Peutz-Jeghers syndrome (PJS) is named after two doctors who first studied and described it in 1921. It is an association of three very specific conditions in any one person. The first condition is the appearance of freckles on parts of the body where freckles are not normally found. The second condition is the presence of multiple gastrointestinal polyps. The third condition is a risk, greater than the risk seen in the general population, of developing certain kinds of cancers.
The freckles associated with PJS are dark brown, dark blue, or greenish black. In almost all people with PJS, these freckles are present at birth on the lining of the cheeks inside the mouth. By the time most children reach one or two years old, freckles develop around the lips, nostrils, eyes, anus, and genitals. This is in contrast to ordinary freckles, which are absent at birth and rarely develop in these locations. The freckles seen in PJS are sometimes called macules (discolored spot or patch on the skin of various colors, sizes, and shapes), or areas of hyperpigmentation (increased pigmentation of the skin).
Some people with PJS also have these freckles on the palms of their hands or feet or on their fingertips. Freckles may merge together. The freckles on the skin often fade or disappear by adolescence, but the freckles inside the mouth generally remain throughout the person's life.
Gastrointestinal polyps can develop in children as young as one or two years old. The age at which polyps appear and the number of polyps vary widely from patient to patient. The polyps can occur in infants and cause spasms and pain in the abdomen. On average, polyps appear by the time a child with PJS is 10 years old. There may be anywhere from dozens to hundreds of polyps throughout the gastrointestinal tract. For this reason, PJS is sometimes called polyposis, which means "too many polyps." Most PJS polyps occur in the small intestine, but they can also develop in the esophagus, stomach, and colon. In some people with PJS, polyps have been found in the mouth or nose.
The polyps seen in PJS have a unique structure. They consist of overgrowths of normal tissue that smooth muscle bands of the stomach and instestines run through. This kind of overgrowth is called a hamartoma. Consequently, PJS is sometimes called hamartomatous intestinal polyposis. A hamartoma is a non-cancerous tumor, and hamartomatous polyps are not cancerous. However, they can take up too much space, causing obstruction, pain, and even bleeding. They can also become cancerous, or malignant, if a genetic change results in uncontrolled cell growth.
It is this potential for malignant change that increases cancer risk in people with PJS. As might be expected, the gastrointestinal tract is the most common site for cancer in people with PJS. The small intestine, stomach, gallbladder, pancreas, colon, and rectum are all susceptible. However, cancer can also occur outside the gastrointestinal tract. When this happens, the sites most likely to be involved are the breasts, ovaries, uterus, cervix, or testicles.
PJS does not affect intelligence or behavior.
Researchers have identified the gene responsible for about seven out of ten PJS cases. The gene is named STK11, and it is located at the 19p13 site on chromosome 19. In some older studies, the same gene is referred to as LKB1. As of 2001, researchers have connected more than 50 different STK11 mutations to cases of PJS.
However, some cases do not appear to be connected to STK11. As a result, PJS qualifies as a genetically heterogeneous condition; this means that it has more than one known genetic cause. Research continues in order to locate the genes involved in the three out of ten cases not related to STK11.
When linked to STK11, PJS is an autosomal dominant disorder. This means that the condition occurs even when an individual inherits only one abnormal copy of STK11 from either parent. In some people with PJS, the condition is limited to freckles on the lining of the cheeks inside the mouth. Many of these people also have gastrointestinal polyps. One abnormal copy of STK11 also increases a person's risk of developing the kinds of cancer associated with PJS.
However, since only one abnormal copy of STK11 is needed to cause PJS, most people with the condition still have one normal copy of the gene. One normal copy is usually enough to protect against the kinds of cancer associated with PJS. This is because STK11 is a tumor suppressor gene. A properly working tumor suppressor gene makes a product that controls cell growth. Since cancer is the result of uncontrolled cell growth, tumor suppressors prevent cancer. Even one working copy of STK11 protects against cancer.
The reason people with PJS have an increased risk of developing cancer is that one STK11 gene is already abnormal at birth. If damage to the normal STK11 gene occurs later, the ability to control cell growth is lost, leading to the kinds of cancers associated with PJS.
