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Peutz-Jeghers Syndrome

Synonym: PJS

, MD, , PhD, , PhD, and , PhD.

Author Information
, MD
Department of Medicine
Milton S Hershey Medical Center
Hershey, Pennsylvania
, PhD
Center for Genomic Medicine
Department of Community and Family Medicine
Geisel School of Medicine
Dartmouth College
Lebanon, New Hampshire
, PhD
Department of Epidemiology
University of Texas MD Anderson Cancer Center
Houston, Texas
, PhD
Department of Epidemiology
University of Texas MD Anderson Cancer Center
Houston, Texas

Initial Posting: ; Last Update: July 25, 2013.

Summary

Disease 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.

Diagnosis/testing. The diagnosis of Peutz-Jeghers syndrome is based on clinical findings. In individuals with a clinical diagnosis of PJS, molecular genetic testing of STK11 (LKB1) reveals disease-causing mutations in 80%-94% of affected individuals.

Management. 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 studied in individuals with PJS, the following could be considered: 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 family mutation is known, offer molecular genetic testing to at-risk relatives so that morbidity and mortality can be reduced by early diagnosis and appropriate surveillance; if the family mutation is not known, offer clinical diagnostic evaluations to identify those 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 de novo gene mutations 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 mutation is 50%. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known.

Diagnosis

Clinical Diagnosis

The diagnosis of Peutz-Jeghers syndrome (PJS) is based on the constellation of family history, mucocutaneous macules, PJS-type intestinal polyps, and presence of a disease-causing mutation in STK11.

PJS-type intestinal polyps. The sine qua non of PJS diagnosis is the hamartomatous gastrointestinal polyp histopathologically characterized by the following:

  • Interdigitating smooth muscle bundles in a characteristic arborizing (branching tree) appearance throughout the polyp [Buck et al 1992]
  • Epithelial misplacement that appears as "pseudocarcinomatous" invasion, i.e., benign polyp epithelium surrounded by smooth muscle bundles that extend into the submucosa, muscularis propria, and even the bowel wall [Petersen et al 2000]
  • Absence of pseudo-invasion in gastric or colorectal polyps

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.

Clinical diagnostic criteria. Based on a European consensus statement [Beggs et al 2010], a clinical diagnosis of PJS may be made when any one of the following is present:

  • 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 a close relative(s)
  • Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in a close relative(s)
  • Any number of PJS-type polyps in an individual who also has characteristic mucocutaneous pigmentation

Note: Diagnostic criteria from the Mayo Clinic also include the finding of a pathogenic mutation in STK11 [Riegert-Johnson et al 2008].

Molecular Genetic Testing

Gene. Currently only mutations in STK11 (previously known as LKB1) have been identified as causative of Peutz-Jeghers syndrome (PJS) [Hemminki et al 1998, Jenne et al 1998].

Evidence for locus heterogeneity. The observations of Olschwang et al [2001] suggest that in addition to STK11, another genetic locus may predispose to the clinical features of PJS, but no other locus has been clearly described to date.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Peutz-Jeghers Syndrome

Gene Symbol 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3, 4
Family History
PositiveNegative
STK11Sequence analysis / mutation scanning 5Sequence variants 655% 770% 7
Deletion/duplication analysis 8(Multi)exonic and whole-gene deletions45% 921% 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. 100% of persons with familial PJS had detectable mutation; 91% of simplex cases (i.e., a single occurrence in a family) who met full diagnostic criteria had a detectable mutation [Aretz et al 2005].

5. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

6. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

7. In a study of 56 individuals with a clinical diagnosis of PJS tested by sequence and deletion/duplication analysis of STK11, the mutation detection rate was 94% [Aretz et al 2005]. In that study:

 • 100% of persons with familial PJS had a mutation identified;

 • 91% of persons who met diagnostic criteria but had no family history of PJS (i.e., simplex cases) had an identifiable mutation.

Additionally, one third of samples in which the PJS status was unknown had a mutation detected by sequence analysis.

8. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

9. Larger deletions including whole-gene deletion of STK11 [Le Meur et al 2004] or smaller intragenic deletions [De Rosa et al 2010] can be detected in approximately 15% of individuals with PJS (see Molecular Genetics).

Interpretation of test results

  • Of the mutations in STK11 that have been detected, 65% affect the protein structure and are likely to abrogate protein function. The significance of missense mutations identified in 35% of individuals/families is more difficult to interpret; the existence of a deduced protein structure [UniProt, Mehenni et al 1998] may facilitate the evaluation of their significance.
  • Clinical misdiagnoses of PJS could account for a decreased mutation detection rate, particularly in simplex cases (i.e., a single occurrence in a family).

