A search for Hirschsprung disease in OMIM under the symbol HSCR reveals 12 entries covering both phenotypes and the specific genes involved. The phenotypes refer to HSCR1 (MIM 142623), largely comprising RET gene mutations; HSCR2 (MIM 600155), comprising EDNRB gene mutations; HSCR3 (MIM 600156), comprising a modifier on chromosome 21; and, congenital failure of autonomic control (MIM 209880). GenBank accession numbers: RET—AL022344, X12949, X15262, AJ243297; GDNF—L19063; EDNRB—D90402, AL139002; EDN3—J05081, AL035250; SOX10—AJ001183, AL031587; NTN—U78110; ECE-1—D43698, AL031005.
Hirschsprung disease (HSCR), or congenital aganglionosis, is defined by the absence of intramural ganglion cells in the myenteric and submucocal plexuses of the gastrointestinal (GI) tract. The disorder is classified into long-segment (L-HSCR: aganglionosis of the splenic flexure and beyond), colon-segment (aganglionosis of the descending colon), and short-segment (aganglionosis of the sigmoid colon and more distal regions) forms; a minority of patients have total colonic aganglionosis (TCA). The diagnosis of HSCR occurs in the neonatal period at a median age of 7.5 days. Clinical symptoms in neonates are variable and commonly include severe constipation, abdominal distension, and failure to pass meconium. Generally, diagnosis involves suction rectal biopsy, but full-thickness biopsy is necessary for differential diagnosis. Contemporary surgical treatment, placement of the bowel with normal peristalsis at the anus to eliminate the tonic contraction of the internal sphincter, has led to excellent prognosis and a normal life span in >75 percent of patients. Nevertheless, enterocolitis and chronic constipation remain as long-term complications in many patients.
HSCR is a neurocristopathy or a disorder of neural crest (NC) cells. The NC is a transient and multipotent embryonic structure that gives rise to neuronal, endocrine and paraendocrine, craniofacial and conotruncal heart, and pigmentary tissues. In particular, the enteric nervous system (ENS) is formed from the craniocaudal migration of vagal-derived NC cells during weeks 5 to 12 of gestation. The embryologic development of the ENS is genetically programmed and known to depend on several proteins which determine and facilitate the orderly migration, proliferation, differentiation, and survival of NC cells in the walls of the GI tract to form the myenteric and submucocal plexuses. The details of ENS development explain phenotypic features of HSCR as well as its association with other syndromes involving the NC.
The population incidence is ≈1/5000 live births with sex-ratio 3:1 male:female; however, there is considerable population variation in both incidence and sex-ratio and other patient characteristics. Among all cases, 18 percent have L-HSCR and 7 percent have TCA. In 70 percent of patients HSCR occurs as an isolated trait, 12 percent have a recognized chromosomal abnormality and 18 percent multiple congenital anomalies. The most common (>90 percent) chromosomal abnormality is trisomy 21, but multiple deletions of segments of chromosomes 2, 10, 13, and 17 have been noted. The congenital anomalies, beyond those associated with trisomy 21, common to HSCR include atresia or stenosis of the GI tract, polydactyly, cleft palate, cardiac septal defects, and craniofacial anomalies, ...