Peutz-Jeghers syndrome

The serine/threonine kinase produced by STK11 (previously known as LKB1) functions as a tumour suppressor in the mTOR pathway. It regulates cell polarity and energy metabolism.

Gene locus and structure

The STK11 gene is located at chromosome 19p13.3, and comprises 10 exons and 433 amino acids.

Prevalence

Peutz-Jeghers syndrome (PJS) is a rare condition caused by a pathogenic variant in STK11. Although estimates vary, it is thought to affect around 1 in 50,000 individuals.

• Loss-of-function variants in STK11 produce a PJS phenotype.
• A significant proportion (around 20%) of pathogenic STK11 variants are whole gene or intragenic deletions.
• There are no confirmed genotype-phenotype correlations, but truncating variants in STK11 have been reported to predispose to a more severe phenotype (earlier onset of gastrointestinal polyps, intussusception and earlier-onset malignancy) than missense variants.

A clinical diagnosis of PJS can be made if any one of the following is present in an individual:

• three or more histologically confirmed PJS-type hamartomatous polyps;
• any number of PJS polyps detected in one individual who has a close relative with PJS;
• characteristic mucocutaneous pigmentation in an individual who has a close relative with PJS; and/or
• any number of PJS polyps in an individual who also has characteristic mucocutaneous pigmentation.

Clinical features of PJS are listed below.

• Gastrointestinal polyposis.
  • PJS-type hamartomatous polyps can occur anywhere in the gastrointestinal tract, but are most commonly found in the small intestine (most common in the jejunum, followed by the ileum, and least common in the duodenum).
  • The age of polyps symptom onset is variable, with some children developing symptoms within the first few years of life.
  • Small bowel obstruction in childhood, due to a polyp causing intussusception, is the most common presentation (risk of intussusception is 50% by 20 years of age). Anaemia, secondary to occult bleeding from polyps, is also common.
• Mucocutaneous pigmentation.
  • Melanocytic macules (dark blue to dark brown) around the mouth, buccal mucosa, eyes, nostrils and perianal area often develop during childhood, but fade in puberty and adulthood. They are a common clinical feature, affecting up to 95% of people with PJS. Freckling can also occur on the fingers and toes.
• Malignancy.
  • There is a high risk of cancer in PJS – about 55% by the age of 60. Commonly affected sites include the gastrointestinal tract, breasts, pancreas, ovaries (mostly sex cord tumour with annular tubules), cervix (adenoma malignum) and testes (sertoli cell tumours).

It should be noted that cancer risks quoted in the literature may be inflated because of ascertainment bias, and may be revised as indications for constitutional (germline) testing of STK11 expands to identify individuals with more subtle phenotypes.

Constitutional (germline) STK11 testing is offered as a single gene test, or as part of several broader multi-gene panels, in the National Genomic Test Directory.

R212 Peutz-Jeghers syndrome

This clinical indication is for individuals fulfilling one of the following criteria:

• ≥2 PJS-type hamartomatous polyps;
• ≥1 PJS-type hamartomatous polyp(s) and characteristic mucocutaneous pigmentation;
• characteristic mucocutaneous pigmentation at under 10 years of age;
• sex cord tumours with annular tubules at any age;
• adenoma malignum of the cervix at any age;
• ≥1 PJS-type hamartomatous polyp(s) and ≥1 first- or second-degree relative(s) with:
  • ≥1 PJS-like feature(s); or
  • ≥2 PJS-related cancers (the cancers can be in the same or different relatives); or
• characteristic mucocutaneous pigmentation and one or more first- or second-degree relative(s) with:
  • ≥1 PJS-like feature(s); or
  • ≥2 PJS-related cancers (the cancers can be in the same or different relatives).

R211 Inherited polyposis and early onset colorectal cancer

This clinical indication can be used if an individual meets one of the following criteria:

• any colorectal cancer diagnosis <40 years;
• ≥5 adenomatous polyps and colorectal cancer;
•  ≥5 adenomatous polyps <40 years;
•  ≥10 adenomatous polyps <60 years;
•  ≥20 adenomatous polyps ≥60 years;
•  ≥5 adenomatous polyps <60 years and a first-degree relative with ≥5 adenomatous polyps <60 years;
• serrated polyposis in which either:
  •  ≥5 serrated lesions or polyps are proximal to the rectum, all at least 5mm in size, with ≥2 being at least 10mm in size; or
  •  ≥20 serrated lesions or polyps of any size are distributed through the large bowel with at least five being proximal to the rectum; or
• hamartomatous polyposis syndrome, with either:
  •  ≥5 hamartomatous polyps of the colon;
  •  ≥2 hamartomatous polyps throughout the gastrointestinal tract; or
  •  ≥1 hamartomatous polyp(s) and a first- or second-degree relative with hamartomatous polyp(s).

R236 Pigmentary skin disorders

This clinical indication can be used if an individual meets one of the following criteria:

• multiple café-au-lait macules where neurofibromatosis type 1 has been excluded either clinically or through genomic testing;
• poikiloderma with a likely genetic cause; or
• other forms of reticulate, patchy or speckled hypo- or hyper-pigmentation with a likely genetic cause.