Testing Strategy

To confirm/establish the diagnosis in a proband. Burt & Neklason [2005] recommend molecular genetic testing of anyone with a PJS polyp or typical perioral pigmentation:

  • Single gene testing. One strategy for molecular diagnosis of a proband suspected of having PJS is sequence and deletion/duplication analysis of STK11.
  • Multi-gene panel. Another strategy for molecular diagnosis of a proband suspected of having PJS is use of a multi-gene panel.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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 [Sommerhaug & Mason 1970, Murday & Slack 1989, Giardiello & Trimbath 2006].

Adenomas also appear with increased prevalence throughout the gastrointestinal tract.

Although benign, Peutz-Jeghers-type hamartomatous 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 [Buck et al 1992]. The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. In a 78-year follow-up study of the original family reported with PJS, 16 of 22 affected members had undergone 33 laparotomies due to bowel obstruction [Westerman et al 1999]. In another series, 68% of affected individuals had undergone laparotomy by age 18 years and 70% had emergency surgery. By age ten years, 30% of individuals with PJS had had a laparotomy [Hinds et al 2004].

Significant interfamilial variability is observed in the age at which polyps are first 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]. In a report from Korea the mean age of onset of GI symptoms was 12.5 years [Choi et al 2000].

Mucocutaneous pigmentation. Melanotic 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 melanotic macules, 73% had melanotic macules that affected the digits, 65% had melanotic macules on the buccal mucosa and 21% had melanotic macules at other sites [Utsunomiya et al 1975].

Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells. There is no malignancy risk 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% cancer risk.

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.

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

Boardman et al [1998] found that individuals with PJS had a 9.9-fold increased relative risk for cancer; relative risks (RR) were highest for gastrointestinal cancer (RR=151) and breast cancer (RR=20.3). The age of onset for many PJS-associated cancers was very young.

Choi et al [2000] found a similar relative risk of 11.1 overall for cancer among individuals with PJS and also noted that this increased risk results from higher risks for cancer among young individuals compared with the low risks in the general population. However, the natural history of cancer development in families and its correlation to offspring is unclear.

Lim et al [2003] found that 37% of individuals with PJS developed cancer by age 65 years, yielding a relative risk of 9.9 for all cancers. In 240 individuals with PJS with STK11 mutations, the risk for cancer at age 20 years, 40 years, 60 years, and 70 years was 1%, 19%, 63%, and 81% respectively [Lim et al 2004]. No gender difference in cancer risk was noted. Similarly in a series of 419 individuals with PJS, of whom 297 had documented STK11 mutations [Hearle et al 2006a], the cumulative risk for any cancer was reported as 17% by age 40 years, 31% by age 50 years, 60% by age 60 years, and 85% by age 70 years.

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. Hearle et al [2006a] estimated the lifetime risk for all gastrointestinal cancers to be 15% by age 50 years and 57% by age 70 years. In a systematic review of 1,644 affected individuals with PJS, colorectal cancer was the most common malignancy, with a mean age at diagnosis of 43 years [van Lier et al 2010].

The risk for pancreatic cancer is greatly increased over the population risk [Giardiello et al 1987]. Hearle et al [2006a] estimated the lifetime risk of pancreatic cancer to be 5% by age 50 years and 17% by age 70 years.

Breast cancer and ovarian cancers can occur at early ages in Peutz-Jeghers syndrome. The breast cancer risk in women with PJS approaches that of women who have a pathogenic mutation in BRCA1 or BRCA2. Some families with PJS report relatives with early-onset breast cancer, suggesting that some family members with a disease-causing mutation may on occasion develop breast or other cancers without having symptoms from the hamartomatous polyps. In the study by Hearle et al [2006a] breast cancer risk was 15% at age 50 years, 33% at age 60 years, and 57% by age 70 years. In the van Lier et al [2010] study, breast cancer was the second most common cancer with a mean age at diagnosis of 44 years. Lim et al [2004] reported that 8% of women with PJS developed breast cancer by age 40 years and 32% by age 60 years.

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

Genotype-phenotype information related to STK11 mutations is lacking. 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 mutation did not influence cancer risk [Lim et al 2004]. Initial reports that mutations in exon 3 [Lim et al 2004] or exon 6 [Mehenni et al 2007] associate with increased cancer risk have not been replicated by subsequent studies. However, in a review of 416 affected individuals a non-significant trend for increased cancer risk with truncating mutations was noted.

