Hirschsprung Inheritance

Genetics and Inheritance

• Is Hirschsprung disease genetic?

Yes, there is a variety of evidence to show that Hirschsprung disease is caused by genetic factors.  The ganglion cells are derived from the “neural crest” of the embryo.  Any failure of these cells to grow, survive, migrate, or mature in the embryonic gut, could result in Hirschsprung disease (HSCR).  These processes are precisely controlled through a complex chemical cascade, and genes are responsible for this.  Studies have been done in mice to show that knocking out these genes severely affects gut development.

Hirschsprung disease commonly appears as part of a syndrome (defined as a combination of birth defects and/or health problems that have the same underlying genetic cause), which also lends support to its genetic basis.  Some of these syndromes also include symptoms of neural crest abnormalities, such as pigmentation changes, and vision or hearing loss.

Finally, it is known that an individual with HSCR is more likely to have a sibling or offspring with HSCR, compared to an unaffected individual.  This is empiric evidence that there is a genetic component to the disease.  (Estimates of the risks are given below.)

There is no environmental factor proven to be linked to the disease, although some have been suggested.  Therefore, there is nothing a mother could have done during pregnancy to cause or prevent HSCR.

• Is Hirschsprung disease inherited?

We know that Hirschsprung disease is caused by genetic changes (mutations) in the DNA sequence.  The genetic changes that lead to Hirschsprung disease can come from several sources.  Some individuals may have a new change, one that is not present in either parent, but arose at the time of conception.  Other individuals may have inherited, from their parents, a particular combination of subtle genetic changes that gave rise to Hirschsprung disease.  The parents may or may not be affected.  In the majority of families, Hirschsprung disease occurs as an isolated case, meaning there is no family history of the disease. 

By comparing the DNA of individuals with the disease and their affected and/or unaffected family members, at least eight different genes have been implicated in causing Hirschsprung disease:

These genes are thought to be important in the correct development of the gut.  So when they are not working correctly, it may lead to disease.

• What is the inheritance pattern of Hirschsprung disease?

The majority of HSCR cases appear to be multigenic, meaning multiple altered genes are involved in causing disease.  Affected individuals may have inherited genetic changes in one or more genes involved in HSCR, from one or both parents.  In the parents, these subtle changes usually do not cause disease, but are “susceptibility factors”.  If a child inherits a specific combination of these changes, however, Hirschsprung disease will result.  Overall, Hirschsprung disease has an unpredictable pattern of inheritance. 

One way to think of the inheritance of Hirschsprung disease is to compare it to filling a cup.  Let’s say Hirschsprung disease results when a certain threshold is crossed (a full cup).  If each of the parents’ genetic cups is partly full, and they pass on a certain amount to their child, the cup of genes may reach high enough levels that it overflows, causing Hirschsprung disease.  The threshold concept is characteristic of multigenic, or “complex”, inheritance.

In a small fraction of HSCR families, the pattern of inheritance appears to be autosomal dominant.  In these families, there are affected individuals in several generations, providing evidence for a dominant-acting mutation that causes disease in those who inherit it.  In these families, the chance for an affected person to have a child with Hirschsprung disease is up to 50%.  However, even in these families it may appear to skip generations.

• What are the chances that our children will also be affected by Hirschsprung disease?

Once a couple has had one child with Hirschsprung disease, the chances of having another are increased over that of the general population.  The chance of passing on Hirschsprung disease, or of having another child with it, depends on many factors, including:

1. whether there are other family members with Hirschsprung disease,

2. length of the segment involved,

3. gender of the person affected,

4. gender of the baby, and

5. whether there is an associated syndrome in the person with Hirschsprung disease.

Epidemiological studies examining population trends can provide approximate recurrence risks based on the above factors.  The relevance of the information provided below to your family should be discussed with your physician!

To demonstrate how to read this table, here is an example:  if you have a son with long-segment HSCR, and your next child is a girl, her chance to have HSCR is 7-9%.  Your son’s chance to have a son with HSCR is 16-19%.

Adapted from Badner et al. Am.J.Hum.Genet. 46: 569-580 (1990).

Predicting recurrence risks will become more specific and more accurate once researchers identify all the genes involved in HSCR and understand the disease at the genetic level. 

The best way to get a personalized risk assessment is to see a geneticist or genetic counselor. You can find one in your area by going to www.nsgc.org, clicking on "Find a Counselor", and then searching by city or zip code. A genetic counselor would also be able to tell you whether the clinically available genetic testing is appropriate for your situation, as it is more likely to provide information for some individuals than others. The counselor would need to coordinate this testing for you, since a referral is necessary.

• Why are more boys affected with HSCR than girls?

There are 4 times as many males born with Hirschsprung disease than females.  The sex ratio is highest in short-segment disease, but is about equal (1:1) for long-segment and total-colonic Hirschsprung disease.  At present, the biological reason for this difference in not known, but it is a question that researchers are investigating.

Syndromes involving Hirschsprung disease

Hirschsprung disease occurs as an isolated health concern in the majority of affected individuals.  However, approximately 30% of individuals with Hirschsprung disease have additional health concerns.  If that is the case, it may be due to chance occurrence, or the person may have a “syndrome”.  A syndrome is a combination of birth defects and/or health problems that have the same underlying genetic cause.  If a syndrome is suspected, evaluation by a geneticist (a genetics doctor) should be sought.  The risk of recurrence in future children may be influenced by whether a syndrome is present.

Chromosome Abnormalities

About 12% of cases of Hirschsprung disease occur as part of a syndrome caused by a chromosome abnormality. The most common chromosome abnormality that includes Hirschsprung disease is Down syndrome. About 2-10% of individuals with Hirschsprung disease have Down syndrome.  (Down syndrome is a chromosome abnormality in which there is an extra copy of chromosome 21; it is associated with characteristic facial features, congenital heart defects, and developmental delays.)  Hirschsprung disease has also been found in patients with certain parts of a chromosome missing, and study of these patients has assisted in the identification of some of the Hirschsprung genes.

Single-gene syndromes

About 18% of cases occur with other congenital anomalies, some of which may be caused by a single-gene defect. 

• Waardenburg syndrome, type IV (WS4) is characterized by pigmentary changes (such as different colored eyes, or a white patch of hair), sensorineural deafness, and Hirschsprung disease.  WS4 is usually caused by mutations in the EDNRB gene, and is most often inherited in an autosomal recessive pattern.

                                    Reproduced from Otolaryngology Houston, www.ghorayeb.com

• Other disorders that can include Hirschsprung disease are: congenital central hypoventilation syndrome (CCHS), Mowat-Wilson syndrome, Goldberg-Shprintzen syndrome, Bardet-Biedl syndrome, and Smith-Lemli-Opitz syndrome.  More information can be found on OMIM.

Hirschsprung disease can also appear with other birth defects, without being classified as a particular syndrome. 

Another condition associated with the RET gene

Multiple Endocrine Neoplasia Type 2 (MEN2) is an inherited cancer syndrome, predisposing to medullary thyroid cancer (MTC), pheochromocytoma (cancer of the adrenal gland), and parathyroid tumors.  MEN2 includes 3 slightly different disorders, including MEN2A, MEN2B, and FMTC (familial MTC).  Similar to Hirschsprung disease, it is caused by mutations in the RET gene; however, a different type of mutation causes MEN2 and the mutations occur in a very specific region of the gene.  Rarely, an individual is described who has both Hirschsprung disease and an MEN2-associated cancer.  A person with a family history of endocrine tumors should see a doctor for diagnosis, testing options, and possible monitoring.