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Peutz-Jeghers Syndrome

Synonym: PJS

, MD, , PhD, and , PhD.

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Initial Posting: ; Last Update: July 14, 2016.

Estimated reading time: 33 minutes


Clinical characteristics.

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by the association of gastrointestinal polyposis, mucocutaneous pigmentation, and cancer predisposition. Peutz-Jeghers-type hamartomatous polyps are most common in the small intestine (in order of prevalence: in the jejunum, ileum, and duodenum) but can also occur in the stomach, large bowel, and extraintestinal sites including the renal pelvis, bronchus, gall bladder, nasal passages, urinary bladder, and ureters. Gastrointestinal polyps can result in chronic bleeding and anemia and also cause recurrent obstruction and intussusception requiring repeated laparotomy and bowel resection. 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. Hyperpigmented macules on the fingers are common. The macules may fade in puberty and adulthood. Individuals with Peutz-Jeghers syndrome are at increased risk for a wide variety of epithelial malignancies (colorectal, gastric, pancreatic, breast, and ovarian cancers). 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. Males occasionally develop large calcifying Sertoli cell tumors (LCST) of the testes, which secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated.


The diagnosis of Peutz-Jeghers syndrome is based on clinical findings. Identification of a heterozygous pathogenic variant in STK11 by molecular genetic testing confirms the diagnosis and allows for family studies.


Treatment of manifestations: Routine endoscopic surveillance with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception. Diagnosis and management of small-bowel polyps is challenging. New advances in small-bowel imaging include video capsule endoscopy, CT enterography, and MR enterography. Balloon-assisted enteroscopy allows for removal of deep small-bowel polyps. Occasionally intraoperative enteroscopy and enterotomy is needed for removal of large distal small-bowel polyps. Intussusception and malignancies should be treated in the standard manner.

Prevention of primary manifestations: Although not specifically studied in individuals with PJS, the following could be considered based on family history or other clinical factors: prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophorectomy after age 35 years or after child bearing has been completed to prevent gynecologic malignancy.

Surveillance: Protocols have been suggested for monitoring stomach, small and large bowel, breasts, testicles, ovaries, uterus, and pancreas by various procedures as early as birth and as frequently as once a year.

Evaluation of relatives at risk: If the pathogenic variant in the family is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and prevention of disease through appropriate surveillance and consideration of prophylactic measures in affected family members. If the family variant is not known, offer clinical diagnostic evaluations to all at-risk family members, who will benefit from early treatment and appropriate surveillance.

Genetic counseling.

Peutz-Jeghers syndrome is inherited in an autosomal dominant manner. However, approximately 45% of affected individuals have no family history of PJS; the exact proportion of cases caused by a de novo pathogenic variant is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. The risk to the offspring of an individual with a pathogenic STK11 variant is 50%. Once the STK11 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.


Suggestive Findings

Peutz-Jeghers syndrome (PJS) should be suspected in individuals with the following:

  • Two or more PJS-type intestinal polyps
  • Mucocutaneous macules
  • Gynecomastia in males as a result of estrogen-producing Sertoli cell testicular tumors
  • History of intussusception, especially in a child or young adult

PJS-type intestinal polyps. The sine qua non of PJS diagnosis is the hamartomatous gastrointestinal polyp, which is histopathologically characterized by distinctive interdigitating smooth muscle bundles in a characteristic arborizing (branching tree) appearance throughout the lamina propria, particularly of small bowel polyps, and lobular organization, particularly of colonic crypts. Pseudo invasion of misplaced crypts is an innate property of the PJS hamartoma, which may reflect the role of STK11 in cell polarity [Tse et al 2013].

Note: Individuals with PJS also develop many other polyps; polyps showing adenomatous changes frequently arise in the colon and may cause confusion with familial adenomatous polyposis. The histology of gastric PJS polyps can be similar to gastric hyperplastic polyps, thus highlighting the importance of a gastrointestinal pathologist in reviewing polyp histology.

Establishing the Diagnosis

The diagnosis of PJS is established in a proband with one of the following, based on a European consensus statement [Beggs et al 2010]:

  • Two or more histologically confirmed PJS-type hamartomatous polyps
  • Any number of PJS-type polyps detected in one individual who has a family history of PJS in at least one close relative
  • Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in at least one close relative
  • Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation

Identification of a heterozygous pathogenic variant in STK11 by molecular genetic testing (see Table 1) also establishes the diagnosis based on diagnostic criteria from the Mayo Clinic [Riegert-Johnson et al 2008].