In contrast, Amos et al [2004] found that individuals who had truncating mutations in STK11 or tested negative for mutations had similar ages of onset for first-reported polyps or polypectomy and those with missense mutations had later onset for these symptoms. Salloch et al [2010] similarly found that persons with truncating mutations had more gastrointestinal surgeries, a higher polyp count, and an earlier age at first polypectomy than persons with non-truncating mutations. The risk for small-bowel intussusception was not influenced by STK11 mutation status [Hearle et al 2006b].

Penetrance

See Natural History for discussion of age at which specific aspects of PJS are manifest.

There are no reports of individuals with mutations in STK11 who do not show a clinical manifestation. Of 212 independent mutations that have been reported, one mutation was associated with precocious gonadotropin-resistant puberty and another with juvenile polyposis syndrome.

Anticipation

Anticipation is not observed.

Nomenclature

The term Peutz-Jeghers syndrome was introduced by Bruwer et al [1954].

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

Prevalence

Birth prevalence has not been reliably established; estimates range widely from 1:25,000 to 1:280,000.

PJS can occur in any racial or ethnic group.

Differential Diagnosis

Table 2 summarizes the differential diagnosis of Peutz-Jeghers syndrome (PJS).

One individual with a clinical diagnosis of PJS who did not have mutation in STK11 was found to be heterozygous for a mutation of the DNA repair gene MUTYH [Alhopuro et al 2008]. See MUTYH-Associated Polyposis.

Juvenile polyposis syndrome (JPS) is characterized by predisposition for 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 lentigines and the histology of polyps. Approximately 20% of individuals with JPS have mutations in SMAD4 (previously called MADH4); about 20% have mutations in BMPR1A. JPS is inherited in an autosomal dominant manner.

Hereditary mixed polyposis syndrome (HMPS). 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 have an increased risk for colorectal cancer. HMPS can be caused either by mutations in 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 mutations.

PTEN hamartoma tumor syndrome (PHTS), an autosomal dominant cancer syndrome caused by mutations in PTEN, includes Cowden syndrome, Bannayan-Riley-Ruvalcaba 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 mutations.

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

Carney complex (also known as NAME or LAMB syndrome) is an autosomal dominant disorder characterized by skin pigmentary abnormalities; myxomas of the skin, heart, and breast; endocrine tumors/overactivity; and schwannomas. Pale brown to black lentigines are the most common presenting feature of Carney complex and typically increase in number at puberty. The endocrine tumors that develop include primary pigmented nodular adrenocortical disease (PPNAD) (which may cause Cushing syndrome), growth hormone-producing pituitary adenomas, large-cell calcifying Sertoli cell tumors (LCCSCT), thyroid adenoma or carcinoma (papillary or follicular), and multiple thyroid nodules. PJS-type polyps do not occur in Carney complex. Despite some clinical overlap between Carney complex and Peutz-Jeghers syndrome, no individuals with Carney complex have been found to have mutations in STK11. About 60% of individuals have mutations in PRKAR1A. Families with Carney complex have been linked to 2p16 as well.

Table 2. Syndromes Showing Signs and Symptoms that Overlap with PJS

SyndromeGene Symbol PigmentationGI Tumors Sertoli Cell Tumors CancersOther
PJSSTK11 Facial++ Mucosal+++Adenoma+
Hamartoma+++
+/-Colon, gastric, cervical, ovarian, breast, pancreatic, lungHyper-estrogenism
JPS SMAD4 -Adenoma+
Hamartoma+++
-ColonHeart defects?
Cowden syndrome PTEN Axillary+ Inguinal+ Facial+Adenoma+
Hamartoma+++
-Breast, brainTrichilemmoma, skin hamartoma, hyperplastic polyps, macrocephaly, breast fibrosis
Carney complex PRKAR1A Facial+ Mucosal+-++ThyroidMyxomas of skin and heart
FAP APC -Adenoma+++-Colon, brainDesmoid tumors, osteomas, CHRPE
HNPCC MLH1, MSH2, MSH3, MSH6, PMS1, PMS2 Adenoma+-Endometrial, gastric, renal pelvis and ureter, ovarianSebaceous adenoma

+ indicates presence of sign/symptom with number of +'s indicating relative frequency of sign/symptom for the condition

