Autosomal Dominant, Autosomal Recessive, or Multigenic
• Genetic heterogeneity
• Incomplete penetrance and variable expressivity
• Genetic modifiers
• Sex-dependent penetrance
Major Phenotypic Features
• Age at onset: Neonatal to adulthood
• Abdominal distention
History and Physical Findings
S.L. and P.L. were referred to the genetics clinic to discuss their risk for having another child with Hirschsprung disease; their daughter had been born with long-segment Hirschsprung disease and was doing well after surgical removal of the aganglionic segment of colon. On examination and by history, the daughter did not have signs or symptoms of other diseases. The mother knew of an uncle and a brother who had died in infancy of bowel obstruction. The genetic counselor explained that in contrast to short-segment Hirschsprung disease, long-segment disease usually segregates as an autosomal dominant trait with incomplete penetrance and is often caused by mutations in the RET (rearranged during transfection) gene, which encodes a cell surface tyrosine kinase receptor. Subsequent testing showed that the affected daughter and the mother were heterozygous for a loss of function mutation in RET.
Disease Etiology and Incidence
Hirschsprung disease (HSCR, MIM 142623) is the congenital absence of parasympathetic ganglion cells in the submucosal and myenteric plexuses along a variable length of the intestine (Fig. C-22); aganglionosis extending from the internal anal sphincter to proximal of the splenic flexure is classified as long-segment disease, whereas aganglionosis with a proximal limit distal to the splenic flexure is classified as short-segment disease. Approximately 70% of HSCR occurs as an isolated trait, 12% in conjunction with a recognized chromosomal abnormality, and 18% in conjunction with multiple congenital anomalies (Waardenburg-Shah syndrome, Mowat-Wilson syndrome, Goldberg-Shprintzen megacolon syndrome, and congenital central hypoventilation syndrome).
FIGURE C-22 A, Barium enema study of a 3-month-old child with Down syndrome with a history of severe constipation. Note the narrowing of the distal colon, with the transition from dilated to narrowed colon demarcated by arrows; subsequent mucosal biopsy showed an absence of myenteric ganglion cells consistent with Hirschsprung disease. B, Normal myenteric ganglion. Myenteric ganglion cells (arrows) are located normally in the plexus between the longitudinal and circular layers of the muscularis propria. C, Aganglionic distal bowel of Hirschsprung disease. See Sources & Acknowledgments.
Isolated or nonsyndromic HSCR is a panethnic, incompletely penetrant, sex-biased disorder with intrafamilial and interfamilial variation in expressivity; it has an incidence from 1.8 per 10,000 live births among Europeans to 2.8 per 10,000 live births among Asians. Long-segment disease, including total colonic aganglionosis, generally segregates as an autosomal dominant low-penetrance disorder; short-segment disease usually exhibits autosomal recessive or multigenic inheritance.
The enteric nervous system forms predominantly from vagal neural crest cells that migrate craniocaudally during the 5th to 12th weeks of gestation. Some enteric neurons also migrate cranially from the sacral neural crest; however, correct migration and differentiation of these cells depend on the presence of vagal neural crest cells.
HSCR arises from premature arrest of craniocaudal migration of vagal neural crest cells in the hindgut and thus is characterized by the absence of parasympathetic ganglion cells in the submucosal and myenteric plexuses of the affected intestine. The genes implicated in HSCR include RET, EDNRB, EDN3, GDNF, and NRTN. How mutations in these genes cause premature arrest of the craniocaudal migration of vagal neural crest cells remains undefined. Regardless of the mechanism, the absence of ganglion cells causes loss of peristalsis and thereby intestinal obstruction.
RET is the major susceptibility gene for isolated HSCR. Nearly all families with more than one affected patient demonstrate linkage to the RET locus. However, mutations in the RET coding sequence can be identified in only approximately 50% of patients with familial HSCR and in 15% to 35% of patients with sporadic HSCR. In addition, within families segregating mutant RET alleles, penetrance is only 65% in males and 45% in females. A common noncoding variant within a conserved, enhancer-like sequence in intron 1 of RET has been shown to be associated with HSCR and accounts for incomplete penetrance and sex differences (see Chapter 8). In addition, the variant is far more frequent in Asians than in whites, explaining the population differences.
