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Gastroenterology > Systemic Disease
Peutz-Jeghers Syndrome
Article Last Updated: Jan 4, 2007
AUTHOR AND EDITOR INFORMATION
Section 1 of 10  
Author: Andrea Duchini, MD, Assistant Professor of Medicine, Associate Medical Director of Liver Transplantation, Division of Transplantation, Department of Surgery, The Methodist Hospital-Cornell University, Houston
Andrea Duchini is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and International Liver Transplantation Society
Coauthor(s):
John M Carethers, MD, Professor of Medicine, Chief, Division of Gastroenterology, Department of Medicine, University of California at San Diego
Editors: Robert J Fingerote, MD, MSc, BSc, FRCPC, Consultant, Clinical Evaluation Division, Biologic and Gene Therapies, Directorate Health Canada; Consulting Staff, Department of Medicine, Division of Gastroenterology, York Central Hospital, Richmond Hill, Ontario; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Noel Williams, MD, Professor Emeritus, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Professor, Department of Internal Medicine, Division of Gastroenterology, University of Alberta, Edmonton, Alberta, Canada; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; Julian Katz, MD, Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania
Author and Editor Disclosure
Synonyms and related keywords:
PJS, intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules, cancer of the GI tract, intestinal polyps, STK11 gene mutation, STK11/LKB1 gene mutation, serine/threonine kinase 11 gene, gastrointestinal polyps, GI polyps, hamartomas, intestinal lesions, intestinal cancer
Background
Peutz-Jeghers syndrome is an autosomal dominant inherited disorder characterized by intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules. Although the intestinal lesions are hamartomas, patients with Peutz-Jeghers syndrome have a 15-fold increased risk of developing intestinal cancer compared to that of the general population. Cancer location includes gastrointestinal and extraintestinal sites. The syndrome was described in 1921 by Peutz, who noted a relationship between the intestinal polyps and the mucocutaneous macules in a Dutch family. Subsequently, Jeghers is credited with the definitive descriptive reports in the 1940s.
The gastrointestinal polyps found in Peutz-Jeghers syndrome are typical hamartomas. Their histology is characterized by extensive smooth muscle arborization throughout the polyp. This may give the lesion the appearance of pseudoinvasion, because some of the epithelial cells, usually from benign glands, are surrounded by the smooth muscle. Nevertheless, cancer may develop in the gastrointestinal tract of patients with Peutz-Jeghers syndrome with a higher frequency than in the general population.
Pathophysiology
The cause of Peutz-Jeghers syndrome appears to be a germline mutation of the STK11/LKB1 (serine/threonine kinase 11) gene in most cases, located on band 19p13.3. Penetrance of the gene is variable, causing varied phenotypic manifestations among patients with Peutz-Jeghers syndrome (eg, inconsistent number of polyps, differing presentation of the macules) and allowing for a variable presentation of cancer.
Because the signaling pathway of the STK11 gene product currently is not identified, the mechanism of hamartomatous polyp formation and mucocutaneous pigmentation is not known. In cancer formation, STK11 inactivation appears to occur early and might be followed by interruption of the APC/ß-catenin and p53 pathways, but this has not been fully elucidated. However, the cyclic adenosine monophosphate (cAMP)–dependent protein kinase A apparently can phosphorylate the murine STK11 protein in vitro; the significance of this currently is not known, but this phosphorylation may be important for STK11 regulation. STK11 may be a tumor suppressor gene in that its overexpression can induce a growth arrest of a cell at the G1 phase of the cell cycle and that somatic inactivation of the unaffected allele of STK11 often is observed in polyps and cancers from patients with Peutz-Jeghers syndrome.
STK11/LKB1 seems to regulate both cell polarity and tumor suppression, predisposing patients to mucosal prolapse first, leading to polypoid lesions and at the same time cancer.
Frequency
United States
Peutz-Jeghers syndrome is rare, with a frequency of encounter from polyposis registries one tenth that of familial adenomatous polyposis. This would place the frequency from 1 case per 60,000 people to 1 case per 300,000 people.
International
International frequency is unknown.
Mortality/Morbidity
- The principal causes of morbidity in Peutz-Jeghers syndrome stem from the intestinal location of the polyps (ie, small intestine, colon, stomach). Morbidity includes small intestinal obstruction and intussusception (43%), abdominal pain (23%), hematochezia (14%), and prolapse of a colonic polyp (7%), and these typically occur in the second and third decades of life.
