Peutz-Jeghers syndrome is caused by a change called a mutation in a gene called STK11. This gene helps control how cells grow, repair themselves and die. When the gene does not work as usual, cells may grow in an unorganized way.

Most people with PJS — about 80% to 90% — inherit the gene mutation from a parent. The other 10% to 20% of people with PJS do not inherit it. Instead, they experience a new gene change called a de novo mutation. Why this happens is not known.

When PJS is inherited, a person only needs to inherit one mutated copy of the gene from a parent to have the condition. This is called an autosomal dominant pattern.

The dark spots and color changes that look like freckling on the lips, around the mouth, or on the genitals, hands and feet are caused by pigment building up in the skin. Sometimes this pigment, called melanin, collects in immune cells in the skin. They are called macrophages. Sometimes the skin layers have more melanin and more of the cells that make melanin, called melanocytes.

The hamartomatous polyps that form in the digestive tract happen when tissue in the tract grows in a way that is not organized. Exactly why hamartomatous polyps form is not known. But researchers think it may be that the STK11 gene change affects how cells grow and divide, which can allow the polyps to develop.

Peutz-Jeghers syndrome (PJS) can be diagnosed based on a person's symptoms, medical history and family history and, sometimes, test results.

How Peutz-Jeghers syndrome is diagnosed

You can be diagnosed with PJS if you have any of the following:

• Two or more hamartomatous polyps in the digestive tract.
• Dark spots on the skin around or inside the mouth or on the genitalia, hands or feet combined with a family history of PJS.
• Any number of hamartomatous polyps when combined with a family history of PJS or with the presence of characteristic dark spots on the skin.
• A genetic test that shows a certain change, called a pathogenic or likely pathogenic change, in the STK11 gene.

Tests to screen for polyps and cancer

To help make the diagnosis and look for polyps and cancer, healthcare professionals sometimes use tests that look directly at the digestive tract. These tests may include:

• Colonoscopy . In this test, a small tube with a light and camera is inserted through the rectum to examine the entire colon. The tube is guided through the colon using air to distend the colon and to get a clear view. Images of the lining of the colon are shown in real time on a video screen. Polyps usually appear as bumps or slightly raised spots or patches on an otherwise smooth lining. If polyps are found, a healthcare professional may use tools inserted through the tube to take out the polyps or take tissue samples to send to a lab for analysis. There also is the possibility of finding other areas of concern in the colon that can be sampled at the time of the exam.
• Upper endoscopy . In this test, a healthcare professional uses a long, narrow tube called an endoscope through your mouth down the esophagus, stomach and upper part of the small intestine. The tube contains a light and a tiny camera to view these areas. If polyps are found, they can be fully or partly removed using tools inserted through the tube.
• Capsule endoscopy . In this test, you swallow a vitamin-sized capsule with a tiny wireless camera and lights inside it. The camera takes pictures as it moves through the digestive tract. This includes areas of the small intestine that a standard endoscope cannot reach. Usually, the capsule leaves the body in a bowel movement within a few days.
• Balloon-assisted enteroscopy. During this procedure, a scope and an overtube with one or two attached balloons are inserted through your mouth or anus into your digestive tract. This method allows your healthcare professional to see areas of the small intestine that a regular endoscope cannot reach. This test may be done to closely examine polyps seen on other tests and, in some cases, remove them.
• Lab tests. If polyps are found during any of these tests, they often are fully or partly removed. A medical professional who studies tissue samples, called a pathologist, looks at the polyp tissue under a microscope to find out what type of polyp it is. This helps confirm whether the polyps match those usually caused by PJS.

If a capsule endoscopy cannot be done, a healthcare professional may suggest an imaging test to view polyps in areas of the small intestine that can't be reached with a regular endoscope. These could include:

• Magnetic resonance imaging (MRI) . This technique uses a magnetic field and computer-generated radio waves to create detailed images of the organs and tissues in the body. Most MRI machines are large, tube-shaped magnets. When you lie inside an MRI machine, the magnetic field inside works with radio waves and hydrogen atoms in your body to create cross-sectional images — like slices in a loaf of bread. The MRI machine also can produce 3D images that can be viewed from different angles. You are not getting radiation when you have an MRI.
• Magnetic resonance (MR) enterography. This test works in a manner that is similar to an MRI. But you also drink a contrast fluid before the exam. And at different times during the exam, you get injections of contrast and glucagon through a tube inserted into a vein, called an IV line. The contrast fluid helps make certain details on the images clearer.The glucagon is a medicine that slows the motion of the small intestine. This helps improve the image quality. You are not getting radiation when you have an MR enterography.
• Computerized tomography (CT) scan . You may have a CT scan — a special X-ray technique that provides more detail than a standard X-ray does. This test looks at the entire intestine as well as tissues outside it. CT enterography is a special CT scan that provides better images of the small intestine. You are getting a small dose of radiation during a CT scan.

