eMedicine Specialties > Gastroenterology > Systemic Disease

Peutz-Jeghers Syndrome

Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC, Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center
Coauthor(s): 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; John M Carethers, MD, Professor of Medicine, Chief, Division of Gastroenterology, Department of Medicine, University of California, San Diego, School of Medicine
Contributor Information and Disclosures

Updated: Apr 9, 2009

Introduction

Background

Peutz-Jeghers syndrome (PJS) 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 (PJS) have a 15-fold increased risk of developing intestinal cancer compared with that of the general population. Such cancer locations includes gastrointestinal and extraintestinal sites.^{1,2,3,4,5,6,7,8}

The syndrome was described in 1921 by Jan Peutz (1886-1957), a Dutch physician who noted a relationship between the intestinal polyps and the mucocutaneous macules in a Dutch family. (The dermatologic component had previously been reported by John McHutchinson in 1896 in identical twins, one of whom subsequently died from intussusception).

Harold Jeghers (1904-1990), an American physician is credited with the definitive descriptive reports of the syndrome when he published "Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits" in 1949 with McKusick and Katz. The eponym Peutz-Jeghers syndrome (PJS) was introduced by the radiologist Andre J. Bruwer in 1954.

The gastrointestinal polyps found in Peutz-Jeghers syndrome (PJS) are typical hamartomas (see image below). 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 (PJS) with a higher frequency than in the general population.⁷

Pathophysiology

The cause of Peutz-Jeghers syndrome (PJS) appears to be a germline mutation of the STK11/LKB1 (serine/threonine kinase 11) tumor suppressor gene in most cases (66-94%), located on band 19p13.3. Penetrance of the gene is variable, causing varied phenotypic manifestations among patients with Peutz-Jeghers syndrome (PJS) (eg, inconsistent number of polyps, differing presentation of the macules) and allowing for a variable presentation of cancer.^{8,9,10,11,12,13,14,15,16}

Because the signaling pathway of the STK11 gene product is not currently 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/β-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 is not currently 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 is often observed in polyps and cancers from patients with Peutz-Jeghers syndrome (PJS).

Hyperactivation of the mammalian target of rapamycin (mTOR) signaling has also been associated with Peutz-Jeghers syndrome (PJS).¹⁶  Wei et al conducted a study of rapamycin on a mouse model of Peutz-Jeghers syndrome (PJS) by measuring polyp size, burden and phosphorylation levels of S6.¹⁷ The authors reported rapamycin decreased tumor burden in rapamycin-treated mice compared with controls, and this inhibition was also associated with a decrease in phosphorylated S6 levels. This finding suggests that rapamycin or its analogues may play a role in the treatment of Peutz-Jeghers syndrome (PJS).¹⁷

Other genes may also play a role in Peutz-Jeghers syndrome (PJS), such as those which encode for the MARK protein, homologues of the Par 1 polarity protein that associates with LKB1. However, de Leng et al performed direct sequencing and probe amplification in 23 families with Peutz-Jeghers syndrome (PJS) and were unable to identify any mutations in the MARK genes.¹⁰ This again supports the evidence that LKB1 defects remains the major cause of Peutz-Jeghers syndrome (PJS), although other mechanisms are involved; however, they remain to be elucidated.¹³

An interesting study by Tobi et al evaluated 8 patients with Peutz-Jeghers syndrome (PJS), 8 patients with juvenile polyposis, and 36 hyperplastic polyp sections as controls.¹⁸ The investigators demonstrated that Adnab-9, a premalignant marker found in Paneth cells, was more common in Peutz-Jeghers syndrome (PJS): 89% of PJS polyps were labeled with Adnab-9 compared with 88% of familial juvenile polyposis sections and 11% of the hyperplastic polyps.¹⁸ This study suggests Adnab-9 labeling may identify polyps at higher risk of malignant degeneration.

