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Peutz-Jeghers syndrome
People with Peutz-Jeghers syndrome develop hamartomatous polyps in the stomach and intestines, often accompanied by characteristic dark freckling around the mouth and on the hands and feet. The condition increases lifetime cancer risk across multiple organs and requires regular surveillance.
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Overview
Peutz-Jeghers syndrome is a rare inherited disorder that primarily affects the gastrointestinal system, though its effects extend to cancer risk across multiple organs. The condition typically becomes apparent during childhood or adolescence, when distinctive dark brown or blue-grey spots appear on the lips, inside the mouth, and on the fingers and toes. These pigmented marks, sometimes called mucocutaneous pigmentation, often fade with age but remain a useful diagnostic clue.
The hallmark feature of Peutz-Jeghers syndrome is the development of hamartomatous polyps throughout the digestive tract. Unlike the adenomatous polyps seen in other cancer syndromes, these are overgrowths of normal tissue arranged in a disorganised pattern. They can occur anywhere from the stomach through the small intestine and into the colon, with the small bowel most commonly affected. These polyps may cause symptoms during childhood or early adult life, and whilst they are not themselves cancerous, their presence signals an underlying genetic change that substantially elevates cancer risk. Prevalence estimates suggest Peutz-Jeghers syndrome affects between 1 in 50,000 and 1 in 200,000 individuals, though the true figure may be higher due to undiagnosed or mild cases.
Beyond the gastrointestinal manifestations, Peutz-Jeghers syndrome increases the lifetime risk of developing cancers in the bowel, pancreas, stomach, breast, ovaries, cervix, testicles, and lungs. This broad cancer susceptibility distinguishes the condition from syndromes that affect only one or two organ systems. The elevated cancer risk begins earlier than in the general population, typically emerging in early to middle adulthood. Coordinated surveillance and proactive management through specialist NHS services are central to reducing complications and detecting cancers at treatable stages.
Symptoms & clinical features
The clinical features of Peutz-Jeghers syndrome develop progressively, with pigmented spots often representing the earliest recognisable sign. These dark marks typically appear during infancy or early childhood on the lips (particularly the lower lip and the area just outside the lip border), inside the mouth on the buccal mucosa, around the eyes, nostrils, and on the hands and feet. The spots are usually small, flat, and range from brown to blue-grey in colour. Whilst distinctive, these marks may fade during adolescence and adulthood, which can complicate diagnosis in individuals who present later in life without a documented childhood history.
Gastrointestinal symptoms most commonly emerge during childhood, adolescence, or young adulthood. Polyps can cause episodes of cramping abdominal pain, often due to a polyp pulling a section of bowel into the adjacent segment, a complication known as intussusception. This can lead to intermittent or acute bowel obstruction, presenting with severe pain, vomiting, and inability to pass stools. Polyps may also bleed, causing anaemia over time or presenting as visible blood in the stool. Some individuals experience no symptoms from their polyps until a complication arises, whilst others have recurrent episodes requiring medical intervention.
Beyond the digestive tract, individuals with Peutz-Jeghers syndrome face an increased risk of developing tumours in multiple organs. Women may develop distinctive ovarian tumours called sex cord tumours with annular tubules, which can occasionally produce hormones leading to early puberty or abnormal menstrual bleeding. Men may develop Sertoli cell tumours of the testes, which can also cause hormonal effects. These tumours are usually benign but require monitoring. Cancer symptoms vary depending on the affected organ and typically emerge in adulthood, emphasising the importance of structured surveillance programmes to detect malignancies before they cause symptoms.
Video: Is cancer in your genes?
Affected organs
The gastrointestinal tract bears the primary disease burden in Peutz-Jeghers syndrome, with hamartomatous polyps developing most frequently in the small intestine, particularly the jejunum and ileum. However, polyps can also arise in the stomach, duodenum, and large bowel. These growths vary in size from a few millimetres to several centimetres and may number from a handful to hundreds throughout the digestive system. The small bowel location is clinically significant because these polyps are harder to detect and remove than those in the colon, which is readily accessible by colonoscopy.
