Hereditary Cancer Predisposition Program at the Cancer Center

Peutz-Jeghers Syndrome (PJS)

What is Peutz-Jeghers syndrome?

Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome identified by the presence of gastrointestinal polyps and altered pigmentation (freckling) of certain skin and mucosal areas. The polyps in individuals with PJS are most often found in the small intestine, but also occur in other parts of the gastrointestinal tract.

In addition to polyps, people with Peutz-Jeghers syndrome are at an increased risk for developing cancers:

• Colorectal cancer
• Gastric (stomach) cancer
• Pancreatic cancer
• Breast cancer
• Uterine and cervical cancer
• Lung cancer
• Benign and malignant tumors of the ovaries and testicles

Because Peutz-Jeghers syndrome is hereditary, the risk of developing the features associated with PJS can be passed from generation to generation in a family.

What causes Peutz-Jeghers syndrome (PJS)?

Peutz-Jeghers syndrome is caused by alterations (mutations), at a specific area in a person’s genetic information. Each of us has a large amount of genetic information that is organized into smaller segments known as "genes." Genes provide the instructions that our cells need to perform different functions within our bodies.

There is a specific gene known as STK11 (also known as LBK1), located on chromosome 19 at position q13.3, that is altered in patients with PJS. The STK11 gene has the ability to produce an enzyme called "serine/threonine kinase 11" that has several important functions:

• It acts as a tumor suppressor — the enzyme keeps cells from growing and dividing too quickly and it promotes cell death.
• It helps certain types of cells correctly orient themselves within tissues.
   
• It helps determine the amount of energy a cell uses.

It is believed that through a combination of these mechanisms, STK11 aids in the prevention of tumors.

How is Peutz-Jeghers syndrome (PJS) inherited?

With the exception of egg and sperm cells, each cell of the body normally has two working copies of the STK11 gene. In patients with PJS, however, each cell contains only one working STK11 copy. While the second copy is present, it is altered so that it does not function properly. Patients are born and develop normally, but are at an increased risk to develop non-cancerous and cancerous growths. These growths are believed to develop because, over time, the second working copy of the STK11 gene may become altered within one or more cells. This can lead to abnormal proliferation of the affected cells, increasing their chance to form tumors or cancer.

A person carrying an alteration in one copy of the STK11 gene has a 50 percent (or 1 in 2) chance of passing this same alteration on to each of his or her children. Children who inherit the altered gene copy will have Peutz-Jeghers syndrome and will therefore be at increased risk to develop cancer and other features associated with this condition.

Approximately 50 percent of patients with Peutz-Jeghers syndrome inherit an altered copy of the STK11 gene from a parent who also has PJS. In the remaining 50 percent of patients, there is no family history of Peutz-Jegher Syndrome. In these individuals, PJS likely results from occurrence of a "new mutation" in one copy of the STK11 gene. Although these individuals will be the first ones in their family to carry the genetic change, each of their future offspring will now have a 50 percent chance of inheriting the same genetic change.

How do you diagnose Peutz-Jeghers syndrome (PJS)?

The diagnosis of Peutz-Jeghers syndrome relies primarily on the presence of certain symptoms, including hamartomatous (benign, non-cancerous) intestinal polyps, altered pigmentation of the skin and mucus membranes, and/or a family history of PJS.

Intestinal polyps

The polyps seen in individuals with Peutz-Jeghers syndrome are most often found in the small intestine, but they can also occur in the stomach and large bowel. During childhood, polyps are typically non-cancerous, but they can bleed and cause anemia (lowering the level of healthy red blood cells) and block the intestines. The age at which polyps are first observed in individuals with PJS can vary among families. One study showed that children most often showed their first gastrointestinal symptoms at 10 years of age, and children most often had their first polyps removal (polypectomy) at 13 years of age (Amos et al., 2004).

Mucocutaneous pigmentation

Mucocutaneous pigmentation (altered coloring of the skin, gums and other mucus membranes) is rarely present at birth, but develops during early childhood (usually before 5 years of age) as dark blue to dark brown flat spots in the following areas:

• Around the mouth, eyes and nostrils
   
• In the peri-anal area
   
• On the gums
   
• On the fingers

The spots can fade in puberty and adulthood. One report estimates that 82 percent of patients with Peutz-Jeghers syndrome have freckling (Amos et al., 2004). That means approximately 18 percent of patients do not have freckling but remain at risk to develop other features of PJS.