Damage to normal genes can occur in anyone. However, it generally takes less time to damage one gene than two genes. Therefore, people with PJS are likely to develop cancer at earlier ages than are people born with two normal STK11 genes.
About half of all PJS cases occur because a child inherits a changed gene from a parent with PJS. The other half are due to a mutation in the cell from which the child develops. A person born with one abnormal gene can pass that gene on to the next generation. One out of two of this person's children will inherit the gene. In addition, if PJS is inherited, each parent or sibling of the affected person has a one out of two chance of carrying the gene.
PJS occurs in about one out of 25,000 people. It affects males and females of all races and ethnic groups. The particular genetic mutation may differ among groups and even among families within a group.
Signs and symptoms
The first sign of PJS, freckling inside the mouth or in unusual places, generally appears in infants. Polyps usually begin causing symptoms by age 10. Polyps make themselves known in a variety of ways. They can cause abdominal pain or intestinal bleeding. Sometimes the blood loss leads to anemia (a condition where there is a reduction in circulating red blood cells, the amount of hemoglobin, or the volume of packed red cells). Polyps sometimes protrude outside the rectum or obstruct the gastrointestinal tract. Untreated obstructions can be fatal.
Tumors may appear in childhood. Children as young as six may develop a particular kind of ovarian or testicular tumor that causes early puberty. Affected boys sometimes begin to develop breasts. These tumors can be non-cancerous, but they have the potential to become malignant.
A few patients develop malignant tumors in the first decade of life. Other patients have stomach, breast, or cervical cancer before age 30. The specific form of cervical cancer is extremely rare in the general population.
Because the peculiar freckling seen in PJS is present so early, doctors familiar with the condition may suspect PJS even before other symptoms occur. This is ideal, since early diagnosis greatly improves the prognosis.
Many children or young adults come to medical attention due to the pain, bleeding, or anemia caused by polyps. Doctors can confirm the presence of multiple polyps using a variety of methods. Noninvasive methods include ultrasound and x ray techniques. Invasive methods use a tube and an optical system to conduct an internal inspection of the gastrointestinal tract. These methods include endoscopy, enteroscopy, and colonoscopy, all of which involve entry to the gastrointestinal tract through an existing body orifice. Laparoscopy is another invasive method; it involves entering the gastrointestinal tract through an incision in the abdomen. All invasive methods allow for removal of polyps found during the exam. Once the polyps are removed and examined, their unique structure and large number lead to diagnosis of PJS. The average age at PJS diagnosis is 17.
Freckles and polyps occur in more than 95% of people with PJS. Sometimes, though, the freckles fade before symptoms of polyps appear. It is important to take a medical history in order to determine if freckles were present on the skin earlier in life. The doctor should also examine the lining of the cheeks inside the mouth, where freckles are likely to remain throughout life.
The number and intensity of the freckles do not predict the severity of gastrointestinal symptoms or the risk of developing cancer. Any patient diagnosed with PJS needs regular cancer screening.
The presence of the rare cervical cancer, ovarian tumor, or testicular tumor associated with PJS leads to diagnosis in some patients.
A family history of PJS is suspicious but not required for diagnosis, since PJS can occur as a new mutation. Once PJS has occurred in a family, parents, siblings, and children of the affected person should seek medical attention.
Genetic testing is available to confirm clinical diagnosis or to determine if a person carries an abnormal STK11 gene. Using a swab, cells are removed from the lining of the cheeks inside the mouth. DNA is extracted and analyzed. The test confirms PJS if analysis reveals an STK11 mutation. However, the test cannot rule out PJS if an STK11 mutation is not found, since some cases are due to other genetic causes.
Prenatal diagnosis of PJS is possible only if the family's specific STK11 mutation has previously been identified. Prenatal testing is done by amniocentesis or chorionic villus sampling. Amniocentesis involves removal of a small amount of amniotic fluid from the uterus. Chorionic villus sampling involves removal of a small sample of placental tissue. In either case, DNA is extracted from sample cells and analyzed.
