⚙

Pathophysiology

8

STK11 germline loss-of-function

Germline heterozygous loss-of-function variants in STK11 (LKB1), a serine/threonine tumor-suppressor master kinase on chromosome 19p13.3, are the primary cause of Peutz-Jeghers syndrome and the hamartomatous polyps that define it. Inheritance is autosomal dominant; ~30% of cases are de novo. Downstream effects propagate through inactivation of the LKB1/AMPK axis, defective stromal TGF-beta signaling, and a permissive state for somatic two-hit loss in tumors.

intestinal smooth muscle cell CL:0002504 enterocyte CL:0000584

STK11 hgnc:11389

signal transduction GO:0007165 ↓ DECREASED regulation of cell proliferation GO:0042127 ↓ DECREASED

small intestine UBERON:0002108 colon UBERON:0001155

Downstream

LKB1/AMPK pathway inactivation Loss of catalytically active LKB1 abolishes T-loop phosphorylation of AMPK and AMPK-related kinases, releasing downstream growth signals.

Stromal mesenchymal LKB1 loss with defective TGF-beta signaling Mesenchymal cell STK11 loss is sufficient to drive hamartomatous polyp formation through reduced stromal TGF-beta production to the epithelium.

COX-2 / prostaglandin biosynthetic upregulation Loss of LKB1 is associated with selective COX-2 (PTGS2) overexpression in PJS hamartomatous polyps, driving prostaglandin biosynthesis.

Two-hit somatic STK11 inactivation and malignant transformation Somatic loss of the remaining STK11 allele (loss of heterozygosity) in epithelium is observed in PJS-associated cancers and contributes to malignant transformation of the hereditary background.

Mucocutaneous melanocyte hyperpigmentation STK11 loss in melanocytes is associated with the characteristic mucocutaneous lentiginous pigmentation, although the precise melanocyte-intrinsic mechanism remains incompletely defined.

Show evidence (2 references)

PMID:37054692 SUPPORT Human Clinical

"Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which..."

Establishes STK11 germline variants as the driver of hamartomatous polyposis in PJS.

PMID:38800180 SUPPORT Human Clinical

"The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation"

Establishes the cellular functions disrupted by STK11 loss in PJS.

LKB1/AMPK pathway inactivation

LKB1 (the STK11 product), in complex with STRAD and MO25, is the master upstream kinase that phosphorylates AMPK at Thr172 and activates the AMPK-related kinase subfamily. Loss of LKB1 catalytic activity in PJS abolishes this T-loop phosphorylation, lowering AMPK activity in polyp tissue and releasing AMPK-mediated repression of mTORC1.

enterocyte CL:0000584

STK11 hgnc:11389

activation of protein kinase activity GO:0032147 ↓ DECREASED

AMP-activated protein kinase activity GO:0004679 ↓ DECREASED

small intestine UBERON:0002108

Downstream

mTORC1 pathway hyperactivation Reduced AMPK activity removes inhibitory phosphorylation of TSC2 and Raptor, derepressing mTORC1 in LKB1-deficient cells and tissues.

Show evidence (2 references)

PMID:14976552 SUPPORT In Vitro

"We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK)"

Establishes LKB1 as the upstream kinase that phosphorylates and activates AMPK.

PMID:38660671 SUPPORT Human Clinical

"phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients"

Direct human-tissue evidence that pathogenic STK11 variants reduce AMPK Thr172 phosphorylation in PJS polyps.

mTORC1 pathway hyperactivation

With AMPK no longer restraining mTORC1, LKB1-deficient mouse and human PJS polyp tissues show elevated mTORC1 signaling, increased HIF-1alpha and GLUT1 expression, and a pro-proliferative translation program. This rationalises the use of mTOR inhibitors (e.g. rapamycin/sirolimus) that reduce polyp number and size in mouse models.

enterocyte CL:0000584

mTORC1 signaling GO:0031929 ↑ INCREASED cell proliferation GO:0008283 ↑ INCREASED

small intestine UBERON:0002108

Downstream

Small intestinal polyposis Sustained mTORC1-driven epithelial proliferation contributes to hamartomatous polyp growth in the small intestine.

Increased cancer risk Chronic mTORC1 activation cooperates with somatic STK11 loss and additional oncogenic events to support malignant transformation in PJS-associated cancers.

Show evidence (3 references)

PMID:15261145 SUPPORT Model Organism

"LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR"

Establishes the LKB1-AMPK-TSC2-mTOR axis and shows mTOR is hyperactive in murine PJS-like polyps.

PMID:19541609 SUPPORT Model Organism

"Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice."

Demonstrates mTORC1 pathway hyperactivation in LKB1-deficient PJS models.

PMID:19541609 SUPPORT Human Clinical

"Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."

Confirms mTORC1 signaling is upregulated in human PJS polyps.

Stromal mesenchymal LKB1 loss with defective TGF-beta signaling

Mouse genetic experiments show that biallelic Stk11 loss restricted to Tagln/SM22-positive mesenchymal cells is sufficient to produce PJS-indistinguishable hamartomatous polyps. Lkb1-deficient stromal fibroblasts produce less TGF-beta and have attenuated SMAD-dependent transcription, which removes a paracrine brake on overlying epithelial proliferation. Defective TGF-beta signaling has also been observed in polyps from PJS patients, supporting a stromal-niche mechanism of polyp formation.

stromal cell of small intestinal lamina propria CL:0009022 fibroblast CL:0000057 myofibroblast CL:0000186

STK11 hgnc:11389

TGF-beta receptor signaling GO:0007179 ↓ DECREASED regulation of cell proliferation GO:0042127 ↑ INCREASED

small intestine UBERON:0002108

Downstream

Arborizing smooth muscle core formation Failed paracrine TGF-beta-driven myofibroblast and smooth-muscle organisation in the polyp stroma yields the disorganized branching smooth-muscle core that defines PJS-type hamartomas.

Small intestinal polyposis Loss of stromal TGF-beta brake on epithelium permits hamartomatous epithelial overgrowth and polyp formation.

Show evidence (3 references)

PMID:18311138 SUPPORT Model Organism

"either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS"

Demonstrates that mesenchymal STK11 loss alone is sufficient for PJS-type polyposis.

PMID:18311138 SUPPORT Human Clinical

"We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS"

Establishes that the stromal TGF-beta paracrine defect is also observed in human PJS polyps, not just the mouse model.

PMID:18840652 SUPPORT In Vitro

"Ablation of Lkb1 in primary mouse embryo fibroblasts (MEFs) leads to attenuated Smad activation and TGFbeta-dependent transcription"

In vitro confirmation that LKB1 loss attenuates SMAD signaling downstream of TGF-beta receptor activation.

COX-2 / prostaglandin biosynthetic upregulation

PJS hamartomatous polyps selectively overexpress cyclooxygenase-2 (PTGS2/COX-2) in epithelial cells and the lamina propria stroma (including muscle), elevating local prostaglandin biosynthesis. This has motivated COX-2-directed chemoprevention strategies and is the rationale for ongoing celecoxib trials in PJS (e.g. NCT06722534).

enterocyte CL:0000584 enteric smooth muscle cell CL:0002504

prostaglandin biosynthetic process GO:0001516 ↑ INCREASED cyclooxygenase pathway GO:0019371 ↑ INCREASED

small intestine UBERON:0002108

Downstream

Small intestinal polyposis Elevated polyp-stromal prostaglandin signaling supports epithelial proliferation and polyp growth, making COX-2 inhibition a chemoprevention candidate.

Increased cancer risk COX-2-driven prostaglandin signaling is a recognised pro-tumorigenic pathway that may contribute to the elevated GI cancer risk in PJS.

Show evidence (2 references)

PMID:12650805 SUPPORT Human Clinical

"COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue"

Direct quantitative evidence of COX-2 upregulation in PJS hamartomas.

PMID:12650805 SUPPORT Human Clinical

"COX-2 expression was noted in the epithelial cells of hamartomatous polyps, and also coursing throughout the stromal tissue of the lamina propria, including muscle cells"

Localises COX-2 overexpression to both epithelial and stromal compartments of the polyp.

Arborizing smooth muscle core formation

Hamartomatous polyps contain branching bundles of smooth muscle fibers that extend from the muscularis mucosae and are covered by hyperplastic mucosa, producing the characteristic phyllodes/Christmas-tree arborizing architecture diagnostic of Peutz-Jeghers polyps. The disorganized smooth-muscle/mucosal architecture mechanically predisposes to obstruction, intussusception and friable bleeding surfaces.

enteric smooth muscle cell CL:0002504

smooth muscle cell differentiation GO:0051145 tissue morphogenesis GO:0048729

small intestine UBERON:0002108

Downstream

Intussusception Pedunculated polyps with bulky arborizing smooth-muscle cores act as lead points for intussusception, particularly in children, with risk sharply rising for polyps >15 mm.

Gastrointestinal hemorrhage Friable polyp surfaces overlying the arborizing core ulcerate and bleed, producing chronic occult or overt GI hemorrhage.

Abdominal pain Polyp-related obstruction and intussusception are a major cause of recurrent abdominal pain in PJS.

Show evidence (1 reference)

PMID:36998347 SUPPORT Human Clinical

"The resected specimen showed a branching bundle of smooth muscle fibers covered by hyperplastic mucosa, consistent with a hamartomatous polyp"

Histologic description supports the arborizing smooth muscle core in PJS polyps.

Two-hit somatic STK11 inactivation and malignant transformation

Cancers arising in STK11 carriers typically show somatic loss of the remaining wild-type allele (loss of heterozygosity), consistent with Knudson two-hit tumor suppressor logic. Mouse Lkb1+/- intestinal polyps recapitulate the human PJS phenotype and provide the genetic framework for the two-hit model in PJS-associated tumorigenesis, although early Lkb1 loss is permissive rather than directly transforming and requires additional cooperating events.

enterocyte CL:0000584

STK11 hgnc:11389

regulation of cell proliferation GO:0042127 ↑ INCREASED

small intestine UBERON:0002108 colon UBERON:0001155

Downstream

Increased cancer risk Somatic LOH at STK11 plus mTORC1/COX-2-driven proliferation and cooperating oncogenic events produces the high lifetime cancer risk observed in PJS across GI, breast, gynecologic, pancreatic and pulmonary sites.

Show evidence (3 references)

PMID:12226664 SUPPORT Model Organism

"Lkb1(+/-) mice develop intestinal polyps identical to those seen in individuals affected with PJS"

Establishes that heterozygous Lkb1 loss recapitulates the PJS polyposis phenotype.

PMID:12226664 PARTIAL Model Organism

"PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential"

Frames the two-hit context for PJS polyps and notes that further events beyond STK11 LOH are required for transformation.

PMID:20051941 SUPPORT Human Clinical

"PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer"

Quantifies the broad multi-organ cancer predisposition that emerges from STK11 loss plus secondary somatic events.

Mucocutaneous melanocyte hyperpigmentation

Characteristic bluish-black to dark brown lentiginous macules of the lips, perioral skin, buccal mucosa, fingertips and perianal region in PJS reflect focal melanocyte hyperactivity and increased melanin deposition along the basal epidermis. The melanocyte-intrinsic consequence of STK11 loss has not been fully delineated; pigmentation typically appears in early childhood, often before GI manifestations.

melanocyte CL:0000148

melanin biosynthetic process GO:0042438 ↑ INCREASED pigmentation GO:0043473 ↑ INCREASED

Downstream

Abnormal lip pigmentation Melanocyte hyperactivity produces the characteristic pigmented macules of the lips that are usually the earliest visible PJS sign.

Abnormal pigmentation of oral mucosa Buccal/perioral melanocyte hyperpigmentation produces intraoral mucosal macules used in PJS diagnosis.

Show evidence (2 references)

PMID:38800180 PARTIAL Human Clinical

"The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes"

Confirms the mucocutaneous lentiginous pigmentation phenotype that is the hallmark of melanocyte involvement in PJS.