Multiple other organ systems face elevated cancer risk. The pancreas, breast, ovaries, uterus, cervix, and testicles all show increased malignancy rates compared with the general population. The lungs and stomach also demonstrate elevated cancer susceptibility, though to a somewhat lesser degree. In women, the reproductive organs require particular attention, as ovarian and cervical cancers may develop at younger ages than typically seen. In men, testicular Sertoli cell tumours, whilst usually benign, can affect fertility and require monitoring. The skin and mucous membranes show the characteristic pigmentation that aids clinical recognition, though these changes themselves do not cause medical complications and often become less prominent with age.
Risks & severity
Peutz-Jeghers syndrome substantially increases lifetime cancer risk across multiple organ systems, with estimates suggesting a cumulative cancer risk of 80-90% by age 70. This represents a marked elevation compared with the general population and reflects the syndrome's broad impact on tumour suppressor function. Gastrointestinal cancers constitute a major concern, with colorectal cancer risk estimated at 39% by age 65, small bowel cancer risk at 13% by age 65, gastric cancer risk at 29% by age 65, and pancreatic cancer risk reaching approximately 11-36% over a lifetime. These cancers typically emerge earlier than in the general population, often presenting in the fourth or fifth decade of life.
For women with Peutz-Jeghers syndrome, breast cancer risk reaches approximately 45-50% by age 70, a level comparable to that seen with pathogenic variants in moderate-penetrance breast cancer genes. Gynaecological cancers also occur at elevated rates, with ovarian cancer risk estimated at 18-21% and cervical cancer at approximately 10% over a lifetime. The distinctive sex cord tumours with annular tubules, whilst usually benign, affect a substantial proportion of women with the syndrome and can cause complications related to hormone production. Men face an elevated risk of testicular tumours, though these are more commonly benign Sertoli cell tumours than malignant germ cell cancers.
The severity of Peutz-Jeghers syndrome varies considerably between individuals, even within the same family. Some people develop numerous polyps requiring multiple surgical interventions during childhood and adolescence, whilst others have relatively few polyps and minimal gastrointestinal symptoms until adulthood. Similarly, cancer risk is statistical rather than deterministic - not everyone with the syndrome develops cancer, and the specific cancer types that arise differ between individuals. Complications from polyps, particularly intussusception and bowel obstruction, represent significant morbidity and may require emergency surgery. Repeated surgical interventions can lead to short bowel syndrome if extensive portions of intestine must be removed, emphasising the importance of polyp surveillance and endoscopic removal where feasible.
Genetic causes
Peutz-Jeghers syndrome results from pathogenic variants in STK11, a gene that encodes serine/threonine kinase 11, a crucial tumour suppressor enzyme. Under normal circumstances, this protein acts as a master regulator of cellular metabolism and growth, coordinating how cells respond to nutrient availability and energy stress. The enzyme functions by adding phosphate groups to other proteins, thereby activating or deactivating cellular pathways that control processes such as cell division, programmed cell death, and the maintenance of normal tissue architecture. When functioning properly, STK11 helps prevent cells from dividing inappropriately and ensures that growth occurs only when conditions are suitable.
Pathogenic changes in STK11 disrupt this regulatory system, reducing or eliminating the protein's ability to suppress uncontrolled growth. Most disease-causing variants result in a shortened, non-functional protein or prevent the protein from being produced altogether. When cells possess only one working copy of STK11 (due to inheriting one altered copy), they retain some tumour suppressor function, which explains why people with Peutz-Jeghers syndrome do not develop cancer immediately. However, if the remaining functional copy is damaged or inactivated in a particular cell through acquired changes over time - a process known as loss of heterozygosity - that cell loses all STK11 function and may begin growing abnormally. This two-hit mechanism underlies both polyp formation and cancer development in the syndrome.
