Peutz-Jeghers syndrome

Genetic MONDO:0008280 Pathograph 27 Show in embeddings browser hamartomatous polyposis syndrome hereditary cancer syndrome intestinal polyposis syndrome

Peutz-Jeghers syndrome is an autosomal dominant hereditary intestinal polyposis and cancer-predisposition syndrome caused primarily by germline pathogenic variants in the tumor suppressor kinase gene STK11/LKB1. The syndrome combines characteristic mucocutaneous pigmentation with GI hamartomatous polyps, especially in the small intestine. Loss of STK11 disrupts LKB1/AMPK signaling, derepresses mTORC1, impairs stromal TGF-beta-mediated epithelial restraint, and creates a permissive background for polyp complications and multi-organ malignancy risk.

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1
Mappings
1
Definitions
1
Inheritance
9
Pathophys.
15
Phenotypes
27
Pathograph
1
Genes
5
Medical Actions
2
Differentials
2
Datasets
2
References
1
Deep Research
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Mappings

MONDO
MONDO:0008280 Peutz-Jeghers syndrome
skos:exactMatch Orphanet ORPHA:2869
Orphanet ORPHA:2869 lists MONDO:0008280 as an exact cross-reference for Peutz-Jeghers syndrome.
📘

Definitions

1
Orphanet Peutz-Jeghers syndrome definition
A genetic intestinal polyposis syndrome with characteristic GI hamartomatous polyps, mucocutaneous pigmentation, and substantially increased risk of GI and extra-GI malignancies.
OTHER
Show evidence (1 reference)
ORPHA:2869 SUPPORT Other
"A genetic intestinal polyposis syndrome characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. This disorder carries a considerably increased risk of GI and extra-GI malignancies."
Orphanet defines the core syndromic triad of PJS.
👪

Inheritance

1
Autosomal dominant inheritance HP:0000006
Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern.
Autosomal dominant inheritance
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"Autosomal dominant"
Orphanet records autosomal dominant inheritance for PJS.
PMID:19916169 SUPPORT Human Clinical
"Peutz-Jeghers syndrome (PJS) is an inherited, autosomal dominant disorder distinguished by hamartomatous polyps in the gastrointestinal tract and pigmented mucocutaneous lesions."
This clinical review describes PJS as an autosomal dominant disorder.
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Pathophysiology

9
STK11 germline loss-of-function
Germline heterozygous pathogenic variants in STK11, encoding the LKB1 serine/threonine kinase, initiate PJS. Loss of tumor-suppressor kinase function perturbs epithelial polarity, growth-control, and stromal paracrine signaling, creating the inherited background for hamartomatous polyposis, mucocutaneous pigmentation, and cancer susceptibility.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology. stromal cell of small intestinal lamina propria CL:0009022 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves stromal cell of small intestinal lamina propria, annotated with stromal cell of lamina propria of small intestine (CL:0009022). CL:0009022 is a cell type from the Cell Ontology.
STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
signal transduction GO:0007165 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased signal transduction (GO:0007165). GO:0007165 is a biological process from the Gene Ontology. ↓ DECREASED regulation of cell proliferation GO:0042127 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of cell proliferation, annotated with regulation of cell population proliferation (GO:0042127). GO:0042127 is a biological process from the Gene Ontology. ↓ DECREASED
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology. colon UBERON:0001155 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in colon (UBERON:0001155). UBERON:0001155 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
LKB1/AMPK pathway inactivation Loss of catalytically active LKB1 reduces AMPK activation and removes AMPK-mediated restraint on mTORC1 signaling.
Stromal TGF-beta signaling defect STK11 loss in mesenchymal/stromal compartments impairs TGF-beta-mediated epithelial growth restraint.
Somatic STK11 second-hit and malignant transformation Germline STK11 loss creates the inherited background on which somatic second hits and cooperating events drive malignancy.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"STK11 | serine/threonine kinase 11 | hgnc:11389 | Disease-causing germline mutation(s) in"
Orphanet identifies STK11 as the disease-causing germline gene for PJS.
PMID:37054692 SUPPORT Human Clinical
"It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"
Clinical guidelines identify germline STK11 variants as the cause of PJS.
LKB1/AMPK pathway inactivation
LKB1 normally activates AMPK-family kinases. In PJS polyp tissue, pathogenic STK11 variants reduce phosphorylated AMPK, weakening energy- and polarity-linked growth control and contributing to downstream mTORC1 hyperactivation.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
activation of protein kinase activity GO:0032147 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased activation of protein kinase activity (GO:0032147). GO:0032147 is a biological process from the Gene Ontology. ↓ DECREASED
AMP-activated protein kinase activity GO:0004679 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased AMP-activated protein kinase activity (GO:0004679). GO:0004679 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
mTORC1 pathway hyperactivation Reduced LKB1/AMPK signaling removes inhibitory control over mTORC1 in PJS polyp tissue.
Show evidence (1 reference)
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"
Human PJS polyp tissue shows reduced AMPK Thr172 phosphorylation.
mTORC1 pathway hyperactivation
LKB1-deficient PJS tissues show increased mTORC1 signaling with elevated HIF-1alpha and GLUT1, supporting proliferative polyp growth and providing a mechanism-directed rationale for investigational mTOR inhibition.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
mTORC1 signaling GO:0031929 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased mTORC1 signaling, annotated with TOR signaling (GO:0031929). GO:0031929 is a biological process from the Gene Ontology. ↑ INCREASED cell proliferation GO:0008283 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cell proliferation, annotated with cell population proliferation (GO:0008283). GO:0008283 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hamartomatous intestinal polyposis mTORC1 activation promotes epithelial growth programs that contribute to hamartomatous polyp burden.
Hamartomatous Polyp Burden and Mechanical Complications mTORC1-supported polyp growth contributes to the polyp burden that causes bleeding, obstruction, intussusception, and abdominal symptoms.
Show evidence (1 reference)
PMID:19541609 SUPPORT Human Clinical
"polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."
Human PJS polyps show upregulated mTORC1 signaling and metabolic targets.
Stromal TGF-beta signaling defect
Mesenchymal/stromal LKB1 loss can drive PJS-like GI polyposis by reducing stromal TGF-beta signaling to the epithelium. This paracrine defect removes a local growth-suppressive brake and helps explain the arborizing stromal architecture of PJS hamartomas.
stromal cell of small intestinal lamina propria CL:0009022 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves stromal cell of small intestinal lamina propria, annotated with stromal cell of lamina propria of small intestine (CL:0009022). CL:0009022 is a cell type from the Cell Ontology. myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology.
STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
TGF-beta receptor signaling GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased TGF-beta receptor signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↓ DECREASED epithelial cell proliferation GO:0050673 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased epithelial cell proliferation (GO:0050673). GO:0050673 is a biological process from the Gene Ontology. ↑ INCREASED
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hamartomatous intestinal polyposis Loss of stromal TGF-beta-mediated epithelial restraint permits local epithelial and stromal overgrowth.
Hamartomatous Polyp Burden and Mechanical Complications Stromal loss of epithelial growth restraint produces GI polyp burden that can mechanically obstruct, bleed, and serve as an intussusception lead point.
Show evidence (2 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"
Mouse mesenchymal Stk11 loss is sufficient to produce PJS-like GI polyps.
PMID:18311138 SUPPORT Human Clinical
"We also noted TGFbeta signaling defects in polyps of individuals with PJS"
The same study observed TGF-beta signaling defects in human PJS polyps.
COX-2 / prostaglandin biosynthetic upregulation
PJS hamartomatous polyps overexpress COX-2/PTGS2 in epithelial and stromal compartments, increasing local prostaglandin biosynthesis. This supports an investigational chemoprevention rationale for COX-2 inhibition.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology. enteric smooth muscle cell CL:0002504 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves enteric smooth muscle cell (CL:0002504). CL:0002504 is a cell type from the Cell Ontology.
prostaglandin biosynthetic process GO:0001516 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased prostaglandin biosynthetic process (GO:0001516). GO:0001516 is a biological process from the Gene Ontology. ↑ INCREASED cyclooxygenase pathway GO:0019371 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cyclooxygenase pathway (GO:0019371). GO:0019371 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Hamartomatous intestinal polyposis Elevated prostaglandin signaling may support polyp growth and persistence.
Show evidence (1 reference)
PMID:12650805 SUPPORT Human Clinical
"COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue"
Human PJS polyp tissue overexpresses COX-2 compared with controls.
Hamartomatous Polyp Burden and Mechanical Complications
Characteristic PJS hamartomatous GI polyps, especially in the small bowel, create a mechanical and bleeding complication branch. Polyp ulceration causes chronic GI hemorrhage and anemia, while large or pedunculated polyps cause recurrent obstruction, intussusception, and abdominal pain.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
small intestine UBERON:0002108 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in small intestine (UBERON:0002108). UBERON:0002108 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Gastrointestinal hemorrhage Polyp bleeding causes occult or overt gastrointestinal hemorrhage.
Anemia Chronic polyp bleeding depletes blood iron and produces anemia.
Intestinal obstruction Large PJS polyps can obstruct the bowel lumen.
Intussusception Pedunculated small-bowel polyps serve as lead points for intussusception.
Abdominal pain Polyp obstruction and intussusception produce abdominal pain.
Show evidence (2 references)
PMID:20301443 SUPPORT Human Clinical
"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"
GeneReviews links PJS GI polyps to bleeding, anemia, obstruction, and intussusception.
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%"
A large cohort quantifies the high cumulative intussusception risk caused by PJS polyps.
Somatic STK11 second-hit and malignant transformation
Germline STK11 pathogenic variants confer inherited susceptibility, while somatic loss of the remaining STK11 allele and cooperating oncogenic events drive the high lifetime risk of GI and extra-GI epithelial malignancies.
intestinal epithelial cell CL:0002563 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves intestinal epithelial cell (CL:0002563). CL:0002563 is a cell type from the Cell Ontology.
STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee.
regulation of cell proliferation GO:0042127 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased regulation of cell proliferation, annotated with regulation of cell population proliferation (GO:0042127). GO:0042127 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Gastrointestinal carcinoma STK11 tumor-suppressor loss plus secondary somatic events produces the high GI carcinoma risk observed in PJS.
Breast carcinoma STK11 tumor-suppressor loss plus secondary somatic events contributes to the extra-GI breast carcinoma risk observed in PJS.
Pancreatic adenocarcinoma STK11 tumor-suppressor loss plus secondary somatic events contributes to the pancreatic adenocarcinoma risk observed in PJS.
Cervix cancer STK11 tumor-suppressor loss plus secondary somatic events contributes to the gynecologic malignancy risk observed in PJS.
Gonadal Sex-Cord Tumor Predisposition PJS tumor-predisposition biology also includes sex-specific ovarian and testicular sex-cord tumors.
Show evidence (3 references)
PMID:10398133 SUPPORT Human Clinical
"This study confirms allelic loss at LKB1 in PJS polyps and shows that LOH also occurs in cancers of the colon, breast, and cervix in PJS patients."
Direct evidence for the somatic second hit at STK11 in Peutz-Jeghers lesions, which is what this node asserts. The systematic-review item below establishes the cancer risk but not the allelic mechanism behind it.
PMID:10398133 SUPPORT Human Clinical
"These results provide molecular evidence that PJS patients are predisposed to cancers at several sites, as a direct result of selection for loss of the 'wild-type' LKB1 allele in tumours."
States the selective mechanism explicitly: the cancer risk follows from selection for loss of the wild-type allele, which ties the second hit to the malignant transformation this node also asserts.
PMID:20051941 SUPPORT Human Clinical
"PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer"
Systematic review evidence supports the multi-organ cancer predisposition in PJS.
Gonadal Sex-Cord Tumor Predisposition
The PJS neoplasia spectrum includes sex-specific gonadal sex-cord tumors: ovarian sex cord tumors with annular tubules in females and estrogen- secreting large calcifying Sertoli cell tumors in males. Estrogen secretion from Sertoli cell tumors can cause gynecomastia.
Downstream
Sex cord tumor with annular tubules PJS predisposes females to ovarian SCTAT.
Large calcifying Sertoli cell tumor PJS predisposes males to large calcifying Sertoli cell tumors of the testes.
Gynecomastia secondary to Sertoli cell tumors Estrogen secretion from PJS-associated Sertoli cell tumors causes gynecomastia.
Show evidence (2 references)
PMID:20301443 SUPPORT Human Clinical
"Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
GeneReviews identifies SCTAT as a PJS-associated ovarian manifestation.
PMID:20301443 SUPPORT Human Clinical
"Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
GeneReviews identifies estrogen-secreting Sertoli cell tumors and gynecomastia in males with PJS.
Mucocutaneous melanocyte hyperpigmentation
PJS causes characteristic dark blue to brown macules around the mouth, eyes, nostrils, perianal area, buccal mucosa, lips, and extremities. The precise melanocyte-intrinsic mechanism remains incompletely defined, but pigmentation commonly appears in childhood before GI complications.
melanocyte CL:0000148 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves melanocyte (CL:0000148). CL:0000148 is a cell type from the Cell Ontology.
pigmentation GO:0043473 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased pigmentation (GO:0043473). GO:0043473 is a biological process from the Gene Ontology. ↑ INCREASED melanin biosynthetic process GO:0042438 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased melanin biosynthetic process (GO:0042438). GO:0042438 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Mucocutaneous pigmentation Melanocyte hyperpigmentation produces the oral, lip, periorificial, and acral macules used in clinical recognition of PJS.
Multiple lentigines The same melanocyte hyperpigmentation branch accounts for multiple lentiginous macules in PJS.
Show evidence (1 reference)
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 describes the characteristic childhood mucocutaneous pigmentation pattern.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Peutz-Jeghers syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

