71: Genetics of Constipation and Hirschsprung Disease

Key Points

• Disease summary:

  • Constipation is defined as having a bowel movement less than three times per week. A newborn or infant that manifests severe congenital constipation may have a diagnosis of Hirschsprung disease (HSCR). HSCR, or congenital intestinal aganglionosis, is characterized by complete absence of neuronal ganglion cells in a portion of the intestinal tract resulting in complete or partial intestinal obstruction. Constipation is common, affecting at least 4 million Americans, and is associated with female gender, pregnancy, lower socioeconomic status, age over 65 years, and following childbirth or surgery. In contrast, HSCR is a relatively rare condition, affecting 1:5000 newborns with a male:female ratio of 4:1.

  • Constipation manifests with stools that are typically hard, dry, small in size, and difficult to pass.

  • Infants with HSCR frequently present in the first 2 months of life with symptoms of impaired intestinal motility such as failure to pass meconium within the first 48 hours of life, constipation, emesis, abdominal pain or distention, and occasionally diarrhea. HSCR should be considered in anyone with lifelong severe constipation, as the diagnosis may not be made until childhood or adulthood.

  • Suction biopsies of rectal mucosa or submucosa are the preferred diagnostic test for HSCR.

  • In 80% of individuals with HSCR, aganglionosis is restricted to the rectosigmoid colon (short-segment disease); in 15% to 20%, aganglionosis extends proximal to the sigmoid colon (long-segment disease); in about 5%, aganglionosis affects the entire large intestine (total colonic aganglionosis). Rarely, the aganglionosis extends into the small bowel or even more proximally to encompass the entire bowel (total intestinal aganglionosis).

  • HSCR may occur as an isolated finding or as part of a multisystem or chromosomal disorder. Syndromes associated with HSCR are diagnosed by clinical findings, cytogenetic analysis, or in some cases, by specific molecular or biochemical tests.

• Differential diagnosis:

  • Constipation is a symptom rather than a disease per se, and often occurs when there is inadequate fiber in the diet, lack of physical activity, or dehydration. Medications can cause constipation, as can irritable bowel syndrome, neurologic disorders (eg, stroke, Parkinson disease), metabolic or endocrine conditions (eg, diabetes, hypothyroidism), and systemic disorders (eg, lupus). The differential diagnosis for newborns with intestinal obstruction includes, in addition to HSCR, gastrointestinal malformations such as atresia or malrotation, meconium ileus due to cystic fibrosis, abnormalities of the enteric nervous system such as chronic intestinal pseudo-obstruction, and acquired factors such as maternal infection or intoxication or congenital hypothyroidism.

• Monogenic forms:

  • No single gene cause of constipation is known. There are six known genes that can cause nonsyndromic HSCR, and multiple causative genes implicated in syndromes associated with HSCR.

• Family history:

  • Constipation often runs in families, suggesting genetic predisposition or environmental factors such as diet. In individuals with nonsyndromic HSCR without a clear etiology, HSCR is considered to be a polygenic disorder with incomplete penetrance, variable expressivity, and a 4:1 predominance in males. The overall risk to siblings of an individual with HSCR is 4%. Syndromic forms of HSCR follow ...