Peutz Jeghers syndrome

Peutz-Jeghers syndrome is a rare inherited disease that is characterized by the development of noncancerous growths called hamartomatous polyps (benign tumors made up of a mixture of mature cells normally found in that tissue) in the gastrointestinal tract particularly the stomach and intestines. Patients with Peutz-Jeghers syndrome have an estimated 15-fold increased risk of developing intestinal cancer compared to the general population ¹⁾. Approximately 50% of patients with Peutz Jeghers syndrome develop and die from cancer by 57 years of age. The overall risk of Peutz-Jeghers syndrome patients developing a cancer over adult life is 93%. Cancers are not only located on the gastrointestinal tract but can occur on many other sites including the breast, ovary, testicle, pancreas, uterus, esophagus and lung.

Children with Peutz-Jeghers syndrome often develop small, dark-colored spots on the lips, around and inside the mouth (buccal mucosa), near the eyes and nostrils, and around the anus (perianal). These spots may also occur on the hands and feet. They appear during childhood and often fade as the person gets older. In addition, most people with Peutz-Jeghers syndrome develop multiple polyps in the stomach and intestines during childhood or adolescence. Polyps can cause health problems such as recurrent bowel obstructions, chronic bleeding, and abdominal pain. Around half of patients with Peutz Jeghers syndrome have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (in the jejunum, specifically) but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhea, intestinal obstruction and rectal bleeding, which can lead to anemia. They can also provoke folding of the intestine into itself (intussusception), which can lead to severe abdominal pain and emergency surgery.

People with Peutz-Jeghers syndrome have a high risk of developing cancer during their lifetimes. Cancers of the gastrointestinal tract, pancreas, cervix, ovary, and breast are among the most commonly reported tumors. Individuals that develop cancer are usually affected around their fifth decade of life (age 40-49). Affected females have an increased risk for a benign ovarian tumor called SCTAT (sex cord tumors with annular tumors) for which symptoms may include irregular or heavy periods or early puberty. Usually before age 20, affected males can develop a tumor in the testes, called Sertoli cells carcinoma that secretes estrogen and can lead to breast development (gynecomastia).

Peutz Jeghers syndrome is caused by changes (mutations) in the STK11 gene and is inherited in an autosomal dominant manner ²⁾. Some people with Peutz Jeghers syndrome do not have mutations in the STK11 gene. In these cases, the cause is unknown ³⁾.

The prevalence of Peutz Jeghers syndrome is uncertain; estimates range from 1 in 25,000 to 300,000 individuals ⁴⁾.

As there is no cure for Peutz Jeghers syndrome, treatment is mostly focused on surveillance and control of symptoms. People with Peutz Jeghers syndrome should be monitored by a health care provider and checked regularly for cancerous polyp changes. Surgery may be needed to remove polyps that cause long-term problems. Iron supplements help counteract blood loss.

Figure 1. Peutz Jeghers syndrome lips

Peutz Jeghers syndrome causes

Mutations in the STK11 gene (also known as LKB1) cause most cases of Peutz-Jeghers syndrome. The STK11 gene is a tumor suppressor gene, which means that it normally prevents cells from growing and dividing too rapidly or in an uncontrolled way. A mutation in this gene alters the structure or function of the STK11 protein, disrupting its ability to restrain cell division. The resulting uncontrolled cell growth leads to the formation of noncancerous polyps and cancerous tumors in people with Peutz-Jeghers syndrome.

A small percentage of people with Peutz-Jeghers syndrome do not have mutations in the STK11 gene. In these cases, the cause of the disorder is unknown.

Peutz Jeghers syndrome inheritance pattern

Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing noncancerous polyps and cancerous tumors. In about half of all cases, an affected person inherits a mutation in the STK11 gene from one affected parent. The remaining cases occur in people with no history of Peutz-Jeghers syndrome in their family. These cases appear to result from new (de novo) mutations in the STK11 gene. For the individual with the condition, the chance of their children inheriting it will be 50%. However, other family members are generally not likely to be at increased risk.

In cases where the autosomal dominant condition does run in the family, the chance for an affected person to have a child with the same condition is 50% regardless of whether it is a boy or a girl. These possible outcomes occur randomly. The chance remains the same in every pregnancy and is the same for boys and girls.