15
Blood 2
Gastrointestinal hemorrhage FREQUENT HP:0002239 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal hemorrhage (HP:0002239). HP:0002239 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0002239 | Gastrointestinal hemorrhage | Frequent (79-30%)"
Orphanet records GI hemorrhage as frequent in PJS.
PMID:20301443 SUPPORT Human Clinical
"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"
GeneReviews links PJS polyps to chronic bleeding and anemia.
Anemia OCCASIONAL HP:0001903 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anemia (HP:0001903). HP:0001903 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0001903 | Anemia | Occasional (29-5%)"
Orphanet records anemia as an occasional PJS phenotype.
PMID:20301443 SUPPORT Human Clinical
"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"
GeneReviews describes anemia as a consequence of GI polyp bleeding.
Breast 2
Breast carcinoma OCCASIONAL HP:0003002 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Breast carcinoma (HP:0003002). HP:0003002 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0003002 | Breast carcinoma | Occasional (29-5%)"
Orphanet records breast carcinoma as an occasional PJS phenotype.
PMID:20051941 SUPPORT Human Clinical
"PJS patients are markedly at risk for several malignancies, in particular gastrointestinal cancers and breast cancer"
A systematic review identifies breast cancer as a major PJS-associated malignancy.
Gynecomastia secondary to Sertoli cell tumors OCCASIONAL HP:0000771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gynecomastia (HP:0000771). HP:0000771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301443 SUPPORT Human Clinical
"Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
GeneReviews links estrogen-secreting Sertoli cell tumors to gynecomastia in males with PJS.
Context-specific annotations (1)
MALE OCCASIONAL
Gynecomastia is a consequence of estrogen secretion by Sertoli cell tumors.
Digestive 3
Hamartomatous intestinal polyposis VERY_FREQUENT Small intestinal polyposis HP:0030256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Small intestinal polyposis (HP:0030256). HP:0030256 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"Abnormality of the gastrointestinal tract | Very frequent (99-80%)"
Orphanet records very frequent GI tract abnormalities in PJS.
PMID:37054692 SUPPORT Human Clinical
"presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation."
Clinical guidelines identify GI hamartomatous polyposis as a defining PJS feature.
Intestinal obstruction OCCASIONAL HP:0005214 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intestinal obstruction (HP:0005214). HP:0005214 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0005214 | Intestinal obstruction | Occasional (29-5%)"
Orphanet records intestinal obstruction as an occasional PJS phenotype.
PMID:20301443 SUPPORT Human Clinical
"GI polyps can result in chronic bleeding, anemia, and recurrent obstruction and intussusception"
GeneReviews links PJS polyps to recurrent obstruction and intussusception.
Pancreatic adenocarcinoma OCCASIONAL HP:0006725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pancreatic adenocarcinoma (HP:0006725). HP:0006725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0006725 | Pancreatic adenocarcinoma | Occasional (29-5%)"
Orphanet records pancreatic adenocarcinoma as an occasional PJS phenotype.
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)"
GeneReviews includes pancreatic cancer in the PJS malignancy spectrum.
Genitourinary 1
Large calcifying Sertoli cell tumor OCCASIONAL Testicular neoplasm HP:0010788 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large calcifying Sertoli cell tumor, annotated with Testicular neoplasm (HP:0010788). HP:0010788 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301443 SUPPORT Human Clinical
"Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
GeneReviews directly identifies large calcifying Sertoli cell tumors as an occasional male PJS manifestation.
Context-specific annotations (1)
MALE OCCASIONAL
Large calcifying Sertoli cell tumor is a male-specific PJS manifestation.
Head and Neck 1
Mucocutaneous pigmentation VERY_FREQUENT Abnormal pigmentation of the oral mucosa HP:0100669 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pigmentation of the oral mucosa (HP:0100669). HP:0100669 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0100669 | Abnormal pigmentation of the oral mucosa | Very frequent (99-80%)"
Orphanet records oral mucosal pigmentation as very frequent 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 gives the distribution and timing of PJS pigmentation.
Constitutional 1
Abdominal pain OCCASIONAL HP:0002027 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abdominal pain (HP:0002027). HP:0002027 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2869 SUPPORT Other
"HP:0002027 | Abdominal pain | Occasional (29-5%)"
Orphanet records abdominal pain as an occasional PJS phenotype.
Other 5
Multiple lentigines VERY_FREQUENT HP:0001003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple lentigines (HP:0001003). HP:0001003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:2869 SUPPORT Other
"HP:0001003 | Multiple lentigines | Very frequent (99-80%)"
Orphanet records multiple lentigines as very frequent in PJS.
Intussusception FREQUENT HP:0002576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intussusception (HP:0002576). HP:0002576 is a phenotype from the Human Phenotype Ontology.
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%"
A large human PJS cohort quantifies high cumulative intussusception risk.
Gastrointestinal carcinoma VERY_FREQUENT HP:0002672 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastrointestinal carcinoma (HP:0002672). HP:0002672 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0002672 | Gastrointestinal carcinoma | Very frequent (99-80%)"
Orphanet records gastrointestinal carcinoma as very frequent in PJS.
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)"
GeneReviews summarizes the multi-organ epithelial cancer risk in PJS.
Cervix cancer OCCASIONAL HP:0030079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adenoma malignum of the cervix, annotated with Cervix cancer (HP:0030079). HP:0030079 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"HP:0030079 | Cervix cancer | Occasional (29-5%)"
Orphanet records cervix cancer as an occasional PJS phenotype.
PMID:20301443 SUPPORT Human Clinical
"Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
GeneReviews identifies adenoma malignum of the cervix as a PJS-associated female-specific neoplasm.
Context-specific annotations (1)
FEMALE
PJS-associated adenoma malignum is a female-specific gynecologic manifestation.
Sex cord tumor with annular tubules Ovarian neoplasm HP:0100615 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sex cord tumor with annular tubules, annotated with Ovarian neoplasm (HP:0100615). HP:0100615 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301443 SUPPORT Human Clinical
"Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
GeneReviews directly identifies SCTAT as an ovarian PJS manifestation.
Context-specific annotations (1)
FEMALE
SCTAT is a female-specific ovarian manifestation of PJS.
🧬