PMID:20301443 SUPPORT Human Clinical

"Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa"

GeneReviews establishes the distribution and timing of the pigmented macules.

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Pathograph

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Phenotypes

8

Blood 2

Gastrointestinal hemorrhage VERY_FREQUENT Gastrointestinal hemorrhage HP:0002239

Show evidence (1 reference)

PMID:20301443 SUPPORT

"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection"

Establishes chronic gastrointestinal bleeding from polyps as a major complication of PJS

Iron deficiency anemia FREQUENT Iron deficiency anemia HP:0001891

Show evidence (1 reference)

PMID:20301443 SUPPORT Human Clinical

"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection"

GeneReviews documents chronic blood loss from PJS polyps causing anemia.

Digestive 1

Small intestinal polyposis VERY_FREQUENT Small intestinal polyposis HP:0030256

Show evidence (1 reference)

PMID:37892343 SUPPORT

"The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis"

Confirms small intestinal polyposis as a hallmark manifestation of PJS

Head and Neck 2

Abnormal pigmentation of oral mucosa VERY_FREQUENT Abnormal pigmentation of the oral mucosa HP:0100669

Show evidence (1 reference)

PMID:20301443 SUPPORT

"Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa"

Oral and mucocutaneous pigmentation is a characteristic diagnostic feature of PJS, often appearing before GI polyps

Abnormal lip pigmentation VERY_FREQUENT Abnormal lip pigmentation HP:0032453

Show evidence (1 reference)

PMID:36970589 SUPPORT

"Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors"

This cohort description identifies lip pigmentation as a characteristic feature of PJS.

Constitutional 1

Abdominal pain VERY_FREQUENT Abdominal pain HP:0002027

Show evidence (1 reference)

PMID:20301443 SUPPORT

"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"

Intussusception from Peutz-Jeghers polyps causes abdominal pain and obstruction

Neoplasm 1

Increased cancer risk FREQUENT Neoplasm HP:0002664

Show evidence (3 references)

PMID:20301443 SUPPORT Human Clinical

"Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers)"

PJS patients have substantially elevated lifetime cancer risk across multiple organ systems

PMID:20051941 SUPPORT Human Clinical

"The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population"

Systematic review quantifies the magnitude of multi-organ cancer risk used to design surveillance.

PMID:33513864 SUPPORT Human Clinical

"The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients"

European hereditary tumor group recognizes comprehensive cancer risk across multiple organ systems as defining feature requiring multisystem management

Other 1

Intussusception VERY_FREQUENT Intussusception HP:0002576

Show evidence (1 reference)

PMID:36970589 SUPPORT Human Clinical

"At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%"

Direct quantitative evidence of cumulative intussusception risk in PJS.

🧬

Genetic Associations

2

STK11 (Serine/threonine kinase 11, also called LKB1)

Show evidence (1 reference)

PMID:37054692 SUPPORT

"It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"

Confirms germline STK11 mutations as the causative genetic basis for Peutz-Jeghers syndrome

PTEN (Phosphatase and tensin homolog)

Show evidence (1 reference)

PMID:37377590 SUPPORT

"Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations"

Alternative genetic mutations including PTEN can account for STK11-negative PJS-like presentations

💊

Medical Actions

5

Endoscopic polypectomy

Action: endoscopic procedure MAXO:0000130

Regular surveillance endoscopy with removal of polyps >10-15 mm reduces bleeding complications and cancer risk. Multiple sessions may be needed given the polyp burden.

Show evidence (1 reference)

PMID:20301443 SUPPORT

"Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception"

Endoscopic polyp removal is the standard therapeutic approach to prevent complications from Peutz-Jeghers polyps

Surgical resection

Action: surgical resection Ontology label: surgical procedure MAXO:0000004

Reserved for cases with severe polyp burden, recurrent intussusception, or malignant transformation.

Show evidence (1 reference)

PMID:34928720 SUPPORT

"The patient underwent exploratory laparotomy during which right hemicolectomy and small bowel resection were performed"

Surgical resection is indicated for intussusception and polyps with neoplastic transformation

COX-2 inhibitor chemoprevention (celecoxib)

Action: Pharmacotherapy NCIT:C15986

Agent: celecoxib CHEBI:41423

COX-2 inhibition with celecoxib is being evaluated as polyp-burden chemoprevention in PJS, motivated by COX-2 overexpression in hamartomas and preclinical reduction of polyp number in mouse models. Investigational; not yet standard of care.

Mechanism Target:

COX-2 / prostaglandin biosynthetic upregulation — Celecoxib inhibits COX-2, directly antagonising the prostaglandin biosynthetic upregulation observed in PJS hamartomas.

Show evidence (1 reference)

clinicaltrials:NCT06722534 PARTIAL Human Clinical

"Cyclooxygenase (COX) is overexpressed in hamartomatous polyp tissue from PJS individuals, which may provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS"

Links the trial directly to the COX-2 mechanism node.

Show evidence (1 reference)

clinicaltrials:NCT06722534 PARTIAL Human Clinical

"Celecoxib, a COX-2 inhibitor, has been shown to reduce polyp burden by 54% in PJS model mice"

Trial rationale documents COX-2 inhibition as a candidate chemoprevention strategy targeting the COX-2 mechanism node.

Sirolimus (mTOR inhibition)

Action: Pharmacotherapy NCIT:C15986

Agent: sirolimus CHEBI:9168

mTORC1 inhibition with sirolimus (rapamycin) suppresses preexisting GI polyps in LKB1+/- mice, providing direct preclinical rationale for targeting the LKB1-AMPK-mTORC1 axis in PJS. Investigational in human PJS and not yet a standard-of-care therapy.

Mechanism Target:

mTORC1 pathway hyperactivation — Sirolimus is an allosteric mTORC1 inhibitor and directly antagonises the mTORC1 hyperactivation downstream of LKB1 loss.

Show evidence (1 reference)

PMID:19541609 SUPPORT Model Organism

"the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice"

Links sirolimus's mechanism to the mTORC1 hyperactivation node in this entry.

Show evidence (1 reference)

PMID:19541609 SUPPORT Model Organism

"Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice"

Direct mouse-model evidence that mTOR inhibition reduces PJS-like polyp burden, motivating clinical evaluation.

Genetic counseling

Action: genetic counseling MAXO:0000079

Family members should receive counseling and cascade genetic testing for STK11 mutations.

Show evidence (1 reference)

PMID:37054692 SUPPORT Human Clinical

"It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"

Autosomal dominant inheritance of pathogenic STK11 variants is the basis for cascade testing and genetic counseling of at-risk relatives.

🌍

Environmental Factors

1

Polyp intussusception risk

Large polyps (>15 mm) are more prone to intussusception, particularly in children and adolescents, which may require endoscopic intervention or surgery.

Show evidence (1 reference)

PMID:36970589 SUPPORT

"At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%"

Age is a critical environmental/clinical factor that significantly increases intussusception risk in PJS patients

🔬

Biochemical Markers

1

Butyric acid (Decreased)

Show evidence (2 references)

PMID:38036954 SUPPORT

"The results showed dysbiosis in the gut microbiota of patients with PJS, and decreased synthesis of short-chain fatty acids."

This study reports reduced short-chain fatty acid synthesis in PJS.

PMID:38036954 SUPPORT

"Furthermore, the butyric acid level was negatively correlated with the frequency of endoscopic surgeries."

Lower butyric acid levels associate with higher polyp-related intervention burden.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Peutz-Jeghers polyp:

Juvenile polyposis syndrome MONDO:0017380

Overlapping Features Juvenile polyps are also hamartomatous but present earlier in childhood, usually multiple but fewer than Peutz-Jeghers polyps. Lack the characteristic oral pigmentation. Juvenile polyposis is caused by BMPR1A or SMAD4 mutations, not STK11.

Distinguishing Features

Juvenile polyps are typically fewer in number and present earlier
No oral pigmentation in juvenile polyposis
Different genetic basis (BMPR1A/SMAD4 vs. STK11)

Show evidence (1 reference)

PMID:35988962 SUPPORT

"JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz-Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations"

Establishes juvenile polyposis as a distinct differential diagnosis that must be excluded when evaluating hamartomatous polyp syndromes like PJS

Cowden syndrome MONDO:0008021

Overlapping Features Hamartomatous polyposis syndrome caused by PTEN mutations with mucocutaneous lesions and increased breast, thyroid, and endometrial cancer risks.

Distinguishing Features

PTEN-related hamartomas with trichilemmomas and papillomatous papules.
Cancer risk profile emphasizes breast, thyroid, and endometrial malignancies.

Show evidence (1 reference)

PMID:36925460 SUPPORT

"Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."

This review lists Cowden syndrome among the major hamartomatous polyposis syndromes that must be distinguished from PJS.

Familial adenomatous polyposis (FAP) MONDO:0021055

Overlapping Features FAP presents with hundreds to thousands of adenomatous polyps. Polyps are adenomas (dysplastic), not benign hamartomas like Peutz-Jeghers. FAP is caused by APC mutations and does not include characteristic oral pigmentation.

Distinguishing Features

FAP polyps are adenomas with high-grade dysplasia; Peutz-Jeghers polyps are benign hamartomas
No lip pigmentation in FAP
Different molecular basis (APC vs. STK11)

Show evidence (1 reference)

PMID:36925460 SUPPORT

"Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)"

Distinguishes PJS as a hamartomatous polyposis syndrome, separate from adenomatous syndromes like FAP

Lynch syndrome MONDO:0005835

Overlapping Features Lynch syndrome involves microsatellite instability and increased cancer risk but does not feature polyp burden or oral pigmentation. Caused by mismatch repair gene mutations, not STK11.

Distinguishing Features

Lynch syndrome lacks prominent polyp burden and oral pigmentation
Cancer risk is primarily colorectal rather than panGI
Molecular basis involves MMR genes, not STK11

Show evidence (1 reference)

PMID:34680270 SUPPORT

"Patients with PJS are at a 15- to 18-fold increased malignancy risk relative to the general population"

PJS carries a distinctive pattern of multi-organ cancer predisposition (GI, breast, lung, genitourinary) that differs from Lynch syndrome's primarily colorectal focus

