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Peutz–Jeghers syndrome
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Created by Dr. Edward Cowen from https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/melanocytic-macules-associated-with-peutz-jeghers-syndrome .
Peutz–Jeghers syndrome (PJS) is a rare autosomal dominant disorder characterized by gastrointestinal polyps, hamartomas, mucocutaneous pigmentation, recurrent abdominal pain from intussusceptions, and an increased risk of intestinal and other malignancies. Clinically and histologically, the pigmented macules of PJS are simple lentigines. They are typically found on the lips and oral mucosa but may involve epithelium around the eyes, nostrils, and anus; they may also be seen on the dorsum or volar aspect of the hands and feet. These brown to black macules are generally round or oval and 1–5 mm in diameter. They may be irregular in shape and may occasionally manifest with a blue–gray hue.
Most patients have a germline mutation of the serine/threonine kinase 11 (STK11/LKB1) tumor suppressor gene, located at chromosome 19p13.3. A second PJS disease locus exists at 19q13.4. Genetic testing may be useful in equivocal cases as well as in counseling at-risk families.
Management Strategy
Management is predicated upon the potential for visceral complications and familial inheritance. PJS must also be distinguished from other hereditary gastrointestinal cancer syndromes. This includes a review of family histories as well as an evaluation for associated findings, such as gastrointestinal polyps, which occur in nearly all PJS patients, gastrointestinal obstruction, recurrent intussusceptions, gastrointestinal bleeding, and a variety of other internal malignancies. Although symptoms may arise in early childhood, the disease is most often discovered between the ages of 10 and 30 years. Any child seen with recurrent, unexplained abdominal pain should raise concern for intussusception, a medical emergency often associated with PJS. Gastrointestinal polyps are most often found in the small bowel but may also be seen in the stomach, large bowel, and rectum; these polyps are at risk for malignant degeneration. Esophagogastroduodenoscopy, capsule endoscopy, balloon enteroscopy, and colonoscopy are important in the evaluation and treatment of gastrointestinal polyposis.
Cancers of the esophagus, stomach, intestines, pancreas, lung, uterus, and testes (Sertoli cell) all have an elevated relative risk in patients with PJS. Women with this disorder also carry an increased risk of bilateral breast cancer. Ovarian neoplasms, especially granulosa cell tumors, may be seen. Both in men and women, sex cord tumors with annular tubules, and sex cord stromal tumors with sexual precocity, may develop.
Genetic testing in suspected cases may identify familial or de novo mutations. Genetic counseling of PJS patients and their relatives is recommended. Patients and families should be reassured that the mucocutaneous macules are benign and may improve or disappear in adulthood. Several aesthetic interventions for these pigmented macules have been described, with varying responses; removal may potentially mask the underlying disorder in patients with undiagnosed PJS.
The Q-switched Nd:YAG laser and ruby laser (Q-switched and short pulsed) have been used in the treatment of labial macules without sequelae or recurrences. Anesthesia is not usually required and minimal wound care is necessary. CO 2 , alexandrite , and argon lasers , as well as intense pulsed light , have also been effective in the treatment of labial macules. Cryosurgery, surgical excision, electrodesiccation, and dermabrasion may lead to scarring and dyspigmentation, often without complete removal of the pigmented macules. Similarly, trichloroacetic acid may not produce total resolution.
Specific Investigations
Optimization of the diagnosis of inherited colorectal cancer using NGS and capture of exonic and intronic sequences of panel genes
Baert-Desurmont S, Coutant S, Charbonnier F, et al. Eur J Hum Genet 2018; 26: 1597–602.
The authors describe a strategy for using next generation sequencing for efficient detection of mutations occurring in several inherited colorectal cancer syndromes, including PJS.
Genetic predisposition to breast and ovarian cancers: how many and which genes to test?
Angeli D, Salvi S, Tedaldi G. Int J Mol Sci 2020; 21(3): 1128. https://doi.org/10.3390/ijms21031128 .
This article reviews the implications of newer molecular techniques and large gene panels in detecting genes predisposing to cancer syndromes. The authors discuss considerations for prevention and personalized treatment for patients and families, including those with STK11/LKB1 mutations.
The STK11 gene mutation in PJS is autosomal dominant and has high penetrance for the risk of breast and ovarian cancers. National Comprehensive Cancer Network (NCCN) guidelines suggest clinical breast examinations every 6 months, plus mammography and breast MRI annually for affected women, beginning at the age of 25. NCCN guidelines also suggest annual pelvic exam plus Pap smear beginning at age 18–20.
Cancer risk in patients with Peutz–Jeghers syndrome: a retrospective cohort study of 336 cases
Chen HY, Jin XW, Li BR, et al. Tumour Biol 2017; 39(6): 1010428317705131. https://doi.org/10.1177/1010428317705131 .
In this retrospective cohort study of patients with PJS in China, the cumulative cancer risk at the age of 60years was 55%.
The authors provide insights into the surveillance of cancer in patients and families with PJS. The article also highlights surveillance of not only colorectal cancers but also cancers of the genital tract.
ACG Clinical Guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes
Syngal S, Brand RE, Church JM, et al. Am J Gastroenterol 2015; 110: 223–63.
A comprehensive document from the American College of Gastroenterology providing guidelines for evaluation, surveillance, and management of patients with a number of hereditary syndromes, including PJS. This review also provides recommendations for surveillance of associated internal malignancies.
Small bowel endoscopy and Peutz–Jeghers syndrome
Korsse SE, Dewint P, Kuipers EJ, et al. Best Practice & Research Clinical Gastroenterology 2012; 26: 263–78.
This is a systematic review of endoscopic techniques used to examine the small bowel in patients with PJS.
Small bowel surveillance is recommended in patients with PJS every 2–3 years from the age of 8–10 years. Visualization of the small bowel is technically challenging.
Peutz–Jeghers syndrome: a systematic review and recommendations for management
Beggs AD, Latchford AR, Vasen HF, et al. Gut 2010; 59: 975–86.
A review of current genotype-phenotype studies and an outline of consensus recommendations for screening and follow-up from a group of European experts who previously produced guidelines for the management of Lynch syndrome and familial adenomatous polyposis.
Surveillance in PJS aims to a) reduce polyp burden and the incidence of intussusceptions in young patients, and b) reduce the burden of cancer. Capsule endoscopy allows for thorough, less invasive surveillance of the small bowel for polyposis. Evaluation of the small bowel with upper gastrointestinal (GI) endoscopy, colonoscopy, and double-balloon enteroscopy has been useful in preventing the need for subsequent surgical polypectomy; because double-balloon enteroscopy is often traumatic, it may be reserved as a treatment modality.
Primary experience of small bowel polypectomy with balloon-assisted enteroscopy in young pediatric Peutz–Jeghers syndrome patients
Li BR, Sun T, Li J, et al. Eur J Pediatr 2020; 179: 611–7.
The authors performed a prospective study and concluded that balloon-assisted enteroscopy of the small bowel is safe and effective in pediatric patients.
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