• When one parent has the abnormal gene, they will pass on either their normal gene or their abnormal gene to their child. Each of their children therefore has a 50% (1 in 2) chance of inheriting the changed gene and being affected by the condition.
• There is also a 50% (1 in 2) chance that a child will inherit the normal copy of the gene. If this happens the child will not be affected by the disorder and cannot pass it on to any of his or her children.

Figure 2 illustrates autosomal dominant inheritance. The example below shows what happens when dad has the condition, but the chances of having a child with the condition would be the same if mom had the condition.

Figure 2. Peutz Jeghers syndrome autosomal dominant inheritance pattern

People with specific questions about genetic risks or genetic testing for themselves or family members should speak with a genetics professional.

Resources for locating a genetics professional in your community are available online:

• The National Society of Genetic Counselors (https://www.findageneticcounselor.com/) offers a searchable directory of genetic counselors in the United States and Canada. You can search by location, name, area of practice/specialization, and/or ZIP Code.
• The American Board of Genetic Counseling (https://www.abgc.net/about-genetic-counseling/find-a-certified-counselor/) provides a searchable directory of certified genetic counselors worldwide. You can search by practice area, name, organization, or location.
• The Canadian Association of Genetic Counselors (https://www.cagc-accg.ca/index.php?page=225) has a searchable directory of genetic counselors in Canada. You can search by name, distance from an address, province, or services.
• The American College of Medical Genetics and Genomics (http://www.acmg.net/ACMG/Genetic_Services_Directory_Search.aspx) has a searchable database of medical genetics clinic services in the United States.

Peutz Jeghers syndrome symptoms

Symptoms of Peutz Jeghers syndrome are:

• Brownish or bluish-gray spots on the lips, gums, inner lining of the mouth, and skin
• Clubbed fingers or toes
• Cramping pain in the belly area
• Dark freckles on and around the lips of a child
• Blood in the stool that can be seen with the naked eye (sometimes)
• Vomiting

Symptoms usually appear during the first decade of life and begin with spots of dark skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers as well as inside the mouth (oral mucosa) and around the anus (perianal). Multiple benign polyps called hamartomas also begin to grow in the gastrointestinal tract of affected individuals around that age. These polyps are located throughout the gastrointestinal tract and can cause nausea, vomiting, abdominal pain, intestinal obstruction and rectal bleeding. Abdominal surgery or endoscopic procedures might be necessary to remove polyps (polypectomy) to prevent polyps-related complications, such as folding of the intestine into itself (intussusception).

Clinical features of Peutz Jeghers syndrome can be divided into two types, cutaneous and gastrointestinal.

Cutaneous features

The most noticeable cutaneous feature of Peutz Jeghers syndrome is the appearance of melanocytic macules (pigmented spots) in 95% of patients. Tan, dark brown, or bluish black flat patches 1 to 5 mm in size are seen around the mouth, lips, gums, inner lining of the mouth, eyes, hands and feet, fingers and toes, anus and genital areas. Pigmentation usually appears before 5 years of age and may fade after puberty.

Gastrointestinal features

Gastrointestinal polyps occur later on in life and are rare in childhood. The polyps may cause bleeding and abdominal pain. They have a high chance of becoming malignant.

Small intestine intussusception (when one portion of an intestine protrudes into another) and intestinal obstruction are also fairly common complications of Peutz-Jeghers syndrome.

Peutz Jeghers syndrome diagnosis

A diagnosis of Peutz-Jeghers syndrome is based on the presence of characteristic signs and symptoms. In people with a clinical diagnosis of Peutz Jeghers syndrome, genetic testing of the STK11 gene confirms the diagnosis in approximately 100% of people who have a positive family history and approximately 90% of people who have no family history of Peutz Jeghers syndrome.

The polyps develop mainly in the small intestine, but also in the large intestine (colon). An exam of the colon called a colonoscopy will show colon polyps. The small intestine is evaluated in two ways. One is a barium x-ray (small bowel series). The other is a capsule endoscopy, in which a small camera is swallowed and then takes many pictures as it travels through the small intestine.

