Genetics of Anorectal Malformations / Imperforate Anus
Michael D. Bates, MD, PhD
Division of Gastroenterology, Hepatology and Nutrition
Division of Developmental Biology
Colorectal Center for Children
Cincinnati Children's Hospital Medical Center
Birth Defects of the Digestive System
The causes of birth defects are largely unknown. As with other human disorders, they likely result from interactions between genes and environment. Both the mother and father contribute equally to a person's complement of genes.
The environment of the womb can be affected by both the presence of toxins (including medications, substances such as alcohol or street drugs, and substances in foods and drinks) and the absence of necessary substances (for instance, the lack of folic acid, which can contribute to the development of spina bifida).
Based on what is known about human development in pregnancy, it is likely that the impact of gene mutations and environmental exposures occurs early in pregnancy.
Anorectal development is largely complete by 7-8 weeks after conception (9-10 weeks after the mother's last period), early enough that it is often before a mother even knows that she is pregnant.
Birth defects of the digestive organs (esophagus, stomach, small intestine, colon, rectum, liver and pancreas) are unfortunately relatively common. The Centers for Disease Control and Prevention reported that birth defects of the digestive system affected 8.4 out of every 10,000 babies born in the United States during 2003, and such defects result in many hospitalizations and substantial medical expenses.
In many cases, treatments are imperfect, and medical problems, though improved, continue even into adulthood. For some disorders, research has discovered genetic causes. An example is Hirschsprung's disease, a disorder in which the nerves in the gut do not develop normally.
At present, about half of the cases of Hirschsprung's disease are known to result from mutations in one of several genes, and others may result from partial defects in combinations of genes. However, in most cases, the cause of the birth defect is unknown, leaving parents (not to mention their doctors) wondering what went wrong, and why, and could it happen again.
Genetic Factors in Anorectal Malformations / Imperforate Anus
Anorectal malformations / ARM are one class of birth defects of the digestive system for which we do not know the cause. Studies from populations around the world indicate that anorectal malformation have a frequency of 2 to 5 per 10,000 live births.
It is not clear whether this variation in frequency results from differences in the genes present in different populations or is due to differences in exposure to toxins in the environment. However, studies of humans and animals suggest that there is an important genetic contribution to the development of anorectal malformations.
Human Studies
Several kinds of evidence suggest genetic involvement in human anorectal malformations.
First, many families have been described in medical journals who have more than one affected member. Of course, this could also occur by chance.
However, in our review of the database of Dr. Alberto Peña's extensive case series (>1800 patients), we found there is a greater incidence than expected by chance alone that a child with an anorectal malformation / imperforate anus will have one or more family members who are also affected. (These data will be presented at a meeting of pediatric surgeons this spring, and we are preparing a medical paper on this topic).
Second, anorectal malformations occur in many patients as part of certain genetic syndromes, and specific gene defects have been found in several of these syndromes.
Animal Studies
Studies in animals also suggest there are genetic causes of anorectal malformations / imperforate anus.
Because the mammalian digestive system develops in a sequence of events that is widely shared among species, studies in animals should provide insights into human digestive system development and related congenital disorders.
Anorectal malformations have been described in a wide variety of animal species, including mice, rats, cows, dogs, pigs, sheep, and llamas. Lines of mice and pigs in which the presence of anorectal malformations is transmitted to offspring as a genetic trait have been reported.
In addition, miniature or toy poodles and Boston terriers have more anorectal malformations than other breeds of dogs. These findings in animals offer the opportunity to identify the responsible genes.
So far, a group of researchers in Italy, Japan and Sweden have been able to assign the responsible pig gene to a small region of one chromosome, and ongoing work will likely identify the specific gene in the next couple of years.
The development and use of sophisticated methods to mutate specific genes in mice have resulted in the discovery of a dozen mouse genes that are required for normal anorectal development.
Some of these genes encode proteins that act as "transcription factors" that regulate other genes, whereas others are important for communication between tissues in development.
Thus, these data from mice not only point to genetic factors in development of anorectal malformations, which might be similar in humans, but they also suggest molecular mechanisms that are altered and may be targets for prevention or therapy.
Taken together, the human and animal data make a compelling case that anorectal malformaitons have an important genetic component. However, the exact nature of the genetic influences in human anorectal malformations remains unknown.
The Future: Toward Finding Specific Causes of Anorectal Malformations
One reason for our lack of knowledge of the cause(s) of anorectal malformations and other birth defects is they are relatively rare. In addition, until recently, it was very difficult to study the genetic causes of human diseases.
However, the Human Genome Project, which determined the complete genetic sequence for humans, has given researchers new tools which can make the study of rare disorders such as birth defects much more practical.
Genetic studies of patients with anorectal malformations will need to include comparisons with their parents (and other family members if there is more than one affected member of the family). Such studies may eventually allow better genetic counseling or even specific testing to determine the risk of having a child with an anorectal malformation.
As mentioned above, human birth defects may result from interactions between genes and environmental factors. Treatment of pregnant rats and mice with one of several compounds has been shown to result in anorectal malformations in their offspring.
Although humans are not exposed to any of these compounds to any similar degree, it will still be important to consider potential environmental exposures as well as genes in studies to find out the cause of anorectal malformations.
We have recently undertaken such a study in the Colorectal Center at Cincinnati Children's Hospital Medical Center, and we hope we will have significant results to share in the future. The ultimate goal is to understand what causes anorectal malformations to occur so that approaches to prevention and more effective treatments can be developed.
For more information or to request an appointment, please contact the Colorectal Center at Cincinnati Children's.