{ }

Source YAML

click to show

name: Peutz-Jeghers polyp
creation_date: '2026-01-20T21:32:08Z'
updated_date: '2026-05-02T00:00:00Z'
category: Genetic
disease_term:
  preferred_term: Peutz-Jeghers polyp
  term:
    id: MONDO:0006365
    label: Peutz-Jeghers polyp
parents:
- Hamartomatous polyp
- Hereditary cancer syndrome
prevalence:
- population: Japan, nationwide 2022 Peutz-Jeghers syndrome survey
  percentage: 0.6 per 100,000
  notes: >-
    This syndrome-level estimate is used because Peutz-Jeghers polyps are the
    defining hamartomatous lesion of Peutz-Jeghers syndrome.
  evidence:
  - reference: PMID:39623880
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 3-year period prevalences of PJS and JPS were 0.6/100000 and 0.15/100000, whereas the incidences in 2021 were 0.07/100000 and 0.02/100000, respectively."
    explanation: This nationwide Japanese survey directly reports Peutz-Jeghers syndrome prevalence at 0.6 per 100,000.
- population: Review-based global estimates for Peutz-Jeghers syndrome
  percentage: 1 in 8,300 to 1 in 280,000
  notes: >-
    Published estimates vary widely across ascertainment settings, but all place
    Peutz-Jeghers syndrome firmly within the rare-disease range.
  evidence:
  - reference: PMID:19916169
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence of PJS is estimated from 1 in 8300 to 1 in 280,000 individuals."
    explanation: This clinical review summarizes the broad range of published prevalence estimates for Peutz-Jeghers syndrome.
pathophysiology:
- name: STK11 germline loss-of-function
  description: >
    Germline heterozygous loss-of-function variants in STK11 (LKB1), a
    serine/threonine tumor-suppressor master kinase on chromosome 19p13.3,
    are the primary cause of Peutz-Jeghers syndrome and the hamartomatous
    polyps that define it. Inheritance is autosomal dominant; ~30% of cases
    are de novo. Downstream effects propagate through inactivation of the
    LKB1/AMPK axis, defective stromal TGF-beta signaling, and a
    permissive state for somatic two-hit loss in tumors.
  evidence:
  - reference: PMID:37054692
    reference_title: "Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"
    explanation: Establishes STK11 germline variants as the driver of hamartomatous polyposis in PJS.
  - reference: PMID:38800180
    reference_title: "Peutz-Jeghers Syndrome: A Comprehensive Review of Genetics, Clinical Features, and Management Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gene serine/threonine kinase 11 (STK11) controls several biological functions, including cell polarity, growth, and proliferation"
    explanation: Establishes the cellular functions disrupted by STK11 loss in PJS.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  cell_types:
  - preferred_term: intestinal smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  biological_processes:
  - preferred_term: signal transduction
    term:
      id: GO:0007165
      label: signal transduction
    modifier: DECREASED
  - preferred_term: regulation of cell proliferation
    term:
      id: GO:0042127
      label: regulation of cell population proliferation
    modifier: DECREASED
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  downstream:
  - target: LKB1/AMPK pathway inactivation
    description: >
      Loss of catalytically active LKB1 abolishes T-loop phosphorylation of
      AMPK and AMPK-related kinases, releasing downstream growth signals.
    causal_link_type: DIRECT
  - target: Stromal mesenchymal LKB1 loss with defective TGF-beta signaling
    description: >
      Mesenchymal cell STK11 loss is sufficient to drive hamartomatous polyp
      formation through reduced stromal TGF-beta production to the epithelium.
    causal_link_type: DIRECT
  - target: COX-2 / prostaglandin biosynthetic upregulation
    description: >
      Loss of LKB1 is associated with selective COX-2 (PTGS2) overexpression
      in PJS hamartomatous polyps, driving prostaglandin biosynthesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Two-hit somatic STK11 inactivation and malignant transformation
    description: >
      Somatic loss of the remaining STK11 allele (loss of heterozygosity) in
      epithelium is observed in PJS-associated cancers and contributes to
      malignant transformation of the hereditary background.
    causal_link_type: DIRECT
  - target: Mucocutaneous melanocyte hyperpigmentation
    description: >
      STK11 loss in melanocytes is associated with the characteristic
      mucocutaneous lentiginous pigmentation, although the precise
      melanocyte-intrinsic mechanism remains incompletely defined.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: LKB1/AMPK pathway inactivation
  description: >
    LKB1 (the STK11 product), in complex with STRAD and MO25, is the master
    upstream kinase that phosphorylates AMPK at Thr172 and activates the
    AMPK-related kinase subfamily. Loss of LKB1 catalytic activity in PJS
    abolishes this T-loop phosphorylation, lowering AMPK activity in
    polyp tissue and releasing AMPK-mediated repression of mTORC1.
  evidence:
  - reference: PMID:14976552
    reference_title: "LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We recently demonstrated that the LKB1 tumour suppressor kinase, in complex with the pseudokinase STRAD and the scaffolding protein MO25, phosphorylates and activates AMP-activated protein kinase (AMPK)"
    explanation: Establishes LKB1 as the upstream kinase that phosphorylates and activates AMPK.
  - reference: PMID:38660671
    reference_title: "Two missense STK11 gene variations impaired LKB1/adenosine monophosphate-activated protein kinase signaling in Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "phosphorylated-AMPK (Thr172) expression was significantly lower in gastric, colonic, and uterine polyps from PJS patients with missense variations than in non-PJS patients"
    explanation: Direct human-tissue evidence that pathogenic STK11 variants reduce AMPK Thr172 phosphorylation in PJS polyps.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  biological_processes:
  - preferred_term: activation of protein kinase activity
    term:
      id: GO:0032147
      label: activation of protein kinase activity
    modifier: DECREASED
  molecular_functions:
  - preferred_term: AMP-activated protein kinase activity
    term:
      id: GO:0004679
      label: AMP-activated protein kinase activity
    modifier: DECREASED
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: mTORC1 pathway hyperactivation
    description: >
      Reduced AMPK activity removes inhibitory phosphorylation of TSC2 and
      Raptor, derepressing mTORC1 in LKB1-deficient cells and tissues.
    causal_link_type: DIRECT
- name: mTORC1 pathway hyperactivation
  description: >
    With AMPK no longer restraining mTORC1, LKB1-deficient mouse and human
    PJS polyp tissues show elevated mTORC1 signaling, increased HIF-1alpha
    and GLUT1 expression, and a pro-proliferative translation program. This
    rationalises the use of mTOR inhibitors (e.g. rapamycin/sirolimus)
    that reduce polyp number and size in mouse models.
  evidence:
  - reference: PMID:15261145
    reference_title: "The LKB1 tumor suppressor negatively regulates mTOR signaling."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "LKB1 is required for repression of mTOR under low ATP conditions in cultured cells in an AMPK- and TSC2-dependent manner, and that Lkb1 null MEFs and the hamartomatous gastrointestinal polyps from Lkb1 mutant mice show elevated signaling downstream of mTOR"
    explanation: Establishes the LKB1-AMPK-TSC2-mTOR axis and shows mTOR is hyperactive in murine PJS-like polyps.
  - reference: PMID:19541609
    reference_title: "mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Among mitogenic signaling pathways, the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice."
    explanation: Demonstrates mTORC1 pathway hyperactivation in LKB1-deficient PJS models.
  - reference: PMID:19541609
    reference_title: "mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, we demonstrate that polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."
    explanation: Confirms mTORC1 signaling is upregulated in human PJS polyps.
  biological_processes:
  - preferred_term: mTORC1 signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: cell proliferation
    modifier: INCREASED
    term:
      id: GO:0008283
      label: cell population proliferation
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Small intestinal polyposis
    description: >
      Sustained mTORC1-driven epithelial proliferation contributes to
      hamartomatous polyp growth in the small intestine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased translation of cyclin D1 and HIF-1alpha targets driving epithelial proliferation
  - target: Increased cancer risk
    description: >
      Chronic mTORC1 activation cooperates with somatic STK11 loss and
      additional oncogenic events to support malignant transformation in
      PJS-associated cancers.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Stromal mesenchymal LKB1 loss with defective TGF-beta signaling
  description: >
    Mouse genetic experiments show that biallelic Stk11 loss restricted to
    Tagln/SM22-positive mesenchymal cells is sufficient to produce
    PJS-indistinguishable hamartomatous polyps. Lkb1-deficient stromal
    fibroblasts produce less TGF-beta and have attenuated SMAD-dependent
    transcription, which removes a paracrine brake on overlying epithelial
    proliferation. Defective TGF-beta signaling has also been observed in
    polyps from PJS patients, supporting a stromal-niche mechanism of
    polyp formation.
  evidence:
  - reference: PMID:18311138
    reference_title: "LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "either monoallelic or biallelic loss of murine Stk11 limited to Tagln-expressing mesenchymal cells results in premature postnatal death as a result of gastrointestinal polyps indistinguishable from those in PJS"
    explanation: Demonstrates that mesenchymal STK11 loss alone is sufficient for PJS-type polyposis.
  - reference: PMID:18311138
    reference_title: "LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also noted TGFbeta signaling defects in polyps of individuals with PJS, suggesting that the identified stromal-derived mechanism of tumor suppression is also relevant in PJS"
    explanation: Establishes that the stromal TGF-beta paracrine defect is also observed in human PJS polyps, not just the mouse model.
  - reference: PMID:18840652
    reference_title: "Lkb1 is required for TGFbeta-mediated myofibroblast differentiation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Ablation of Lkb1 in primary mouse embryo fibroblasts (MEFs) leads to attenuated Smad activation and TGFbeta-dependent transcription"
    explanation: In vitro confirmation that LKB1 loss attenuates SMAD signaling downstream of TGF-beta receptor activation.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  cell_types:
  - preferred_term: stromal cell of small intestinal lamina propria
    term:
      id: CL:0009022
      label: stromal cell of lamina propria of small intestine
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    modifier: DECREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  - preferred_term: regulation of cell proliferation
    modifier: INCREASED
    term:
      id: GO:0042127
      label: regulation of cell population proliferation
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Arborizing smooth muscle core formation
    description: >
      Failed paracrine TGF-beta-driven myofibroblast and smooth-muscle
      organisation in the polyp stroma yields the disorganized branching
      smooth-muscle core that defines PJS-type hamartomas.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Attenuated SMAD-dependent myofibroblast differentiation in stromal fibroblasts
  - target: Small intestinal polyposis
    description: >
      Loss of stromal TGF-beta brake on epithelium permits hamartomatous
      epithelial overgrowth and polyp formation.
    causal_link_type: DIRECT
- name: COX-2 / prostaglandin biosynthetic upregulation
  description: >
    PJS hamartomatous polyps selectively overexpress cyclooxygenase-2
    (PTGS2/COX-2) in epithelial cells and the lamina propria stroma
    (including muscle), elevating local prostaglandin biosynthesis. This
    has motivated COX-2-directed chemoprevention strategies and is the
    rationale for ongoing celecoxib trials in PJS (e.g. NCT06722534).
  evidence:
  - reference: PMID:12650805
    reference_title: "Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue"
    explanation: Direct quantitative evidence of COX-2 upregulation in PJS hamartomas.
  - reference: PMID:12650805
    reference_title: "Overexpression of cyclooxygenase 2 in hamartomatous polyps of Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "COX-2 expression was noted in the epithelial cells of hamartomatous polyps, and also coursing throughout the stromal tissue of the lamina propria, including muscle cells"
    explanation: Localises COX-2 overexpression to both epithelial and stromal compartments of the polyp.
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  - preferred_term: enteric smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  biological_processes:
  - preferred_term: prostaglandin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0001516
      label: prostaglandin biosynthetic process
  - preferred_term: cyclooxygenase pathway
    modifier: INCREASED
    term:
      id: GO:0019371
      label: cyclooxygenase pathway
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Small intestinal polyposis
    description: >
      Elevated polyp-stromal prostaglandin signaling supports epithelial
      proliferation and polyp growth, making COX-2 inhibition a
      chemoprevention candidate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased cancer risk
    description: >
      COX-2-driven prostaglandin signaling is a recognised pro-tumorigenic
      pathway that may contribute to the elevated GI cancer risk in PJS.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Arborizing smooth muscle core formation
  description: >
    Hamartomatous polyps contain branching bundles of smooth muscle fibers
    that extend from the muscularis mucosae and are covered by hyperplastic
    mucosa, producing the characteristic phyllodes/Christmas-tree
    arborizing architecture diagnostic of Peutz-Jeghers polyps. The
    disorganized smooth-muscle/mucosal architecture mechanically
    predisposes to obstruction, intussusception and friable bleeding
    surfaces.
  evidence:
  - reference: PMID:36998347
    reference_title: "Endoscopic resection for a solitary Peutz-Jeghers type polyp in the duodenum: A case report with literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The resected specimen showed a branching bundle of smooth muscle fibers covered by hyperplastic mucosa, consistent with a hamartomatous polyp"
    explanation: Histologic description supports the arborizing smooth muscle core in PJS polyps.
  cell_types:
  - preferred_term: enteric smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle cell differentiation
    term:
      id: GO:0051145
      label: smooth muscle cell differentiation
  - preferred_term: tissue morphogenesis
    term:
      id: GO:0048729
      label: tissue morphogenesis
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Intussusception
    description: >
      Pedunculated polyps with bulky arborizing smooth-muscle cores act as
      lead points for intussusception, particularly in children, with risk
      sharply rising for polyps >15 mm.
    causal_link_type: DIRECT
  - target: Gastrointestinal hemorrhage
    description: >
      Friable polyp surfaces overlying the arborizing core ulcerate and
      bleed, producing chronic occult or overt GI hemorrhage.
    causal_link_type: DIRECT
  - target: Abdominal pain
    description: >
      Polyp-related obstruction and intussusception are a major cause of
      recurrent abdominal pain in PJS.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Polyp-induced bowel obstruction and intussusception
- name: Two-hit somatic STK11 inactivation and malignant transformation
  description: >
    Cancers arising in STK11 carriers typically show somatic loss of the
    remaining wild-type allele (loss of heterozygosity), consistent with
    Knudson two-hit tumor suppressor logic. Mouse Lkb1+/- intestinal
    polyps recapitulate the human PJS phenotype and provide the genetic
    framework for the two-hit model in PJS-associated tumorigenesis,
    although early Lkb1 loss is permissive rather than directly
    transforming and requires additional cooperating events.
  evidence:
  - reference: PMID:12226664
    reference_title: "Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Lkb1(+/-) mice develop intestinal polyps identical to those seen in individuals affected with PJS"
    explanation: Establishes that heterozygous Lkb1 loss recapitulates the PJS polyposis phenotype.
  - reference: PMID:12226664
    reference_title: "Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "PJS polyps are unusual neoplasms characterized by marked epithelial and stromal overgrowth but have limited malignant potential"
    explanation: Frames the two-hit context for PJS polyps and notes that further events beyond STK11 LOH are required for transformation.
  - reference: PMID:20051941
    reference_title: "High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer"
    explanation: Quantifies the broad multi-organ cancer predisposition that emerges from STK11 loss plus secondary somatic events.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  biological_processes:
  - preferred_term: regulation of cell proliferation
    modifier: INCREASED
    term:
      id: GO:0042127
      label: regulation of cell population proliferation
  cell_types:
  - preferred_term: enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  - preferred_term: colon
    term:
      id: UBERON:0001155
      label: colon
  downstream:
  - target: Increased cancer risk
    description: >
      Somatic LOH at STK11 plus mTORC1/COX-2-driven proliferation and
      cooperating oncogenic events produces the high lifetime cancer risk
      observed in PJS across GI, breast, gynecologic, pancreatic and
      pulmonary sites.
    causal_link_type: DIRECT
- name: Mucocutaneous melanocyte hyperpigmentation
  description: >
    Characteristic bluish-black to dark brown lentiginous macules of the
    lips, perioral skin, buccal mucosa, fingertips and perianal region in
    PJS reflect focal melanocyte hyperactivity and increased melanin
    deposition along the basal epidermis. The melanocyte-intrinsic
    consequence of STK11 loss has not been fully delineated; pigmentation
