Peutz-Jeghers Syndrome – Definition
Peutz-Jeghers syndrome (PJS, OMIM #175200) is a genetic disease caused by a heterozygous pathogenic variant in the STK11 gene. It is characterized by the association of gastrointestinal polyps, mucocutaneous pigmentation, and a predisposition to malignant diseases.
Synonym:
PJS
Gene:
STK11
Gene products:
STK11 (serine/threonine protein kinase)
Function:
Tumor suppressor
- Apoptosis mediated by interaction with the p53 signaling pathway
- Activation of TSC2 leads to the accumulation of mTOR
Pattern of inheritance:
Autosomal dominant, around 25% de novo mutations
Prevalence:
Unknown
Genotype-phenotype correlation
Not clear
Penetrance:
Clinical manifestations have not yet been found in any of the patients with a pathogenic variant STK11.
Peutz-Jeghers Syndrome – Diagnosis
Suspected Diagnosis
Peutz-Jeghers syndrome is suspected when the following findings apply:
- ≥ 2 intestinal PJS-type polyps (hamartomatous, intestinal polyps)
- Mucocutaneous pigment spots
- Gynecomastia in men as the result of estrogen-producing Sertoli cell testicular tumors
- Condition following invagination, especially in children or young adults
Genetic Diagnostics
The diagnosis of “Peutz-Jeghers syndrome” is confirmed by the detection of a heterozygous pathogenic germline variant in the STK11 gene through sequence analysis and, if necessary, a subsequent deletion/duplication analysis. Panel examinations consisting of multiple genes, as well as exome or genome sequencing, may also be helpful.
Diagnostic Criteria
The diagnosis of “Peutz-Jeghers syndrome” is considered to be confirmed when there is evidence of a heterozygous pathogenic germline variant in the STK11 gene or one of the following findings:
- ≥ 2 histologically confirmed harmartomatous PJS-type polyps
- Any number of PJS-type polyps in a person who has at least one close relative with PJS
- Characteristic mucocutaneous pigmentation in a person who has at least one close relative with PJS
- Any number of PJS-type polyps in a person with characteristic mucocutaneous pigmentation
Differential Diagnoses
- Juvenile Polyposis Syndrome (JPS)
- Hereditary Mixed Polyposis Syndrome
- PTEN Hamartoma Tumor Syndrome, also Cowden Syndrome
- Unexplained Hamartomatous Mixed Polyposis
- Carney Complex
- Familial Adenomatous Polyposis (FAP)
- Hereditary Non-Polyposis Colorectal Carcinoma (HNPCC), also Lynch Syndrome
Clinical Presentation
What is characteristic of Peutz-Jeghers Syndrome is the association of gastrointestinal polyps and mucocutaneous pigmentation. The risk of gastrointestinal and extraintestinal malignancies is significantly increased.
Polyps
Polyps may occur throughout the entire gastrointestinal tract but are most common in the small intestine (with the highest density in the jejunum, followed by the ileum and the duodenum). Polyps can occur outside of the gastrointestinal tract as well (renal pelvis, urinary bladder, ureters, lungs, nose, and gall bladder). Their malignant potential is currently unclear. The polyps can cause complications such as intestinal obstructions, rectal prolapse, or severe gastrointestinal hemorrhaging.
The average age when the first gastrointestinal symptoms appear is 10 years of age, with the first polypectomy on average being performed at the age of 13.
Mucocutaneous Pigmentation
It is rare for the characteristic melanocytic maculae to exist at birth already; they typically develop by age 5. The pigmentation fades during puberty and adulthood. The maculae are dark blue to dark brown in color and occur most commonly in the perioral region, on the eyes and nostrils, on the buccal mucosa, and in the perianal region. Hyperpigmented maculae on the fingers are also common. No risk of malignancy is associated with melanocytic maculae.
Gonadal Tumors
Female PJS patients have an increased risk of sex cord tumors with annular tubules (SCTAT) and mucinous tumors of the ovaries and tubes, which regularly develop bilaterally and have a benign progression.
Male PJS patients have an increased risk of large calcifying Sertoli cell tumors (LCST) of the testicles. These tumors release estrogen and generally do not exhibit any malignant transformation.
Malignancies
| Manifestation Location | Risk of | Manifestation Age |
|---|---|---|
| Colorectal | 39% | 42 – 46 years |
| Stomach | 29% | 30-40 years |
| Small intestine | 13% | 37-42 years |
| Mammary | 32% – 54% | 37-59 years |
| Ovary (mostly SCTAT) | 21% | 28 years |
| Cervix (adenoma malignum) | 10% | 34-40 years |
| Uterus | 9% | 43 years |
| Pancreas | 11% – 36% | 41-52 years |
| Testicles (Sertoli cell tumor) | 9% | 6-9 years |
| Lung | 7% – 17% | 47 years |
Special Features of Treatment
Polyps > 1 cm in size should be removed prophylactically to prevent long-term complications and reduce the risk of a malignant transformation.
Malignant diseases should be treated according to the pertinent protocols.
Diagnosis of Peutz-Jeghers Syndrome- What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Diagnosis of Peutz-Jeghers Syndrome - What's Next?
Once diagnosed, it is recommended that a cancer predisposition specialist manage the patient. The following section explains whether cancer screening tests or other measures are necessary and how they should be performed. Some additional information, including links to support groups, is also included at the end of this page.
Recommendations for Early Detection in Your Patients
According to the latest AACR guidelines, the following screening tests are recommended for patients with Perlman syndrome:
Gastrointestinal Tract
- Esophagogastroduodenoscopy, video capsule endoscopy, or colonoscopy at 8 years of age
- If there are polyps → repeat every 3 years
- If there are no polyps → repeat at the age of 18
- If VCE is not available, magnetic resonance imaging may be performed as an alternative
- Information about the symptoms of intussusception!
Ovaries, Cervix, Uterus
- Annual clinical examination, especially with regard to early puberty in girls from childhood
- Annual gynaecological examination with transvaginal ultrasound and serum CA 125 from 18-20 years of age
Breast
- Annual breast cancer screening from the age of 25
Testicles
- Annual clinical examination, particularly for gynaecomastia, testicular masses and testicular volume, and percentile growth in boys
Pancreas
- MRCP or endoscopic ultrasound every 1-2 years from age 30