Genetic Associations

1
STK11 germline pathogenic variants
Gene: STK11 hgnc:11389 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is STK11 (hgnc:11389). hgnc:11389 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (4 references)
ORPHA:2869 SUPPORT Other
"STK11 | serine/threonine kinase 11 | hgnc:11389 | Disease-causing germline mutation(s) in"
Orphanet identifies STK11 germline mutations as disease-causing in PJS.
PMID:37054692 SUPPORT Human Clinical
"It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance"
Clinical guidelines support STK11 as the causal gene.
PMID:19541609 SUPPORT Human Clinical
"PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life"
This paper summarizes the near-complete penetrance of GI hamartomas in PJS patients.
+ 1 more reference
🗃️

External Assertions

1
Orphanet Peutz-Jeghers syndrome record
Orphanet structured disease record ORPHA:2869
Orphanet's ORPHA:2869 structured record provides the exact MONDO and OMIM mappings, autosomal dominant inheritance, syndrome definition, STK11 gene assertion, epidemiology, natural-history rows, and HPO phenotype rows used in this curation.
Show evidence (2 references)
ORPHA:2869 SUPPORT Other
"MONDO:0008280 | Exact"
Orphanet maps ORPHA:2869 exactly to the MONDO identifier used here.
ORPHA:2869 SUPPORT Other
"OMIM:175200 | Exact"
Orphanet maps ORPHA:2869 exactly to OMIM:175200.
💊

Medical Actions

5
Endoscopic surveillance and polypectomy
Action: endoscopic procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is endoscopic procedure (NCIT:C16546). NCIT:C16546 is a clinical intervention from the NCI Thesaurus. Ontology label: Endoscopic Procedure NCIT:C16546
Routine endoscopic surveillance with removal of clinically significant GI polyps reduces emergency laparotomy and bowel loss from intussusception.
Show evidence (1 reference)
PMID:20301443 SUPPORT Human Clinical
"Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception"
GeneReviews supports endoscopic polypectomy as standard complication prevention in PJS.
Extra-Intestinal Cancer Surveillance
Action: surveillance for malignanciesNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surveillance for malignancies, annotated with Cancer Screening (NCIT:C15406). NCIT:C15406 is a clinical intervention from the NCI Thesaurus. Ontology label: Cancer Screening NCIT:C15406
Beyond gastrointestinal polyp surveillance, Peutz-Jeghers syndrome confers a markedly increased lifetime risk of extraintestinal malignancies (including breast, pancreatic, gynecologic — cervical and ovarian sex-cord — and testicular cancers). Lifelong multi-organ surveillance of the organs at increased cancer risk is therefore a core component of management, distinct from endoscopic polyp surveillance.
Show evidence (4 references)
PMID:35487765 SUPPORT Human Clinical
"The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer."
The U.S. Multi-Society Task Force guideline centers PJS management on surveillance of organs at increased cancer risk, alongside polyp complication prevention.
PMID:35487765 SUPPORT Human Clinical
"The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors."
Establishes the elevated risk of both intestinal and extraintestinal tumors that multi-organ surveillance targets.
PMID:31764758 SUPPORT Human Clinical
"The most common hereditary cancer syndromes related to women's cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer."
ACOG identifies PJS among the hereditary syndromes conferring breast and gynecologic cancer risk that warrant surveillance.
+ 1 more reference
Genetic counseling and cascade testing
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Autosomal dominant STK11-associated PJS warrants genetic counseling and testing of at-risk relatives.
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 provides the basis for counseling and cascade testing.
COX-2 inhibitor chemoprevention
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: celecoxib CHEBI:41423 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses celecoxib (CHEBI:41423). CHEBI:41423 is a therapeutic agent from Chemical Entities of Biological Interest.
COX-2 inhibition with celecoxib is investigational for reducing PJS polyp burden, based on COX-2 overexpression in PJS hamartomas and preclinical rationale; it is not established standard care.
Mechanism Target:
COX-2 / prostaglandin biosynthetic upregulation — Celecoxib inhibits COX-2 and therefore directly targets the prostaglandin biosynthetic mechanism observed in PJS hamartomas.
Show evidence (1 reference)
PMID:12650805 SUPPORT Human Clinical
"COX-2 overexpression was noted in hamartomatous polyp tissue from PJS patients compared with normal control and PJS tissue"
Human PJS hamartomas overexpress the COX-2 target of celecoxib.
Show evidence (1 reference)
clinicaltrials:NCT06722534 SUPPORT 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"
The active trial rationale links COX overexpression to possible celecoxib chemoprevention.
Sirolimus mTOR inhibition
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sirolimus CHEBI:9168 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sirolimus (CHEBI:9168). CHEBI:9168 is a therapeutic agent from Chemical Entities of Biological Interest.
mTOR inhibition is investigational in PJS. Mouse-model data show rapamycin suppression of preexisting GI polyps, supporting mechanism-directed interest in the LKB1/AMPK/mTORC1 axis.
Mechanism Target:
mTORC1 pathway hyperactivation — Sirolimus inhibits mTORC1 signaling, the pathway hyperactivated in human PJS polyps.
Show evidence (1 reference)
PMID:19541609 SUPPORT Human Clinical
"polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."
Human PJS polyps show the mTORC1 pathway activity targeted by sirolimus.
Show evidence (1 reference)
PMID:19541609 SUPPORT Model Organism
"rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice"
Mouse-model evidence supports investigational mTOR inhibition for PJS-like polyp burden.
📈