    typically appears in early childhood, often before GI manifestations.
  evidence:
  - reference: PMID:38800180
    reference_title: "Peutz-Jeghers Syndrome: A Comprehensive Review of Genetics, Clinical Features, and Management Approaches."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "The pigmentation commonly appears as prominent bluish-black macules and frequently affects the skin and mucous membranes"
    explanation: Confirms the mucocutaneous lentiginous pigmentation phenotype that is the hallmark of melanocyte involvement in PJS.
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa"
    explanation: GeneReviews establishes the distribution and timing of the pigmented macules.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: melanin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0042438
      label: melanin biosynthetic process
  - preferred_term: pigmentation
    modifier: INCREASED
    term:
      id: GO:0043473
      label: pigmentation
  downstream:
  - target: Abnormal lip pigmentation
    description: >
      Melanocyte hyperactivity produces the characteristic pigmented
      macules of the lips that are usually the earliest visible PJS sign.
    causal_link_type: DIRECT
  - target: Abnormal pigmentation of oral mucosa
    description: >
      Buccal/perioral melanocyte hyperpigmentation produces intraoral
      mucosal macules used in PJS diagnosis.
    causal_link_type: DIRECT
phenotypes:
- name: Small intestinal polyposis
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >
    Multiple hamartomatous polyps predominantly in the small intestine.
    These polyps are benign but can grow large and cause complications.
  evidence:
  - reference: PMID:37892343
    reference_title: "Small Intestinal Polyp Burden in Pediatric Peutz-Jeghers Syndrome Assessed through Capsule Endoscopy: A Longitudinal Study."
    supports: SUPPORT
    snippet: "The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis"
    explanation: "Confirms small intestinal polyposis as a hallmark manifestation of PJS"
  phenotype_term:
    preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
- name: Gastrointestinal hemorrhage
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >
    Bleeding from polyps can occur, presenting as hematemesis, melena, or positive fecal occult blood.
    Chronic blood loss may lead to iron deficiency anemia.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    snippet: "GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection"
    explanation: "Establishes chronic gastrointestinal bleeding from polyps as a major complication of PJS"
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
- name: Abdominal pain
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >
    Abdominal pain due to polyp-related obstruction, intussusception, or inflammation.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    snippet: "GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"
    explanation: "Intussusception from Peutz-Jeghers polyps causes abdominal pain and obstruction"
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
- name: Abnormal pigmentation of oral mucosa
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >
    Characteristic dark brown macules on the lips and intraoral mucosa, often present before gastrointestinal manifestations appear.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    snippet: "Mucocutaneous hyperpigmentation presents in childhood as dark blue to dark brown macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa"
    explanation: "Oral and mucocutaneous pigmentation is a characteristic diagnostic feature of PJS, often appearing before GI polyps"
  phenotype_term:
    preferred_term: Abnormal pigmentation of oral mucosa
    term:
      id: HP:0100669
      label: Abnormal pigmentation of the oral mucosa
- name: Abnormal lip pigmentation
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >
    Pigmented macules on the lips that often precede gastrointestinal symptoms.
  evidence:
  - reference: PMID:36970589
    reference_title: "Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases."
    supports: SUPPORT
    snippet: "Peutz-Jeghers syndrome (PJS) is a clinically rare disease with pigmented spots on the lips and mucous membranes and extremities, scattered gastrointestinal polyps, and susceptibility to tumors"
    explanation: This cohort description identifies lip pigmentation as a characteristic feature of PJS.
  phenotype_term:
    preferred_term: Abnormal lip pigmentation
    term:
      id: HP:0032453
      label: Abnormal lip pigmentation
- name: Intussusception
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >
    Pedunculated small-intestinal hamartomatous polyps act as lead points,
    with cumulative intussusception risk of approximately 50% by age 20
    and >70% by age 40. Polyps >15 mm carry the highest risk and are the
    main rationale for prophylactic device-assisted enteroscopy and
    polypectomy.
  evidence:
  - reference: PMID:36970589
    reference_title: "Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%"
    explanation: Direct quantitative evidence of cumulative intussusception risk in PJS.
  phenotype_term:
    preferred_term: Intussusception
    term:
      id: HP:0002576
      label: Intussusception
- name: Iron deficiency anemia
  category: Hematologic
  frequency: FREQUENT
  description: >
    Chronic occult or overt blood loss from polyp surfaces produces iron
    deficiency anemia, which is often the presenting laboratory
    abnormality and clinical trigger for surveillance endoscopy.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection"
    explanation: GeneReviews documents chronic blood loss from PJS polyps causing anemia.
  phenotype_term:
    preferred_term: Iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
- name: Increased cancer risk
  category: Systemic
  frequency: FREQUENT
  description: >
    Significantly elevated lifetime risk of gastrointestinal cancers
    (stomach, duodenal, colorectal, pancreatic) and non-GI cancers
    (breast, lung, ovarian, gynecologic). Reported lifetime risk for any
    cancer ranges from 37% to 93%, with relative risk roughly 10-18 fold
    versus the general population.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with PJS are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers)"
    explanation: "PJS patients have substantially elevated lifetime cancer risk across multiple organ systems"
  - reference: PMID:20051941
    reference_title: "High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The reported lifetime risk for any cancer varied between 37 and 93%, with RRs ranging from 9.9 to 18 in comparison with the general population"
    explanation: Systematic review quantifies the magnitude of multi-organ cancer risk used to design surveillance.
  - reference: PMID:33513864
    reference_title: "The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients"
    explanation: "European hereditary tumor group recognizes comprehensive cancer risk across multiple organ systems as defining feature requiring multisystem management"
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
biochemical:
- name: Butyric acid
  presence: Decreased
  notes: >
    Short-chain fatty acids, including butyric acid, are reduced in PJS and
    correlate with polyp burden.
  biomarker_term:
    preferred_term: butyric acid
    term:
      id: NCIT:C68327
      label: Butyric Acid
  evidence:
  - reference: PMID:38036954
    reference_title: "Changes of gut microbiota and short chain fatty acids in patients with Peutz-Jeghers syndrome."
    supports: SUPPORT
    snippet: "The results showed dysbiosis in the gut microbiota of patients with PJS, and decreased synthesis of short-chain fatty acids."
    explanation: This study reports reduced short-chain fatty acid synthesis in PJS.
  - reference: PMID:38036954
    reference_title: "Changes of gut microbiota and short chain fatty acids in patients with Peutz-Jeghers syndrome."
    supports: SUPPORT
    snippet: "Furthermore, the butyric acid level was negatively correlated with the frequency of endoscopic surgeries."
    explanation: Lower butyric acid levels associate with higher polyp-related intervention burden.
genetic:
- name: STK11 (Serine/threonine kinase 11, also called LKB1)
  notes: >
    Germline mutations in STK11 cause autosomal dominant Peutz-Jeghers syndrome. Over 400 different mutations have been identified.
    The second STK11 allele is somatically inactivated in polyp tissue (two-hit model). Mutation types include nonsense, frameshift, splice site, and missense mutations.
  evidence:
  - reference: PMID:37054692
    reference_title: "Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults."
    supports: SUPPORT
    snippet: "It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"
    explanation: "Confirms germline STK11 mutations as the causative genetic basis for Peutz-Jeghers syndrome"
- name: PTEN (Phosphatase and tensin homolog)
  notes: >
    Rare STK11-negative Peutz-Jeghers-like cases have PTEN mutations. PTEN loss further enhances mTORC1 pathway activation.
  evidence:
  - reference: PMID:37377590
    reference_title: "Peutz-Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients."
    supports: SUPPORT
    snippet: "Among 19 patients with no detectable STK11 mutations, six had no pathogenic germline mutations of other genes, while 13 had other genetic mutations"
    explanation: "Alternative genetic mutations including PTEN can account for STK11-negative PJS-like presentations"
environmental:
- name: Polyp intussusception risk
  notes: >
    Large polyps (>15 mm) are more prone to intussusception, particularly in children and adolescents, which may require endoscopic intervention or surgery.
  evidence:
  - reference: PMID:36970589
    reference_title: "Clinical features, diagnosis, and treatment of Peutz-Jeghers syndrome: Experience with 566 Chinese cases."
    supports: SUPPORT
    snippet: "At 40 years of age, the cumulative risk of intussusception in PJS was approximately 72.0%, and at 50 years, the cumulative risk of intussusception in PJS was approximately 89.6%"
    explanation: "Age is a critical environmental/clinical factor that significantly increases intussusception risk in PJS patients"
treatments:
- name: Endoscopic polypectomy
  description: >
    Regular surveillance endoscopy with removal of polyps >10-15 mm reduces bleeding complications and cancer risk.
    Multiple sessions may be needed given the polyp burden.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    snippet: "Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception"
    explanation: "Endoscopic polyp removal is the standard therapeutic approach to prevent complications from Peutz-Jeghers polyps"
  treatment_term:
    preferred_term: endoscopic procedure
    term:
      id: MAXO:0000130
      label: endoscopic procedure
- name: Surgical resection
  description: >
    Reserved for cases with severe polyp burden, recurrent intussusception, or malignant transformation.
  evidence:
  - reference: PMID:34928720
    reference_title: "Small bowel intussusception and concurrent jejunal polyp with neoplastic transformation: a new diagnosis of Peutz-Jeghers syndrome."
    supports: SUPPORT
    snippet: "The patient underwent exploratory laparotomy during which right hemicolectomy and small bowel resection were performed"
    explanation: "Surgical resection is indicated for intussusception and polyps with neoplastic transformation"
  treatment_term:
    preferred_term: surgical resection
    term:
      id: MAXO:0000004
      label: surgical procedure
- name: COX-2 inhibitor chemoprevention (celecoxib)
  description: >
    COX-2 inhibition with celecoxib is being evaluated as polyp-burden
    chemoprevention in PJS, motivated by COX-2 overexpression in
    hamartomas and preclinical reduction of polyp number in mouse models.
    Investigational; not yet standard of care.
  evidence:
  - reference: clinicaltrials:NCT06722534
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Celecoxib, a COX-2 inhibitor, has been shown to reduce polyp burden by 54% in PJS model mice"
    explanation: Trial rationale documents COX-2 inhibition as a candidate chemoprevention strategy targeting the COX-2 mechanism node.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: celecoxib
      term:
        id: CHEBI:41423
        label: celecoxib
  target_mechanisms:
  - target: COX-2 / prostaglandin biosynthetic upregulation
    description: >
      Celecoxib inhibits COX-2, directly antagonising the prostaglandin
      biosynthetic upregulation observed in PJS hamartomas.
    evidence:
    - reference: clinicaltrials:NCT06722534
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Cyclooxygenase (COX) is overexpressed in hamartomatous polyp tissue from PJS individuals, which may provide an avenue for possible effective chemoprevention of polyp formation and growth in PJS"
      explanation: Links the trial directly to the COX-2 mechanism node.
- name: Sirolimus (mTOR inhibition)
  description: >
    mTORC1 inhibition with sirolimus (rapamycin) suppresses preexisting GI
    polyps in LKB1+/- mice, providing direct preclinical rationale for
    targeting the LKB1-AMPK-mTORC1 axis in PJS. Investigational in human
    PJS and not yet a standard-of-care therapy.
  evidence:
  - reference: PMID:19541609
    reference_title: "mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistent with a central role for mTORC1 in these tumors, rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice"
    explanation: Direct mouse-model evidence that mTOR inhibition reduces PJS-like polyp burden, motivating clinical evaluation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  target_mechanisms:
  - target: mTORC1 pathway hyperactivation
    description: >
      Sirolimus is an allosteric mTORC1 inhibitor and directly antagonises
      the mTORC1 hyperactivation downstream of LKB1 loss.
    evidence:
    - reference: PMID:19541609
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the mammalian-target of rapamycin complex 1 (mTORC1) pathway is hyperactivated in tissues and tumors derived from LKB1-deficient mice"
      explanation: Links sirolimus's mechanism to the mTORC1 hyperactivation node in this entry.
- name: Genetic counseling
  description: >
    Family members should receive counseling and cascade genetic testing for STK11 mutations.
  evidence:
  - reference: PMID:37054692
    reference_title: "Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"
    explanation: Autosomal dominant inheritance of pathogenic STK11 variants is the basis for cascade testing and genetic counseling of at-risk relatives.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
differential_diagnoses:
- name: Juvenile polyposis syndrome
  description: >
    Juvenile polyps are also hamartomatous but present earlier in childhood, usually multiple but fewer than Peutz-Jeghers polyps.
    Lack the characteristic oral pigmentation. Juvenile polyposis is caused by BMPR1A or SMAD4 mutations, not STK11.
  disease_term:
    preferred_term: juvenile polyposis syndrome
    term:
      id: MONDO:0017380
      label: juvenile polyposis syndrome
  distinguishing_features:
  - Juvenile polyps are typically fewer in number and present earlier
  - No oral pigmentation in juvenile polyposis
  - Different genetic basis (BMPR1A/SMAD4 vs. STK11)
  evidence:
  - reference: PMID:35988962
    reference_title: "Juvenile polyposis syndrome: An overview."
    supports: SUPPORT
    snippet: "JPS should be clinically suspected when the other hamartomatous polyposis syndromes are excluded (i.e., Peutz-Jeghers and Cowden), in presence of numerous juvenile polyps in the colorectum or in other GI locations"
    explanation: "Establishes juvenile polyposis as a distinct differential diagnosis that must be excluded when evaluating hamartomatous polyp syndromes like PJS"
- name: Cowden syndrome
  description: >
    Hamartomatous polyposis syndrome caused by PTEN mutations with mucocutaneous
    lesions and increased breast, thyroid, and endometrial cancer risks.
  disease_term:
    preferred_term: Cowden syndrome
    term:
      id: MONDO:0008021
      label: Cowden syndrome 1
  distinguishing_features:
  - PTEN-related hamartomas with trichilemmomas and papillomatous papules.
  - Cancer risk profile emphasizes breast, thyroid, and endometrial malignancies.
  evidence:
  - reference: PMID:36925460
    reference_title: "Hamartomatous polyps: Diagnosis, surveillance, and management."
    supports: SUPPORT
    snippet: "Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."
    explanation: This review lists Cowden syndrome among the major hamartomatous polyposis syndromes that must be distinguished from PJS.
- name: Familial adenomatous polyposis (FAP)
  description: >
    FAP presents with hundreds to thousands of adenomatous polyps. Polyps are adenomas (dysplastic), not benign hamartomas like Peutz-Jeghers.
    FAP is caused by APC mutations and does not include characteristic oral pigmentation.
  disease_term:
    preferred_term: classic familial adenomatous polyposis
    term:
      id: MONDO:0021055
      label: classic familial adenomatous polyposis
  distinguishing_features:
  - FAP polyps are adenomas with high-grade dysplasia; Peutz-Jeghers polyps are benign hamartomas
  - No lip pigmentation in FAP
  - Different molecular basis (APC vs. STK11)
  evidence:
  - reference: PMID:36925460
    reference_title: "Hamartomatous polyps: Diagnosis, surveillance, and management."
    supports: SUPPORT
    snippet: "Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)"
    explanation: "Distinguishes PJS as a hamartomatous polyposis syndrome, separate from adenomatous syndromes like FAP"
- name: Lynch syndrome
  description: >
    Lynch syndrome involves microsatellite instability and increased cancer risk but does not feature polyp burden or oral pigmentation.
    Caused by mismatch repair gene mutations, not STK11.
  disease_term:
    preferred_term: Lynch syndrome
    term:
      id: MONDO:0005835
      label: Lynch syndrome
  distinguishing_features:
  - Lynch syndrome lacks prominent polyp burden and oral pigmentation
  - Cancer risk is primarily colorectal rather than panGI
  - Molecular basis involves MMR genes, not STK11
  evidence:
  - reference: PMID:34680270
    reference_title: "Peutz-Jeghers Syndrome and the Role of Imaging: Pathophysiology, Diagnosis, and Associated Cancers."
    supports: SUPPORT
    snippet: "Patients with PJS are at a 15- to 18-fold increased malignancy risk relative to the general population"
    explanation: "PJS carries a distinctive pattern of multi-organ cancer predisposition (GI, breast, lung, genitourinary) that differs from Lynch syndrome's primarily colorectal focus"
datasets: []
references:
- reference: PMID:20301443
  title: "Peutz-Jeghers Syndrome."
  tags:
  - GeneReviews
  findings: []

