Definition

Peutz-Jeghers syndrome (PJS, OMIM #175200) is a genetic disease caused by a heterozygous mutation in the STK11 gene. It is characterized by the association of gastrointestinal polyps, mucocutaneous pigmentation, and a predisposition to malignant diseases.

Key Data
Diagnosis
Differential Diagnoses
Clinical Presentation
Therapeutic Considerations
Surveillance Recommendations
Additional Information

Key Data

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Synonym	PJS
Gene	STK11
Gene product	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
Heredity	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 STK11 mutation.

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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 germline mutation in the STK11 gene through sequence analysis and, if necessary, a subsequent deletion/duplication analysis. The use of panel examinations consisting of multiple genes as well as exome or genome sequencing may be helpful as well.

Diagnostic Criteria

The diagnosis of “Peutz-Jeghers syndrome” is considered to be confirmed when there is evidence of a heterozygous germline mutation 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-pPolyposis 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	Manifestation Age
Colorectal	39%	42 – 46 years
Stomach	29%	30-40 years
Small intestine	13%	37-42 years
Breasts	32% – 54%	37-59 years
Ovaries (usually SCTAT)	21%	28 years
Cervix (malignant adenoma)	10%	34-40 years
Uterus	9%	43 years
Pancreas	11% – 36%	41-52 years
Testicles (Sertoli cell tumor)	9%	6-9 years
Lungs	7% – 17%	47 years

Therapeutic Considerations

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.

Surveillance Recommendations

Gastrointestinal Tract

Esophagogastroduodenoscopy, video capsule endoscopy, or magnetic resonance enterography and colonoscopy at 8 years (or earlier if symptoms occur)
- If there are polyps -> repeated every 3 years
- If there are no polyps -> repeated at the age of 18

Gonads, Breasts, Ovaries, Cervix, Uterus

Annual clinical examination, particularly with regard to gynecomastia or space-occupying lesions of the testicles in boys and premature puberty in girls from birth to adolescence
Annual breast cancer screening as of 25 years of age
Annual gynecological examination with a transvaginal ultrasound and CA 125 in the serum as of 18-20 years of age