Peutz-Jeghers Syndrome

Disease Overview

Summary

Peutz-Jeghers syndrome (PJS) is a very rare genetic condition characterized by the development of benign polyps in the stomach and the intestines (gastrointestinal tract) and by distinctive dark spots on the skin and mucous membranes.^1,2 Symptoms usually appear during the first decade of life and begin with spots of dark skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers as well as inside the mouth (oral mucosa) and around the anus (perianal). Non-cancerous polyps called hamartomas also begin to grow in the gastrointestinal tract of affected individuals around that age. These polyps are located throughout the gastrointestinal tract and can cause nausea, vomiting, abdominal pain, intestinal obstruction and rectal bleeding.^1,3,4

Peutz-Jeghers syndrome is caused by changes (variants) in the STK11/LKB1 gene. Inheritance is autosomal dominant. It affects 1/25,000 to 300,000 individuals.^3,4

Abdominal surgery or endoscopic procedures might be necessary to remove polyps (polypectomy) to prevent polyps-related complications such as folding of the intestine into itself (intussusception). Affected individuals have an increased risk for intestinal and other cancers. Frequent medical exams and testing are necessary to allow early detection of polyps and cancer.¹

Introduction

Peutz-Jeghers syndrome is part of a diverse group of disorders known as hamartomatous polyposis syndromes that involve the growth of multiple polyps in the gastrointestinal tract.

Peutz-Jeghers syndrome was first described in 1895 and was named by the doctors who defined it as a syndrome.

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Synonyms

• PJS
• hamartomatous intestinal polyposis
• polyps and spots syndrome
• intestinal polyposis-cutaneous pigmentation syndrome
• periorificial lentiginosis syndrome
• Peutz-Jeghers polyposis
• lentiginosis, perioral
• polyposis, intestinal, II
• Hutchinson Weber-Peutz syndrome

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Signs & Symptoms

PJS is characterized by the presence of benign growths within the mucous lining of the gastrointestinal system (called polyps or hamartomas) and spots of dark blue to dark brown skin freckling (melanocytic macules) around the mouth, eyes, nostrils, fingers, oral mucosa and anus (perianal). Symptoms can occur throughout life, with onset and severity varying widely. People with PJS may have poor mental health due to their syndrome.^5,6

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 those inside the mouth usually persist.

Polyps also begin to grow within the first decade of life, but associated symptoms typically arise between 10 to 30 years of age. Polyps most often tend to develop in the small intestine (in the jejunum, specifically) 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 the following symptoms:¹

• Abdominal pain
• Vomiting
• Diarrhea
• Blockage in the intestines (intestinal obstruction)
• Bleeding from the rectum which may lead to anemia (low red blood cells) causing weakness and fatigue
• Intestinal folding (intussusception) – a serious condition that can cause severe abdominal pain and may require emergency surgery

People with PJS have a higher risk of developing cancer, especially in the digestive system and other organs. The cancers linked to PJS include:¹

• Breast cancer
• Colorectal cancer
• Stomach cancer
• Pancreatic cancer
• Lung cancer
• Small intestine cancer
• Cervical, uterine and ovarian cancer (including a rare type called sex cord tumors with annular tubules – SCTAT)
• Testicular cancer (specifically Sertoli cell tumors)

These tumors require early monitoring, especially SCTAT for females (causing irregular or heavy periods) and Sertoli cell tumors for males (causing breast development).⁴ The lifetime risk of developing cancer in affected people varies between 37% to 93%.⁷

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Causes

Around 94% of people diagnosed with  PJS have an identified variant in the STK11 gene.¹⁰ The penetrance of these variants is thought to be essentially 100%, meaning that a person carrying a pathogenic variant in the STK11 gene will always develop features characteristic of PJS.¹¹

People in whom no  variant can be identified may have less severe disease with fewer small intestine polyps and a lower cumulative risk for intussusception.¹² There is not  much difference in the cancer rate between people with and without a detectable STK11 variants but longer follow-up of these patients may be necessary.