📚

References & Deep Research

References

1

PMID:20301443

Peutz-Jeghers Syndrome.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 32 citations 2026-04-30T20:49:37.484005

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Peutz-Jeghers polyp
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Peutz-Jeghers polyp covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Disease Characteristics Research Report: Peutz–Jeghers polyp (Peutz–Jeghers–type hamartomatous polyp)

Executive summary

Peutz–Jeghers (PJ) polyps are distinctive hamartomatous gastrointestinal polyps characterized histologically by arborizing smooth-muscle bundles extending from the muscularis mucosae into the polyp, producing a branching “tree/christmas-tree” appearance with lobular/cystically dilated glands/crypts. PJ polyps most commonly occur as part of Peutz–Jeghers syndrome (PJS), an autosomal-dominant hereditary cancer predisposition syndrome driven primarily by germline STK11 (LKB1) loss-of-function, which substantially increases lifetime cancer risk and causes clinically significant morbidity through bleeding/anemia, obstruction, and intussusception. Recent 2023–2024 guidance emphasizes early small-bowel surveillance beginning in childhood (≈8 years), use of noninvasive small-bowel evaluation (SB capsule endoscopy or MR enterography) to guide targeted device-assisted enteroscopy (DAE) polypectomy, and removal of large small-bowel polyps (>15 mm) to reduce intussusception risk. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 5-6, pennazio2023smallbowelcapsuleendoscopy pages 21-21)

Target disease

Disease name (entry focus): Peutz–Jeghers polyp (Peutz–Jeghers–type hamartomatous polyp)
Related syndrome: Peutz–Jeghers syndrome (PJS)
MONDO ID: MONDO:0008280 (Peutz–Jeghers syndrome) (MONDO ID for “Peutz–Jeghers polyp” was not present in retrieved evidence) (zhang2025intussusceptionsecondaryto pages 5-6)
Category: Genetic (typically syndromic)

1. Disease information

What is the disease?

A Peutz–Jeghers polyp is a hamartomatous GI polyp with characteristic histology. In a 2023 review, PJ polyps are described on H&E as having a “characteristic phyllodes appearing epithelial component” with a glandular/cystic component extending toward deeper layers. (gorji2023hamartomatouspolypsdiagnosis pages 1-2)

In a 2024 multicenter endoscopy study, PJS-type hamartomatous polyps are described histologically as interdigitating smooth muscle bundles with an arborizing/branching-tree (“christmas-tree”) appearance and lobular mucosal crypts. (elfeky2024deviceassistedenteroscopyin pages 1-2)

Key identifiers

MONDO: MONDO:0008280 (Peutz–Jeghers syndrome) (zhang2025intussusceptionsecondaryto pages 5-6)
OMIM / Orphanet / ICD-10/ICD-11 / MeSH: not explicitly present in retrieved full-text evidence; should be curated from dedicated disease-identifier resources for the knowledge base. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5)

Synonyms / alternative names

For PJS (syndrome-level), reported synonyms include polyp-and-spots syndrome, Hutchinson–Weber–Peutz syndrome, and perioral lentiginosis. (bandaru2024areviewon pages 1-2)

Evidence type note

Most available evidence is aggregated disease-level (PJS) literature; “Peutz–Jeghers polyp” is most often discussed as the key lesion within PJS. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5)

2. Etiology

Disease causal factors

Primary cause (syndromic PJ polyps): germline pathogenic variants in STK11/LKB1 (tumor suppressor serine/threonine kinase) on chromosome 19p13.3, inherited in an autosomal-dominant pattern; de novo cases occur. (amru2024peutzjegherssyndromea pages 1-2, amru2024peutzjegherssyndromea pages 4-5)

A mechanistic framing from a 2023 review states that PJS is an autosomal dominant disorder involving “the mammalian target of rapamycin (mTOR) pathway” as a result of germline STK11/LKB1 mutation; STK11/LKB1 modulates cellular proliferation, responds to energy deficits, and controls cellular polarity. (gorji2023hamartomatouspolypsdiagnosis pages 1-2)

Risk factors

Genetic risk factor: carrying a germline STK11/LKB1 pathogenic variant (core causal factor). (amru2024peutzjegherssyndromea pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 1-2)
Polyp-size risk factor for intussusception: small-bowel polyp size >15 mm is emphasized as a key risk factor for intussusception and related complications. (pennazio2023smallbowelcapsuleendoscopy pages 21-21)

Protective factors

No specific genetic/environmental protective factors were identified in the retrieved evidence.

