NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Thomas J. McGarrity, MD, Department of Medicine, Milton S. Hershey Medical Center, for assistance in the preparation of this report.
Peutz Jeghers syndrome (PJS) is an autosomal dominant genetic condition affecting around 1/50,000 and 1/200,000 individuals. 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). Affected individuals 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 is part of a heterogeneous group of disorders, known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract of affected individuals. It was first described in a pair of twin sisters with dark pigment spots on their lips and oral mucosa by Dr. J.T. Connor in 1895. These symptoms were attributed to a familial syndrome in 1921, when Dr. Jan Peutz described four affected siblings. The syndrome was then defined as a distinct entity by Dr. Harold Jeghers in 1949 when he described 10 cases and was subsequently named Peutz Jeghers syndrome in 1954 by Dr. Andre Bruwer. The gene causing PJS (STK-11/LKB1) was identified in 1998 and allows early detection of the disease and screening of family members.
PJS is characterized by the growth of multiple benign polyps called hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus (perianal). These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS 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.
Individuals with Peutz Jeghers syndrome are at a highly increased risk of developing gastrointestinal and other cancers including breast, cervical, uterine, pancreas, and lung. The lifetime risk of developing cancer in affected individuals can be as high as 93%. 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 an autosomal dominant genetic condition caused by mutations in the STK11/LKB1 gene. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.
Approximately 60-78% of individuals with PJS have an affected relative. Around 80-94% of PJS patients have an identified mutation in the STK11 gene, which means that other genes are possibly involved in the disease. More than 200 disease-causing (pathogenic) mutations have been reported and the penetrance of these mutations is thought to be 100%, meaning that an individual carrying a pathogenic mutation will necessarily develop the disease.
The STK11 gene produces a protein that is involved in the regulation of cell division and programmed cell death (apoptosis). It also interacts with p53, a major tumor suppression protein. Pathogenic mutations in STK11 lead to either cessation or dysfunction of protein production by the gene and uncontrolled cell growth, which can in turn lead to the development of benign polyps (hamartomas) and cancer.
The dark pigmented spots (melanocytic macules) are thought to be caused by inflammation and blockage of melanin migration from cells where it is produced (melanocytes) to cells forming the outermost layer of the skin (keratinocytes).
Peutz Jeghers syndrome is a rare disorder that affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. Limited evidence shows that the disease might be more prevalent in certain countries such as the Netherlands and China. Women are at a higher risk of developing cancer compared to men, as PJS increases the likelihood of developing breast, ovarian, cervical, and uterine cancer.
A clinical diagnosis of Peutz Jeghers syndrome can be made when any one of the following criteria is present:
The melanocytic macules can be identified with a physical examination. Polyps can be detected by endoscopy, x-ray examination, or wireless capsule endoscopy and are classified as PJS polyps by microscopic examination.
Genetic testing for the identification of disease-causing (pathogenic) mutations in the STK11 gene is recommended when any one of the following criteria is present:
Genetic testing is particularly useful when a pathogenic mutation has already been identified in a family. The penetrance of the STK11 gene mutation is thought to be 100% (which means that someone with a pathogenic mutation has a 100% chance of developing the disease), so genetic testing can give a definite diagnosis before symptoms appear. About half of PJS patients are diagnosed with genetic testing before the appearance of symptoms.
A consultation with a clinical geneticist or genetic counselor should be offered. As there is no cure for Peutz Jeghers syndrome, treatment is mostly focused on surveillance and control of symptoms. 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, MRE) or by swallowing a capsule that records internal images from inside the gastrointestinal tract (video capsule endoscopy, VCE). 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 PJS 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.
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.
A few medications based on the molecular biology of PJS and testing in animal models have shown promise for prevention of polyps in PJS patients. However, human clinical trial data is very limited as of 2018.
Polyps present in Peutz Jeghers syndrome overexpress and enzyme called COX2. A drug called celecoxib, which is a COX2 inhibitor, has been showed to reduce the number of polyps in mice models of PJS and might be helpful in humans to reduce polyp burden.
STK11 (the gene involved in PJS) is normally producing a protein that is involved in the inhibition of mTOR, a protein promoting cellular growth and proliferation. mTOR inhibitors such as rapamycin and everolimus have successfully reduced polyp burden in mice models.
Peutz-Jeghers polyps from mouse models and humans were associated with STAT-3 activation and increased interleukin-6, interleukin 11, and CXCL2.
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