Progression

1
Childhood pigmentation and later GI manifestations
Age: Childhood to adulthood
Orphanet records childhood, adolescent, and adult onset. Mucocutaneous pigmentation often appears in childhood, while polyp-related bleeding, obstruction, intussusception, and malignancy risks emerge with age.
Show evidence (3 references)
ORPHA:2869 SUPPORT Other
"Age of onset: Childhood"
Orphanet records childhood onset for PJS.
ORPHA:2869 SUPPORT Other
"Age of onset: Adolescent"
Orphanet records adolescent onset for PJS.
ORPHA:2869 SUPPORT Other
"Age of onset: Adult"
Orphanet records adult onset for PJS.
📊

Prevalence

2
Europe
Point Prevalence 0.1–0.9 per 100,000 1–9 per 1,000,000
Orphanet records European point prevalence in the rare-disease range.
Show evidence (1 reference)
ORPHA:2869 SUPPORT Other
"1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"
Orphanet records European point prevalence for PJS.
Review-based estimates
Point Prevalence 0.357143–12.048193 per 100,000 1–9 per 100,000
Published prevalence estimates vary widely by ascertainment setting.
Show evidence (1 reference)
PMID:19916169 SUPPORT Human Clinical
"Prevalence of PJS is estimated from 1 in 8300 to 1 in 280,000 individuals."
This review summarizes published PJS prevalence estimates.
🔀

Differential Diagnoses

2

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

Juvenile polyposis syndrome MONDO:0017380
Overlapping Features Another hamartomatous polyposis syndrome, usually caused by SMAD4 or BMPR1A variants, but lacking the classic PJS mucocutaneous pigmentation and STK11-driven mechanism.
Distinguishing Features
  • Different causal genes, commonly SMAD4 or BMPR1A rather than STK11.
  • Lacks the characteristic mucocutaneous pigmentation pattern of PJS.
Show evidence (1 reference)
PMID:36925460 SUPPORT Human Clinical
"Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."
This review places juvenile polyposis in the same differential category as PJS.
Cowden syndrome MONDO:0008021
Overlapping Features PTEN hamartoma tumor syndrome can include GI hamartomas and cancer risk but has PTEN-driven mucocutaneous findings and a different cancer spectrum.
Distinguishing Features
  • PTEN-related trichilemmomas, papillomatous papules, and thyroid/endometrial risks.
  • Different causal gene and syndrome-specific surveillance pattern.
Show evidence (1 reference)
PMID:36925460 SUPPORT Human Clinical
"Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."
This review identifies Cowden syndrome as a major hamartomatous polyposis differential.
📊

Related Datasets

2
Immune profiling of premalignant lesions in patients with Peutz-Jeghers Syndrome geo:GSE196711
RNA sequencing was performed in a total of 26 colorectal tissues from 26 unrelated patients including PJS polyps (n=6), familial adenomatous polyposis (FAP) polyps (n=9), paracancerous colonic mucosae (ConA) (n=9) as well as non-PJS and non-FAP sporadic polyps (ConB) (n=5)
human BULK RNA SEQ n=29
PMID:39174496
Identified by GEO DataSets index search for Peutz-Jeghers syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Differential gene expression profile of germline STK11 deletion in patient derived fibroblasts geo:GSE251755
Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder hallmarked by mucocutaneous melanocytic macules and gastrointestinal hamartomatous polyposis associated with germline/somatic pathogenic variants in the tumor suppressor STK11. PJS is clinically heterogeneous, however, the relationship between clinical phenotype and genotype remains elusive. Here, we report a family with variable severity PJS who harbor a heterozygous STK11 whole gene deletion combined with heterozygous variants in PMS2 and TP53AIP1 that segregate with disease severity in the family.
human BULK RNA SEQ n=6
PMID:40860288
Identified by GEO DataSets index search for Peutz-Jeghers syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
{ }