Gene–environment interactions

Not specifically described in retrieved evidence; variable expressivity is attributed to genetic modifiers, environment, and somatic events in at least one 2024 review. (amru2024peutzjegherssyndromea pages 2-4)

3. Phenotypes

Core phenotypes (clinical signs/symptoms)

1) Hamartomatous GI polyps / polyposis - Distribution: Polyps most frequently involve the small intestine (~75% in one 2024 review), especially proximal jejunum, distal ileum, and duodenum; stomach involvement ~25%. (amru2024peutzjegherssyndromea pages 2-4) - Age of onset: median age of initial polyp development ~12 years; ~50% symptomatic by age 20 (review-level data). (gorji2023hamartomatouspolypsdiagnosis pages 1-2) - HPO suggestions: HP:0004396 (Hamartomatous polyposis), HP:0004780 (Intestinal polyposis) - UBERON suggestions: UBERON:0002108 (small intestine), UBERON:0002114 (jejunum), UBERON:0002116 (ileum), UBERON:0002110 (duodenum)

2) Mucocutaneous pigmentation (lentiginosis) - Typically bluish-black macules on lips, buccal mucosa, perioral region, and digits; often appear in early childhood. (amru2024peutzjegherssyndromea pages 2-4, amru2024peutzjegherssyndromea pages 4-5) - HPO suggestions: HP:0000992 (Cutaneous pigmentation), HP:0001053 (Hyperpigmentation)

3) GI bleeding → anemia - A 2023 review states the “primary clinical manifestation is chronic bleeding from GI polyps causing anemia.” (gorji2023hamartomatouspolypsdiagnosis pages 1-2) - HPO suggestions: HP:0001892 (Bleeding), HP:0001903 (Anemia), HP:0002140 (Melena) (when present)

4) Intussusception / bowel obstruction - Quantitative natural history: intussusception risk reported as ≈44% by age 10 and ≈50% by age 20, with higher risk in polyps ≥15 mm. (gorji2023hamartomatouspolypsdiagnosis pages 2-4) - AACR 2024 pediatric guidance notes intussusception risk “over 20% by age 10 and over 50% by age 20,” and emphasizes family education for symptoms. (macfarland2024pediatriccancerscreening pages 5-6) - HPO suggestions: HP:0002250 (Intussusception), HP:0002024 (Abdominal pain), HP:0001744 (Bowel obstruction)

Quality of life impact

While multiple sources describe substantial morbidity (repeated hospitalizations/endoscopy, prior surgeries), quantitative QoL instrument results (e.g., EQ-5D/SF-36) were not present in the retrieved evidence. Surgical burden is indirectly supported by the fact that 75% of a DAE cohort had prior small-bowel surgery before index DAE. (elfeky2024deviceassistedenteroscopyin pages 1-2)

4. Genetic / molecular information

Causal gene(s)

STK11 (LKB1) is the principal causal gene for PJS-associated PJ polyps. (amru2024peutzjegherssyndromea pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 1-2)

Pathogenic variants (examples and classes)

Large deletions/duplications of STK11 are recognized as an important mutational mechanism; sequencing can detect point mutations, small indels, and larger duplications/deletions. (amru2024peutzjegherssyndromea pages 4-5, amru2024peutzjegherssyndromea pages 6-7)
Missense variants & functional signaling impact: 2024 work describes STK11 missense VUS and ties them to impaired LKB1/AMPK signaling (article title) and provides variant-level family data, including “De novo” cases and examples such as “c.1062C>G.” (liu2024twomissensestk11 pages 1-2)
Frameshift example and mosaicism: 2025 Familial Cancer report identifies NM_000455.4:c.842del (p.Pro281Argfs*6) in a child with PJS and documents maternal tissue-restricted mosaicism (2.7% VAF in cervical tissue) after initial “de novo” interpretation based on blood testing, supporting mosaic phenomena in hereditary cancer counseling. (jiang2025gastrictypeendocervicaladenocarcinoma pages 2-4)

Functional consequences

STK11/LKB1 is described as regulating cellular polarity, growth/proliferation, and energy-sensing pathways; disruption is linked to mTOR-axis dysregulation and downstream proliferative effects contributing to hamartomatous polyp formation and cancer predisposition. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 1-2)

Epigenetic information

A 2024 review reports increased methylation of the LKB1 promoter in PJS polyps (bisulfite PCR/Sanger sequencing). (amru2024peutzjegherssyndromea pages 2-4)

5. Environmental information

No specific toxins/lifestyle/infectious triggers were identified in the retrieved evidence for PJ polyps; the condition is primarily genetically driven (syndromic). (amru2024peutzjegherssyndromea pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 1-2)

6. Mechanism / pathophysiology

Proposed causal chain (current understanding)

1) Germline STK11/LKB1 loss-of-function (often inherited AD, sometimes de novo/mosaic) reduces tumor-suppressor kinase function. (amru2024peutzjegherssyndromea pages 1-2, jiang2025gastrictypeendocervicaladenocarcinoma pages 2-4) 2) Cell polarity and energy-sensing dysregulation and mTOR-axis pathway perturbation alter epithelial–stromal organization and proliferation controls. (gorji2023hamartomatouspolypsdiagnosis pages 1-2) 3) Hamartomatous polyp growth with arborizing smooth muscle and disorganized mucosal architecture leads to mucosal bleeding, anemia, and mechanical complications (obstruction/intussusception), especially with larger polyps. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 2-4) 4) Cancer predisposition emerges with age, with elevated cumulative cancer risk across GI and extraintestinal organs. (kamiya2023feasibilityandsafety pages 1-2, elfeky2024deviceassistedenteroscopyin pages 1-2)

Pathways and processes (ontology suggestions)

GO biological process: GO:0008283 (cell population proliferation), GO:0030010 (establishment of cell polarity), GO:0006091 (generation of precursor metabolites and energy)
Reactome/KEGG concepts (by description in evidence): mTOR signaling axis; LKB1/AMPK signaling (gorji2023hamartomatouspolypsdiagnosis pages 1-2, liu2024twomissensestk11 pages 1-2)

Cell types (CL suggestions; inferred from lesion biology)

CL:0000066 (epithelial cell), CL:0000187 (smooth muscle cell) (These are ontology suggestions; cell-type–resolved single-cell evidence was not present in retrieved sources.)

7. Anatomical structures affected

Primary organs/sites: small intestine (jejunum/ileum/duodenum), colon, stomach (polyps may occur), mucocutaneous sites (lips/buccal mucosa/perioral skin/digits). (amru2024peutzjegherssyndromea pages 2-4, amru2024peutzjegherssyndromea pages 4-5)
Complication-related structures: intestinal lumen (intussusception/obstruction). (gorji2023hamartomatouspolypsdiagnosis pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 2-4)
UBERON suggestions: small intestine (UBERON:0002108), colon (UBERON:0001155), stomach (UBERON:0000945)

8. Temporal development

Onset: typically pediatric/childhood; mucocutaneous pigmentation often appears at birth or early childhood; polyps develop in childhood (median ~12 years). (gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 2-4)
Progression/course: chronic lifelong predisposition; complication risk (intussusception) increases with polyp growth and size; cancer risk increases with age, with mean age of index cancer reported ~41 years in one review. (gorji2023hamartomatouspolypsdiagnosis pages 1-2)

9. Inheritance and population

Epidemiology

Reported incidence/prevalence varies widely across sources: - Incidence range: ~1:8,300 to 1:200,000 (review-level range). (gorji2023hamartomatouspolypsdiagnosis pages 1-2) - Additional estimates include prevalence 1:50,000–1:200,000 (review). (amru2024peutzjegherssyndromea pages 4-5)

Inheritance pattern

Autosomal dominant inheritance with ~50% transmission risk to offspring; de novo mutations are common (~30% in one review). (amru2024peutzjegherssyndromea pages 1-2)
Mosaicism can explain apparent de novo cases and has reproductive-counseling implications. (jiang2025gastrictypeendocervicaladenocarcinoma pages 2-4)

Penetrance/expressivity

Variable expressivity is reported; contributors include genetic modifiers, environment, and somatic events. (amru2024peutzjegherssyndromea pages 2-4)

10. Diagnostics

Clinical criteria

Criteria include any number of PJ polyps with family history; ≥2 PJ polyps; pigmentation plus family history; or PJ polyps plus pigmentation. (gorji2023hamartomatouspolypsdiagnosis pages 1-2)

Histopathology

Diagnostic polyp histology includes arborizing smooth muscle with branching-tree appearance and lobular/cystic gland architecture. (gorji2023hamartomatouspolypsdiagnosis pages 1-2, elfeky2024deviceassistedenteroscopyin pages 1-2)

Imaging/endoscopy

Small-bowel evaluation: capsule endoscopy (SBCE/VCE) and CT/MR enterography are key modalities. (gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 13-14)
Modality selection for small-bowel tumors/lesions: a 2024 review of small-bowel tumor diagnosis recommends three-phase enhanced CT first-line; if CT shows mass/stenosis/wall thickening, use balloon-assisted endoscopy; if CT negative and no obstructive symptoms, use capsule endoscopy. (yano2024endoscopicdiagnosisof pages 1-2)

Genetic testing

STK11/LKB1 sequencing can detect point mutations, indels, and larger duplications/deletions; genetic counseling is recommended. (amru2024peutzjegherssyndromea pages 4-5)

Differential diagnosis (context)

PJ polyps are part of the broader hamartomatous polyposis syndromes spectrum, which includes juvenile polyposis and Cowden/PTEN hamartoma tumor syndrome; distinguishing features include syndromic extraintestinal findings and molecular testing. (gorji2023hamartomatouspolypsdiagnosis pages 1-2)

11. Outcome / prognosis

Cancer risk and timing

One study reports age-stratified cumulative cancer risk estimates of 1%, 3%, 19%, 32%, 63%, 81% at ages 20, 30, 40, 50, 60, and 70 years, respectively. (kamiya2023feasibilityandsafety pages 1-2)
A multicenter DAE paper reports lifetime cancer risk “as high as 93% for developing any cancer by age 64,” and average lifetime risks for colorectal, gastric, and small-bowel cancer of 39%, 29%, and 13%, respectively. (elfeky2024deviceassistedenteroscopyin pages 1-2)

Morbidity

Morbidity is driven by bleeding/anemia and mechanical complications (intussusception/obstruction). (gorji2023hamartomatouspolypsdiagnosis pages 1-2, gorji2023hamartomatouspolypsdiagnosis pages 2-4)

Mortality/survival

Direct mortality rates and life expectancy were not available in retrieved evidence. (elfeky2024deviceassistedenteroscopyin pages 1-2)

12. Treatment

Standard of care / real-world implementations

Endoscopic surveillance and prophylactic polypectomy are the mainstay to prevent intussusception/obstruction and manage bleeding.

Polypectomy thresholds: ESGE-referenced recommendations summarized in a 2023 review include elective removal of small-bowel polyps >15–20 mm, and removal of symptomatic polyps <15 mm. (gorji2023hamartomatouspolypsdiagnosis pages 2-4)

Guideline emphasis (ESGE 2022 update, published 2023): a guideline excerpt states that “large (> 15 mm), symptomatic, or rapidly growing polyps should be promptly removed” and advises targeted enteroscopy after prior noninvasive SB evaluation; complication rates of DAE polypectomy in PJS are reported as 4%–6% in cited evidence. (pennazio2023smallbowelcapsuleendoscopy pages 21-21)

Device-assisted enteroscopy (DAE/DBE) outcomes (2024): In a multicenter retrospective cohort (3 US referral centers), 46 DAEs in 23 PJS patients achieved 131 polypectomies with an adverse event rate of 1.5% and no emergent surgery for small-bowel hamartoma adverse events over 336 aggregated follow-up years. The authors’ conclusion states: “Endoscopic management of small bowel polyps in patients with PJS using DAE is an effective strategy for prophylactic removal of hamartomas.” (elfeky2024deviceassistedenteroscopyin pages 1-2)

Alternative endoscopic techniques: A 2023 retrospective study of endoscopic ischemic polypectomy (EIP) in 22 PJS patients reports treatment of 607 polyps across 124 sessions, and reports no small-bowel complications or intussusceptions in that series during follow-up. (kamiya2023feasibilityandsafety pages 1-2)

Clinical trials / investigational therapies (selected)

Cold snare polypectomy for small-bowel polyps (enteroscopy-based): NCT06001476 (Phase 4; estimated start 2023-08-20; primary completion 2024-12-31) evaluates feasibility/safety of cold snare polypectomy for 5–9 mm small-bowel polyps, with endpoints including bleeding/perforation/pancreatitis within 28 days. URL: https://clinicaltrials.gov/study/NCT06001476 (NCT06001476 chunk 1)
Celecoxib chemoprevention: NCT06722534 (randomized, double-blind, placebo-controlled; start 2025-02-01; recruiting) tests celecoxib 200 mg BID for 6 months vs placebo, with a composite endpoint for “progression of small bowel disease.” URL: https://clinicaltrials.gov/study/NCT06722534 (NCT06722534 chunk 1)
Pancreatic surveillance in high-risk cohorts including PJS: CAPS5 NCT02000089 (recruiting) evaluates early pancreatic cancer markers in pancreatic juice and related endpoints in high-risk individuals including PJS. URL: https://clinicaltrials.gov/study/NCT02000089 (NCT02000089 chunk 2)

MAXO suggestions (treatment/prevention actions)

MAXO:0000011 (Endoscopy), MAXO:0000567 (Polypectomy), MAXO:0000058 (Cancer surveillance), MAXO:0000127 (Genetic counseling) (These are ontology suggestions; MAXO IDs should be verified against the MAXO ontology release used by the knowledge base.)