- Almost 50% of patients with Peutz-Jeghers syndrome develop and die from cancer by age 57 years. The mean age at first diagnosis of cancer is 42.9 years, add or subtract 10.2 years. The cumulative risk for developing any cancers associated with Peutz-Jeghers syndrome in patients aged 15–64 years is 93%. The cumulative risks of developing a particular cancer from ages 15-64 years are as follows: esophagus 0.5%, stomach 29%, small intestine 13%, colon 39%, pancreas 36%, lung 15%, testes 9%, breast 54%, uterus 9%, ovary 21%, and cervix 10%. In a meta-analysis of 210 patients with Peutz-Jeghers syndrome, the following organ sites had a statistically significant elevated relative risk (RR) for cancer formation over the general population (with confidence intervals [CI]): all cancers (RR 15.2, CI 12-19), esophagus (RR 57, CI 2.5-557), stomach (RR 96, CI 96-368), small intestine (RR 520, CI 220-1306), colon (RR 84, CI 47-137), pancreas (RR 132, CI 44-261), lung (RR 17, CI 5.4-39), breast (RR 15.2, CI 7.6-27), uterus (RR 16.0, CI 1.9-56), and ovary (RR 27, CI 7.3-68).
- Intestinal obstruction can occur in about 50% of patients and is usually localized in the small bowel. Obstruction can be complete or incomplete and is caused by the polyp itself or by the subsequent intussusception that may occur.
Race
Peutz-Jeghers syndrome has been described in all races. Peutz described the syndrome in a Dutch family in 1921.
Sex
The occurrence of cases in males and females is about equal.
Age
The average age at diagnosis is 23 years in men and 26 years in women. Pigmented lesions are present in the first years of life and may fade at puberty, except for those on the buccal mucosa, making diagnosis possible in pediatric patients with a high level of suspicion.
History
Peutz-Jeghers syndrome is characterized by the combination of pigmented lesions in the buccal mucosa and gastrointestinal polyps. The number, as well as the size and the location, of polyps may vary from patient to patient. Isolated melanotic mucocutaneous pigmentation without gastrointestinal polyps has also been described because of the genetic variability of the syndrome. The risk of cancer remains elevated with disregard to the presence or the absence, as well as the number, of gastrointestinal polyps.
- Family history of Peutz-Jeghers syndrome
- Repeated bouts of abdominal pain in patients younger than 25 years
- Unexplained intestinal bleeding in a young patient
- Prolapse of tissue from the rectum
- Menstrual irregularities in females (due to hyperestrogenism from sex cord tumors with annular tubules)
- Gynecomastia in males (possible due to the production of estrogens from Sertoli cell testicular tumors)
- Precocious puberty
- Gastrointestinal intussusception with bowel obstruction
Physical
Mucocutaneous pigmentation and melanin spots are typical of patients with Peutz-Jeghers syndrome and are present in more than 95% of cases. They appear as small, flat, brown or dark blue spots with an appearance of freckles, most commonly in the peribuccal area.
- Cutaneous pigmentation (1- to 5-mm macules) is usually located in the perioral region, crossing the vermilion border (94%), in the perinasal and perioral areas.
- They may be present on the fingers and the toes, on the dorsal and volar aspects of the hands and the feet (62-74%), and around the anus and genitalia.
- They may fade after puberty.
- Mucous membrane pigmentation, primarily the buccal mucosa (66%) and rarely the intestinal mucosa
- Localization in the oral mucosa is typical of patients with Peutz-Jeghers syndrome and does not happen with other types of dermatologic pigmented lesions, such as common lentigo. Freckles do not localize in the buccal mucosa.
- A rectal mass (rectal polyp) may be found during a rectal examination. In rare cases (7% of cases), the polyp can prolapse outside the anus if it reaches a significant size.
- Gynecomastia and growth acceleration (due to Sertoli cell tumor)
- Testicular mass
Causes
The cause of Peutz-Jeghers syndrome appears to be a germline mutation of the STK11 gene, located on band 19p13.3. This protein is likely regulated by phosphorylation by cAMP-dependent protein kinase A.
Familial Adenomatous Polyposis
Other Problems to be Considered
Bannayan-Riley-Ruvalcaba syndrome
Cowden disease
Cronkhite-Canada syndrome
Gardner variant of familial adenomatous polyposis
Juvenile polyposis syndrome
Lab Studies
- The polyps may ulcerate and be a source of blood loss and anemia. Gastrointestinal bleeding may be massive but also microscopic with subsequent iron deficiency. Cell counts and iron studies should be monitored.
- The carcinoembryonic antigen (CEA) test has been used by some physicians for screening and monitoring of cancer degeneration.
- Hemoccult, a type of fecal occult blood test (FOBT), should be performed to check for blood in the stool.
Imaging Studies
- Enteroclysis study (preferred) and dedicated small bowel follow-through x-rays are used to determine the presence and the location of small intestinal polyps.
- Esophagogastroduodenoscopy
- Colonoscopy
- Capsule enteroscopy
- Push enteroscopy, intraoperative enteroscopy, and double-balloon enteroscopy (diagnostic and therapeutic options)
- Imaging studies of the liver and the pancreas are indicated because of the risk of pancreatic cancer as well as of gallbladder polyps and cancer. These imaging studies may include ultrasonography as well as CT with pancreatic details or magnetic resonance cholangiopancreatography (MRCP).