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of STK11 is performed first and followed by gene-targeted deletion/duplication analysis. Sequence analysis and gene-targeted deletion/duplication analysis of STK11 may also be performed concurrently to reduce turnaround time.
  • A multigene panel that includes STK11 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes STK11) fails to confirm a diagnosis in an individual with features of PJS. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Peutz-Jeghers Syndrome

Gene 1Proportion of Peutz-Jeghers Syndrome Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 2 Detectable by Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
STK1194%-96% 5~81% 6~15% 7
Unknown 8NA

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


In a large Dutch study, 73 (96%) of 76 individuals with PJS had an STK11 pathogenic variant [van Lier et al 2010]. In another study 65 (94%) of 69 individuals with PJS had an STK11 pathogenic variant, including 20 (87%) of 23 familial cases and 45 (97.8%) of 46 sporadic cases [Resta et al 2013].


Includes larger deletions, such as whole-gene deletions of STK11 and smaller intragenic deletions [Le Meur et al 2004, De Rosa et al 2010, Borun et al 2015].


Of 25 individuals who had PJS but did not have a detectable STK11 pathogenic variant, one had a heterozygous pathogenic variant of the DNA repair enzyme MUTYH that was not observed in 1015 controls [Alhopuro et al 2008]. Of note, pathogenic variants in MUTYH ordinarily cause an autosomal recessive form of adenomatous polyposis coli.

Clinical Characteristics

Clinical Description

Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. The risk for gastrointestinal and extraintestinal malignancies is significantly increased. Distinct benign and malignant gonadal and gynecologic tumors can also be seen. Variable expressivity is common; for example, some affected individuals in families with PJS may have only polyps or perioral pigmentation.

Gastrointestinal polyposis. Peutz-Jeghers-type hamartomatous polyps can occur anywhere in the GI tract, but occur most commonly in the small intestine. The density of polyps is greatest in the jejunum, followed by the ileum, then the duodenum. Polyps can occur elsewhere in the GI tract, including the stomach and large bowel. Polyps have also been reported in the renal pelvis, urinary bladder, ureters, lungs, nares, and gallbladder.

Adenomas also appear with increased prevalence throughout the gastrointestinal tract.

The malignant potential of Peutz-Jeghers-type hamartomatous polyps is unknown; however, the polyps can cause significant complications including bowel obstruction, rectal prolapse, and/or severe gastrointestinal bleeding with secondary anemia requiring multiple emergency laparotomies and bowel resections. The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. In one series, 68% of affected individuals had undergone emergency laparotomy by age 18 years. By age ten years, 30% of individuals with PJS had undergone a laparotomy [Hinds et al 2004]. One small single-center retrospective study of 15 individuals concluded that endoscopic management of small-bowel polyps in PJS using double-balloon endoscopy decreased the occurrence of urgent laparotomy by decreasing the mean number of resected polyps larger than 20 mm with each procedure [Sakamoto et al 2011].

Significant interfamilial variability in the age at which polyps first appear is observed, suggesting that the natural history of polyps in a family may be a predictor of severity for offspring. In studies from MD Anderson Cancer Center, the median age at which GI symptoms first appeared was ten years, while the median age at first polypectomy was 13 years [Amos et al 2004]. These data have prompted an earlier start date for surveillance procedures to detect and remove gastrointestinal polyps to decrease malignancy and complications of bowel obstruction [van Lier et al 2010, Latchford et al 2011].

Mucocutaneous pigmentation. Melanocytic macules (MM) are rarely present at birth; they become pronounced in most children before the fifth year, but then may fade in puberty and adulthood. Children often present with dark blue to dark brown mucocutaneous macules around the mouth, eyes, and nostrils, in the perianal area, and on the buccal mucosa. Hyperpigmented macules on the fingers are also common. In one series, 94% of individuals with PJS had perianal MM, 73% had MM that affected the digits, 65% had MM on the buccal mucosa, and 21% had MM at other sites [Utsunomiya et al 1975].

Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells. No malignancy risk is associated with MM.

Gonadal tumors. Females with PJS are at risk for ovarian sex cord tumors with annular tubules (SCTATs) and mucinous tumors of the ovaries and fallopian tubes. Symptoms include irregular or heavy menstrual periods and, occasionally, precocious puberty due to hyperestrogenism. SCTATs in PJS are bilateral multifocal small tumors with focal calcification and a typically benign course [Young 2005]. In contrast, sporadic SCTATs are large, unilateral, and associated with a 20% risk of malignancy.

In an Italian series of 61 females with PJS, three had ovarian cancer, one was a malignant SCTAT [Resta et al 2013]. In a Dutch series of 69 females with PJS, 2 females had malignant Sertoli cell ovarian tumors and one had ovarian small cell cancer [van Lier et al 2010].

Males occasionally develop large cell calcifying Sertoli cell tumors (LCST) of the testes derived from sperm cord cells. These tumors may secrete estrogen and can lead to gynecomastia, advanced skeletal age, and ultimately short stature, if untreated. Multifocal calcifications are typically seen on testicular ultrasound. Malignant transformation is unusual. Aromatase inhibitors help reverse the hormonal effects of Sertoli cell tumors including reduction of gynecomastia and slowing of linear bone growth and bone age [Crocker et al 2014]. In a series including 64 males with PJS, one testicular seminoma was reported [van Lier et al 2010].