The symptoms of Peutz-Jeghers syndrome can vary within a family. Some affected individuals may have only polyps or altered pigmentation, while others may develop more extensive symptoms. Since people with PJS often show subtle symptoms, it is possible that this condition is under-diagnosed in families and that more individuals with Peutz-Jeghers syndrome have inherited the condition from their parents than currently thought.

Family history

A careful and detailed review of a person's medical and family history is important in diagnosing Peutz-Jeghers syndrome. A doctor or genetic counselor may construct a pedigree, or a multi-generation family tree, that shows which members of the family have developed cancer, the types of cancer and the ages of onset, as well as the presence of any symptoms. If the pattern of symptoms and/or cancers is suggestive of PJS, the physician or counselor may recommend that genetic testing be performed.

How do you test for Peutz-Jeghers syndrome (PJS)?

In order to confirm on a molecular level that an individual has Peutz-Jeghers syndrome, he or she can undergo the process of genetic testing:

• First, a blood or saliva sample is obtained.
• DNA is isolated from the sample and the two copies of the STK11 gene are evaluated using a variety of methods and compared to the normal reference sequence for STK11.
• If an alteration in one STK11 gene copy is identified, the genetic counselor can next examine whether the alteration has been previously reported in other individuals with Peutz-Jeghers syndrome.

This information could further strengthen the conclusion that the STK11 alteration was the cause of the symptoms in the individual. In individuals with a clinical diagnosis of PJS, molecular genetic testing of the STK11 gene reveals disease-causing alterations in approximately 100 percent of individuals who have a positive family history. Approximately 90 percent of individuals who have no family history of Peutz-Jeghers syndrome are found to have an alteration in STK11. However, it is important to remember that not all patients with Peutz-Jeghers syndrome carry a detectable alteration in the STK11 gene. Therefore, the failure to identify an alteration in the STK11 gene does not exclude a diagnosis of PJS.

STK11 genetic test results can also provide important information for other family members. Knowing the specific alteration that is present in a person with Peutz-Jeghers syndrome allows other family members to undergo testing to determine whether they also carry the alteration and could therefore develop the features of PJS.

Reproductive options for people with an STK11 gene alteration

Reproductive options exist for an individual with an alteration in the STK11 gene who does not wish to pass this alteration on to future children:

• Prenatal diagnosis — DNA is isolated from the cells of the developing baby though one of two procedures (chorionic villus sampling (CVS) or amniocentesis) and is analyzed for alterations in the STK11 gene. With appropriate counseling, a parent can then decide whether to carry the pregnancy to term or to end the pregnancy.
• Preimplantation Genetic Diagnosis (PGD) — For couples using in vitro fertilization to become pregnant, embryos can be tested for genetic disorders before transferring them into the uterus. Only healthy embryos carrying two working copies of the STK11 gene would be implanted.

Before one can proceed with prenatal testing or PGD, a STK11 mutation must be identified in a parent with PJS.

What are the cancer risks in children and adults with Peutz-Jeghers syndrome?

Individuals carrying an alteration in one copy of the STK11 gene are born and develop normally, but they are at an increased risk to develop a variety of cancers, including:

• Colorectal cancer
• Gastric cancer
• Pancreatic cancer
• Breast cancer
• Ovarian cancer
• Uterine cancer
• Cervical cancer
• Lung cancer
• Certain benign and malignant gynecologic and gonadal tumors.

One study (Hearle et al.) showed that people with Peutz-Jeghers syndrome had an increased risk of cancer over time:

• At age 20, the risk was 2 percent
• At age 30, the risk was 5 percent
• At age 40, the risk was 17 percent
• At age 50, the risk was 31 percent
• At age 60, the risk was 60 percent
• At age 70 years, the risk 85 percent

The types of cancer most frequently found in people with Peutz-Jeghers syndrome are:

• Gastrointestinal cancer - occurred in:
  • 1 percent of 30-year-olds
  • 9 percent of 40-year-olds
  • 15 percent of 50-year-olds
  • 3 percent of 60-year-olds
• Breast cancer - estimated risk is:
  • 8 percent for 40-year-olds
  • 31 percent for 60-year-olds
• Gynecologic cancer - estimated risk is:
  • 1 percent for 30-year-olds
  • 3 percent for 40-year-olds
  • 8 percent for 50-year-olds
  • 18 percent for 60-year-olds
  • 18 percent for 70-year-olds
• Pancreatic cancer - estimated risk is:
  • 3 percent for 40-year-olds
  • 5 percent for 50-year-olds
  • 7 percent for 60-year-olds
  • 11 percent for 70-year-olds
• Lung cancer - estimated risk is:
  • 1 percent for 40-year-olds
  • 4 percent for 50-year-olds
  • 13 percent for 60-year-olds
  • 17 percent for 70-year-olds

What cancer screenings should people with Peutz-Jeghers syndrome (PJS) have?