Even without genetic testing, diagnosis of PJS is fairly straightforward. Although several other conditions cause multiple intestinal polyps or hyperpigmentation, the distinctive structure of PJS polyps and the unusual location of PJS freckles eliminate other conditions from consideration.
Treatment and management
For people with a family history of PJS, treatment and management of the condition may begin even before diagnosis. If PJS freckles do not appear at birth and if there are no symptoms of polyps, affected families may desire genetic testing for their children.
For most genetic conditions, testing is delayed until children are old enough to understand the disease, its consequences, and the advantages and disadvantages of genetic screening. However, since PJS can affect children under the age of 10, any delay could be risky. Therefore, it is appropriate for families with PJS to consider genetic testing for their children. Children who do carry an STK11 mutation can begin a preventive care program immediately, and children who do not carry an STK11 mutation can avoid unnecessary intervention.
The decision to seek genetic testing requires careful consideration. A positive test for PJS cannot predict the
Parents, siblings, and children of people with STK11 mutations may not wish to undergo genetic testing. In this case, they should have a thorough clinical exam to confirm or rule out PJS. The exam includes a careful inspection for freckles. In addition, people age 10 or older require gastrointestinal screening, abdominal ultrasound, and a blood test for anemia. Males over age 10 should have a testicular exam. Females should have a pelvic exam and ultrasound, pap smear, and breast exam annually, by age 20. Women age 35 or older should have a mammogram.
For people with no family history of PJS, treatment and management usually begin when PJS is diagnosed.
In past generations, polyp complications such as intestinal obstruction or hemorrhage were a frequent cause of death in PJS patients. However, treatment of polyps is now widely available. The doctor performs a polypectomy to remove the polyps. Polypectomy may be done at the same time as endoscopy, enteroscopy, colonoscopy, or laparoscopy. Anesthesia is used to make the patient more comfortable.
To manage polyps and screen for early signs of cancer, all people who have PJS and are age 10 or older need preventive screening on a regular basis. Gastrointestinal screening is the first test, and polypectomy is performed at the same time. Also at age 10, the person begins an annual screening program that includes a blood test for anemia and a testicular exam for boys.
After age 10, gastrointestinal screening with polypectomy is performed every two years.
By age 20, annual screening is expanded to include an abdominal ultrasound for both males and females, as well as a pelvic exam and ultrasound, pap smear, and breast exam for females.
By age 35, a woman with PJS should have her first mammogram; mammograms should be repeated every two years until the woman is 50. At that time, a mammogram should be added to the annual screening program.
Polyps found during preventive screening are immediately treated by polypectomy. Preventive screening may also reveal suspicious growths in the gastrointestinal tract or outside of it. These growths require urgent medical attention, since they may be precancerous or cancerous. Diagnosis may require additional tests or biopsy. Treatment is determined on an individual basis, depending on the patient's medical condition and the nature of the growth.
Some people with PJS do not care for the appearance of their freckles. Removal of freckles using laser therapy is an available treatment option.
Many people with PJS find the preventive screening program psychologically exhausting, and young children can find it frightening. These individuals often need the ongoing support and understanding of friends, family, and community. Several organizations composed of people with PJS, their family members, and medical professionals offer additional support and information. There is also an on-line support group dedicated to PJS.
People with PJS may find it helpful to consult a genetic counselor. Genetic counselors can provide up-to-date information about PJS research, therapy, and management.
Early detection of PJS is the key to its prognosis. Polyps cause less pain and fewer complications when found and removed early. In addition, the patient can begin a preventive screening program at an early age. This increases the likelihood of finding suspicious growths before they become malignant.
Unless they undergo regular screening, people with PJS have a one in two chance of dying from cancer before the age of 60. Moreover, the average age of cancer death in unscreened people with PJS is 39.
Researchers are actively investigating cancer screening, prevention, and treatment methods. In the meantime, regular preventive screening may reduce the illness and premature death associated with PJS.
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Avis L. Gibons