Three nerve plexuses innervate the intestine: the submucosal (Meissner) plexus, the myenteric (Auerbach) plexus (between the longitudinal and circular muscle layers), and the smaller mucosal plexus.

Normal motility is primarily under the control of intrinsic neurons. In the absence of extrinsic signals, bowel function remains adequate, owing to the complex reflexive architecture of the enteric nervous system (ENS). For this reason, the ENS is often referred to as the “second brain.” Intestinal smooth muscle contraction and relaxation are under the control of enteric ganglia. Most enteric nervous activation causes muscle relaxation, mediated by nitric oxide and other enteric neurotransmitters. Extrinsic neural afferents to the ENS contain cholinergic and adrenergic fibers. The cholinergic fibers generally cause contraction, whereas the adrenergic fibers mainly cause inhibition.

In patients with Hirschsprung disease, both myenteric and submucosal plexuses are absent. The anus is invariably affected, and aganglionosis continues proximally for a variable distance. In the absence of ENS reflexes, control of the intestinal smooth muscle is overwhelmingly extrinsic. The activity of both the cholinergic system and the adrenergic system is 2-3 times that of normal intestine. The cholinergic (excitatory) system is thought to predominate over the adrenergic (inhibitory) system, leading to an increase in smooth muscle tone. With the loss of the intrinsic enteric relaxing impulses, the increased muscle tone is unopposed. This phenomenon leads to an imbalance of smooth muscle contractility, uncoordinated peristalsis, and a functional obstruction.

Enteric ganglion cells are derived from the neural crest during embryonic development. In normal development, the neuroblasts are found in the esophagus by the fifth week of gestation, and they migrate to the small intestine by the seventh week and to the colon by the twelfth week. [3] One possible etiology of Hirschsprung disease is the arrest of aboral neuroblast migration. Alternatively, although normal cell migration may occur, neuroblasts may be subject to apoptosis, failure of proliferation, or improper differentiation within the affected distal intestinal segment. Fibronectin, laminin, neural cell adhesion molecule (NCAM), and neurotrophic factors present in the intestinal stroma are necessary for normal enteric ganglion development, whereas their absence or dysfunction may also have a role in the etiology of Hirschsprung disease. [4, 5, 6]

Investigators have also identified several genes whose improper expression results in a Hirschsprung disease phenotype. Genome-wide association studies (GWAS) in Europeans and Asians have identified three common disease-susceptibility variants at the RET, SEMA3, and NRG1 loci. [7] Rs80227144 is a low-frequency variant of SEMA3 that has been associated with Europeans, and a conditional analysis indicates that rs9282834, low-frequency missense variant encoding RETp.Asp489Asn, is specific to Asians. [7]

The RET protooncogene has been implicated in several studies of Hirschsprung pathogenesis.

So and colleagues discovered that rare variants of RET were associated with more severe phenotypes among Chinese Hirschsprung patients. [8] Leon and colleagues determined that sporadic RET coding sequence mutations in Hirschsprung patients resulted in protein truncations that would deter cell membrane translocation and anchoring. [9]

Qin and colleagues performed microarray analyses of aganglionic colon and normal tissue; they discovered 622 genes with anomalous expression in the aganglionic tissue, and myenteric HAND2 expression was significantly attenuated. [10]

In a comparison of gene expression among normal and aganglionic colon, Chen and colleagues determined that overexpression of DVL1 and DVL3 genes was associated with the Hirschsprung phenotype. [11]

In a review, Butler Tjaden and colleagues reported that mutations in the genes, RET, GDNF, GFRα1, NRTN, EDNRB, ET3, ZFHX1B, PHOX2b, SOX10, and SHH are present in approximately 50% of Hirschsprung disease patients. [12]

These studies indicate the complexity of Hirschsprung pathogenesis. Ongoing studies of genetic and environmental factors will continue to elucidate this problematic disease in the future.

Although enteric ganglion cells are the primary pathogenic entity in Hirschsprung disease, some studies suggest that other cell types may also be implicated. [13, 14, 15,16, 17] When extrinsically stimulated, smooth muscle cells in aganglionic colon are electrically inactive. [13] Furthermore, interstitial cells of Cajal, pacemaker cells connecting enteric nerves and intestinal smooth muscle, have also been postulated as an important contributing factor. [14, 15, 16] These findings suggests that Hirschsprung pathophysiology is not limited to cells normally present within the enteric ganglia, alone.