A clinical diagnosis of Peutz Jeghers syndrome can be made when any one of the following criteria is present:

• Presence of at least two Peutz Jeghers syndrome polyps
• Any number of Peutz Jeghers syndrome polyps and at least one close relative diagnosed with Peutz Jeghers syndrome Characteristic dark pigmented spots (melanocytic macules) and at least one close relative diagnosed with Peutz Jeghers syndrome
• Any number of Peutz Jeghers syndrome polyps and characteristic dark pigmented spots
• Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors
• History of intussusception, especially in a child or young adult

Additional exams may show:

• Part of the intestine folded in on itself (intussusception)
• Benign (noncancerous) tumors in the ear

Laboratory tests may include:

• Complete blood count — may reveal anemia
• Stool guaiac, to look for blood in stool
• Total iron-binding capacity (TIBC) — may be linked with iron-deficiency anemia

Peutz Jeghers syndrome treatment

Individuals with Peutz Jeghers syndrome have an increased risk for intestinal and other cancers. Frequent medical examination and testing is necessary to allow early detection of polyps and cancer. Peutz Jeghers syndrome management typically includes high-risk screening for associated polyps and cancers ⁵⁾. There is no specific treatment for Peutz Jeghers syndrome but the main goal is to manage and prevent associated problems of intestinal obstruction and intussusception, and cancer development.

Management of Peutz Jeghers syndrome patients should include:

• Annual complete blood count (CBC). The polyps of Peutz-Jeghers syndrome may ulcerate and be a source of blood loss and anemia; gastrointestinal bleeding may be massive but also microscopic, with subsequent iron deficiency, therefore, cell counts and iron studies should be monitored.
• Iron studies
• Fecal occult blood: Hemoccult should be performed to check for occult blood in the stool
• Carcinoembryonic antigen (CEA): This test has been used by some clinicians for screening and monitoring of cancer degeneration.
• Cancer antigen (CA)–19-9 and CA-125: CA-125 testing is indicated every year starting at age 18 years, and CA 19-9 is indicated every 1-2 years starting at age 25 years ⁶⁾
• Annual physical examination of breasts, abdomen, pelvis and testes
• Repeated removal of bleeding or large polyps (>5 mm) by endoscopic polypectomy
• Laparotomy and resection as required for repeated or persistent intestinal intussusception, obstruction, or persistent bleeding
• Surgical removal of cancers as they are diagnosed

After initial diagnosis, it is recommended that individuals older than 8 years or having symptoms undergo endoscopic and small bowel examination. The latter can be done with magnetic resonance imaging of the intestines (magnetic resonance enterography) or by swallowing a capsule that records internal images from inside the gastrointestinal tract (video capsule endoscopy). Gynecologic and breast examination are also recommended for women older than 18 years. Testicular examination is recommended for men.

Following initial workup after the diagnosis, endoscopy, colonoscopy, and small bowel examination should be performed every 2-3 years to detect polyps and potential tumors. An annual mammogram is recommended for women. Testicular ultrasound can be done every two years for men.

As Peutz Jeghers syndrome increases the risk of breast, uterine, and ovarian cancer, it is possible for affected women to undergo preventive mastectomy, hysterectomy or salpingo-oophorectomy (surgical removal of the breasts, uterus, and fallopian tubes and ovaries, respectively).

Polyps over 1 cm in size are removed with endoscopic techniques to avoid polyps-related complications such as bleeding and intussusception. These complications might require surgical interventions to be corrected. If a patient undergoes surgery, endoscopic removal of polyps (polypectomy) is performed at the same time as surgery to reduce the risk of recurrence of complications and surgery.

The freckling may be less obvious with careful sun protection. In some cases, the pigmentation may be lessened by cosmetic treatment. Cosmetic camouflage may also be useful. In cases where dark pigmented spots (melanocytic macules) have a greatly negative psychological impact on affected individuals, they can be partially removed with laser treatment.

DNA screening may be offered to family members to see if they have inherited the gene mutation. If so, they should also undergo regular screening for disease; however, not all families with Peutz-Jeghers syndrome map to the STK11/LKB1 locus ⁷⁾. Thus, a negative genetic test does not exclude the diagnosis.