Hereditary hamartosis Peutz–Jeghers; Hutchinson–Weber–Peutz syndrome; Lentiginosis polyposa Peutz; Peutz–Touraine syndrome; PJS
Peutz–Jeghers syndrome is an autosomal dominantly inherited disorder that is characterized by the combination of:
- Lentiginosis, i.e., typical pigmented lesions.
- Hamartomatous polyposis that occurs mainly in the small intestine but also in the colon and the stomach. Extraintestinal hamartomas are rare; possible localizations include the gallbladder, the urinary bladder, the heart, and the respiratory tract.
- Increased risk for various types of cancer (e.g., pancreas, gastrointestinal tract, bilateral breast cancer, rare gynecological tumors).
The clinical diagnosis is considered established when either two or more hamartomas or at least one hamartoma together with pigment spots or one hamartoma and positive familial history are found (Fig. 1).
Although Peutz–Jeghers syndrome is autosomal dominantly inherited, a large number of sporadic cases (possibly new mutations) occur. The disease is equally distributed between the sexes and the races. The clinical problems are bleeding, pain, and intussusception caused by the intestinal hamartosis and the increased risk for various tumors. Initial studies showed mutations in the coding region or splice sites of the LKB1/STK11 gene in 35–70 % of PJS cases. A second (yet unknown) gene that also causes PJS was therefore discussed. Since then, the ability to identify large deletions provided evidence suggesting that all PJS cases may be due to STK11 germline mutations.
Lentiginosis (pigment spots)
The typical pigmented spots occur mainly around the mouth, on the lips, and in the buccal mucosa but may also be found on the hands, the fingers, the feet, and around nose and eyes. In size, the spots range from few millimeters up to ~1 cm in diameter. They are not elevated above skin level. Their color may vary from light brown to nearly black. They may be present at birth or can emerge during the first years of life, although in some cases first spots appear in higher age. In most patients, the spots change during life, loosing intensity with increasing age. Histopathologically, they show an increase of melanin and melanocytes in the basal layer of the epidermal epithelium. No malignant transformation has ever been reported. If they represent a cosmetical problem, laser treatment is possible. Of the PJS patients, 5–50 % have no pigmented spots.
Fig. 1. Typical pigmented lesions perioral and on the lips
The hamartomatous polyps are mainly localized in the jejunum followed by the duodenum, the ileum, the colon, and the stomach. Other localizations like the esophagus, the gall bladder, the urinary bladder, the heart, and the respiratory tract have been described but remain extremely rare.
The main problems caused by the intestinal polyps are intussusception, bleeding, and pain. Intussusception leading to bowel obstruction and necrosis is the main cause for emergency surgery in those patients. The age range where symptoms are initiated reaches from newborn babies to old age. Initial clinical symptoms first occur in 33 % of patients in the first decade of life, further 33 % in the second.
The polyps in the intestine show a typical histopathological picture: intact intestinal goblet cell-rich mucosa covers branching bundles of smooth muscle from the lamina muscularis mucosa. These polyps are usually benign, but in some cases, adenomatous and carcinomatous changes have been reported, leading to the suggestion of a hamartoma–adenoma–carcinoma sequence.
Increased risk for malignant tumors
An increased risk for a wide variety of malignant tumors in PJS patients has been reported by several authors. In a meta-analysis, the risk ratio for all cancers was 15.2 with a cumulative risk of 93 % from age 15 to 64 years old. The most frequent tumor sites include the gastrointestinal tract (stomach, small intestine, colon), the pancreas, the lung, and the female breast (often bilateral). Furthermore, many patients develop tumors of the urogenital tract. In males Sertoli-cell tumors are found. In females, rare tumors, such as the benign bilateral form of the sex cord tumor with annular tubes (SCTAT) and the adenoma malignum of the uterine cervix, are found next to the normal carcinomata of the ovaries, the cervix, and the myometrium. Furthermore, malignant tumors in PJS patients have been found in almost all organ systems. It is therefore impossible to exclude any tumor from the spectrum found in PJ syndrome.
In most cases of PJS, an inactivating mutation in the STK11 or LKB1 gene can be shown. Initial studies showed mutations in the coding region or splice sites of the LKB1/STK11 gene in 35–70% of PJS cases. A second (yet unknown) gene that also causes PJS was therefore discussed. Since then, the ability to identify large deletions provided evidence suggesting that all PJS cases may be due to STK11 germline mutations. But still, a second gene responsible for PJS remains possible.
The gene product has a strong homology to the serine–threonine protein kinase XEEK1 from Xenopus. The STK11/LKB1 protein is nuclear as well as cytoplasmic. Furthermore, LKB1 is involved in other human disorders like diabetes and lung adenocarcinoma. The gene has been also investigated in many other sporadic tumors like colorectal, gastric, testicular, pancreatic, ovarian, and breast cancer, in malignant melanoma, as well as in different tumor cell lines. Mutations of the STK11/LKB1 gene were rare in these tumors, suggesting a minor role in the evolvement of sporadic tumors besides lung adenocarcinoma.
Loss of heterozygosity of the wild-type allele has been demonstrated in the hamartomatous polyps and in 70–100 % of the malignant tumors investigated from PJS patients.
Besides surgical or endoscopic removal of polyps and tumors, there is no established therapy for PJS. However, recent results give reason for hope that in the future medications will be able to favorably influence the course of disease. One possible target for medication could be the cyclooxygenase-2 (COX-2), an enzyme which is frequently elevated in PJS hamartomas. Pharmacological suppression of COX-2 is possible and leads to encouraging results in mouse model and a small series of patients by reducing polyp burden in some cases. Due to adverse events reported from patients treated with COX-2 inhibitors, further studies are on hold.
Regular examinations of PJS patients have two different aims: (i) to avoid complications caused by intestinal polyps such as bleeding, pain, intussusception, and bowel obstruction and (ii) to avoid complications caused by the early diagnosis of cancer or precursor lesions.
For the first aim, regular screening of the gastrointestinal tract is recommended. The second one is more difficult to achieve since malignant tumors have been reported in virtually all organ systems of PJS patients. To date, there is no consensus to what is the most adequate screening program for people at risk.
The “Deutsche Krebshilfe” (German Cancer Aid Society) recommends annual physical examinations, starting at age 12. Endoscopy of colon and stomach and imaging of the small intestine by either capsule endoscopy, MR-Sellink procedure, or double balloon enteroscopy should start at age 12 and be repeated every 2 years.
However, in a case report, first symptoms of PJS have been described as early as within the first days of life. It has also been shown that one third of patients become symptomatic during the first decade of life. The 12-year-old threshold as a starting point for regular examinations is therefore debatable.
Should symptoms occur in people at a younger age that carry the gene or that are, with an otherwise unknown genetic status, at risk, immediate clarification is warranted.
In female patients, regular gynecological examination including vaginal ultrasound should start at the age of 18 and be repeated on an annual basis. In male patients, regular examination of the genital organs is required in order to detect Sertoli-cell tumors.
At the age of 25, bilateral breast sonography in females should commence on an annual basis. At age 35, bilateral mammography or MRT of the female breast and pancreaticobiliary MRT (MRCP) is recommended to be carried out every other year.
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Udd L, Katajisto P, Rossi DJ et al (2004) Suppression of Peutz-Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology 127(4):1030–1037