Source YAML

click to show 
name: Peutz-Jeghers syndrome
category: Genetic
creation_date: '2026-05-04T01:04:44Z'
synonyms:
- PJS
- Hamartomatous intestinal polyposis
description: >
  Peutz-Jeghers syndrome is an autosomal dominant hereditary intestinal
  polyposis and cancer-predisposition syndrome caused primarily by germline
  pathogenic variants in the tumor suppressor kinase gene STK11/LKB1. The
  syndrome combines characteristic mucocutaneous pigmentation with GI
  hamartomatous polyps, especially in the small intestine. Loss of STK11
  disrupts LKB1/AMPK signaling, derepresses mTORC1, impairs stromal
  TGF-beta-mediated epithelial restraint, and creates a permissive background
  for polyp complications and multi-organ malignancy risk.
disease_term:
  preferred_term: Peutz-Jeghers syndrome
  term:
    id: MONDO:0008280
    label: Peutz-Jeghers syndrome
parents:
- hamartomatous polyposis syndrome
- hereditary cancer syndrome
- intestinal polyposis syndrome
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008280
      label: Peutz-Jeghers syndrome
    mapping_predicate: skos:exactMatch
    mapping_source: Orphanet ORPHA:2869
    mapping_justification: >
      Orphanet ORPHA:2869 lists MONDO:0008280 as an exact cross-reference for
      Peutz-Jeghers syndrome.
external_assertions:
- name: Orphanet Peutz-Jeghers syndrome record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:2869
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=2869
  description: >
    Orphanet's ORPHA:2869 structured record provides the exact MONDO and OMIM
    mappings, autosomal dominant inheritance, syndrome definition, STK11 gene
    assertion, epidemiology, natural-history rows, and HPO phenotype rows used
    in this curation.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MONDO:0008280 | Exact"
    explanation: Orphanet maps ORPHA:2869 exactly to the MONDO identifier used here.
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:175200 | Exact"
    explanation: Orphanet maps ORPHA:2869 exactly to OMIM:175200.
definitions:
- name: Orphanet Peutz-Jeghers syndrome definition
  definition_type: OTHER
  description: >
    A genetic intestinal polyposis syndrome with characteristic GI
    hamartomatous polyps, mucocutaneous pigmentation, and substantially
    increased risk of GI and extra-GI malignancies.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A genetic intestinal polyposis syndrome characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. This disorder carries a considerably increased risk of GI and extra-GI malignancies."
    explanation: Orphanet defines the core syndromic triad of PJS.
inheritance:
- name: Autosomal dominant inheritance
  description: Peutz-Jeghers syndrome is inherited in an autosomal dominant pattern.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Autosomal dominant"
    explanation: Orphanet records autosomal dominant inheritance for PJS.
  - reference: PMID:19916169
    reference_title: "Peutz-Jeghers syndrome: diagnostic and therapeutic approach"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peutz-Jeghers syndrome (PJS) is an inherited, autosomal dominant disorder distinguished by hamartomatous polyps in the gastrointestinal tract and pigmented mucocutaneous lesions."
    explanation: This clinical review describes PJS as an autosomal dominant disorder.
prevalence:
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_low: 0.1
  rate_high: 0.9
  percentage: 1-9 per 1,000,000
  notes: Orphanet records European point prevalence in the rare-disease range.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 1 000 000 | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet records European point prevalence for PJS.
- population: Review-based estimates
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 0.357143
  rate_high: 12.048193
  percentage: 1 in 8,300 to 1 in 280,000
  notes: Published prevalence estimates vary widely by ascertainment setting.
  evidence:
  - reference: PMID:19916169
    reference_title: "Peutz-Jeghers syndrome: diagnostic and therapeutic approach"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence of PJS is estimated from 1 in 8300 to 1 in 280,000 individuals."
    explanation: This review summarizes published PJS prevalence estimates.
progression:
- phase: Childhood pigmentation and later GI manifestations
  age_range: Childhood to adulthood
  notes: >
    Orphanet records childhood, adolescent, and adult onset. Mucocutaneous
    pigmentation often appears in childhood, while polyp-related bleeding,
    obstruction, intussusception, and malignancy risks emerge with age.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset for PJS.
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adolescent"
    explanation: Orphanet records adolescent onset for PJS.
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Adult"
    explanation: Orphanet records adult onset for PJS.
pathophysiology:
- name: STK11 germline loss-of-function
  conforms_to: "germline_two_hit_tumor_predisposition#Constitutional First-Hit Tumor Suppressor Inactivation"
  description: >
    Germline heterozygous pathogenic variants in STK11, encoding the LKB1
    serine/threonine kinase, initiate PJS. Loss of tumor-suppressor kinase
    function perturbs epithelial polarity, growth-control, and stromal
    paracrine signaling, creating the inherited background for hamartomatous
    polyposis, mucocutaneous pigmentation, and cancer susceptibility.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "STK11 | serine/threonine kinase 11 | hgnc:11389 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies STK11 as the disease-causing germline gene for PJS.
  - 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: Clinical guidelines identify germline STK11 variants as the cause of PJS.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: stromal cell of small intestinal lamina propria
    term:
      id: CL:0009022
      label: stromal cell of lamina propria of small intestine
  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
    causal_link_type: DIRECT
    description: >
      Loss of catalytically active LKB1 reduces AMPK activation and removes
      AMPK-mediated restraint on mTORC1 signaling.
  - target: Stromal TGF-beta signaling defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Mesenchymal STK11 loss and impaired SMAD-dependent paracrine signaling
    description: >
      STK11 loss in mesenchymal/stromal compartments impairs TGF-beta-mediated
      epithelial growth restraint.
  - target: Somatic STK11 second-hit and malignant transformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Germline STK11 loss creates the inherited background on which somatic
      second hits and cooperating events drive malignancy.
- name: LKB1/AMPK pathway inactivation
  description: >
    LKB1 normally activates AMPK-family kinases. In PJS polyp tissue,
    pathogenic STK11 variants reduce phosphorylated AMPK, weakening energy-
    and polarity-linked growth control and contributing to downstream mTORC1
    hyperactivation.
  evidence:
  - 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: Human PJS polyp tissue shows reduced AMPK Thr172 phosphorylation.
  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: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  downstream:
  - target: mTORC1 pathway hyperactivation
    causal_link_type: DIRECT
    description: >
      Reduced LKB1/AMPK signaling removes inhibitory control over mTORC1 in
      PJS polyp tissue.
- name: mTORC1 pathway hyperactivation
  description: >
    LKB1-deficient PJS tissues show increased mTORC1 signaling with elevated
    HIF-1alpha and GLUT1, supporting proliferative polyp growth and providing
    a mechanism-directed rationale for investigational mTOR inhibition.
  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: HUMAN_CLINICAL
    snippet: "polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."
    explanation: Human PJS polyps show upregulated mTORC1 signaling and metabolic targets.
  biological_processes:
  - preferred_term: mTORC1 signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  - preferred_term: cell proliferation
    term:
      id: GO:0008283
      label: cell population proliferation
    modifier: INCREASED
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  downstream:
  - target: Hamartomatous intestinal polyposis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Increased mTORC1-dependent translation and HIF-1alpha/GLUT1 metabolic signaling
    description: >
      mTORC1 activation promotes epithelial growth programs that contribute to
      hamartomatous polyp burden.
  - target: Hamartomatous Polyp Burden and Mechanical Complications
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Hamartomatous intestinal polyposis
    description: >
      mTORC1-supported polyp growth contributes to the polyp burden that causes
      bleeding, obstruction, intussusception, and abdominal symptoms.
- name: Stromal TGF-beta signaling defect
  description: >
    Mesenchymal/stromal LKB1 loss can drive PJS-like GI polyposis by reducing
    stromal TGF-beta signaling to the epithelium. This paracrine defect removes
    a local growth-suppressive brake and helps explain the arborizing stromal
    architecture of PJS hamartomas.
  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: Mouse mesenchymal Stk11 loss is sufficient to produce PJS-like GI polyps.
  - 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"
    explanation: The same study observed TGF-beta signaling defects in human PJS polyps.
  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: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: TGF-beta receptor signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DECREASED
  - preferred_term: epithelial cell proliferation
    term:
      id: GO:0050673
      label: epithelial cell proliferation
    modifier: INCREASED
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Hamartomatous intestinal polyposis
    causal_link_type: DIRECT
    description: >
      Loss of stromal TGF-beta-mediated epithelial restraint permits local
      epithelial and stromal overgrowth.
  - target: Hamartomatous Polyp Burden and Mechanical Complications
    causal_link_type: DIRECT
    description: >
      Stromal loss of epithelial growth restraint produces GI polyp burden that
      can mechanically obstruct, bleed, and serve as an intussusception lead
      point.
- name: COX-2 / prostaglandin biosynthetic upregulation
  description: >
    PJS hamartomatous polyps overexpress COX-2/PTGS2 in epithelial and stromal
    compartments, increasing local prostaglandin biosynthesis. This supports an
    investigational chemoprevention rationale for COX-2 inhibition.
  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: Human PJS polyp tissue overexpresses COX-2 compared with controls.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  - preferred_term: enteric smooth muscle cell
    term:
      id: CL:0002504
      label: enteric smooth muscle cell
  biological_processes:
  - preferred_term: prostaglandin biosynthetic process
    term:
      id: GO:0001516
      label: prostaglandin biosynthetic process
    modifier: INCREASED
  - preferred_term: cyclooxygenase pathway
    term:
      id: GO:0019371
      label: cyclooxygenase pathway
    modifier: INCREASED
  downstream:
  - target: Hamartomatous intestinal polyposis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Elevated prostaglandin signaling may support polyp growth and persistence.
- name: Hamartomatous Polyp Burden and Mechanical Complications
  description: >
    Characteristic PJS hamartomatous GI polyps, especially in the small bowel,
    create a mechanical and bleeding complication branch. Polyp ulceration causes
    chronic GI hemorrhage and anemia, while large or pedunculated polyps cause
    recurrent obstruction, intussusception, and abdominal pain.
  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"
    explanation: GeneReviews links PJS GI polyps to bleeding, anemia, obstruction, and intussusception.
  - 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: A large cohort quantifies the high cumulative intussusception risk caused by PJS polyps.
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  locations:
  - preferred_term: small intestine
    term:
      id: UBERON:0002108
      label: small intestine
  downstream:
  - target: Gastrointestinal hemorrhage
    causal_link_type: DIRECT
    description: Polyp bleeding causes occult or overt gastrointestinal hemorrhage.
    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"
      explanation: GeneReviews directly links GI polyps to chronic bleeding.
  - target: Anemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic gastrointestinal bleeding
    description: Chronic polyp bleeding depletes blood iron and produces anemia.
    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"
      explanation: GeneReviews directly links PJS polyp bleeding to anemia.
  - target: Intestinal obstruction
    causal_link_type: DIRECT
    description: Large PJS polyps can obstruct the bowel lumen.
    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"
      explanation: GeneReviews directly links PJS polyps to recurrent obstruction.
  - target: Intussusception
    causal_link_type: DIRECT
    description: Pedunculated small-bowel polyps serve as lead points for intussusception.
    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: The large cohort supports intussusception as a common polyp complication.