Malignancy. Individuals with PJS are at increased risk for intestinal and extraintestinal malignancies.

Table 2.

Cumulative Risk of Cancers in Peutz-Jeghers Syndrome

Cancer SiteGeneral Population RiskPeutz-Jeghers Syndrome
RiskMean Age at Diagnosis
Colorectal5%39%42-46 years
Stomach<1%29%30-40 years
Small Bowel<1%13%37-42 years
Breast12.4%32%-54%37-59 years
Ovarian (mostly SCTAT)1.6%21%28 years
Cervix (adenoma malignum)<1%10%34-40 years
Uterus2.7%9%43 years
Pancreas1.5%11%-36%41-52 years
Testicular (Sertoli cell tumor)<1%9%6-9 years
Lung6.9%7%-17%47 years

Adapted from Syngal et al [2015]

SCTAT = sex-cord tumor with annular tubules

Colorectal and gastric cancers can arise from adenomas that are commonly found in individuals with PJS. A marked increase in cancer incidence after age 50 years is notable.

Breast cancer and ovarian cancers can occur at early ages in Peutz-Jeghers syndrome. The breast cancer risk in women with PJS may approach that of women who have a pathogenic variant in BRCA1 or BRCA2. Some families with PJS report relatives with early-onset breast cancer, suggesting that some family members with a pathogenic variant may on occasion develop breast or other cancers without having symptoms from the hamartomatous polyps.

Cervical cancer. Adenoma malignum is a rare well-differentiated adenocarcinoma of the uterine cervix. Presenting symptoms include bleeding or a mucoid, watery vaginal discharge. Histologic diagnosis can be difficult on small pathologic samples. The five-year survival after surgery is 60% [Tsuda et al 2005].

Genotype-Phenotype Correlations

Data on genotype-phenotype correlation related to STK11 pathogenic variants are conflicting. Further analysis of pooled registry data is needed to better characterize genotype-phenotype correlations and confirm malignancy risks.

In a study of 297 individuals with PJS, the type or site of the STK11 pathogenic variant did not influence cancer risk [Lim et al 2004]. Initial reports that pathogenic variants in exon 3 [Lim et al 2004] or exon 6 [Mehenni et al 2007] were associated with an increased cancer risk have not been replicated by subsequent studies. A review of 419 affected individuals found that the variant type and site within the functional domains of the expressed protein did not affect cancer risk [Hearle et al 2006a].

In contrast, Amos et al [2004] found that individuals who had pathogenic STK11 variants that predicted premature truncation and those who tested negative for pathogenic variants had similar ages of onset for first-reported polyps or polypectomy, and those with missense variants had later onset for these symptoms. Salloch et al [2010] similarly found that persons with pathogenic STK11 variants that predicted premature truncation had more gastrointestinal surgeries, a higher polyp count, an earlier age of first polypectomy, and a greater risk of melanoma than persons with other pathogenic variants.

The risk for small-bowel intussusception was not influenced by STK11 variant status [Hearle et al 2006b].

Pathogenic variants affecting protein kinase domain XI correlated with a 90% (9/10) incidence of GI polyp dysplasia compared to an 11.8% (2/17) incidence of polyp dysplasia in individuals with pathogenic variants affecting other regions of the protein [Wang et al 2014].


To date all reported individuals with pathogenic variants in STK11 have shown clinical manifestations.


The following terms have also been used for PJS:

  • Polyp and spots syndrome
  • Inherited hamartomatous polyps in association with mucocutaneous melanocyte macules
  • Hutchinson Weber-Peutz syndrome
  • Perioral lentiginosis (sometimes used inappropriately as a synonym for PJS)


Birth prevalence has not been reliably established; estimates range widely from 1:25,000 to 1:280,000 [Tchekmedyian et al 2013].

PJS can occur in any racial or ethnic group.

Differential Diagnosis

Table 3 summarizes the differential diagnosis of Peutz-Jeghers syndrome (PJS).

Juvenile polyposis syndrome (JPS) is characterized by a predisposition to multiple hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp, not the age of onset of polyps. Juvenile polyps are hamartomas that show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria. Most individuals with JPS have some polyps by age 20 years. The number of polyps is highly variable. Most are benign. The risk of developing GI cancers in families with JPS ranges from 9% to 50%. Although most of this increased risk is attributed to colon cancer, cancers of the stomach, upper GI tract, and pancreas have been reported. JPS is distinguished from PJS by the lack of melanotic macules and the histology of polyps. Approximately 20% of individuals with JPS have pathogenic variants in SMAD4; about 20% have pathogenic variants in BMPR1A. JPS is inherited in an autosomal dominant manner.

Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228). A family history of JPS is found in 20%-50% of individuals with hereditary mixed polyposis syndrome. HMPS is an autosomal dominant condition with variable penetrance consisting of multiple types of colorectal polyps including juvenile and adenomatous polyps. Affected individuals are at increased risk for colorectal cancer. HMPS can be caused either by mutation of BMPR1A or by a duplication of 15q15.3q22.1 that leads to increased expression of GREM1 [Jaeger et al 2012]. Some families with mixed hereditary polyposis syndrome have SMAD4 pathogenic variants.