The hamartomatous polyps characteristic of Peutz-Jeghers syndrome reflect abnormal tissue organisation rather than frank malignancy. Research suggests these polyps arise when loss of STK11 function disrupts normal developmental signals in the intestinal lining, leading to overgrowth of multiple tissue types in a disorganised pattern. The same underlying defect in growth regulation explains the syndrome's broad cancer susceptibility - without adequate STK11 function, multiple cell types throughout the body become vulnerable to malignant transformation when they accumulate additional genetic changes. Nearly all individuals with a clear clinical diagnosis of Peutz-Jeghers syndrome carry identifiable pathogenic variants in STK11, confirming the gene's central role in the condition.
- STK11 serine/threonine kinase 11The STK11 gene provides instructions for making serine/threonine kinase 11, a crucial enzyme that acts as a tumour suppressor, regulating cell growth, division, and energy use.
Inheritance pattern
Peutz-Jeghers syndrome follows an autosomal dominant inheritance pattern, meaning a pathogenic variant in just one copy of STK11 is sufficient to cause the condition. Each child of an affected parent has a 50% chance of inheriting the altered gene and therefore the syndrome. The condition affects males and females equally, and individuals who inherit the genetic change will typically develop features of the syndrome, though the severity and specific manifestations vary considerably.
Approximately 30-50% of individuals with Peutz-Jeghers syndrome have no family history of the condition, indicating their genetic change arose spontaneously (as a de novo variant) in the egg, sperm, or very early embryo. Once a new pathogenic variant has occurred, that individual can pass it to their children in the standard autosomal dominant pattern. Families with an established history of the syndrome may observe the condition across multiple generations, though variable severity can sometimes make the pattern less obvious - a mildly affected grandparent might not have been diagnosed, whilst their more severely affected grandchild receives the diagnosis.
For relatives of someone with Peutz-Jeghers syndrome, genetic testing can clarify individual risk. Siblings of an affected person have a 50% chance of carrying the familial variant if one parent is affected, but very low risk if the variant arose de novo in their sibling (though germline mosaicism is theoretically possible). Children of an affected individual have a 50% chance of inheriting the condition. Genetic counselling is strongly recommended for families navigating these questions, as understanding inheritance patterns influences decisions about testing, surveillance, and family planning. Prenatal testing and preimplantation genetic diagnosis are technically available for families with a known pathogenic STK11 variant, though these options involve complex personal considerations best explored with specialist genetic counsellors.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosing Peutz-Jeghers syndrome typically combines clinical findings with genetic testing to confirm the underlying STK11 variant. The classical clinical presentation - hamartomatous polyps in the gastrointestinal tract accompanied by characteristic mucocutaneous pigmentation - strongly suggests the diagnosis, particularly when polyps are identified in the small bowel, a location uncommon for polyps in the general population. Formal diagnostic criteria exist, with a diagnosis established if someone has two or more Peutz-Jeghers-type polyps confirmed by microscopic examination, or any number of these polyps plus characteristic pigmentation, or any number of polyps plus a family history of Peutz-Jeghers syndrome, or characteristic pigmentation plus a family history.
Genetic testing provides definitive confirmation when a pathogenic or likely pathogenic variant in STK11 is identified. This testing is typically arranged through NHS clinical genetics services following referral from a gastroenterologist, oncologist, or general practitioner when clinical features raise suspicion. The test examines the entire STK11 gene sequence and looks for deletions or duplications that might not be detected by standard sequencing. Identifying the specific familial variant enables predictive testing for at-risk relatives, allowing those who have not inherited the genetic change to avoid unnecessary surveillance whilst ensuring those who carry the variant receive appropriate monitoring. Within the NHS Genomic Medicine Service framework, Peutz-Jeghers syndrome is recognised under the R207.1 code (Inherited polyposis and early onset colorectal cancer) or R208.1 (Inherited breast cancer and ovarian cancer), depending on the clinical presentation, facilitating access to genetic testing and specialist care pathways.