  - target: Abdominal pain
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Polyp-related obstruction
    - Intussusception
    description: Polyp obstruction and intussusception produce abdominal pain.
    evidence:
    - reference: ORPHA:2869
      reference_title: "Peutz-Jeghers syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0002027 | Abdominal pain | Occasional (29-5%)"
      explanation: Orphanet records abdominal pain among PJS phenotypes.
- name: Somatic STK11 second-hit and malignant transformation
  conforms_to: "germline_two_hit_tumor_predisposition#Somatic Second-Hit Inactivation of the Wild-Type Allele"
  description: >
    Germline STK11 pathogenic variants confer inherited susceptibility, while
    somatic loss of the remaining STK11 allele and cooperating oncogenic events
    drive the high lifetime risk of GI and extra-GI epithelial malignancies.
  evidence:
  - reference: PMID:10398133
    reference_title: "Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study confirms allelic loss at LKB1 in PJS polyps and shows that LOH
      also occurs in cancers of the colon, breast, and cervix in PJS patients.
    explanation: >-
      Direct evidence for the somatic second hit at STK11 in Peutz-Jeghers
      lesions, which is what this node asserts. The systematic-review item below
      establishes the cancer risk but not the allelic mechanism behind it.
  - reference: PMID:10398133
    reference_title: "Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz-Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These results provide molecular evidence that PJS patients are predisposed
      to cancers at several sites, as a direct result of selection for loss of
      the 'wild-type' LKB1 allele in tumours.
    explanation: >-
      States the selective mechanism explicitly: the cancer risk follows from
      selection for loss of the wild-type allele, which ties the second hit to
      the malignant transformation this node also asserts.
  - 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: Systematic review evidence supports the multi-organ cancer predisposition in PJS.
  genes:
  - preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  biological_processes:
  - preferred_term: regulation of cell proliferation
    term:
      id: GO:0042127
      label: regulation of cell population proliferation
    modifier: INCREASED
  cell_types:
  - preferred_term: intestinal epithelial cell
    term:
      id: CL:0002563
      label: intestinal epithelial cell
  downstream:
  - target: Gastrointestinal carcinoma
    causal_link_type: DIRECT
    description: >
      STK11 tumor-suppressor loss plus secondary somatic events produces the
      high GI carcinoma risk observed in PJS.
  - target: Breast carcinoma
    causal_link_type: DIRECT
    description: >
      STK11 tumor-suppressor loss plus secondary somatic events contributes to
      the extra-GI breast carcinoma risk observed in PJS.
  - target: Pancreatic adenocarcinoma
    causal_link_type: DIRECT
    description: >
      STK11 tumor-suppressor loss plus secondary somatic events contributes to
      the pancreatic adenocarcinoma risk observed in PJS.
  - target: Cervix cancer
    causal_link_type: DIRECT
    description: >
      STK11 tumor-suppressor loss plus secondary somatic events contributes to
      the gynecologic malignancy risk observed in PJS.
  - target: Gonadal Sex-Cord Tumor Predisposition
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      PJS tumor-predisposition biology also includes sex-specific ovarian and
      testicular sex-cord tumors.
- name: Gonadal Sex-Cord Tumor Predisposition
  description: >
    The PJS neoplasia spectrum includes sex-specific gonadal sex-cord tumors:
    ovarian sex cord tumors with annular tubules in females and estrogen-
    secreting large calcifying Sertoli cell tumors in males. Estrogen secretion
    from Sertoli cell tumors can cause gynecomastia.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
    explanation: GeneReviews identifies SCTAT as a PJS-associated ovarian manifestation.
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
    explanation: GeneReviews identifies estrogen-secreting Sertoli cell tumors and gynecomastia in males with PJS.
  downstream:
  - target: Sex cord tumor with annular tubules
    causal_link_type: DIRECT
    description: PJS predisposes females to ovarian SCTAT.
    evidence:
    - reference: PMID:20301443
      reference_title: "Peutz-Jeghers Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
      explanation: GeneReviews directly identifies SCTAT as a PJS-associated ovarian tumor.
  - target: Large calcifying Sertoli cell tumor
    causal_link_type: DIRECT
    description: PJS predisposes males to large calcifying Sertoli cell tumors of the testes.
    evidence:
    - reference: PMID:20301443
      reference_title: "Peutz-Jeghers Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
      explanation: GeneReviews directly identifies large calcifying Sertoli cell tumors in male PJS.
  - target: Gynecomastia secondary to Sertoli cell tumors
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Estrogen secretion from Sertoli cell tumor
    description: Estrogen secretion from PJS-associated Sertoli cell tumors causes gynecomastia.
    evidence:
    - reference: PMID:20301443
      reference_title: "Peutz-Jeghers Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
      explanation: GeneReviews links Sertoli-cell-tumor estrogen secretion to gynecomastia.
- name: Mucocutaneous melanocyte hyperpigmentation
  description: >
    PJS causes characteristic dark blue to brown macules around the mouth,
    eyes, nostrils, perianal area, buccal mucosa, lips, and extremities. The
    precise melanocyte-intrinsic mechanism remains incompletely defined, but
    pigmentation commonly appears in childhood before GI complications.
  evidence:
  - 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 describes the characteristic childhood mucocutaneous pigmentation pattern.
  cell_types:
  - preferred_term: melanocyte
    term:
      id: CL:0000148
      label: melanocyte
  biological_processes:
  - preferred_term: pigmentation
    term:
      id: GO:0043473
      label: pigmentation
    modifier: INCREASED
  - preferred_term: melanin biosynthetic process
    term:
      id: GO:0042438
      label: melanin biosynthetic process
    modifier: INCREASED
  downstream:
  - target: Mucocutaneous pigmentation
    causal_link_type: DIRECT
    description: >
      Melanocyte hyperpigmentation produces the oral, lip, periorificial, and
      acral macules used in clinical recognition of PJS.
  - target: Multiple lentigines
    causal_link_type: DIRECT
    description: >
      The same melanocyte hyperpigmentation branch accounts for multiple
      lentiginous macules in PJS.
    evidence:
    - reference: ORPHA:2869
      reference_title: "Peutz-Jeghers syndrome"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HP:0001003 | Multiple lentigines | Very frequent (99-80%)"
      explanation: Orphanet records multiple lentigines as a very frequent PJS phenotype.
phenotypes:
- name: Hamartomatous intestinal polyposis
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >
    Characteristic hamartomatous polyps throughout the GI tract, especially the
    small intestine, define the syndrome and cause bleeding, obstruction, and
    intussusception.
  phenotype_term:
    preferred_term: Small intestinal polyposis
    term:
      id: HP:0030256
      label: Small intestinal polyposis
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Abnormality of the gastrointestinal tract | Very frequent (99-80%)"
    explanation: Orphanet records very frequent GI tract abnormalities in PJS.
  - 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: "presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation."
    explanation: Clinical guidelines identify GI hamartomatous polyposis as a defining PJS feature.
- name: Mucocutaneous pigmentation
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >
    Dark macules on the lips, oral mucosa, periorificial skin, and acral sites
    are a hallmark and often present early in childhood.
  phenotype_term:
    preferred_term: Abnormal pigmentation of the oral mucosa
    term:
      id: HP:0100669
      label: Abnormal pigmentation of the oral mucosa
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100669 | Abnormal pigmentation of the oral mucosa | Very frequent (99-80%)"
    explanation: Orphanet records oral mucosal pigmentation as very frequent 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 gives the distribution and timing of PJS pigmentation.
- name: Multiple lentigines
  category: Dermatologic
  frequency: VERY_FREQUENT
  description: >
    Multiple lentiginous macules are part of the characteristic cutaneous PJS
    pigmentation pattern.
  phenotype_term:
    preferred_term: Multiple lentigines
    term:
      id: HP:0001003
      label: Multiple lentigines
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001003 | Multiple lentigines | Very frequent (99-80%)"
    explanation: Orphanet records multiple lentigines as very frequent in PJS.
- name: Gastrointestinal hemorrhage
  category: Gastrointestinal
  frequency: FREQUENT
  description: >
    Polyp ulceration and chronic bleeding cause occult or overt GI hemorrhage
    and can lead to anemia.
  phenotype_term:
    preferred_term: Gastrointestinal hemorrhage
    term:
      id: HP:0002239
      label: Gastrointestinal hemorrhage
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002239 | Gastrointestinal hemorrhage | Frequent (79-30%)"
    explanation: Orphanet records GI hemorrhage as frequent in PJS.
  - 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"
    explanation: GeneReviews links PJS polyps to chronic bleeding and anemia.
- name: Anemia
  category: Hematologic
  frequency: OCCASIONAL
  description: >
    Chronic GI blood loss from polyps can produce anemia.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001903 | Anemia | Occasional (29-5%)"
    explanation: Orphanet records anemia as an occasional PJS phenotype.
  - 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"
    explanation: GeneReviews describes anemia as a consequence of GI polyp bleeding.
- name: Intestinal obstruction
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >
    Large polyps can cause recurrent obstruction and serve as lead points for
    intussusception.
  phenotype_term:
    preferred_term: Intestinal obstruction
    term:
      id: HP:0005214
      label: Intestinal obstruction
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005214 | Intestinal obstruction | Occasional (29-5%)"
    explanation: Orphanet records intestinal obstruction as an occasional PJS phenotype.
  - 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"
    explanation: GeneReviews links PJS polyps to recurrent obstruction and intussusception.
- name: Intussusception
  category: Gastrointestinal
  frequency: FREQUENT
  description: >
    Pedunculated small-intestinal polyps act as lead points for
    intussusception, with cumulative risk increasing through adulthood.
  phenotype_term:
    preferred_term: Intussusception
    term:
      id: HP:0002576
      label: Intussusception
  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: A large human PJS cohort quantifies high cumulative intussusception risk.
- name: Abdominal pain
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >
    Abdominal pain results from polyp-related obstruction, intussusception, and
    other GI complications.
  phenotype_term:
    preferred_term: Abdominal pain
    term:
      id: HP:0002027
      label: Abdominal pain
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002027 | Abdominal pain | Occasional (29-5%)"
    explanation: Orphanet records abdominal pain as an occasional PJS phenotype.
- name: Gastrointestinal carcinoma
  category: Neoplastic
  frequency: VERY_FREQUENT
  description: >
    PJS carries high risk of GI malignancies, including colorectal, gastric,
    pancreatic, small intestinal, and other epithelial cancers.
  phenotype_term:
    preferred_term: Gastrointestinal carcinoma
    term:
      id: HP:0002672
      label: Gastrointestinal carcinoma
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002672 | Gastrointestinal carcinoma | Very frequent (99-80%)"
    explanation: Orphanet records gastrointestinal carcinoma as very frequent in PJS.
  - 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: GeneReviews summarizes the multi-organ epithelial cancer risk in PJS.
- name: Breast carcinoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: >
    Breast carcinoma is part of the extra-GI malignancy spectrum in women with
    PJS.
  phenotype_term:
    preferred_term: Breast carcinoma
    term:
      id: HP:0003002
      label: Breast carcinoma
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003002 | Breast carcinoma | Occasional (29-5%)"
    explanation: Orphanet records breast carcinoma as an occasional PJS phenotype.
  - 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: A systematic review identifies breast cancer as a major PJS-associated malignancy.
- name: Pancreatic adenocarcinoma
  category: Neoplastic
  frequency: OCCASIONAL
  description: >
    Pancreatic adenocarcinoma is one of the GI and extra-intestinal cancers
    included in PJS surveillance recommendations.
  phenotype_term:
    preferred_term: Pancreatic adenocarcinoma
    term:
      id: HP:0006725