Please note that the National Genomic Test Directory criteria for diagnostic constitutional (germline) testing does not directly align with clinical diagnostic criteria. If your patient fulfils the clinical criteria for a diagnosis of PJS but does not meet the criteria for constitutional (germline) testing, you should discuss the case with a specialist multidisciplinary team and with your local laboratory team.

• PJS is inherited in an autosomal dominant pattern. This means that first-degree relatives of an individual with an inherited variant in STK11 have a 50% chance of having the familial variant themselves.
• Predictive testing can be offered to children from three years of age to enable interpretation of any gastrointestinal symptoms that might indicate intussusception.
• There is significant inter- and intra-familial variability.
• Referral to clinical genetics should be arranged for newly identified individuals with pathogenic or likely pathogenic variants in STK11 to discuss onward management, family planning implications and cascade testing of at-risk relatives.

Screening in patients with PJS

• PJS patients are screened for gastrointestinal polyposis, which aims to identify and remove polyps if indicated.
  • Baseline oesophagogastroduodenoscopy (OGD) and colonoscopy is recommended at eight years of age.
    • • If polyps are found during this baseline examination, OGD and colonoscopy should be repeated every three years.
      • Elective polypectomy is recommended to prevent polyp-related complications.
      • If baseline OGD and colonoscopy are negative, routine OGDs and colonoscopies are recommended from 18 years of age, or sooner if symptoms develop.
  • Small bowel gastrointestinal surveillance by video capsule endoscopy or magnetic resonance (MR) enterorrhaphy should commence at eight years of age and continue every one to three years, depending on polyp phenotype.
  • Small bowel polyps greater than 1.5cm to 2cm in size (or smaller if symptomatic – for example, causing abdominal pain or anaemia) should be considered for elective resection to prevent intussusception.
• Women with PJS should also participate in the very high-risk breast cancer screening programme (annual breast MRI or mammogram or a combination of both, depending on age), which commences from 30 years of age.
• • The role of chemo- or surgical prophylaxis in women with PJS is uncertain. The European Hereditary Tumour Group (EHTG) does not support prophylactic mastectomy in an asymptomatic individual unless there are specific risk factors indicating high breast cancer risk. Decisions regarding contralateral prophylaxis in a woman with PJS who has been diagnosed with breast cancer should be made on a case-by-case basis within the context of a specialist multidisciplinary team meeting.

Management of other cancer risks

• There are no clear data to support survival benefit from pancreatic surveillance. The current recommendation of the UK Cancer Genetics Group and the EHTG is that screening should be undertaken only within the context of a formal, ethically approved research study. Patients should be provided with advice regarding symptom awareness.
• The optimum gynaecological screening strategy for women with PJS is unclear. The EHTG has proposed that:
  • surveillance for non-epithelial ovarian cancers should involve bimanual pelvic examination with a transvaginal ultrasound if there is suspicion of a pelvic mass (CA125 testing is not indicated); and
  • surveillance for cervical adenocarcinomas (adenoma malignum) should involve speculum examination and cervical screening (‘pap smear’) including cytology, even in an HPV-negative sample.
• Men with PJS should be provided with advice regarding testicular symptom awareness, and should be counselled to regularly self-examine their testes.
• There is currently no evidence to support screening of other organs, but a high index of suspicion should be maintained if any symptoms develop.

The Human Fertilisation and Embryology Authority has approved the use of preimplantation genetic testing for monogenic disorders (PGT-M – previously known as preimplantation genetic diagnosis) for couples in whom one intended parent has a likely pathogenic or pathogenic variant in STK11. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father has the pathogenic variant) with termination of affected embryos, adoption, gamete donation and natural conception and pregnancy with testing of children later in life.

For clinicians

• GeneReviews: Peutz-Jeghers syndrome
• InSiGHT: Peutz Jeghers syndrome
• NHS England: National Genomic Test Directory (note that somatic (tumour) tests are listed in the test directory for cancer, while constitutional (germline) tests are listed in the test directory for rare and inherited disease)

References:

• Borun P, De Rosa M, Nedoszytko B and others. ‘Specific Alu elements involved in a significant percentage of copy number variations of the STK11 gene in patients with Peutz-Jeghers syndrome’. Familial Cancer 2015: volume 14, pages 455–461. DOI: 10.1007/s10689-015-9800-5
• Daniell J, Plazzer JP,  Perera A and others. ‘An exploration of genotype-phenotype link between Peutz-Jeghers syndrome and STK11: A review’. Familial cancer 2018: volume 17, pages 421–427. DOI: 10.1007/s10689-017-0037-3
• Wagner A, Aretz S, Auranen A and others. ‘The management of Peutz-Jeghers syndrome: European Hereditary Tumour Group (EHTG) guideline’. Journal of Clinical Medicine 2021: volume 10, issue 3, page 473. DOI: 10.3390/jcm10030473

For patients

• PolyposisPatient
• St Mark’s Hospital: An introduction to Peutz-Jeghers syndrome (PDF, 16 pages)