Even without genetic confirmation, individuals meeting clinical diagnostic criteria should enter appropriate surveillance programmes, as a small percentage of people with convincing Peutz-Jeghers syndrome do not have detectable STK11 variants with current testing methods. Imaging studies, particularly magnetic resonance enterography or video capsule endoscopy, help assess small bowel polyp burden. Standard colonoscopy and gastroscopy examine the colon, stomach, and duodenum. Histological examination of polyps is essential, as the distinctive microscopic appearance of Peutz-Jeghers polyps - smooth muscle extending into the polyp in a tree-like branching pattern - helps distinguish them from other polyp types. Clinical genetics input and genetic counselling are integral to the diagnostic pathway, supporting informed decision-making about testing and its implications for the patient and their family.
Management & lifestyle
Management of Peutz-Jeghers syndrome centres on surveillance to detect complications early and interventions to reduce cancer risk, delivered through coordinated multidisciplinary care within NHS specialist centres. Gastrointestinal surveillance forms the cornerstone of management, with guidelines typically recommending baseline upper endoscopy and colonoscopy in late childhood or early adolescence (around age 8-12 years, though exact timing depends on symptoms and family history). Small bowel imaging, often using magnetic resonance enterography or video capsule endoscopy, is recommended from late adolescence onwards. Surveillance intervals are usually every 2-3 years for the upper and lower gastrointestinal tract, with small bowel imaging every 2-3 years, though frequency may be adjusted based on polyp burden and symptoms.
When polyps are detected, endoscopic removal is preferred where feasible to avoid surgical resection and preserve bowel length. However, larger polyps or those causing symptoms such as bleeding or intussusception may require surgical intervention. Laparoscopic-assisted endoscopy, where a surgeon makes small incisions to help an endoscopist reach and remove small bowel polyps, can sometimes avoid full bowel resection. Because repeated surgeries carry cumulative risks, including short bowel syndrome, the approach aims to balance polyp removal with bowel preservation. Some centres use intraoperative endoscopy during necessary surgeries to clear as many polyps as possible in a single intervention.
Cancer surveillance extends beyond the gastrointestinal tract. Women with Peutz-Jeghers syndrome are recommended to have annual breast surveillance, typically including mammography and magnetic resonance imaging from around age 25-30 years, similar to protocols for other high-risk groups. Cervical screening follows enhanced protocols, often with annual smears and consideration of human papillomavirus testing from age 25. Transvaginal ultrasound may be considered for ovarian surveillance, though evidence for its effectiveness remains limited. For pancreatic surveillance, some guidelines suggest magnetic resonance imaging or endoscopic ultrasound starting around age 30-35 years, though pancreatic screening protocols are still evolving as evidence accumulates. Testicular examination should be performed regularly, particularly during adolescence when Sertoli cell tumours may develop.
Lifestyle measures that reduce cancer risk in the general population - maintaining a healthy weight, limiting alcohol intake, not smoking, and staying physically active - are sensible for people with Peutz-Jeghers syndrome, though no specific dietary interventions have been proven to reduce polyp formation or cancer risk in this condition. Regular engagement with specialist genetic services ensures surveillance protocols remain current with evolving evidence. Genetic counselling provides ongoing support for family planning decisions and helps relatives understand their own risk. Psychosocial support is valuable, as living with elevated cancer risk and managing frequent surveillance can affect mental wellbeing. Patient support groups provide peer connection and practical advice for navigating life with the condition.
UK care pathway
Within the NHS Genomic Medicine Service, individuals with suspected or confirmed Peutz-Jeghers syndrome typically access care through clinical genetics services, often following referral from gastroenterology, oncology, or primary care. The condition falls under the R207.1 testing pathway (Inherited polyposis and early onset colorectal cancer) or R208.1 (Inherited breast cancer and ovarian cancer), depending on presenting features. These pathways ensure access to appropriate genetic testing through accredited NHS laboratories and connect patients with specialist genetic counsellors who provide pre-test information and post-test support.