      label: Pancreatic adenocarcinoma
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0006725 | Pancreatic adenocarcinoma | Occasional (29-5%)"
    explanation: Orphanet records pancreatic adenocarcinoma as an occasional PJS phenotype.
  - 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: GeneReviews includes pancreatic cancer in the PJS malignancy spectrum.
- name: Cervix cancer
  category: Neoplastic
  frequency: OCCASIONAL
  description: >
    Females with PJS are at risk for adenoma malignum of the cervix, a rare
    aggressive cervical cancer.
  phenotype_term:
    preferred_term: Adenoma malignum of the cervix
    term:
      id: HP:0030079
      label: Cervix cancer
  phenotype_contexts:
  - sex: FEMALE
    notes: PJS-associated adenoma malignum is a female-specific gynecologic manifestation.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030079 | Cervix cancer | Occasional (29-5%)"
    explanation: Orphanet records cervix cancer as an occasional PJS phenotype.
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
    explanation: GeneReviews identifies adenoma malignum of the cervix as a PJS-associated female-specific neoplasm.
- name: Sex cord tumor with annular tubules
  category: Neoplastic
  description: >
    Females with PJS are at risk for ovarian sex cord tumors with annular
    tubules; HPO lacks a specific SCTAT term, so this is bound to the broader
    ovarian neoplasm term.
  phenotype_term:
    preferred_term: Sex cord tumor with annular tubules
    term:
      id: HP:0100615
      label: Ovarian neoplasm
  phenotype_contexts:
  - sex: FEMALE
    notes: SCTAT is a female-specific ovarian manifestation of PJS.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Females are at risk for sex cord tumors with annular tubules (SCTAT), a benign neoplasm of the ovaries, and adenoma malignum of the cervix, a rare aggressive cancer."
    explanation: GeneReviews directly identifies SCTAT as an ovarian PJS manifestation.
- name: Large calcifying Sertoli cell tumor
  category: Neoplastic
  frequency: OCCASIONAL
  description: >
    Males with PJS can develop estrogen-secreting large calcifying Sertoli cell
    tumors of the testes.
  phenotype_term:
    preferred_term: Large calcifying Sertoli cell tumor
    term:
      id: HP:0010788
      label: Testicular neoplasm
  phenotype_contexts:
  - sex: MALE
    frequency: OCCASIONAL
    notes: Large calcifying Sertoli cell tumor is a male-specific PJS manifestation.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
    explanation: GeneReviews directly identifies large calcifying Sertoli cell tumors as an occasional male PJS manifestation.
- name: Gynecomastia secondary to Sertoli cell tumors
  category: Endocrine
  frequency: OCCASIONAL
  description: >
    Estrogen secretion from PJS-associated Sertoli cell tumors can cause
    gynecomastia in affected males.
  phenotype_term:
    preferred_term: Gynecomastia
    term:
      id: HP:0000771
      label: Gynecomastia
  phenotype_contexts:
  - sex: MALE
    frequency: OCCASIONAL
    notes: Gynecomastia is a consequence of estrogen secretion by Sertoli cell tumors.
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males occasionally develop large calcifying Sertoli cell tumors of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated."
    explanation: GeneReviews links estrogen-secreting Sertoli cell tumors to gynecomastia in males with PJS.
genetic:
- name: STK11 germline pathogenic variants
  gene_term:
    preferred_term: STK11
    term:
      id: hgnc:11389
      label: STK11
  variant_origin: GERMLINE
  relationship_type: CAUSATIVE
  notes: >
    STK11/LKB1 pathogenic variants cause most molecularly confirmed PJS. Tumor
    and polyp progression can involve somatic inactivation of the remaining
    allele. GI hamartomas are reported with essentially complete penetrance,
    often in the second decade of life.
  evidence:
  - reference: ORPHA:2869
    reference_title: "Peutz-Jeghers syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "STK11 | serine/threonine kinase 11 | hgnc:11389 | Disease-causing germline mutation(s) in"
    explanation: Orphanet identifies STK11 germline mutations as disease-causing in PJS.
  - 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: Clinical guidelines support STK11 as the causal gene.
  - 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: "PJS patients develop gastrointestinal hamartomas with 100% penetrance often in the second decade of life"
    explanation: This paper summarizes the near-complete penetrance of GI hamartomas in PJS patients.
  - reference: CGGV:assertion_89685102-ac40-4932-96e7-c2e9e9280858-2023-12-20T180000.000Z
    reference_title: "STK11 / Peutz-Jeghers syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "STK11 | HGNC:11389 | Peutz-Jeghers syndrome | MONDO:0008280 | AD | Definitive"
    explanation: ClinGen classifies the STK11-Peutz-Jeghers syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
treatments:
- name: Endoscopic surveillance and polypectomy
  description: >
    Routine endoscopic surveillance with removal of clinically significant GI
    polyps reduces emergency laparotomy and bowel loss from intussusception.
  treatment_term:
    preferred_term: endoscopic procedure
    term:
      id: NCIT:C16546
      label: Endoscopic Procedure
  evidence:
  - reference: PMID:20301443
    reference_title: "Peutz-Jeghers Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception"
    explanation: GeneReviews supports endoscopic polypectomy as standard complication prevention in PJS.
- name: Extra-Intestinal Cancer Surveillance
  description: >
    Beyond gastrointestinal polyp surveillance, Peutz-Jeghers syndrome confers a
    markedly increased lifetime risk of extraintestinal malignancies (including
    breast, pancreatic, gynecologic — cervical and ovarian sex-cord — and
    testicular cancers). Lifelong multi-organ surveillance of the organs at
    increased cancer risk is therefore a core component of management, distinct
    from endoscopic polyp surveillance.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: PMID:35487765
    reference_title: "Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer."
    explanation: The U.S. Multi-Society Task Force guideline centers PJS management on surveillance of organs at increased cancer risk, alongside polyp complication prevention.
  - reference: PMID:35487765
    reference_title: "Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors."
    explanation: Establishes the elevated risk of both intestinal and extraintestinal tumors that multi-organ surveillance targets.
  - reference: PMID:31764758
    reference_title: "Hereditary Cancer Syndromes and Risk Assessment: ACOG COMMITTEE OPINION, Number 793."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common hereditary cancer syndromes related to women's cancer include hereditary breast and ovarian cancer syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, Peutz-Jeghers syndrome, and hereditary diffuse gastric cancer."
    explanation: ACOG identifies PJS among the hereditary syndromes conferring breast and gynecologic cancer risk that warrant surveillance.
  - reference: PMID:39689429
    reference_title: "Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome."
    explanation: NCCN lists PJS among hereditary syndromes conferring endometrial cancer risk, supporting gynecologic surveillance.
- name: Genetic counseling and cascade testing
  description: >
    Autosomal dominant STK11-associated PJS warrants genetic counseling and
    testing of at-risk relatives.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  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 provides the basis for counseling and cascade testing.
- name: COX-2 inhibitor chemoprevention
  description: >
    COX-2 inhibition with celecoxib is investigational for reducing PJS polyp
    burden, based on COX-2 overexpression in PJS hamartomas and preclinical
    rationale; it is not established standard care.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: celecoxib
      term:
        id: CHEBI:41423
        label: celecoxib
  evidence:
  - reference: clinicaltrials:NCT06722534
    reference_title: "Celecoxib for Prevention of Progression in Peutz-Jeghers Syndrome: A Double-blind, Randomized, Placebo-controlled Trial"
    supports: SUPPORT
    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: The active trial rationale links COX overexpression to possible celecoxib chemoprevention.
  target_mechanisms:
  - target: COX-2 / prostaglandin biosynthetic upregulation
    description: >
      Celecoxib inhibits COX-2 and therefore directly targets the prostaglandin
      biosynthetic mechanism observed in PJS hamartomas.
    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: Human PJS hamartomas overexpress the COX-2 target of celecoxib.
- name: Sirolimus mTOR inhibition
  description: >
    mTOR inhibition is investigational in PJS. Mouse-model data show rapamycin
    suppression of preexisting GI polyps, supporting mechanism-directed
    interest in the LKB1/AMPK/mTORC1 axis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sirolimus
      term:
        id: CHEBI:9168
        label: sirolimus
  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: "rapamycin as a single agent results in a dramatic suppression of preexisting GI polyps in LKB1+/- mice"
    explanation: Mouse-model evidence supports investigational mTOR inhibition for PJS-like polyp burden.
  target_mechanisms:
  - target: mTORC1 pathway hyperactivation
    description: >
      Sirolimus inhibits mTORC1 signaling, the pathway hyperactivated in human
      PJS polyps.
    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: HUMAN_CLINICAL
      snippet: "polyps from human Peutz-Jeghers patients similarly exhibit up-regulated mTORC1 signaling, HIF-1alpha, and GLUT1 levels."
      explanation: Human PJS polyps show the mTORC1 pathway activity targeted by sirolimus.
differential_diagnoses:
- name: Juvenile polyposis syndrome
  description: >
    Another hamartomatous polyposis syndrome, usually caused by SMAD4 or
    BMPR1A variants, but lacking the classic PJS mucocutaneous pigmentation and
    STK11-driven mechanism.
  disease_term:
    preferred_term: juvenile polyposis syndrome
    term:
      id: MONDO:0017380
      label: juvenile polyposis syndrome
  distinguishing_features:
  - Different causal genes, commonly SMAD4 or BMPR1A rather than STK11.
  - Lacks the characteristic mucocutaneous pigmentation pattern of PJS.
  evidence:
  - reference: PMID:36925460
    reference_title: "Hamartomatous polyps: Diagnosis, surveillance, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."
    explanation: This review places juvenile polyposis in the same differential category as PJS.
- name: Cowden syndrome
  description: >
    PTEN hamartoma tumor syndrome can include GI hamartomas and cancer risk but
    has PTEN-driven mucocutaneous findings and a different cancer spectrum.
  disease_term:
    preferred_term: Cowden syndrome
    term:
      id: MONDO:0008021
      label: Cowden syndrome 1
  distinguishing_features:
  - PTEN-related trichilemmomas, papillomatous papules, and thyroid/endometrial risks.
  - Different causal gene and syndrome-specific surveillance pattern.
  evidence:
  - reference: PMID:36925460
    reference_title: "Hamartomatous polyps: Diagnosis, surveillance, and management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS)."
    explanation: This review identifies Cowden syndrome as a major hamartomatous polyposis differential.
references:
- reference: ORPHA:2869
  title: Peutz-Jeghers syndrome
  findings: []
- reference: PMID:20301443
  title: "Peutz-Jeghers Syndrome."
  tags:
  - GeneReviews
  findings: []
review_notes: >-
  This entry curates the syndrome-level disorder ORPHA:2869/MONDO:0008280.
  The pre-existing Peutz_Jeghers_polyp entry covers the defining lesion; shared
  STK11/LKB1 pathway evidence is reused here where it supports the broader PJS
  syndrome.
datasets:
- accession: geo:GSE196711
  title: Immune profiling of premalignant lesions in patients with Peutz-Jeghers Syndrome
  description: RNA sequencing was performed in a total of 26 colorectal tissues from 26 unrelated patients including PJS polyps (n=6), familial adenomatous polyposis (FAP) polyps (n=9), paracancerous colonic mucosae (ConA) (n=9) as well as non-PJS and non-FAP sporadic polyps (ConB) (n=5)
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 29
  publication: PMID:39174496
  notes: Identified by GEO DataSets index search for Peutz-Jeghers syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE251755
  title: Differential gene expression profile of germline STK11 deletion in patient derived fibroblasts
  description: Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant disorder hallmarked by mucocutaneous melanocytic macules and gastrointestinal hamartomatous polyposis associated with germline/somatic pathogenic variants in the tumor suppressor STK11. PJS is clinically heterogeneous, however, the relationship between clinical phenotype and genotype remains elusive. Here, we report a family with variable severity PJS who harbor a heterozygous STK11 whole gene deletion combined with heterozygous variants in PMS2 and TP53AIP1 that segregate with disease severity in the family.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  publication: PMID:40860288
  notes: Identified by GEO DataSets index search for Peutz-Jeghers syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