PTEN hamartoma tumor syndrome (PHTS), an autosomal dominant cancer syndrome caused by mutation of PTEN, includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, and a Proteus-like syndrome. The extraintestinal manifestations are more pronounced than intestinal polyposis. The features of Cowden syndrome that distinguish it from PJS include facial trichilemmomas, mucosal papillomas, acral keratoses, macrocephaly, and tumors of the thyroid, breast, and endometrium. The distinguishing features of Bannayan-Riley-Ruvalcaba syndrome include macrocephaly, intestinal polyposis, and lipomas. Proteus-like syndrome is undefined but refers to individuals with significant clinical features of Proteus syndrome who do not meet the diagnostic criteria for Proteus syndrome.

Unexplained hamartomatous mixed polyposis. In a study of 49 unrelated persons with unexplained hamartomatous mixed polyposis, Sweet et al [2005] determined that 22% had various germline pathogenic variants.

  • Of 14 individuals with juvenile-type polyposis: two had pathogenic variants in ENG (encoding endoglin), a gene associated with hereditary hemorrhagic telangiectasia; one had a hemizygous deletion encompassing PTEN and BMPR1A; and one had a SMAD4 pathogenic variant.
  • Of 23 individuals with hyperplastic/mixed polyposis, two had PTEN pathogenic variants.
  • Of nine individuals with an unknown hamartomatous polyposis, pathogenic variants were seen in STK11 (4), BMPR1A (2), and SMAD4 (1).

Carney complex is an autosomal dominant disorder characterized by skin pigmentary abnormalities; myxomas, endocrine tumors or overactivity, and schwannomas. Pale brown to black lentigines are the most common presenting feature of Carney complex and typically increase in number at puberty. Cardiac myxomas occur at a young age, may occur in any or all cardiac chambers, and manifest as intracardiac obstruction of blood flow, embolic phenomena, and/or heart failure. Other sites for myxomas include the skin, breast, oropharynx, and female genital tract. Primary pigmented nodular adrenocortical disease, which causes Cushing syndrome, is the most frequently observed endocrine tumor, occurring in approximately 25% of affected individuals. Large-cell calcifying Sertoli cell tumors are observed in one third of affected males within the first decade and in almost all adult males. Up to 75% of individuals have multiple thyroid nodules, most of which are thyroid follicular adenomas. Clinically evident acromegaly from a growth hormone (GH)-producing adenoma is evident in approximately 10% of adults. Psammomatous melanotic schwannoma, a rare tumor of the nerve sheath, occurs in an estimated 10% of affected individuals. Despite some clinical overlap between Carney complex and Peutz-Jeghers syndrome, no individuals with Carney complex have been found to have pathogenic variants in STK11. About 60% of individuals have pathogenic variants in PRKAR1A.

Table 3.

Hereditary Cancer Syndromes Showing Signs and Symptoms that Overlap with PJS

SyndromeGene(s)PigmentationGI TumorsSertoli Cell TumorsCancersOther
PJSSTK11Facial++ Mucosal+++Adenoma+
+/–Colon, gastric, cervical, ovarian, breast, pancreatic, lungHyper-estrogenism
ColonHeart defects?
CSPTENAxillary+ Inguinal+ Facial+Adenoma+
Breast, thyroid, endometriumTrichilemmoma, skin hamartoma, hyperplastic polyps, macrocephaly, breast fibrosis
CCPRKAR1AFacial+ Mucosal+++ThyroidMyxomas of skin & heart
FAPAPCAdenoma+++Colon, brainDesmoid tumors, osteomas, CHRPE
Adenoma+Endometrial, gastric, renal pelvis & ureter, ovarianSebaceous adenoma

= presence of sign/symptom (# of +s indicates relative frequency of sign/symptom for the condition); ± = an occasional or rare sign/symptom; ? = anecdotal association; CC = Carney complex; CHRPE = congenital hypertrophy of the retinal pigment epithelium; CS = Cowden syndrome; FAP = familial adenomatous polyposis; HNPCC = hereditary non-polyposis colorectal cancer; JPS = juvenile polyposis syndrome

The differential diagnosis of oral pigmented lesions includes the following:

  • The Laugier-Hunziker syndrome is characterized by the presence of perioral, digit and nailbed lentiginosis (small, well-demarcated; dark-brown to blue-black in color). It occurs in 1:8,300 to 1:29,000 births. This condition usually develops in adults and the hyperpigmentation is progressive. Laugier-Hunziker syndrome has not been associated with any known exposure and has not been reported to occur in families [Wang et al 2012].
  • A fixed drug reaction
  • A normal variant, especially in African Americans [Bishop et al 2004]

The differential diagnosis of some of the rare tumors observed in PJS includes:

  • Sex cord tumors with annular tubules (SCTAT); 50% are associated with Peutz-Jeghers syndrome; the remainder may occur as an isolated finding.
  • Calcifying Sertoli tumors of the testes and adenoma malignum of the cervix in women; these may also occur as an isolated finding or in other disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease and need for clinical follow up in an individual diagnosed with Peutz-Jeghers syndrome (PJS), the following initial evaluations are recommended:

  • Upper endoscopy plus small bowel examination (MR enterography or wireless capsule endoscopy) beginning at age eight years or when symptoms occur
  • Colonoscopy beginning at age eight years
  • In women, gynecologic and breast examinations and (after age 18 years) MRI
  • In men, testicular examination and testicular ultrasound examination, if clinically indicated
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Polyps. Once the burden of gastrointestinal polyps has been established by endoscopy and imaging studies, prophylactic polypectomy of polyps >1cm is performed. This strategy has two goals:

  • To decrease the sequelae of large polyps including bleeding, anemia, obstruction, and intussusception
  • To reduce the risk for cancer by the malignant transformation of PJS-type polyps

The luminal polyp-related complications arise in childhood whereas cancer in PJS is typically seen in adulthood. Some evidence indicates that routine endoscopy and intraoperative enteroscopy with polypectomy decreases the frequency of emerging laparotomy and bowel loss [Pennazio & Rossini 2000, Edwards et al 2003, Oncel et al 2004]. From St. Mark’s PJS registry of 51 affected individuals who underwent surveillance endoscopies, none had emergency surgical interventions and no GI luminal cancers were diagnosed [Latchford et al 2011]. In surveillance endoscopies in affected individuals by age 18 years, 17/28 had large gastroduodenal or colonic polyps (>1 cm). These studies demonstrate that endoscopic surveillance and polypectomy in PJS is safe.

Distal small-bowel polyps that are beyond the reach of conventional endoscopy have been difficult to manage. Until recently, barium contrast upper-gastrointestinal series with a small-bowel follow through has been recommended. However, recent advances allow better diagnosis and eradication of small-bowel polyps, oftentimes without laparotomy and with a decrease in the radiation burden related to frequent surveillance:

  • Video capsule endoscopy (VCE) allows for better visualization of the small-bowel polyps than barium x-rays and is recommended as a first-line surveillance procedure. In children, the capsule can be deployed in the duodenum after upper endoscopy [Parsi & Burke 2004, Burke et al 2005, Mata et al 2005, Schulmann et al 2005]. See Note.
  • Magnetic resonance enterography (MRE) is a reliable procedure for the detection of larger small-bowel polyps with similar sensitivity to VCE and avoids the radiation exposure of CT enterography [Caspari et al 2004, Gupta et al 2010]. CT and MR enteroclysis are alternative procedures but are less well tolerated. See Note.
  • Balloon-assisted enteroscopy can remove distal small-bowel polyps with or without laparotomy [Ohmiya et al 2005, Ross et al 2006, Gao et al 2010]. Safety in those with PJS has been demonstrated in a few studies. Balloon-assisted enteroscopy and polypectomy should decrease the need for intraoperative enteroscopy or enterotomy, and should be reserved for affected individuals with many large and distal small-bowel polyps.

Note: (1) VCE was preferred by individuals and detected more large polyps than MRE [Urquhart et al 2014]. (2) In three individuals in a study by Gupta et al [2010], MRE detected polyps >15 mm that were not detected by VCE.

Intussusception should be treated in a standard manner.

Malignancies should be treated in a standard manner. Conservative management of gonadal tumors in males and females is appropriate.

Prevention of Primary Manifestations

Although not specifically studied in PJS, prophylactic mastectomy may be considered to manage the increased risk for breast cancer based on the family history or other clinical factors. Prophylactic hysterectomy and bilateral salpingo-oophorectomy to prevent gynecologic malignancy in women may be considered. In some disorders with a high risk for malignancy (e.g., HNPCC), evidence supports this strategy [Schmeler et al 2006].


The surveillance program for the multiple organs at risk for cancer is outlined in Table 4. Note: The effect of such surveillance on morbidity and mortality has not been evaluated in controlled trials.

From birth, an annual history and physical examination with attention to testicular examination and routine blood work is recommended. A boy age 13 years with PJS was recently described as developing an unusually early presentation of small-bowel adenocarcinoma, thus supporting screening in childhood as illustrated in Table 4 [Wangler et al 2013].

Table 4.