13. Prevention

Primary prevention of the genetic condition is not available; prevention focuses on secondary/tertiary prevention: - Secondary prevention: early surveillance beginning in childhood (≈8 years) and polypectomy to prevent intussusception/obstruction and detect early malignancy. (macfarland2024pediatriccancerscreening pages 5-6, gorji2023hamartomatouspolypsdiagnosis pages 2-4) - Cascade testing and genetic counseling: early genetic testing in familial cases to enable timely surveillance is recommended by the AACR Childhood Cancer Predisposition Working Group update. (macfarland2024pediatriccancerscreening pages 5-6)

14. Other species / natural disease

No naturally occurring veterinary/other-species PJ polyp data were identified in retrieved evidence.

15. Model organisms

A 2023 review notes sirolimus (rapamycin) reduced polyp number/size in a mouse model and mentions prospective study, but detailed model-phenotype mapping was not available in retrieved evidence. (gorji2023hamartomatouspolypsdiagnosis pages 2-4)

Recent developments (2023–2024) and expert analysis

1) Shift to structured, targeted small-bowel management: 2023 ESGE guidance emphasizes noninvasive mapping (SBCE/MRE) followed by targeted DAE polypectomy and prompt removal of large (>15 mm) or symptomatic polyps, reflecting a safety/benefit balancing in a technically demanding procedure with known complication rates. (pennazio2023smallbowelcapsuleendoscopy pages 21-21) 2) Multicenter real-world evidence for DAE safety/effectiveness: 2024 multicenter data demonstrate low adverse event rates (1.5%) and potential avoidance of emergent surgery over long follow-up, supporting referral-center implementation of prophylactic DAE programs. (elfeky2024deviceassistedenteroscopyin pages 1-2) 3) Pediatric screening harmonization: AACR 2024 update provides a pragmatic pediatric pathway: baseline endoscopy/colonoscopy/small-bowel study at ~8 years, surveillance every 2–3 years if polyps, and deferral to ~18 years if baseline negative and asymptomatic, with explicit family education about high intussusception risk. (macfarland2024pediatriccancerscreening pages 5-6, macfarland2024pediatriccancerscreening pages 13-14)

Visual guideline evidence

The ESGE guideline table region containing Peutz–Jeghers syndrome small-bowel surveillance and recommendations for DAE polypectomy is available as an extracted figure/table image. (pennazio2023smallbowelcapsuleendoscopy media 9eea28e2)

Structured summary tables

Item	Details	Evidence
Disease scope: Peutz-Jeghers polyp	A Peutz-Jeghers polyp (PJP) is a hamartomatous gastrointestinal polyp with characteristic arborizing/smooth-muscle architecture. In reviewed sources, PJPs are distinguished from the broader syndrome and are described as most characteristic in the small bowel; gastric polyps in PJS may resemble hyperplastic polyps and are not always classified as true PJPs.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 2-4, elfeky2024deviceassistedenteroscopyin pages 1-2)
Disease scope: Peutz-Jeghers syndrome	Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant cancer-predisposition/polyposis syndrome defined by hamartomatous GI polyps plus characteristic mucocutaneous pigmentation, usually caused by germline STK11/LKB1 pathogenic variants.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5, amru2024peutzjegherssyndromea pages 1-2)
Relationship between polyp and syndrome	The “Peutz-Jeghers polyp” is a lesion/histopathologic entity; “Peutz-Jeghers syndrome” is the inherited multisystem disorder in which such polyps occur together with pigmentation and elevated cancer risk. A solitary PJP is therefore narrower than syndromic PJS.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5, elfeky2024deviceassistedenteroscopyin pages 1-2)
Synonyms / alternative names	Reported synonyms for PJS include polyp-and-spots syndrome, Hutchinson-Weber-Peutz syndrome, and perioral lentiginosis. Abbreviation: PJS.	(bandaru2024areviewon pages 1-2)
Key identifier available from evidence	MONDO:0008280 — Peutz-Jeghers syndrome (from Open Targets disease-target association output in the retrieved evidence).	(zhang2025intussusceptionsecondaryto pages 5-6)
Key identifiers not recovered in provided sources	OMIM, Orphanet, ICD-10/ICD-11, and MeSH identifiers were not explicitly present in the retrieved full-text evidence snippets used here; these should be curated separately from disease databases before KB ingestion.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5, amru2024peutzjegherssyndromea pages 6-7)
Core diagnostic criteria	Clinical criteria reported in reviewed sources include: (1) any number of PJ polyps with a family history of PJS; (2) two or more PJ polyps; (3) characteristic mucocutaneous pigmentation with a family history of PJS; or (4) any number of PJ polyps with mucocutaneous pigmentation. Another cited formulation uses ≥2 PJS-type hamartomatous polyps or such polyps plus pigmentation/family history.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, elfeky2024deviceassistedenteroscopyin pages 1-2)
Core clinical hallmarks	Hallmark features are mucocutaneous melanotic macules (often lips, buccal mucosa, perioral skin, digits) appearing in childhood and GI hamartomatous polyps, most often in the small intestine; complications include bleeding, anemia, obstruction, and intussusception.	(amru2024peutzjegherssyndromea pages 1-2, amru2024peutzjegherssyndromea pages 2-4, gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 4-5)
Histopathologic hallmarks of PJP	Histology shows a hamartomatous polyp with arborizing/interdigitating smooth-muscle bundles extending from the muscularis mucosae, creating a phyllodes / branching-tree / christmas-tree appearance, with lobular or cystically dilated mucosal glands/crypts.	(gorji2023hamartomatouspolypsdiagnosis pages 1-2, amru2024peutzjegherssyndromea pages 2-4, elfeky2024deviceassistedenteroscopyin pages 1-2)

Table: This table distinguishes the lesion-level concept of a Peutz-Jeghers polyp from the syndrome-level diagnosis of Peutz-Jeghers syndrome, and summarizes synonyms, identifiers, diagnostic criteria, and histopathologic hallmarks from the retrieved evidence.

Organ/site	Modality	Start age	Interval	Key thresholds/notes	Evidence (citation IDs)
Upper GI (stomach/duodenum)	EGD / upper endoscopy	8 years	Every 1–3 years; if baseline at 8 is negative, routine surveillance can resume at 18	Used to detect and remove accessible hamartomatous polyps; Amru 2024 also describes yearly or biannual EGD beginning in youth or when symptomatic	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, amru2024peutzjegherssyndromea pages 5-6, bandaru2024areviewon pages 1-2, macfarland2024pediatriccancerscreening pages 5-6, macfarland2024pediatriccancerscreening pages 13-14)
Colon/rectum	Colonoscopy	8 years	Every 1–3 years; if baseline at 8 is negative, routine surveillance can resume at 18	Amru 2024 notes colonoscopy may begin around puberty/age 15 and be repeated annually in some practices, especially with rapid/gigantic polyp growth or early family CRC	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, amru2024peutzjegherssyndromea pages 5-6, macfarland2024pediatriccancerscreening pages 5-6, macfarland2024pediatriccancerscreening pages 13-14)
Small bowel surveillance	SBCE / VCE or CT/MR enterography (MRE preferred alternative when VCE unavailable)	8 years	Every 2–3 years; if baseline at ≥8 is negative, repeat around 18 if asymptomatic	Noninvasive small-bowel evaluation should guide therapy; small-bowel polyps are the major source of intussusception risk	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, bandaru2024areviewon pages 1-2, macfarland2024pediatriccancerscreening pages 5-6, macfarland2024pediatriccancerscreening pages 13-14, pennazio2023smallbowelcapsuleendoscopy pages 21-21)
Small bowel therapeutic management	DAE / DBE polypectomy after prior SBCE/MRE	Not a screening age-based test; used when target polyps identified	Targeted/as needed; some cohorts averaged about one DAE exam every 2.5 years	ESGE: promptly remove large (>15 mm), symptomatic, or rapidly growing polyps; Gorji 2023 cites elective removal of >15–20 mm and symptomatic polyps <15 mm; DAE/DBE can reduce laparotomy but carries procedural risk	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, elfeky2024deviceassistedenteroscopyin pages 1-2, pennazio2023smallbowelcapsuleendoscopy pages 21-21)
Small bowel complication prevention	Family education for intussusception symptoms	At diagnosis / childhood	Ongoing counseling	AACR 2024 emphasizes education because intussusception risk exceeds 20% by age 10 and 50% by age 20; risk is highest with polyps ≥15 mm	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 5-6, macfarland2024pediatriccancerscreening pages 13-14)
Pancreas	EUS or MRCP/ERCP; some sources also mention MRI/MRCP	30 years	Annually	Gorji 2023 recommends annual pancreatic imaging from 30; later adult guidance in broader reviews supports pancreas surveillance in adulthood because of elevated cancer risk	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, amru2024peutzjegherssyndromea pages 4-5)
Breast	Self-exam	18 years	Annually	Early self-surveillance recommended in women with PJS due to increased lifetime breast-cancer risk	(gorji2023hamartomatouspolypsdiagnosis pages 2-4)
Breast	MRI / mammography	25 years	Annual imaging	Gorji 2023 lists MRI/mammography from 25; AACR 2024 notes adult-onset breast screening begins at or after about 25 years	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 6-7)
Cervix / gynecologic tract	Cervical smear	20 years	Annually	Used as part of adult gynecologic surveillance in PJS	(gorji2023hamartomatouspolypsdiagnosis pages 2-4)
Pelvic / ovarian surveillance	Pelvic ultrasound; annual gynecologic exam/physical examination	25 years for annual pelvic US; childhood onward for physical exam in AACR update	Annual	AACR 2024 recommends annual physical exam of ovaries/cervix in childhood; pelvic ultrasound is advised for girls with precocious puberty or concerning symptoms	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 13-14, macfarland2024pediatriccancerscreening pages 6-7)
Testes	Testicular exam with/without ultrasound	From birth / childhood	Yearly	Gorji 2023 recommends yearly testicular exam/ultrasound from birth; AACR 2024 does not support routine screening ultrasound for all boys, instead emphasizing annual physical examination and selective imaging when indicated	(gorji2023hamartomatouspolypsdiagnosis pages 2-4, macfarland2024pediatriccancerscreening pages 13-14, macfarland2024pediatriccancerscreening pages 6-7)
Genetics / family management	STK11 testing, counseling, predictive testing for relatives	At diagnosis / early childhood in familial cases	One-time diagnostic test with cascade testing as indicated	Sequencing can detect point mutations, indels, and larger deletions/duplications; early genetic confirmation enables surveillance planning; preimplantation/prenatal testing may be considered in families with known variants	(amru2024peutzjegherssyndromea pages 4-5, macfarland2024pediatriccancerscreening pages 5-6, bandaru2024areviewon pages 3-3)

Table: This table summarizes 2023–2024 surveillance and management recommendations for Peutz-Jeghers syndrome/polyps across organ systems. It integrates practical start ages, intervals, and key intervention thresholds from recent reviews, guidelines, and pediatric screening updates.