2
ORPHA:2869
Peutz-Jeghers syndrome
No top-level findings curated for this source.
PMID:20301443
Peutz-Jeghers Syndrome.
No top-level findings curated for this source.

Deep Research

1
Manual Fallback ▸
Peutz-Jeghers Syndrome Research Fallback

Peutz-Jeghers Syndrome Research Fallback

Deep-research provider attempts were made after the ORPHA:2869 direct Orphanet/MONDO target was selected:

  • timeout 120 just research-disorder falcon Peutz_Jeghers_Syndrome
  • timeout 120 just research-disorder openai Peutz_Jeghers_Syndrome

Both commands printed the initial provider line, then stalled without producing a research output file and were terminated by the timeout. The curation therefore used the structured Orphanet cache plus already-fetched PubMed, GeneReviews, and ClinicalTrials.gov cache records as the auditable evidence base.

Literature Scope Checked

  • references_cache/ORPHA_2869.md: direct Orphanet leaf record for Peutz-Jeghers syndrome, including definition, autosomal dominant inheritance, exact MONDO and OMIM mappings, STK11 gene assertion, prevalence, age of onset, and HPO phenotype rows.
  • references_cache/PMID_19916169.md: clinical review supporting autosomal dominant inheritance and prevalence range.
  • references_cache/PMID_20301443.md: GeneReviews record supporting childhood mucocutaneous pigmentation, GI polyp complications, malignancy spectrum, and endoscopic surveillance with polypectomy.
  • references_cache/PMID_37054692.md: clinical guideline supporting germline STK11 pathogenic variants and autosomal dominant inheritance.
  • references_cache/PMID_38660671.md: human PJS polyp evidence for impaired LKB1/AMPK signaling.
  • references_cache/PMID_19541609.md: human PJS and LKB1 mouse-model evidence for mTORC1 hyperactivation and preclinical rapamycin response.
  • references_cache/PMID_18311138.md: mesenchymal LKB1/TGF-beta mechanism, with both mouse-model and human-polyp evidence.
  • references_cache/PMID_12650805.md: human PJS hamartoma evidence for COX-2 overexpression.
  • references_cache/PMID_20051941.md: systematic review of high PJS cancer risk.
  • references_cache/PMID_36970589.md: 566-case human cohort quantifying cumulative intussusception risk.
  • references_cache/clinicaltrials_NCT06722534.md: trial rationale for investigational celecoxib chemoprevention.

Curation Conclusions

  • Disease identity is the syndrome-level disorder ORPHA:2869, exact to MONDO:0008280 and OMIM:175200.
  • The core disease mechanism is germline STK11/LKB1 tumor-suppressor loss with downstream AMPK impairment, mTORC1 activation, stromal TGF-beta signaling defects, COX-2/prostaglandin upregulation, and somatic second-hit-driven malignancy risk.
  • Orphanet directly supports the syndrome phenotype profile, including oral mucosal pigmentation, multiple lentigines, GI hemorrhage, anemia, intestinal obstruction, abdominal pain, GI carcinoma, breast carcinoma, and pancreatic adenocarcinoma.
  • Evidence-backed management includes endoscopic surveillance with polypectomy, genetic counseling/cascade testing, and investigational mechanism-directed pharmacotherapy with COX-2 or mTOR inhibition.