Screening and Surveillance Guidelines for Peutz-Jeghers Syndrome

SiteProcedureAge at Initial Screening (yrs)Interval
StomachUpper endoscopy8, 18 13 yrs 1
Small intestineCapsule endoscopy or MRE 28, 18 33 yrs
Large intestineColonoscopy8, 18 13 yrs 1
BreastBreast self-examination181x/mo
Clinical breast exam6 mos
Breast MRI or digital mammography 4, 5, 6251 yr
Ovary, cervix, uterusTransvaginal ultrasound & serum CA 125;
pelvic exam w/pap smear 6
18-201 yr
PancreasMRI-MRCP or endoscopic ultrasound301-2 yrs
TestesTesticular exam; ultrasound if symptomatic or abnormality on examBirth to teen yrs1 yr

Adapted from Syngal et al [2015]

MRCP = magnetic resonance cholangiopancreatography; MRE = magnetic resonance enterography


If significant polyps are present at baseline, repeat upper endoscopy/colonoscopy every three years. If no significant polyps are present at baseline, repeat at age 18 years and then every three years.


CT enterography may be used as an alternative. The use of MR enterography allows for simultaneous surveillance for pancreatic cancer.


If few or no polyps at baseline, repeat at age 18 years.


Digital mammography if MRI not available


Discuss prophylactic mastectomy.


Discuss prophylactic hysterectomy and oophorectomy.

Agents/Circumstances to Avoid

No agents that increase the risk for polyp development or for cancers have been described.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

If the pathogenic variant in the family is known, it is appropriate to offer molecular genetic testing for the known pathogenic or likely pathogenic variant to at-risk relatives. Morbidity and mortality can be reduced in those individuals identified to have the family-specific variant by means of:

  • Early diagnosis and treatment;
  • Surveillance as outlined in Surveillance.

If the pathogenic variant in the family is not known, it is appropriate to offer:

  • Clinical diagnostic evaluations to identify those family members who will benefit from early treatment;
  • Surveillance as outlined in Surveillance to all first-degree relatives whether or not they meet diagnostic criteria.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


Several animal models of PJS have been generated using STK11 knockout mice [Karuman et al 2001, Bardeesy et al 2002, Miyoshi et al 2002, Nakau et al 2002, Wei et al 2005]. Gastrointestinal hamartomatous polyposis in STK11+/– mice mimics human PJS polyps with the unique smooth muscle arborization. In these animal models, upregulation of cyclooxygenase-2 (COX-2) in polyp tissue was noted [Rossi et al 2002]. Overexpression of COX-2 in human PJS hamartomas and PJS-associated cancers has also been detected [McGarrity et al 2003, Wei et al 2003]. COX-2 inhibition in mice using celecoxib suppresses polyp growth [Udd et al 2004]. Polyp burden in STK11 (Lkb1) heterozygous (+/–) knockout mice was reduced by 86% among mice who had developed polyps and were then treated with 1500-ppm celecoxib.

Selective COX-2 inhibitors have been approved for the prevention of colorectal polyps in familial adenomatous polyposis [Lynch 2010]; to date, however, no clinical trials in the US are studying efficacy of COX-2 inhibitors in reducing polyp formation in individuals with PJS. Increased cardiovascular and cerebrovascular adverse events with selective COX-2 inhibitors limit their use.

Observation of hyperactivation of mTOR in hereditary harmartoma syndrome and a variety of cancers suggests that mTOR inhibitors may be useful in the management of PJS [van Veelen et al 2011]. Wei et al [2008] and Wei et al [2009] reported significant reduction in tumor burden in STK11+/– mice treated with rapamycin compared with that in mice without rapamycin treatment. Treatment begun before the onset of polyposis resulted in more dramatic reduction than treatment begun after onset. In another study in STK11+/– mice oral rapamycin intake was associated with a significant reduction in microvessel growth in polyps as well as in tumor burden [Robinson et al 2009].

In addition, in two small trials in persons with tuberous sclerosis complex, treatment with rapamycin induced regression of the astrocytomas [Franz et al 2006] and reduced facial angiofibroma [Hofbauer et al 2008]. Whether rapamycin would decrease polyp growth in PJS has not been documented in human studies. The mTOR inhibitor, everolimus, caused partial regression of a pancreatic cancer in an individual with PJS. Induction of apoptosis in colon polyps was also noted [Klümpen et al 2011].

These findings suggest that mTOR inhibitors are an option to investigate for management of polyposis in PJS.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Peutz-Jeghers syndrome (PJS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • In large series, 60%-78% of individuals with PJS had affected relatives and 17%-40% of individuals represented isolated cases within their families [Lim et al 2004, van Lier et al 2010, Resta et al 2013].
  • Of the cases in which there was a single occurrence in a family, many appear to be caused by a de novo pathogenic variant in STK11. The exact proportion of cases caused by a de novo pathogenic variant is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient.
  • Recommendations for the evaluation of parents of a proband with PJS and no known family history of PJS include:
    • Molecular genetic testing if an STK11 pathogenic variant has been identified in the proband;
    • Examination of the buccal mucosa and skin of the digits and genital area for hyperpigmented macules; upper and lower gastrointestinal endoscopy; mammography; bimanual pelvic examination and ovarian ultrasound examination (females); and testicular examination (males).
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include germline mosaicism in a parent [Hernan et al 2004] or a de novo somatic/germline pathogenic variant in the proband.
    Somatic mosaicism was reported in four of 300 individuals analyzed using Sanger sequencing and MLPA. Two individuals were mosaic for single-nucleotide variants and two were mosaic for partial deletions. None of these individuals had a family history of PJS; however, the daughter of one of these individuals had clinical features of PJS and was found to have the deletion (in a non-mosaic form) identified in her father [McKay et al 2016].
  • The family history of some individuals diagnosed with PJS may appear to be negative because of failure to recognize the disorder in family members or early death of the parent (and other relatives) before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the STK11 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. See Parents of a proband.