Data gaps and curation notes (for knowledge-base ingestion)

Controlled identifiers for the polyp entity (OMIM/Orphanet/ICD/MeSH/MONDO) were not present in retrieved evidence; only MONDO:0008280 for PJS was available. (zhang2025intussusceptionsecondaryto pages 5-6)
Quantitative quality-of-life and health-economic metrics were not captured in the retrieved evidence, despite qualitative indications of high morbidity and surgical burden. (elfeky2024deviceassistedenteroscopyin pages 1-2)
Variant allele frequencies in population databases (gnomAD), ClinVar classifications, and formal genotype–phenotype penetrance estimates were not present in retrieved full-text snippets and would require dedicated database extraction.

References

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(gorji2023hamartomatouspolypsdiagnosis pages 2-4): Leva Gorji and Peter Albrecht. Hamartomatous polyps: diagnosis, surveillance, and management. World Journal of Gastroenterology, 29:1304-1314, Feb 2023. URL: https://doi.org/10.3748/wjg.v29.i8.1304, doi:10.3748/wjg.v29.i8.1304. This article has 16 citations.
(macfarland2024pediatriccancerscreening pages 5-6): Suzanne P. MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P. Kuiper, Harry Lesmana, Julia Meade, Kim E. Nichols, Christopher C. Porter, Sharon A. Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, and Sharon E. Plon. Pediatric cancer screening in hereditary gastrointestinal cancer risk syndromes: an update from the aacr childhood cancer predisposition working group. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:4566-4571, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-24-0953, doi:10.1158/1078-0432.ccr-24-0953. This article has 19 citations.
(pennazio2023smallbowelcapsuleendoscopy pages 21-21): Marco Pennazio, Emanuele Rondonotti, Edward J. Despott, Xavier Dray, Martin Keuchel, Tom Moreels, David S. Sanders, Cristiano Spada, Cristina Carretero, Pablo Cortegoso Valdivia, Luca Elli, Lorenzo Fuccio, Begona Gonzalez Suarez, Anastasios Koulaouzidis, Lumir Kunovsky, Deirdre McNamara, Helmut Neumann, Enrique Perez-Cuadrado-Martinez, Enrique Perez-Cuadrado-Robles, Stefania Piccirelli, Bruno Rosa, Jean-Christophe Saurin, Reena Sidhu, Ilja Tacheci, Erasmia Vlachou, and Konstantinos Triantafyllou. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: european society of gastrointestinal endoscopy (esge) guideline – update 2022. Endoscopy, 55:58-95, Nov 2023. URL: https://doi.org/10.1055/a-1973-3796, doi:10.1055/a-1973-3796. This article has 353 citations and is from a domain leading peer-reviewed journal.
(zhang2025intussusceptionsecondaryto pages 5-6): Jing Zhang, Tian-Hao Xie, Yan Fu, Xiao-Shi Jin, Qiang Wang, and Zheng Niu. Intussusception secondary to peutz-jeghers syndrome: a case report and literature review of diagnostic and therapeutic advances. Frontiers in Medicine, Oct 2025. URL: https://doi.org/10.3389/fmed.2025.1687958, doi:10.3389/fmed.2025.1687958. This article has 1 citations.
(elfeky2024deviceassistedenteroscopyin pages 1-2): Omar Wahid Mohamed Elfeky, Suraj Panjwani, David Cave, Daniel Wild, and Daniel Raines. Device-assisted enteroscopy in the surveillance of intestinal hamartomas in peutz-jeghers syndrome. Endoscopy International Open, 12:E128-E134, Nov 2024. URL: https://doi.org/10.1055/a-2197-8554, doi:10.1055/a-2197-8554. This article has 6 citations and is from a peer-reviewed journal.
(amru2024peutzjegherssyndromea pages 4-5): Rohan L Amru and Archana Dhok. Peutz-jeghers syndrome: a comprehensive review of genetics, clinical features, and management approaches. Cureus, Apr 2024. URL: https://doi.org/10.7759/cureus.58887, doi:10.7759/cureus.58887. This article has 20 citations.
(bandaru2024areviewon pages 1-2): Lakshmi Himaja Bandaru. A review on peutz-jeghers syndrome. Journal of Clinical and Pharmaceutical Research, pages 8-10, Oct 2024. URL: https://doi.org/10.61427/jcpr.v4.i4.2024.144, doi:10.61427/jcpr.v4.i4.2024.144. This article has 0 citations.
(amru2024peutzjegherssyndromea pages 1-2): Rohan L Amru and Archana Dhok. Peutz-jeghers syndrome: a comprehensive review of genetics, clinical features, and management approaches. Cureus, Apr 2024. URL: https://doi.org/10.7759/cureus.58887, doi:10.7759/cureus.58887. This article has 20 citations.
(amru2024peutzjegherssyndromea pages 2-4): Rohan L Amru and Archana Dhok. Peutz-jeghers syndrome: a comprehensive review of genetics, clinical features, and management approaches. Cureus, Apr 2024. URL: https://doi.org/10.7759/cureus.58887, doi:10.7759/cureus.58887. This article has 20 citations.
(amru2024peutzjegherssyndromea pages 6-7): Rohan L Amru and Archana Dhok. Peutz-jeghers syndrome: a comprehensive review of genetics, clinical features, and management approaches. Cureus, Apr 2024. URL: https://doi.org/10.7759/cureus.58887, doi:10.7759/cureus.58887. This article has 20 citations.
(liu2024twomissensestk11 pages 1-2): Jin Liu, Si-Cong Zeng, An Wang, Hai-Ying Cheng, Qian-Jun Zhang, and Guang-Xiu Lu. Two missense stk11 gene variations impaired lkb1/adenosine monophosphate-activated protein kinase signaling in peutz-jeghers syndrome. World Journal of Gastrointestinal Oncology, 16:1532-1546, Apr 2024. URL: https://doi.org/10.4251/wjgo.v16.i4.1532, doi:10.4251/wjgo.v16.i4.1532. This article has 0 citations.
(jiang2025gastrictypeendocervicaladenocarcinoma pages 2-4): Anqi Jiang, Yingfei Ye, Haowen Tan, Xiang Tao, Fenghua Ma, Hui Wang, Congjian Xu, and Yu Kang. Gastric-type endocervical adenocarcinoma in situ as the presenting feature in a mosaic stk11 pathogenic variant carrier with a peutz-jeghers syndrome child. Familial Cancer, Jul 2025. URL: https://doi.org/10.1007/s10689-025-00485-5, doi:10.1007/s10689-025-00485-5. This article has 1 citations and is from a peer-reviewed journal.
(kamiya2023feasibilityandsafety pages 1-2): Kenji J. L. Limpias Kamiya, Naoki Hosoe, Kaoru Takabayashi, Anna Okuzawa, Hinako Sakurai, Yukie Hayashi, Ryoichi Miyanaga, Tomohisa Sujino, Haruhiko Ogata, and Takanori Kanai. Feasibility and safety of endoscopic ischemic polypectomy and clinical outcomes in patients with peutz–jeghers syndrome (with video). Digestive Diseases and Sciences, 68:252-258, Apr 2023. URL: https://doi.org/10.1007/s10620-022-07477-w, doi:10.1007/s10620-022-07477-w. This article has 15 citations and is from a peer-reviewed journal.
(macfarland2024pediatriccancerscreening pages 13-14): Suzanne P. MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P. Kuiper, Harry Lesmana, Julia Meade, Kim E. Nichols, Christopher C. Porter, Sharon A. Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, and Sharon E. Plon. Pediatric cancer screening in hereditary gastrointestinal cancer risk syndromes: an update from the aacr childhood cancer predisposition working group. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:4566-4571, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-24-0953, doi:10.1158/1078-0432.ccr-24-0953. This article has 19 citations.
(yano2024endoscopicdiagnosisof pages 1-2): Tomonori Yano and Hironori Yamamoto. Endoscopic diagnosis of small bowel tumor. Cancers, 16:1704, Apr 2024. URL: https://doi.org/10.3390/cancers16091704, doi:10.3390/cancers16091704. This article has 8 citations.
(NCT06001476 chunk 1): Xiuli Zuo. Cold Snare Polypectomy for Small Bowel Polyps in Patients With Peutz-Jeghers Syndrome. Shandong University. 2023. ClinicalTrials.gov Identifier: NCT06001476
(NCT06722534 chunk 1): Yanglin Pan. Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome. Air Force Military Medical University, China. 2025. ClinicalTrials.gov Identifier: NCT06722534
(NCT02000089 chunk 2): The Cancer of the Pancreas Screening-5 CAPS5)Study. Johns Hopkins University. 2014. ClinicalTrials.gov Identifier: NCT02000089
(pennazio2023smallbowelcapsuleendoscopy media 9eea28e2): Marco Pennazio, Emanuele Rondonotti, Edward J. Despott, Xavier Dray, Martin Keuchel, Tom Moreels, David S. Sanders, Cristiano Spada, Cristina Carretero, Pablo Cortegoso Valdivia, Luca Elli, Lorenzo Fuccio, Begona Gonzalez Suarez, Anastasios Koulaouzidis, Lumir Kunovsky, Deirdre McNamara, Helmut Neumann, Enrique Perez-Cuadrado-Martinez, Enrique Perez-Cuadrado-Robles, Stefania Piccirelli, Bruno Rosa, Jean-Christophe Saurin, Reena Sidhu, Ilja Tacheci, Erasmia Vlachou, and Konstantinos Triantafyllou. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: european society of gastrointestinal endoscopy (esge) guideline – update 2022. Endoscopy, 55:58-95, Nov 2023. URL: https://doi.org/10.1055/a-1973-3796, doi:10.1055/a-1973-3796. This article has 353 citations and is from a domain leading peer-reviewed journal.
(amru2024peutzjegherssyndromea pages 5-6): Rohan L Amru and Archana Dhok. Peutz-jeghers syndrome: a comprehensive review of genetics, clinical features, and management approaches. Cureus, Apr 2024. URL: https://doi.org/10.7759/cureus.58887, doi:10.7759/cureus.58887. This article has 20 citations.
(macfarland2024pediatriccancerscreening pages 6-7): Suzanne P. MacFarland, Kerri Becktell, Kami Wolfe Schneider, Roland P. Kuiper, Harry Lesmana, Julia Meade, Kim E. Nichols, Christopher C. Porter, Sharon A. Savage, Kris Ann Schultz, Hamish Scott, Lisa States, Uri Tabori, Chieko Tamura, Gail Tomlinson, Kristin Zelley, Carol Durno, Andrew Bauer, and Sharon E. Plon. Pediatric cancer screening in hereditary gastrointestinal cancer risk syndromes: an update from the aacr childhood cancer predisposition working group. Clinical cancer research : an official journal of the American Association for Cancer Research, 30:4566-4571, Aug 2024. URL: https://doi.org/10.1158/1078-0432.ccr-24-0953, doi:10.1158/1078-0432.ccr-24-0953. This article has 19 citations.
(bandaru2024areviewon pages 3-3): Lakshmi Himaja Bandaru. A review on peutz-jeghers syndrome. Journal of Clinical and Pharmaceutical Research, pages 8-10, Oct 2024. URL: https://doi.org/10.61427/jcpr.v4.i4.2024.144, doi:10.61427/jcpr.v4.i4.2024.144. This article has 0 citations.

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Disease Characteristics Research Report: Peutz–Jeghers polyp (Peutz–Jeghers–type hamartomatous polyp)

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