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 as cancer. Although the LKB1 gene is located on the short arm of chromosome 19, which is frequently deleted in tumors of sporadic origin, this has not been observed in non – small cell lung cancer, in which nearly 50% of these tumors harbor mutations of LKB1.¹⁹

Frequency

United States

Peutz-Jeghers syndrome (PJS) 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

The international frequency of Peutz-Jeghers syndrome (PJS) is unknown, but given the rarity of this condition, the frequency is probably similar to that reported in the US. Specific mutations of the STK11/LKB1 gene, however, may be more common in ceratin ethnic groups. For example, Zuo et al reported 2 new mutations in 3 Chinese families which were previously not described in white families.²⁰

Mortality/Morbidity

• The principal causes of morbidity in Peutz-Jeghers syndrome (PJS) 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 (PJS) develop and die from cancer by age 57 years. The mean age at first diagnosis of cancer is 42.9 years, +/– 10.2 years.
  • The cumulative risk for developing any cancers associated with Peutz-Jeghers syndrome (PJS) 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 (PJS), the following organ sites had a statistically significant elevated relative risk (RR) for cancer formation relative to the general population (with confidence intervals [CIs])⁶ : 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).
• Due to the increased risk of pancreatic adenocarcinoma in Peutz-Jeghers syndrome (PJS), screening with endoscopic ultrasound has emerged as a relatively new tool for early diagnosis (see image below).^21,22
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    Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.

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    Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.

• Intestinal obstruction can occur in about 50% of patients, and it 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, as shown in the images below.
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    Barium enema shows intussusception in the descending colon.

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    Barium enema shows intussusception in the descending colon.

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    Computed tomography scan reveals the classic yin-yang sign of an intussusceptum inside an intussuscipiens.

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    Computed tomography scan reveals the classic yin-yang sign of an intussusceptum inside an intussuscipiens.

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    Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.

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    Abdominal ultrasonography reveals the classic target sign of an intussusceptum inside an intussuscipiens.

• A retrospective study by Burkhart et al examined the incidence of sporadic Peutz-Jeghers syndrome (PJS) polyps over a 22-year period.²³ The investigators reported that sporadic PJS polyps are very rare, but individuals who may have even a single PJS polyp may have an accumulative lifetime risk of cancer that is similar to those with the syndrome.

Race

Peutz-Jeghers syndrome (PJS) has been described in all races. Peutz described the syndrome in a Dutch family in 1921.

Sex

The occurrence of Peutz-Jeghers syndrome (PJS) cases in males and females is about equal.

Age

The average age at Peutz-Jeghers syndrome (PJS) 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 lesions on the buccal mucosa, making the diagnosis possible in pediatric patients with a high level of suspicion (see image below).

Clinical

History

Peutz-Jeghers syndrome (PJS) 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 the 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 regardless of 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)²⁴
• Precocious puberty
• Gastrointestinal intussusception with bowel obstruction

Physical

Mucocutaneous pigmentation and melanin spots are typical of patients with Peutz-Jeghers (PJS) syndrome, and they 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 (see image below).
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    Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border.

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    Facial photograph of a patient with Peutz-Jeghers syndrome. Note the mucocutaneous pigmentation that crosses the vermilion border.

  • 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 appears on the buccal mucosa (66%) but rarely in the intestinal mucosa.
• Localization in the oral mucosa is typical of patients with Peutz-Jeghers syndrome (PJS) and does not happen with other types of dermatologic pigmented lesions, such as common lentigo (see image below). Freckles do not localize in the buccal mucosa.
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    Woman with solar lentigo.

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    Woman with solar lentigo.

• 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)²⁴
• Testicular mass

Causes

Linkage studies in 1997 mapped Peutz-Jeghers syndrome (PJS) to chromosome 19 band p13.3.¹⁴ The cause of Peutz-Jeghers syndrome (PJS) appears to be a germline mutation of the serine threonine kinase (STK11) gene which is present in a majority of patients.^11,12 This protein is likely regulated by phosphorylation by cAMP-dependent protein kinase A.

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