The exact mechanism for the dark pigmented spots (melanocytic macules) is unknown, but one idea is that they are 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).¹⁴

PJS follows autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

Peutz-Jeghers syndrome is a rare disorder that 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 1/25,000 and 300,000.¹ Affected females are at a slightly higher risk of developing cancer compared to males, as PJS increases the likelihood of developing breast, ovarian, cervical and uterine cancer.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Peutz-Jeghers syndrome. Comparisons may be useful for a differential diagnosis:

Juvenile polyposis syndrome is an autosomal dominant genetic disorder caused by a variant in either the SMAD4 or BMPR1A gene. The condition characterized by a specific type of hamartomatous polyp referred to as a juvenile polyp. Most polyps are benign but affected individuals are at an increased risk for colon and other cancers.¹⁵

Serrated polyposis syndrome (SPS) is an autosomal dominant genetic disorder characterized by a specific type of polyp referred to as a serrated (saw-tooth) polyp located in the colorectum. For most people with SPS, no cause is identifiable although variants in the RNF43 gene have been identified in rare cases. Most polyps in this condition are benign but serrated polyposis is associated with an increased personal and family history of colorectal cancer.¹⁶

Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps). If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by variants in the APC gene.¹⁷

Turcot syndrome is a historical term used to describe the association of adenomatous polyps in the mucous lining of the gastrointestinal tract with tumors of the central nervous system. Polyps may cause diarrhea, bleeding from the end portion of the large intestine (rectum), fatigue, abdominal pain and weight loss. Affected individuals may also have neurological symptoms, depending upon the type, size and location of the associated tumor. Researchers think that Turcot syndrome is a variant of familial adenomatous polyposis or Lynch syndrome (previously known as hereditary nonpolyposis colorectal cancer).¹⁸

Hereditary mixed polyposis syndrome is an autosomal dominant genetic disorder characterized by the development of multiple types of polyps (atypical juvenile polyps, hyperplastic polyps, sessile serrated adenomas and adenomatous polyps) in the gastrointestinal tract. It is caused by a variant in the GREM1 gene. There is an increased risk for colorectal cancer.¹⁹

PTEN hamartoma tumor syndrome (PHTS), previously referred to as Cowden syndrome, is a spectrum of disorders caused by variants in the PTEN tumor suppressor gene. These disorders are characterized by multiple hamartomas that can affect various areas of the body. There is also an increased risk for certain types of cancer and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.²⁰

Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss and nail growth problems. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease.²¹

Multiple endocrine neoplasia type 2 (MEN2) is a rare genetic disorder due to a variant in the RET proto-oncogene.  It is characterized by an increased risk of developing a specific form of thyroid cancer (medullary thyroid carcinoma) and benign tumors affecting additional glands of the endocrine system. Individuals with one type of the syndrome, called MEN2B, can develop benign growths arising from nerve cells called ganglion cells (ganglioneuromatosis). These growths occur in the gastrointestinal tract and may cause swelling (distention) of the abdomen, diarrhea, constipation and an abnormally enlarged colon (megacolon). Affected infants often fail to gain weight and grow at the expected rate for age and sex (failure to thrive).²²

Carney complex, due to variants in the PRKAR1A gene, is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common and most often are found in the heart where they may cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. There are many hormonal problems. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi).²³

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Diagnosis

A clinical diagnosis of Peutz-Jeghers syndrome can be made when a person has two or more of the following features: ²⁴

• Two or more PJS polyps of the gastrointestinal tract
• Melanocytic macules of the mouth, lips, nose, eyes, genitalia, or fingers
• Family history of PJS

Melanocytic macules can be identified with a physical examination. Polyps can be detected from an endoscopy, colonoscopy, or small-bowel endoscopy, which are minimally invasive procedures that use a flexible tube with a camera to view the gastrointestinal tract.

Genetic testing is recommended for any person meeting the above clinical diagnostic criteria or with a family history of PJS. Genetic testing is very useful when a STK11 variant has already been identified in a family member. People with a disease-causing STK11 variant essentially have a 100% chance of developing PJS features.

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Standard Therapies

Treatment

There is no cure for PJS, so treatment focuses on regular monitoring to detect and manage polyps, symptoms and cancer risks as early as possible. Below are the latest screening guidelines for children and for adults developed by the National Comprehensive Cancer Network (NCCN version 3.2024).²⁴ 

Surveillance for children

The goal is to detect polyps and cancers early. If symptoms appear earlier or complications arise, testing should start sooner.

