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Hirschsprung disease (HSCR)

HSCR (OMIN 142623) is clinically characterized by failure of passing the first stool within 48 hours after birth, a distended abdomen, vomiting or a neonatal enterocolitis. Chronic constipation is the major presentation in childhood. HSCR results from a failure of neural crest cells to migrate, proliferate, differentiate or survive in the bowel wall to form the enteric nervous system.

Hofstra3

Absence of parasympathetic ganglion cells (nerve cells) in the myenteric and submucosal plexuses distal of the dilated part of the colon as schematically shown in figure b. resulting in severe and sometimes life-threatening constipation with abdominal distension, resulting in congenital megacolon. A short segment of HSCR is seen in figure c

In the majority of cases the lack of ganglia is restricted to the sigmoid. In 20% of cases the aganglionosis is extended proximally. The estimated prevalence in the population is 1:5000 live born children. HSCR is mainly seen as a sporadic disorder and in most cases this is S-HSCR. In a minority of cases (10-15%), the disease shows a clear familial occurrence with a Mendelian autosomal dominant pattern of inheritance. One in three children has additional congenital anomalies. However, in only a minority of these children a syndrome diagnosis is established. Syndrome diagnoses in HSCR patients include syndromes caused by chromosomal abnormalities (like trisomy 21) and monogenic inherited ones.


Hirschprung disease
HSCR HSCR is considered an inherited disease, based on the facts that familial cases occur (in ~5% of all cases), there is an elevated risk for sibs, chromosomal abnormalities are found and HSCR can be part of a syndrome. The modes of inheritance can be dominant or recessive (often wit reduce penetrance) in the familial cases. However, in the isolated cases the mode of inheritance is considered polygenic.

Genetic dissection has led to the identification of 15 genes and 6 loci for HSCR disease susceptibility.

The major gene in HSCR is RET as about 50% of the familial cases and 15% in simplex cases have a RET coding mutation. These mutations of RET cause a loss of RET function, and these are responsible for a dominant form of HSCR disease. A variety of mutations within RET are found and these are scattered throughout the RET coding sequence.

Mutations in the other genes are rare and are found in no more that 10% of the patients. Approximately half of these are in EDNRB.

Most of the identified genes are involved in syndromic forms of HSCR, where patients show besides HSCR also other malformations.

fig-hirschprung