Excerpt from Peutz-Jeghers Syndrome

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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.

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