Procedures
- Hemorrhagic or large polyps (>5 mm) should be removed by endoscopic polypectomy to confirm the diagnosis and help control symptoms.
- Laparotomy and resection should be performed for repeated or persistent small intestinal intussusception, obstruction, or persistent intestinal bleeding.
Histologic Findings
Characteristic histology of Peutz-Jeghers polyps includes extensive smooth muscle arborization throughout the polyp, with the appearance of pseudoinvasion because some of the epithelial cells, usually from benign glands, are surrounded by the smooth muscle.
Medical Care
Peutz-Jeghers syndrome should be promptly diagnosed in patients as early as possible. Genetic counseling should also be provided. Many of the gastrointestinal lesions will start developing early in life even if the syndrome is clinically apparent in the second and third decades of life. Proper screening for both intestinal cancers and extraintestinal cancers should be implemented.
- Annual physical examination that includes evaluation of the breasts, abdomen, pelvis, and testes
- Annual complete blood count
- Removal of hemorrhagic or large polyps (>5 mm) by endoscopic polypectomy
- Some suggestions for surveillance for cancer include the following:
- Small intestine with small bowel radiography every 2 years
- Esophagogastroduodenoscopy and colonoscopy every 2 years
- Ultrasound of the pancreas yearly
- Ultrasound of the pelvis (women) and testes (men) yearly
- Mammography (women) at ages 25, 30, 35, and 38 years, then every 2 years until age 50 years, then annually
- Papanicolaou (Pap) test every year
Surgical Care
Patients with Peutz-Jeghers syndrome usually undergo numerous surgeries during their lives. These surgeries include laparotomies and laparoscopies for both gastrointestinal problems and extraintestinal problems.
- Push enteroscopy and interoperative enteroscopy with polypectomy are used to remove larger polyps and may defer the need for repeated small bowel resections.
- Laparotomy and resection, as indicated, for small intestinal intussusception, obstruction, or persistent intestinal bleeding may be necessary.
- Surgical treatment of extraintestinal cancers detected by surveillance and diagnosis is required.
Consultations
- Follow-up care should be supervised by a gastroenterologist familiar with Peutz-Jeghers syndrome.
- Genetic consultation and counseling as well as urological and gynecological consultations are required in the management of these patients.
Activity
No activity restraints should be made.
Complications
- In young patients, small intestinal obstruction and intussusception are the main complications of Peutz-Jeghers syndrome. This is due to the small intestinal location of the polyps.
- Cancer is the main consequence as patients with Peutz-Jeghers syndrome age (93% cumulative risk by age 64 y). The major sites of cancer occurrence in order of RR over the general population are small intestine (RR 520), stomach (RR 213), pancreas (RR 132), colon (RR 84), esophagus (RR 57), ovary (RR 27), lung (RR 17), uterus (RR 16), and breast (RR 15.2). In addition, other reproductive site cancers have been associated with Peutz-Jeghers syndrome, including adenoma malignum of the cervix, Sertoli cell tumors, and sex cord tumors with annular tubules.
- Adhesions and intestinal obstruction or short bowel syndrome from repeated abdominal surgeries: This can be limited with use of endoscopic methods for intestinal polyp resection, such as intraoperative enteroscopy and push enteroscopy.
Prognosis
- Forty-eight percent of patients with Peutz-Jeghers syndrome develop and die from cancer by age 57 years. Others potentially may have a normal life span.
Patient Education
- The patient with Peutz-Jeghers syndrome should be educated on the potential symptoms of intestinal obstruction and instructed on the need for cancer surveillance.
Medical/Legal Pitfalls
- Lack of adequate follow-up and cancer surveillance is a potential pitfall.
- In wake of the discovery of the genetic cause(s) of Peutz-Jeghers syndrome, genetic counseling by someone knowledgeable in this disease should be provided if genetic testing is being considered. Genetic counseling relays the risks and benefits and consequences of genetic testing to the patient. It also informs the patient of the consequences of a positive, negative, or inconclusive genetic test result. Genetic counseling also includes information on risk of transmission to offspring and may provide guidance for the patient regarding testing of other family members. Genetic testing is provided only in specialized laboratories. Further developments are anticipated.
Special Concerns
- Follow-up care should be supervised by a gastroenterologist familiar with Peutz-Jeghers syndrome.
- Consultation with surgery, oncology, urology, and gynecology may be necessary in the management of these patients.
- Genetic counseling is recommended for the patients and their families.
- Breast cancer in patients with Peutz-Jeghers syndrome may occur at a young age and also may be bilateral.
| Media file 1:
Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border. |
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Media type: Photo
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Peutz-Jeghers Syndrome excerpt Article Last Updated: Jan 4, 2007
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