Genetic testing

Genetic testing looks for a specific change in the STK11 gene using a blood sample. Finding this change can confirm a diagnosis of PJS. However, if you don't have the gene change, it doesn't rule out PJS. Some people with PJS do not have the gene change. In those people, the diagnosis can be based on the features of the polyps, the presence of the typical skin freckling pattern around the mouth, genitals, hands and feet, or a family history of PJS. If a gene change is found, genetic testing may be recommended for family members. This can allow for early treatment to help prevent complications.

Ongoing screening

Once a person is diagnosed with PJS, it's common to have some regular tests to check for polyps, cancer and other complications. If polyps are found, they may be removed during the procedure.

Which screening tests and how often they're done depends on your age, sex and personal history. Some of the tests are the same ones used to diagnose PJS. Screening tests may include the following:

• Colonoscopy and upper endoscopy, often starting between ages 8 and 10. These tests are used to check for polyps in the colon and stomach. The tests may be done earlier if you have symptoms. If no polyps are found, testing may start again at age 18. If polyps are found, or after the age of 18, these tests may be done every 2 to 3 years. Sometimes the tests are done more often.
• Capsule endoscopy or MR or CT enterography, often starting between ages 8 and 10. These tests are done to check for polyps in the small intestine. The tests may be done earlier if you have symptoms. If polyps are found, or after the age of 18, these tests may be done every 2 to 3 years. Sometimes the tests are done more often.
• A physical exam, usually starting at age 8 or when diagnosed in girls. These are done once a year to check for signs of early puberty. A blood test also can check for iron deficiency anemia, which can be a sign of bleeding polyps.
• A physical exam, usually starting at ages 8 to 10 in boys. These are done once a year to check the testicles for signs of tumors and the body for breast growth called gynecomastia. The breast growth can be caused by a type of tumor in the testicles. A blood test also can check for iron deficiency anemia, which can be a sign of bleeding polyps.
• A pelvic exam, pap smear and transvaginal ultrasound, often starting around ages 18 to 20 in women. These tests are done once a year to check for cervical, ovarian and uterine cancers.
• A clinical breast exam, mammogram and breast MRI, often starting around age 30 in women. Breast exams are needed every 6 to 12 months. Mammography and a breast MRI are needed once a year.
• MRI, MR cholangiopancreatography or endoscopic ultrasound, usually starting around age 30. One or more of these tests may be done to check for pancreatic cancer once a year. MR cholangiopancreatography is a special type of magnetic resonance imaging used to view the pancreas.

Conditions with similar symptoms

When diagnosing Peutz-Jeghers syndrome, healthcare professionals may consider other inherited conditions that can cause digestive tract polyps or skin changes.

Usually genetic testing can help make the diagnosis clear. But when the genetic testing results are not clear, some of these other conditions are considered. All are caused by different gene changes and affect the body in different ways.

• Juvenile polyposis syndrome. When comparing Peutz-Jeghers syndrome vs juvenile polyposis syndrome, both conditions can cause multiple hamartomatous polyps in the digestive tract and increase the risk of cancer. A key difference is that juvenile polyposis syndrome does not cause the dark spots in and outside the mouth and on the genitals, hands and feet that PJS does. Juvenile polyposis syndrome is linked to changes in genes other than the STK11 gene change that causes Peutz-Jeghers. These include changes in BMPR1A and SMAD4.
• Familial adenomatous polyposis (FAP). When comparing Peutz-Jeghers syndrome vs FAP, both involve digestive tract polyps and can lead to cancer. But FAP most often causes many adenomatous polyps in the large intestine. PJS causes mainly hamartomatous polyps that can appear throughout the digestive tract. FAP also does not cause dark spots on the skin, which are common with PJS. FAP is caused by changes in the APC gene, not STK11.
• Hereditary hemorrhagic telangiectasia, also called Osler-Weber-Rendu syndrome. When comparing Peutz-Jeghers syndrome vs hereditary hemorrhagic telangiectasia (HHT), they are different inherited conditions but can happen together in about 20% of people with PJS. HHT does not cause polyps like PJS does. But both conditions can cause skin symptoms. HHT can cause lacy red vessels or tiny red spots, mostly on the lips, face, fingertips, tongue and inside the mouth. These are called telangiectasias. HHT also often causes nosebleeds. HHT usually happens from changes in the ENG gene or ACVRL, not STK11.

These conditions are not the same as Peutz-Jeghers syndrome, even though some symptoms are similar.