• Digestive system checks (ages 8-10):
  • Upper endoscopy and high-quality colonoscopy (with polyp removal, if needed) to examine the stomach and colon
    • If polyps are found, repeat testing every 2-3 years
    • If no polyps are found, the next screening should be at age 18
  • Small intestine imaging (video capsule endoscopy or CT/MRI enterography) should also be done at ages 8-10 and follow-up timing depends on the results
    • A colonoscopy is a medical procedure that allows a doctor to examine the lining of the colon (large intestine) using a thin, flexible tube called a colonoscope which has a small camera and light at one end.
    • CT enterography and MRI enterography are noninvasive imaging tests that help diagnose small bowel disorders. CT enterography uses X-rays and contrast material to create detailed images of the small intestine and the MRI enterography uses a magnetic field to create detailed images of the small intestine.
• Other screening in children includes:
  • Girls (starting at age 8):
    • Annual physical exams to check for early puberty and signs of sex cord tumors with annular tubules (SCTAT)
  • Boys (starting at age 10):
    • Annual testicular exams and monitoring for feminine features to check for Sertoli cell tumors 

Surveillance for adults

More screenings are introduced in adulthood to continue monitoring for polyps and cancers.

• Digestive system checks (starting at 18, then every 2-3 years):
  • High-quality colonoscopy to check the colon
  • Upper endoscopy to check the stomach, a medical procedure that allows a doctor to examine the internal organs and structures of the body using a thin, flexible tube called an endoscope that has a small camera and light at its tip which provides real-time images of the examined area on a monitor
  • Small intestine imaging (video capsule endoscopy, a procedure that uses a tiny wireless camera to take pictures of the gastrointestinal tract) or CT/MRI enterography)
• Pancreatic imaging (ages 30-35):
  • MRI/MRCP (magnetic resonance cholangiopancreatography (MRCP), a contrast MRI, where an MRI scanner takes images as an intravenous dye travels through the pancreatic and biliary systems) or endoscopic ultrasound (EUS), a medical imaging procedure that combines endoscopy and ultrasound to provide detailed images of the gastrointestinal (GI) tract and surrounding organs to check for pancreatic cancer
• Lung cancer awareness:
  • There are no set screening guidelines, but patients should watch for symptoms and avoid smoking
• Males:
  • Annual testicular exams and checking for new feminine features to screen for Sertoli cell tumors
• Females:
  • Starting at 18-20 years old:
    • Annual pelvic exams and a Pap smear also known as a Papanicolaou test, a screening procedure that examines cells from the cervix to check for cervical cancer
    • If there is abnormal bleeding, an endometrial biopsy, a procedure that involves taking a small sample of tissue from the lining of the uterus (endometrium) for examination under a microscope
    • Annual pelvic ultrasound to monitor the ovaries for SCTAT tumors
  • Starting at 30:
    • Breast cancer screenings:
      • Clinical breast exam every 6-12 months
      • Mammogram and breast MRI every year

Women who do not plan to have more children may consider a total hysterectomy (removal of the uterus and cervix) to reduce cancer risk.

Polyps larger than 1 cm are removed to prevent complications such as:⁴

• • Bleeding (which can lead to anemia)
  • Intestinal blockage
  • The intestine folding into itself (intussusception)
  • Reducing cancer risk

If the dark pigmented spots (melanocytic macules) cause major emotional impact, laser treatment may help partially lighten or remove them.²⁵

Genetic testing and counseling are recommended for people with PJS and their family members to help them understand their risks and management options.

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Clinical Trials and Studies

Some research has hypothesized that COX-2 inhibitors may reduce polyp size in affected individuals but there is currently not enough evidence.²⁶ Some researchers have stated that an mTOR inhibitor (rapamycin 1) was successful in achieving a partial remission in the treatment of pancreatic cancer in a patient with Peutz-Jeghers syndrome.²⁷