Once diagnosed, patients are usually managed through specialist inherited cancer or polyposis clinics that coordinate surveillance across multiple organ systems. These multidisciplinary teams include clinical geneticists, genetic counsellors, gastroenterologists with expertise in polyposis syndromes, oncologists, and specialist nurses. The coordinated approach ensures surveillance schedules are followed, results are reviewed promptly, and any concerning findings trigger timely investigation or intervention. Family cascade testing - offering predictive genetic testing to at-risk relatives once a pathogenic variant is identified in the family - is facilitated through genetic counselling services, allowing relatives to make informed choices about testing and enabling those who carry the variant to begin appropriate surveillance. Access to genetic counsellors remains available throughout the patient journey, not only at diagnosis, supporting decisions about surveillance, risk-reducing interventions, and family communication.
Frequently asked questions
Will my children definitely inherit Peutz-Jeghers syndrome if I have it?
Each of your children has a 50% chance of inheriting the STK11 variant that causes Peutz-Jeghers syndrome. This means roughly half of your children would be expected to inherit the condition, though the actual outcome in any individual family may differ due to chance. Genetic counselling can help you understand testing options for children and the timing of surveillance if they do inherit the variant.
Do the dark spots on my lips mean I definitely have cancer?
No, the pigmented spots themselves are not cancerous and do not directly cause cancer. They are a visible sign of the underlying genetic change in STK11, which increases cancer risk over time. The spots help doctors recognise the syndrome and prompt appropriate surveillance to detect cancers early if they develop, but having the spots does not mean cancer is present or inevitable.
How often will I need to have endoscopies and scans?
Surveillance schedules are individualised but typically include colonoscopy and upper endoscopy every 2-3 years, with small bowel imaging at similar intervals. Breast imaging for women and other organ-specific surveillance occur annually or every few years depending on the protocol. Your specialist team will tailor the schedule based on your polyp burden, symptoms, age, and current guidelines, balancing thoroughness with practical considerations.
Can I do anything to prevent polyps from forming or reduce my cancer risk?
Currently, no specific dietary changes or medications are proven to prevent polyps in Peutz-Jeghers syndrome. General cancer-prevention advice - maintaining a healthy weight, not smoking, limiting alcohol, and staying active - is sensible but does not eliminate the elevated risk associated with STK11 variants. Regular surveillance remains the most effective approach to detect and manage polyps and cancers early.
If I have several polyps removed, will that reduce my cancer risk?
Removing polyps that are present reduces immediate complications such as bleeding or bowel obstruction, and removing any polyps with abnormal cellular changes may prevent progression to cancer in those specific areas. However, polypectomy does not address the underlying genetic predisposition, so new polyps can develop and cancer risk in other organs remains elevated. This is why ongoing surveillance across multiple organ systems continues even after successful polyp removal.
References
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- Sato E, Goto T, Honda H. Peutz-Jeghers Syndrome. JAMA dermatology. 2022. PMID: 36197686
- Tomlinson IP, Houlston RS. Peutz-Jeghers syndrome. Journal of medical genetics. 1997. PMID: 9429144
- Jelsig AM, Karstensen JG, Overeem Hansen TV. Progress report: Peutz-Jeghers syndrome. Familial cancer. 2024. PMID: 38493229
- Sengupta S, Bose S. Peutz-Jeghers Syndrome. The New England journal of medicine. 2019. PMID: 30699321
- Wei T, Li C. Peutz-Jeghers Syndrome. Journal of cutaneous medicine and surgery. 2026. PMID: 41830593
- Giardiello FM, Trimbath JD. Peutz-Jeghers syndrome and management recommendations. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2006. PMID: 16616343
- Dos Santos VM, Dos Santos LAM, Modesto LC. Peutz-Jeghers syndrome: revisited. Autopsy & case reports. 2022. PMID: 35642203