by Monzur Ahmed
Here is an unusual case which most gastroenterologists won’t see too often. A 36 year old lady presented at the age of 16 with abdominal pain. She was noted to have oral pigmentation and a clinical diagnosis of Peutz-Jeghers syndrome was made. There was no family history of this condition. A small bowel enema showed 3 large ileal polyps causing intussusception and she underwent small bowel (SB) resection and polyp excision. At the age of 21, she had a right hemicolectomy, SB resection and SB polypectomy, again for intussusception.
Over the years, she had numerous surveillance OGDs, colonoscopies and gynaecological / breast screening. Two years ago, a video capsule endoscopy showed duodenal/ jejunal polyps. Hence a oral route double balloon enteroscopy (DBE) was performed and 3 upper SB polyps were resected. A year ago, a further video capsule endoscopy showed ileal polyps, including one measuring ~2cm. Therefore, she now attends for rectal route DBE to remove the ileal polyp (see video)...
Peutz-Jeghers syndrome (PJS) is part of a heterogeneous group of disorders, known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract of affected individuals. PJS first described in a pair of twin sisters with dark pigment spots on their lips and oral mucosa by J.T. Connor in 1895. These symptoms were attributed to a familial syndrome in 1921, when Jan Peutz described four affected siblings. The syndrome was then defined as a distinct entity by Harold Jeghers in 1949 when he described 10 cases and was subsequently named Peutz Jeghers syndrome in 1954. The gene causing PJS (STK-11/LKB1) was identified in 1998 and allows early detection of the disease and screening of family members.
PJS affects males and females in equal numbers and can occur in any racial or ethnic group. The birth prevalence of PJS is estimated to be between 1/50,000 and 1/200,000. PJS is characterised by multiple hamartomas on the mucous lining of the gastrointestinal system and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus. These melanocytic macules can appear as early as the first year of life and are present in most affected children under five years of age. They tend to fade away with age and might completely disappear in puberty or adulthood, although they tend to persist in the oral mucosa. Polyps also begin to grow within the first years of life, but associated symptoms typically arise between 10 to 30 years of age. Around half of patients with PJS have to undergo surgery by age 18 because of polyps-related complication. Polyps most often tend to develop in the small intestine (60-90%), especially in the jejunum, but can also arise in the stomach and large intestine. Rarely, polyps can grow outside the gastrointestinal tract and affect the ureters, bladder, lungs, bronchi, and gallbladder. Gastrointestinal polyps can cause abdominal pain, vomiting, diarrhoea, intestinal obstruction and rectal bleeding, which can lead to anaemia. They can also provoke intussusception, which can lead to severe abdominal pain and emergency surgery.
Individuals with PJS are at a highly increased risk of developing gastrointestinal and other cancers including breast, cervical, uterine, pancreas, and lung. The lifetime risk of developing cancer in affected individuals can be as high as 93%. The cumulative risk of GI cancers (excluding pancreatic cancer) has been reported to be around 33% at the age of 60, increasing to 57 % at the age of 70 years. Individuals that develop cancer are usually affected around their fifth decade of life (age 40-49 years). Affected females have an increased risk for a benign ovarian tumour called SCTAT (sex cord tumours with annular tumours) for which symptoms may include irregular or heavy periods or early puberty. Usually before age 20, affected males can develop Sertoli cells carcinoma of the testes that secretes oestrogen and can lead to gynaecomastia.
PJS is an autosomal dominant condition caused by mutations in the STK11/LKB1 gene which is located at 19p13.3. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (de novo) in the affected individual. Approximately 60-78% of individuals with PJS have an affected relative. Around 80-94% of PJS patients have an identified mutation in the STK11 gene, which means that other genes are possibly involved in the disease. The penetrance of the STK11 gene mutation is thought to be 100% (which means that someone with a pathogenic mutation has a 100% chance of developing the disease), so genetic testing can give a definite diagnosis before symptoms appear. The STK11 gene produces a protein that is involved in the regulation of cell division and apoptosis (programmed cell death). It also interacts with p53, a major tumour suppression protein. Pathogenic mutations in STK11 lead to either cessation or dysfunction of protein production by the gene and uncontrolled cell growth, which can in turn lead to the development of hamartomas and cancer.
The dark pigmented spots (melanocytic macules) are thought to be caused by inflammation and blockage of melanin migration from cells where it is produced (melanocytes) to cells forming the outermost layer of the skin (keratinocytes).
A clinical diagnosis of PJS can be made when any one of the following criteria is present:
1. Presence of at least 2 histologically confirmed PJS polyps
2. Any number of PJS polyps with a positive family history of PJS
3. Presence of characteristic mucocutaneous pigmentations with a positive family history of PJS
4. Any number of PJS polyps in an individual with characteristic mucocutaneous pigmentation
Surveillance of the GI tract in PJS patients has two purposes:
1. To detect GI polyps that may cause complications (bleeding, anaemia, intussusception) and should be removed (in particular small-bowel polyp-related complications are the predominant clinical problem);
2. To detect cancer (mainly occurring in adults) at an early stage.
After initial diagnosis, it is recommended that individuals older than 8 years or having symptoms undergo endoscopic and small bowel examination. The latter can be done with magnetic resonance imaging of the intestines (magnetic resonance enterography, MRE) or video capsule endoscopy, (VCE). Gynaecologic and breast examination are also recommended for women older than 18 years. Testicular examination is recommended for men.
The ESGE recommendations for PJS are:
1. Perform a baseline OGD and colonoscopy at the age of 8 years in asymptomatic individuals with PJS.
2. Start routine OGD and colonoscopy surveillance at the age of 18 if the baseline endoscopy is negative.
3. An interval of 1 – 3 years based on phenotype for OGD and colonoscopy.
4. Small-bowel surveillance from the age of 8 years in asymptomatic individuals with PJS.
5. An interval of 1 – 3 years based on phenotype for small-bowel surveillance.
6. Either MRI studies or video capsule enteroscopy for small-bowel surveillance.
7. Elective polypectomy should be performed for small-bowel polyps >15–20mm to prevent intussusception. In a symptomatic patient, smaller polyps causing obstructive symptoms should be removed.
8. Device-assisted enteroscopy for the removal of polyps. Based on phenotype, intraoperative enteroscopy could be considered.
These guidelines are similar to those of the BSG / ACPGBI/ UKCGG.
1. Beggs AD, Latchford AR, Vasen HFA et al; Gut 2010 Jul;59(7):975-86.
Peutz-Jeghers syndrome: a systematic review and recommendations for management
2.Peutz Jeghers Syndrome, NORD
3.van Leerdam ME, Roos VH, van Hooft JE et al, Endoscopy 2019; 51
Endoscopic management of polyposis syndromes: European Society of Gastrointestinal Endoscopy (ESGE) guideline
4.Monahan KJ, Bradshaw N, Dolwani S, Hereditary CRC guidelines eDelphi consensus group, et al. Gut 2020;69:411-444.
Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)