Offspring of a proband

  • Each child of an individual with PJS and an identified STK11 pathogenic variant has a 50% chance of inheriting the STK11 variant. Children of rare individuals who are mosaic for STK11 variants would be at risk of inheriting an STK11 pathogenic variant.
  • The risk to the offspring of a proband with a negative family history and no identified STK11 pathogenic variant is unknown.

Other family members. The risk to other family members depends on the status of the proband's first-degree relatives: if a relative is affected and is heterozygous for a STK11 pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Genetic heterogeneity. PJS findings occurring in individuals who do not have a family history of PJS may be caused by mutation of genes other than STK11 and be inherited in a different manner from STK11-related PJS. See Differential Diagnosis.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – Health Professional Version (part of PDQ®, National Cancer Institute).

Testing of at-risk asymptomatic family members. If an STK11 pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk family members to determine the need for continued clinical surveillance is appropriate (see Evaluation of Relatives at Risk).

Testing of at-risk individuals younger than age 18 years for Peutz-Jeghers syndrome is possible once the STK11 pathogenic variant has been identified in an affected family member. Because early detection of at-risk individuals who have an STK11 pathogenic variant affects medical management – particularly surveillance (see Table 3) – testing of at-risk individuals during childhood is beneficial [American Society of Clinical Oncology 2003]. Such testing may also provide some insight concerning age of onset for disease, as individuals with missense variants of STK11 had a later onset than individuals with truncating variants [Amos et al 2004]; however, the age of onset distribution is highly variable among individuals.

Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures in a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and their children.

Other issues to consider. It is recommended that physicians ordering PJS molecular genetic testing and individuals considering undergoing testing understand the risks, benefits, and limitations of the testing prior to sending a sample to a laboratory. Referral to a genetic counselor and/or a center in which testing is routinely offered is recommended.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the STK11 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for PJS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Collaborative Group of the Americas on Inherited Gastrointestinal Cancer (CGA-IGC)
  • Hereditary Colon Cancer Takes Guts
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
  • Prospective Registry of MultiPlex Testing (PROMPT)
    PROMPT is an online research registry for patients and their families that helps researchers answer the question: “How do genetic variants affect your cancer risk?”

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Peutz-Jeghers Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
STK1119p13​.3Serine/threonine-protein kinase STK11STK11 databaseSTK11STK11

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Peutz-Jeghers Syndrome (View All in OMIM)


Molecular Pathogenesis

Dysregulation of mTOR may be a common molecular pathway for hamartoma syndromes [Inoki et al 2005]. Tuberous sclerosis complex, an autosomal dominant disorder with multiple hamartomas noted in the skin, brain, kidneys, and heart, results from mutation of either TSC1 or TSC2 [Northrup & Krueger 2013]. STK11 acts as a suppressor by activating TSC2 through an AMP-dependent protein kinase [Corradetti & Guan 2006] leading to accumulation of mTOR, which is critical for protein translation. PTEN also effects TSC2 and mTOR pathway via AKT (AKT1), a potent pro-survival protein.

Gene structure. The gene structure (NM_000455.4) includes ten exons, nine of which are translated. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 300 STK11 pathogenic variants have been reported in persons with Peutz-Jeghers syndrome. All types of variants have been reported, from missense variants to whole-gene deletion. (see Table A, Locus Specific and HGMD).

Intragenic homologous recombination has been noted as a mechanism that can lead to deletion of exons 4-7 of STK11 [Ankala et al 2012].

It was also noted that recombination among Alu elements is a frequent cause of deletions of exons 2 and 3 [Borun et al 2015].

