Although less than 5% of cases first present in adolescence or even adulthood, HSCR, notably internal anal sphincter achalasia, should remain on the differential diagnosis for patients with chronic constipation.Prompt recognition and evaluation is essential to reduce the risk of Hirschsprung-associated enterocolitis (HAEC), which is the major cause of morbidity and carries a mortality rate of up to 10%. Its pathogenesis is multifactorial, with aganglionosis and obstruction resulting in bacterial translocation, reduced immunoglobulin A secretion, and white blood cell dysfunction, all predisposing to infection. HAEC can present variably, from a subtle onset with insidious abdominal pain and distention to dehydration, fever, and foul-smelling bloody diarrhea, to life-threatening septicemia and shock. Known risk factors for HAEC include delay in diagnosis beyond 1 week of age in a neonate and the presence of trisomy 21. Even postoperatively, after corrective surgery for HSCR, HAEC remains a risk, with an incidence of up to 40%. Clinically, the use of a 16-item HAEC scoring system improves early diagnosis and reduces mortality: diarrhea, poor peripheral perfusion, lethargy, and dilated bowel loops are most predictive. Prompt treatment is required with rectal irrigations, fluid resuscitation, and systemic antibiotics. An ongoing area of investigation is the gut microbiota: patients with HAEC seem to have a microbiota more limited than normal in its variety.Because the clinical presentation of HSCR usually includes signs and/or symptoms suggestive of obstruction, evaluation should be guided by concern for malrotation with volvulus and other obstructive etiologies. After an appropriate history and physical examination, the initial imaging modality is abdominal radiography to assess intestinal gas pattern. Once an acute abdomen is excluded, screening for HSCR is usually performed with either an unprepared water-soluble contrast enema or anorectal manometry (ARM). Suggestive findings on contrast enema include a transition zone with dilated bowel proximally, microcolon, and retention of contrast on postevacuation radiographs. At centers where the technology and interpretive expertise are available, ARM is the preferred screening tool because it does not involve radiation: a catheter with pressure sensors and a balloon tip is inserted into the rectum to measure the rectoanal inhibitory reflex, which is the reflex relaxation of the internal anal sphincter in response to rectal dilation. Absence of the rectoanal inhibitory reflex is suggestive of HSCR. Performance of ARM can require sedation with midazolam for a young child who cannot cooperate.Patients with a positive or equivocal screen should undergo gold standard testing with either rectal suction biopsy or, in an older child, full-thickness biopsy. Rectal suction biopsy, which can be performed at the bedside without sedation, requires a specialized rectal biopsy instrument that enables a syringe to create negative pressure to capture the mucosal specimen. The barrel is inserted into the anal canal, and biopsies are taken at the 2-, 3-, and 4-cm marks above the anal verge. Full-thickness biopsy requires general anesthesia in the operating room. Confirmatory diagnosis depends on the identification of aganglionosis and hypertrophic nerve fibers using hematoxylin and eosin stain, and increase in acetylcholinesterase-positive hypertrophic nerve fibers using acetylcholinesterase stain. Additional procedures to improve specificity and sensitivity include an assay for calretinin (its absence indicating aganglionosis) and measurement of nerve fiber trunk diameter (>40 µm indicating hypertrophy). Histopathological analysis by an experienced pathologist is imperative to identify conditions that clinically resemble HSCR but have ganglion cells present, including intestinal neuronal disorders (neuronal dysplasia, ganglioneuromatosis, and hypoganglionosis) and congenital smooth muscle cell disorders (megacystis microcolon intestinal hypoperistalsis syndrome).Preoperative management aims to optimize surgical outcomes by preventing enterocolitis and reducing colonic distention. Stabilization of the clinically septic patient involves hydration, broad spectrum antimicrobial coverage, and nil by mouth status. Serial rectal irrigation with 10 to 20 mL/kg of warm 0.9% sodium chloride solution decompresses the bowel and reduces the risk of enterocolitis.The primary aim of corrective surgery for HSCR is to remove the aganglionic segment and transition zone and to restore intestinal continuity. The currently used pull-through procedures (Swenson, Soave, or Duhamel) all involve resection with primary anastomosis proximal to the dentate line to avoid injury to the internal anal sphincter. In some cases, delayed anastomosis with formation of a diverting stoma is the first step. However, the surgical management of the 5% of patients with TCA often requires formation of a jejunostomy without resection of the aganglionic segment, in anticipation of likely autologous intestinal reconstruction. In the interim, myectomy-myotomy or lengthening procedures can be performed to enhance residual bowel function and reduce parenteral nutrition requirements.Although national standards of care are lacking, postoperative management should include regular follow-up by a multidisciplinary team to monitor for early and late complications. Patients are monitored for stricture of the anastomosis with obstructive symptoms, constipation, HAEC, failure to thrive, and fecal incontinence arising from dysfunctional bowel, sphincter, or anal canal injury, leading to perianal excoriation. Strictures can often be managed with a Hegar dilator, even with continued treatment at home by the parents along with rectal irrigations. Otherwise, an examination under anesthesia may be performed 30 days postoperatively with or without prophylactic botulinum toxin injection at the internal anal sphincter to reduce obstructive symptoms. Fortunately, fewer than 10% of cases require surgical revision. Constipation and associated fecal incontinence not related to stricture of the anastomosis can be managed with fiber, hydration, and/or laxative therapy, making timely toilet training possible. Unfortunately, because of the extensive resection required with TCA, enterocolitis and intestinal failure/short bowel syndrome are more prevalent postoperative complications.The overall future is bright for patients with HSCR. Our understanding of this disease has led to an expanding field of research into developing novel therapies with the goal of decreasing morbidity and mortality and increasing functional outcomes.We last published an In Brief on HSCR 15 or so years ago, and at that time I commented on the complexity of its genetics, with the hope that newer genetic techniques would bring more clarity and thus enable more exact counseling for affected families. But isolated HSCR seems to be multifactorial in its inheritance, resulting from the interplay of both genetic and environmental factors, making the likelihood of recurrence in a given family impossible to predict accurately, even knowing that the overall average is approximately 4%. As part of a multitude of syndromes involving pigmentary abnormalities (Waardenburg syndrome), endocrinopathies (multiple endocrine neoplasia type 2A), and the central nervous system (congenital central hypoventilation syndrome, Mowat-Wilson syndrome), HSCR follows an autosomal dominant pattern of inheritance, but with variable penetrance. It is also associated with syndromes having autosomal recessive inheritance (Bardet-Biedl syndrome, Smith-Lemli-Opitz syndrome) and with syndromes usually resulting from sporadic mutations (Pitt-Hopkins syndrome). And, of course, HSCR can be a feature of a chromosomal abnormality, as with trisomy 21.This heterogeneity of its inheritance suggests that in reality HSCR is not one disease but an end point of multiple different pathways.