❓What Is Hirschsprung’s Disease (HSCR)?
Hirschsprung’s disease is a disorder in which certain nerve fibers are absent in parts of the gut, resulting in severe bowel obstruction.
❓What Is the Cause of Hirschsprung’s Disease?
Hirschsprung’s disease is caused when specific nerve cells, more specifically parasympathetic ganglion cells, in the wall of the large intestine (colon), do not develop before birth.
This condition is called ‘‘aganglionosis,’’ and causes constriction in a segment of the bowel.
Without these nerves being developed, the affected part of the large intestine cannot relax and move bowel contents along. Due to this, the section above the constricted area expands due to stool becoming trapped, causing a dilation of the colon (so-called megacolon).
The length of bowel segments affected by Hirschsprung’s disease varies but most commonly involves the region around the rectum. However, in up to 10% of children, the entire large intestines and part of the small intestine are affected.
🍭 What Are the Types of Hirschsprung’s Disease?
Hirschsprung’s disease can be classified into two groups based on the length of the affected intestine:
Short–segment Hirschsprung’s disease (S–HSCR) is the most common form of Hirschsprung’s disease and occurs in roughly 80% of patients. In this form, the aganglionosis does not extend beyond the sigmoid colon. The sigmoid colon is the last segment of the colon before it transits into the rectum.
The long–segment variant (L–HSCR) of Hirschsprung’s disease is diagnosed in approximately 20% of the patients in which the aganglionosis extends beyond the sigmoid colon.
🧬 Genetics of Hirschsprung’s Disease
⚠️ Hirschsprung’s disease occurs early in fetal development when there is either failure of ganglion cell development, failure of nerve cell migration, or arrest in nerve cell development in a segment of the bowel. The absence of these nerve fibers, which help control the movement of bowel contents, is what results in intestinal obstruction accompanied by other symptoms.
⚠️ 🧬 There is a variety of evidence indicating that genetic factors cause the onset of Hirschsprung’s disease. A complex genetic pattern is emerging, and mutations in at least eight different genes have been implicated in causing Hirschsprung’s disease. The genes associated with Hirschsprung’s disease are RET, GNDF, NRTN, EDNRB, EDN3, ECE1, SOX10, and ZFHX1B/SMADIP.
The genes mentioned above are essential for the gut's healthy development, and when they are not working correctly, it may lead to Hirschsprung’s disease.
⚠️ For example, germline mutations in the RET gene have been found in approximately 50% of familial cases and 30% of isolated cases.
The RET gene encodes a protein involved in signaling within cells, and it is essential for the normal development of several kinds of nerve cells, including nerves in the intestine.
The RET mutations result in a nonfunctional version of the RET protein that cannot interact with growth factors or transmit signals within cells. Without RET signaling, enteric nerves do not develop properly. Because these nerves control contractions that move stool through the intestine, their absence leads to the intestinal symptoms of Hirschsprung’s disease.
👪🏻 What Is the Type of Inheritance of Hirschsprung’s Disease?
⚠️ The inheritance pattern for L–HSCR is autosomal dominant, whereas the inheritance of the much more common S–HSCR is thought to be multifactorial.
🧬 Besides mutations in the RET gene, mutations have been found in a few cases in four other genes, all of which are within functional pathways involving the RET gene, and those are:
🧬 The GDNF gene that encodes glial cell line-derived neurotrophic factor (GDNF), which is a soluble ligand of RET
🧬 The EDNRB gene that encodes the endothelin B receptor (EDNRB) is also involved in the RET signaling pathway.
🧬 The EDN3 gene that encodes endothelin 3 (EDN3)
🧬 The SOX10 gene regulates EDNRB expression.
⚠️ Also, studies indicate that interactions between variants of these genes affect the penetrance and severity of the disorder.
In addition, a chromosomal abnormality is present in approximately 12% of individuals with Hirschsprung’s disease. Down syndrome (trisomy 21) is the most common chromosomal abnormality associated with the disease, which occurs in 2%–10% of all individuals with Hirschsprung’s disease.
Although individuals with Down syndrome are at a 100-fold higher risk for Hirschsprung’s disease than the general population, none of the identified Hirschsprung’s single genes reside on chromosome 21; thus, the association between Down syndrome and Hirschsprung’s disease remains unknown.
Other chromosomal abnormalities associated with Hirschsprung’s disease include deletions that encompass Hirschsprung’s–associated genes such as del13q22 (EDNRB), del10q11.2 (RET), and del2q22 (ZFHX1B).
📊 How Common Is Hirschprung’s Disease?
⚠️The incidence of Hirschprung’s disease in the United States is about one in about 5,000 live births.
There is a significant variation in the incidence of Hirschprung’s disease among different ethnic groups:
ℹ️ In Hispanics, 1 in 10,000 live births
ℹ️ In Caucasians–Americans, 1.5 in 10,000 live births
ℹ️In African–Americans, 2.1 in 10,000 live births
ℹ️ In Asians, 2.8 in 10,000 live births
Also, Hirschprung’s is four to five times more common in males than females, but its prevalence varies by region.
⚠️ Approximately 50% of children affected with this disease are diagnosed before age one, and almost all children are diagnosed before age two.