An Overview of Juvenile Polyposis
By Joy Larsen Haidle, MS, CGC
University of Iowa

Juvenile polyposis (JP) is a rare (1/100,000) inherited condition that predisposes individuals to the development of multiple polyps in the colon, rectum, small bowel, and stomach. JP may account for as many as 10% of gastrointestinal polyposis cases. The presence of polyps in the gastrointestinal tract in turn leads to an increased chance of developing cancer. In some families, there is also an increased chance of developing pancreatic cancer. The current diagnostic criteria for JPinclude:

• More than 5 juvenile polyps of the colon or rectum; or
• Juvenile polyps in other parts of the gastrointestinal tract; or
• Any number of juvenile polyps and a positive family history of JP.

There is a great degree of variation in the numbers of polyps, symptoms, or complications that a person may have as a result of JP. For example, some individuals with JP will only have 4-5 polyps while others will have 50-100 polyps. Most people who have JP at some point in their life will notice blood from their rectum or become anemic. Although JP can be diagnosed at any age, the average age at which symptoms first occur is 32 years.

Nevertheless, some individuals with JPhave had symptoms as early as infancy and as late as 68 years. Anticipation has been reported in juvenile polyposis families. Anticipation means that the age of onset of symptoms of juvenile polyposis is younger with each generation. This may, in part, be due to increased awareness and better surveillance options for the younger generations.

Research studies in JP families have helped to identify gene changes responsible for the JP. Researchers have identified two genes that are known to cause JP. The name of one of the genes is SMAD4 and it is located on chromosome number 18, and the other gene is PTEN located on chromosome 10. Studies have estimated that SMAD4 mutations may be responsible for JP in an estimated 23-60% of JP families. The most common SMAD4 mutation, affecting an estimated 25% of JP families, is a 4-base-pair deletion from the SMAD4 gene. A deletion means that a section of DNA (the body's instructions) is missing. Even though the missing piece of instructions is very small, it causes the instructions encoded by the SMAD4 gene to stop too early and, therefore, does not allow the SMAD4 gene to function properly.

PTEN mutations occur in an estimated 0-21% of JP families. However, it is possible that some families with gene changes in PTEN who were thought to have JP, actually have another condition called Cowden Syndrome that also predisposes to colon polyps, but commonly has skin findings that are not seen in JP. Also, when using a microscope, polyps in Cowden syndrome appear different than the polyps seen in JP.

Yet, some families with JP and some individuals who have been diagnosed with JP but have no family history of the condition, who do not have an identifiable gene change. In time, researchers will likely identify additional genes responsible for JP.

When deciding whether or not to get tested for JP gene mutations, one must consider the risks, benefits, and limitations of the tests. The gene change in some families is identifiable on a research basis. Often, the best person in the family to be tested first is the one who has had symptoms of JP. If a gene change is identified, accurate presymptomatic diagnosis may be available for at-risk relatives. Assuming this gene change is responsible for JP in a family, a negative gene test may reassure relatives, that they are not at increased risk of developing JP. However, a negative result cannot guarantee that a person will remain free of cancer. Regardless of family history, everyone in the general population has a chance to develop cancer. Even in families with an identified SMAD4 mutation, sporadic cases of cancer can even occur in individuals who do not carry a mutation. In this scenario, no annual surveillance is needed, though, baseline screening and periodic evaluations (every 10 years) are still recommended.

On the other hand, finding a SMAD4 mutation in an unaffected person does not mean that cancer is inevitable. In fact, the chance of developing cancer at some point in his or her lifetime, as a result of juvenile polyposis may be in the range of 50%, though the true chances are not known. The chance of having the gene change and remaining asymptomatic for either polyps, anemia, bleeding, or cancer is also not known. The SMAD4 test cannot determine who will develop cancer nor can it predict the age of onset. At this early stage of our ability to predict cancer, there is still no consensus on the appropriate management of asymptomatic individuals who have a SMAD4 mutation.

The current surveillance guidelines for individuals who have inherited a JP gene or who are at increased risk for a mutation based on their family history, are based on expert opinion. Not on scientific proof, as case controlled studies have not yet been done. Thus, we recommend discussing surveillance options with your physician to determine the appropriate follow-up plan for you. Listed below are the guidelines that were reviewed by Howe et al. in the journal, Surgery, 1999.

Surveillance after a Positive Gene Test:

Screening should begin in the early teens or when symptoms first appear, whichever comes first. A person with known polyps should have an annual upper and lower endoscopy (with removal of polyps) and a complete blood count (CBC). This regimen may be modified to every 3 years if these studies do not identify any polyps. Individuals who have diffuse polyposis may need a colectomy (removal of the colon) or gastrectomy (removal of the stomach) . An asymptomatic person without polyps should have an upper and lower endoscopy and a CBC (complete blood count) every 3 years as long as no polyps are identified.

Surveillance after a Negative gene test:

If a person who tests negative in a family whose mutation is known, at this time, the recommendations are to have a baseline screening via upper and lower endoscopy in their teen years. An upper and lower endoscopy every ten years until they reach 45 years of age, at which time, guidelines for screening the general population for colon cancer should be followed. The specific age at which individuals with JP definitively show the first symptoms in unknown, but most individuals with JP have symptoms by their twenties.

An additional issue in JP is what to do with results of the DNA testing in children who are less than 18 years of age. At the University of Iowa, we have chosen the age of 15 years to begin routine surveillance for JP and therefore, may be a reasonable age to discuss DNA test results to help determine the frequency of the surveillance. At the age of 15, most teenagers should be involved in their medical care and informed of surveillance recommendations and what this means for them. Also, 15 year-old members of a JP family will likely have seen multiple relatives with symptoms of JP and/or cancer diagnoses and be aware of the concerns raised by surveillance. They may also be mature enough to adjust to the diagnoses of JP and should play a role in deciding whether or not they want to learn their JP status. If parents are concerned about their child's ability to cope with the significance of test results, the disclosure of the DNA information can be delayed, but not surveillance. If symptoms of JP appear before age 15, surveillance should begin at that time and disclosure of DNA test results may be a reasonable option, as likely the test results will be confirming the diagnosis that may have already been assigned based on symptoms. It is important to consider the risks and benefits of learning this information at a young age and how to approach discussions with the children about the information and answering their questions. A genetic counselor can help in these situations.

Previous generations of JP families did not have the benefit of surveillance or current medical technology, and cancer diagnoses were prevalent. Now with increased awareness, education, and the benefits of screening/polypectomy, successive generations have more options for early detection and prevention. The goal of surveillance is to catch a potential problem early and improve the quality of life for individuals with JP. While not everyone desires genetic testing, it may become a valuable tool for determining which relatives need additional surveillance and which surveillance options are the most appropriate. In all cases, surveillance is very important for individuals known to have JP and/or individuals who are at-risk for the condition.

Howe, Jim, et. Al. "Direct Genetic Testing for SMAD4 Mutations in Patients at risk for Juvenile Polyposis." Surgery: 126(2) ppg 162-169.