Phenotype and Natural History
Patients with HSCR usually present early in life with impaired intestinal motility; however, 10% to 15% of patients are not identified until after a year of life. Approximately 50% to 90% of patients fail to pass meconium within the first 48 hours of life. After the newborn period, patients can present with constipation (68%), abdominal distention (64%), emesis (37%), or occasionally diarrhea; 40% of these patients have a history of delayed passage of meconium.
Untreated, HSCR is generally fatal. Failure to pass stool sequentially causes dilatation of the proximal bowel, increased intraluminal pressure, decreased blood flow, deterioration of the mucosal barrier, bacterial invasion, and enterocolitis. Recognition of HSCR before the onset of enterocolitis is essential to reducing morbidity and mortality.
HSCR frequently occurs as part of a syndrome or complex of malformations. As a neurocristopathy, HSCR is part of a continuum of diseases involving tissues of neural crest origin such as peripheral neurons, Schwann cells, melanocytes, conotruncal cardiac tissue, and endocrine and paraendocrine tissues. An illustration of this continuum is Waardenburg syndrome type IV, which is characterized by HSCR, deafness, and the absence of epidermal melanocytes.
The diagnosis of HSCR requires histopathological demonstration of the absence of enteric ganglion cells in the distal rectum (see Fig. C-22C). Biopsy specimens for such testing are usually obtained by suction biopsies of the rectal mucosa and submucosa.
Definitive treatment of HSCR involves removal or bypassing of the aganglionic segment of bowel. The surgical procedure also usually involves the anastomosis of innervated bowel to the anal sphincter rather than a permanent colostomy. The prognosis for surgically treated patients is generally good, and most patients achieve fecal continence; however, a few patients have postoperative problems including enterocolitis, strictures, prolapse, perianal abscesses, and incontinence.
Nonsyndromic HSCR has a 4 : 1 predominance in males versus females as well as variable expressivity and incomplete penetrance. The empirical recurrence risk for HSCR in siblings is dependent on the sex of the proband, the length of aganglionosis in the proband, and the sex of the sibling (see Table).
Prenatal counseling is complicated by the incomplete penetrance and variable expressivity. Even if a mutation has been identified in a family, generally neither the prediction of short- or long-segment HSCR nor the prediction of nonsyndromic or syndromic HSCR is possible. Moreover, prenatal diagnosis is currently further complicated by the poor availability of molecular testing.
Sex-Dependent Recurrence Risk in Siblings of a Proband with HSCR
HSCR, Hirschsprung disease.
From Parisi M: Hirschsprung disease overview. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1439/.
Questions for Small Group Discussion
1. Mutations in the RET gene also cause multiple endocrine neoplasia; how do these mutations generally differ from those observed in HSCR disease? On occasion, the same mutation can cause both HSCR and multiple endocrine neoplasia; discuss possible explanations for this.
2. Discuss how stochastic, genetic, and environmental factors can cause incomplete penetrance, and give examples of each.
3. Haddad syndrome (congenital central hypoventilation and HSCR) has also been associated with mutations of RET, GDNF, and EDN3. Describe the developmental relationship and pathology of HSCR and congenital central hypoventilation.
4. Mutations of the transcription factor SOX10 cause Waardenburg syndrome type IV plus dysmyelination of the central and peripheral nervous system. Mutations of the endothelin pathway cause HSCR and Waardenburg syndrome type IV without dysmyelination. Mutations of RET and its ligands cause HSCR but not Waardenburg syndrome type IV or dysmyelination. Discuss what these observations say about the relationship between these three pathways and their regulation of neural crest cells.
5. Compare and contrast the various forms of multigenic inheritance, that is, additive, multiplicative, mixed multiplicative, and epistatic inheritance.
Emison E, McCallion AS, Cashuk CS, et al. A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature. 2005;434:857–863.
Langer JC. Hirschsprung disease. Curr Opin Pediatr. 2013;25:368–374.
Parisi MA. Hirschsprung disease overview. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK1439/.