Regardless of whether one decides to pursue testing for STK11 mutations, the following surveillance recommendations, which are listed on the www.genetests.org Web site, are strongly recommended.

General cancer screening

Stomach, small and large bowel cancer screening:

• Upper and lower endoscopy (a procedure that lets the doctor see the inside lining of the digestive tract) beginning at age 8-10 years (for baseline screening) and repeated every two years into adulthood
• Small bowel follow-through (X-ray examination of the small bowels) or wireless capsule endoscopy (imaging the bowels with a microscopic camera inside a pill that is swallowed) beginning at age 8-10 years (for baseline screening) and repeated every two years
• Colonoscopy beginning at age 25 years and repeated every two years (or earlier if symptoms arise)

Pancreatic cancer screening:

• Endoscopic ultrasound (a procedure that combines endoscopy and ultrasound to obtain images and information about the digestive tract and the surrounding tissue and organs) or abdominal ultrasound screen for pancreatic cancer beginning at age 30 years and repeated every one to two years

Cancer screening for women

Breast:

• Monthly breast self-examination and yearly clinical breast examination beginning at age 20 years
• Mammograms every two to three years beginning at age 20 years and yearly mammograms beginning at age 40 years

Gynecologic (ovary and uterus):

• Yearly gynecologic examination including Pap test
• Yearly transvaginal ultrasound (a test where a small ultrasound probe is inserted like a speculum for a pelvic examination to obtain better imaging of the uterus) beginning at age 20 years

Cancer screening for men

Testicle:

• Yearly testicular examination and consideration of ultrasound beginning by age 10 years

Lung cancer screening

Currently, there are no guidelines regarding surveillance for development of lung cancer in people with Peutz-Jeghers syndrome. However, patients should consider having annual chest X-rays starting five years before the earliest diagnosis of lung cancer in the family, if cancer is present.

Healthy lifestyle

In addition to following recommended cancer surveillance guidelines, children and adults with Peutz-Jeghers syndrome should be encouraged to lead as healthy a lifestyle as possible, using these safeguards:

• Avoidance of excess sun exposure
• Use of sunblock and a hat when out in the sun
• Avoidance of tobacco use
• Limited exposure to tobacco smoke

Patients and parents should be alert to signs and symptoms of illness and pursue medical attention promptly should these occur.

What support resources are there for people with Peutz-Jeghers syndrome (PJS)?  

Clinical services

We recommend that children with a diagnosis of Peutz-Jeghers syndrome, or those suspected of having Peutz-Jeghers syndrome, contact the Division of Gastroenterology, Hepatology and Nutrition at The Children's Hospital of Philadelphia to discuss issues related to the management of this condition. Please call 215-590-3630 to schedule an appointment.

Adults who have Peutz-Jeghers syndrome or who would like more information about Peutz-Jeghers syndrome may contact the Gastrointestinal (GI) Cancer Risk Evaluation Program at the Hospital of the University of Pennsylvania by calling the coordinator, Samatha Halter, at 215-898-0154 or scadieux@mail.med.upenn.edu.

Resources

American Cancer Society (for information on regional support)
1599 Clifton Rd. NE
Atlanta, GA 30329
Phone: 1-800-227-2345
www.cancer.org

Colon Cancer Alliance
1200 G Street, NW
Ste 800
Washington, DC 20005
Phone: 1-877-422-2030
http://www.ccalliance.org/index.html

National Library of Medicine Genetics Home Reference: Peutz-Jeghers syndrome
GeneReviews: Peutz-Jeghers syndrome

 

References

1. Amos, C.I., et al. (2004). Genotype-phenotype correlations in Peutz-Jeghers syndrome. J Med Genet, 41, 327-33.
2. Hearle, N., et al. (2006). Frequency and spectrum of cancers in Peutz-Jeghers syndrome. Clin Cancer Res, 12, 3209-15.

Reviewed by: Kim Nichols, MD, The Children's Hospital of Philadelphia
Date: January 2011