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

1. Wu M, Krishnamurthy K. Peutz-Jeghers Syndrome. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535357/ Accessed Feb 20, 2025.
2. Keller JJ, Offerhaus GJA, Giardiello FM, Menko FH. Jan Peutz, Harold Jeghers and a remarkable combination of polyposis and pigmentation of the skin and mucous membranes. Fam Cancer. 2001;1(3):181-185. doi:10.1023/A:1021149327174
3. Peutz-Jeghers syndrome: MedlinePlus Genetics. February 1, 2013. https://medlineplus.gov/genetics/condition/peutz-jeghers-syndrome/ Accessed Feb 20, 2025.
4. McGarrity TJ, Amos CI, Baker MJ. Peutz-Jeghers Syndrome. 2001 Feb 23 [Updated 2021 Sep 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1266/ Accessed Feb 20, 2025.
5. van Lier MG, Mathus-Vliegen EM, van Leerdam ME, et al. Quality of life and psychological distress in patients with Peutz-Jeghers syndrome. Clin Genet. 2010;78(3):219-226. doi:10.1111/j.1399-0004.2010.01469.x
6. Woo A, Sadana A, Mauger DT, Baker MJ, Berk T, McGarrity TJ. Psychosocial impact of Peutz-Jeghers Syndrome. Fam Cancer. 2009;8(1):59-65. doi:10.1007/s10689-008-9202-z
7. 7. van Lier MG, Wagner A, Mathus-Vliegen EM, Kuipers EJ, Steyerberg EW, van Leerdam ME. High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations. Am J Gastroenterol. 2010;105(6):1258-1265. doi:10.1038/ajg.2009.725
8. Definition of autosomal dominant inheritance – NCI Dictionary of Genetics Terms – NCI. July 20, 2012. https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/autosomal-dominant-inheritance Accessed Feb 20, 2025.
9. Jelsig AM, Karstensen JG, Overeem Hansen TV. Progress report: Peutz–Jeghers syndrome. Fam Cancer. 2024;23(4):409-417. doi:10.1007/s10689-024-00362-7
10. Korsse SE, Peppelenbosch MP, van Veelen W. Targeting LKB1 signaling in cancer. Biochim Biophys Acta BBA – Rev Cancer. 2013;1835(2):194-210. doi:10.1016/j.bbcan.2012.12.006
11. Volikos E, Robinson J, Aittomäki K, et al. LKB1 exonic and whole gene deletions are a common cause of Peutz‐Jeghers syndrome. J Med Genet. 2006;43(5):e18. doi:10.1136/jmg.2005.039875
12. “STK11”[GENE] – ClinVar – NCBI. https://www.ncbi.nlm.nih.gov/clinvar/?term=%22stk11%22%5BGENE%5D&redir=gene Accessed February 20, 2025
13. Jiang LX, Chen YR, Xu ZX, et al. Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients. World J Gastroenterol. 2023;29(21):3302-3317. doi:10.3748/wjg.v29.i21.3302
14. Banse-Kupin LA, Douglass MC. Localization of Peutz-Jeghers Macules to Psoriatic Plaques. Arch Dermatol. 1986;122(6):679-683. doi:10.1001/archderm.1986.01660180085021
15. juvenile polyposis syndrome – National Organization for Rare Disorders. https://rarediseases.org/mondo-disease/juvenile-polyposis-syndrome/ Accessed Feb 20, 2025.
16. Mankaney G, Rouphael C, Burke CA. Serrated Polyposis Syndrome. Clin Gastroenterol Hepatol. 2020;18(4):777-779. doi:10.1016/j.cgh.2019.09.006
17. Familial Adenomatous Polyposis – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/familial-adenomatous-polyposis/#complete-report Accessed Feb 20, 2025.
18. Turcot Syndrome – Symptoms, Causes, Treatment | NORD. Accessed December 3, 2024. https://rarediseases.org/rare-diseases/turcot-syndrome/#complete-report Accessed Feb 20, 2025.
19. hereditary mixed polyposis syndrome – National Organization for Rare Disorders. https://rarediseases.org/mondo-disease/hereditary-mixed-polyposis-syndrome/ Accessed Feb 20, 2025.
20. PTEN Hamartoma Tumor Syndrome – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/pten-hamartoma-tumor-syndrome/#complete-report Accessed Feb 20, 2025.
21. Cronkhite-Canada Syndrome – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/cronkhite-canada-syndrome/#complete-report Accessed Feb 20, 2025.
22. multiple endocrine neoplasia type 2 – National Organization for Rare Disorders. 24. https://rarediseases.org/mondo-disease/multiple-endocrine-neoplasia-type-2/ Accessed Feb 20, 2025.
23. Carney Complex – Symptoms, Causes, Treatment | NORD. https://rarediseases.org/rare-diseases/carney-complex/#complete-report Accessed Feb 20, 2025.
24. National Comprehensive Cancer Network – Home. NCCN. https://www.nccn.org/ Accessed Feb 20, 2025.
25. Medeiros Y de L, Faria LV, Chandretti PC de S, Mainenti P. Laser therapy and light sources for labial lentigines in patients with Peutz-Jeghers syndrome. Dermatol Ther. 2022;35(7):e15519. doi:10.1111/dth.15519
26. Udd L, Katajisto P, Rossi DJ, et al. Suppression of Peutz—Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology. 2004;127(4):1030-1037. doi:10.1053/j.gastro.2004.07.059
27. mTOR Inhibitor Treatment of Pancreatic Cancer in a Patient With Peutz-Jeghers Syndrome | Journal of Clinical Oncology. Accessed December 3, 2024. https://ascopubs.org/doi/10.1200/JCO.2010.32.7825

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