Normal gene product. This serine/threonine-protein kinase has a prenylation motif suggesting involvement in protein-protein interactions and membrane binding [Collins et al 2000]. The predicted protein structure also shows an autophosphorylation domain, along with a cyclic AMP-dependent protein kinase phosphorylation site. STK11 is expressed ubiquitously in fetal and adult tissue and plays a role in regulatory cellular proliferation and apoptosis. In addition STK11 cell polarity plays an important role in metabolism and energy homeostasis [Beggs et al 2010]. STK11 expression was shown to cause apoptosis in epithelial cells [Marignani 2005]. The transport of STK11 to the mitochondria appears to be an early step in apoptosis. STK11 colocalizes with p53 during apoptosis and the ability of STK11 to induce apoptosis also depends on p53. These results suggest that signaling through STK11 may be an early event leading to apoptosis through p53 pathways. Tiainen et al [2002] showed that STK11 affects G1 cell cycle arrest and that growth suppression by STK11 is mediated through signaling of cytoplasmic STK11. Inhibition of cellular proliferation by STK11 may occur through induction of WAF1, a cyclin-dependent kinase inhibition [Tiainen et al 2002, Spicer et al 2003]. By forming a complex with STRAD and MO25, STK11 was reported to phosphorylate AMPK and several other members of the AMPK-related subfamily of kinases including the microtubule affinity-regulating kinases (MARKs) to regulate cell polarity [Tanwar et al 2012]. Pathogenic variants in the C-terminal non-catalytic region decreased mediation of AMP-activated kinase and cell polarity. AMPK is an evolutionally conserved Ser/Thr kinase that functions as a key regulator of cellular energy metabolism [Herrmann et al 2011]. Through activation of AMPK by phosphorylation, STK11 plays a role in energy metabolism [Udd & Mäkelä 2011]. In summary, STK11 is a multi-tasking tumor suppressor that has a role in apoptosis, cell cycle arrest, cell proliferation, cell polarity, and energy metabolism.

Abnormal gene product. Nezu et al [1999] suggest that truncating variants resulting in deletion of amino acids 1-310 abrogate the kinase activity of STK11. Tiainen et al [2002] demonstrated that expression of mutated STK11 in kinase-deficient cultured cells predominantly displayed nuclear immunostaining, suggesting aberrant signal transduction. Mehenni et al [1998] discussed the potential impact that several missense variants may have on the protein structure. Hemminki et al [1998] found that nonsense variants predicted a truncated protein and loss of kinase activity in all 23 familial cases and two simplex cases (i.e., single occurrence in a family) studied. More recently, a few individuals with PJS with pathogenic variants in the C-terminal non-catalytic region have been identified [Forcet et al 2005].

Cancer and Benign Tumors

Non-small cell lung cancer. Sporadic pathogenic variants in STK11 are observed in one third of non-small cell lung cancers; STK11 is the third most commonly mutated gene, following p53 and K-RAS [Ji et al 2007, Sanchez-Cespedes 2007]. A substantial percentage of STK11 alterations in non-small cell lung carcinomas are large intragenic deletions, single-nucleotide variants, and small insertions and deletions (indels) [Sanchez-Cespedes 2007].

Demographically, STK11 variants in lung tumors appear to be frequent in male smokers of northern European background, and are associated with poorly differentiated tumors [Zhong et al 2006, Onozato et al 2007]. In addition, STK11 pathogenic variants are more frequently observed in association with concomitant activating K-RAS pathogenic variants. Such digenic variants have been associated with a poorer prognosis compared to a K-RAS pathogenic variant alone [Pécuchet et al 2017]. The high prevalence of STK11 pathogenic variants in non-small cell lung cancers suggests that cigarette smoking could be particularly harmful for individuals with pathogenic variants in STK11. The presence of STK11 pathogenic variants in these types of cancers may indicate a more aggressive tumor that has a poorer prognosis and is seen more often in younger individuals and smokers [Pécuchet et al 2017]

Cervical cancer. Sporadic pathogenic variants in STK11 are observed in at least 20% of cervical cancer [Wingo et al 2009]. Among the variants observed in tumors, half are single-nucleotide variants or small indels, and the other half are large-fragment deletions in either one allele or both alleles. STK11 inactivation in primary cervical tumors has been associated with accelerated disease progression. These results suggest that STK11 is a major cervical tumor suppressor for sporadic cancers.


Published Guidelines / Consensus Statements

  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. [PubMed: 12692171]
  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 7-3-19.

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Chapter Notes

Author Notes

Dr Amos holds a grant from the American Cancer Society investigating the molecular genetics of Peutz-Jeghers syndrome. Dr McGarrity is a gastroenterologist who partially specializes in the diagnosis and treatment of Peutz-Jeghers syndrome. Dr Baker is a genetic counselor and medical geneticist who specializes in the recognition of hereditary cancer predisposition syndromes.

Author History

Christopher I Amos, PhD (2001-present)
Maria J Baker, PhD (2016-present)
Marsha L Frazier, PhD; University of Texas MD Anderson Cancer Center (2001-2016)
Thomas J McGarrity, MD (2001-present)
Chongjuan Wei, PhD; University of Texas MD Anderson Cancer Center (2001-2016)

Revision History

  • 14 July 2016 (sw) Comprehensive update posted live
  • 25 July 2013 (me) Comprehensive update posted live
  • 22 February 2011 (me) Comprehensive update posted live
  • 2 November 2010 (me) Comprehensive update posted live
  • 15 May 2007 (me) Comprehensive update posted live
  • 19 May 2004 (ca) Revision: Genetic Counseling
  • 26 November 2003 (me) Comprehensive update posted live
  • 23 February 2001 (me) Review posted live
  • 11 July 2000 (ca) Original submission
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