+/- indicates an occasional or rare sign/symptom

? indicates anecdotal association

JPS = juvenile polyposis syndrome

FAP = familial adenomatous polyposis

CHRPE = congenital hypertrophy of the retinal pigment epithelium

HNPCC = hereditary non-polyposis colorectal cancer

The differential diagnosis of oral pigmented lesions includes the following:

  • The Laugier-Hunziker syndrome; the presence of perioral lentiginosis (small, well-demarcated; dark-brown to blue-black in color); it occurs in 1:8,300 to 1:29,000 births. The term perioral lentiginosis is sometimes used inappropriately as a synonym for PJS.
  • 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 age eight years
  • Medical genetics consultation
  • Women. Gynecologic and breast examinations and (after age 18 years) MRI
  • Men. Testicular examination and testicular ultrasound examination, if clinically indicated

Treatment of Manifestations

Polyps. Once the burden of gastrointestinal polyps has been established by endoscopy and imaging studies, prophylactic polypectomy of larger polyps 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 typically cancer in PJS is seen in adulthood. There is some evidence to support 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].
  • Magnetic resonance enterography 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.
  • 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, which should be reserved for affected individuals with many large and distal small-bowel polyps.

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 studied in PJS, prophylactic mastectomy to manage high risk for breast cancer and prophylactic hysterectomy and bilateral salpingo-oophrectomy to prevent gynecologic malignancy in women after age 35 years or after child bearing could be considered. In other disorders with a high risk for malignancy (e.g., HNPCC), evidence supports this strategy [Schmeler et al 2006].

Surveillance

The surveillance program for the multiple organs at risk for cancer is outlined in Table 3. 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.

Table 3. Screening and Surveillance Guidelines for Peutz-Jeghers Syndrome

SiteProcedureAge at Initial Screening (yrs)Interval (yrs)
StomachUpper endoscopy 183
Small intestineCapsule endoscopy or MR enterography 283
Large intestineColonoscopy 1, 483
BreastBreast self-examination18Monthly
MRI 5, 625 61
OvaryTransvaginal ultrasound and serum CA 125 7181
Cervix and uterusPelvic exam with pap smear 7181
PancreasMRI-MRCP or endoscopic ultrasound and CA 19-9251-2
TestesTesticular exam; ultrasound if symptomatic or abnormality on examBirth1

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

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

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

4. After age 50 years increase frequency of colonoscopy to every 1-2 years.

5. Mammography if MR not available

6. Discuss prophylactic mastectomy.

7. 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

Family mutation known. If the disease-causing mutation has been identified, it is appropriate to offer molecular genetic testing to at-risk relatives. Morbidity and mortality can be reduced in those individuals identified to have the family-specific mutation by means of:

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

Family mutation not known. If the disease-causing mutation 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 ClinicalTrials.gov 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.

Other

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 developed in Stk11+/- mice which mimic 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 1500ppm 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 PJS hamartomas suggests that mTOR inhibitors may be useful in the management of PJS [Shaw et al 2004]. 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 the onset. In another study in Stk11+/– mice oral rapamycin intake showed 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

  • About 55% of probands have an affected parent and about 45% appear to be simplex cases (i.e., PJS in a single family member).
  • Of the simplex cases (i.e., a single occurrence in a family), many appear to be caused by de novo mutations in STK11. The exact proportion of cases caused by de novo gene mutations is unknown as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. It is appropriate to evaluate the parents of a proband clinically, and with molecular genetic testing if a disease-causing STK11 mutation has been identified in the proband.
  • Recommendations for the evaluation of parents of a proband with Peutz-Jeghers syndrome and no known family history of PJS include: 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).

Note: Family history 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. In addition, the cause of Peutz-Jeghers syndrome in families with only one affected member may be heterogeneous, so that some cases may not be the result of autosomal dominant inheritance of a disease susceptibility locus.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If one parent is affected, the risk to sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of the either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband [Hernan et al 2004]. No instances of germline mosaicism have yet been reported.

Offspring of a proband

  • Every child of an individual with Peutz-Jeghers syndrome with a positive family history and/or a mutation identified in STK11 has a 50% chance of inheriting the mutation.
  • The risk to the offspring of a proband with a negative family history and no identified STK11 mutation is unknown. Since the cause of Peutz-Jeghers syndrome in one family member only could be heterogeneous, risk assessment for offspring of individuals without an identified STK11 mutation is difficult.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, 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 occurring in individuals who do not have a family history of PJS may be caused by mutations in genes other than STK11 and could have been inherited differently from STK11-related PJS. See Differential Diagnosis.

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

Testing of at-risk asymptomatic adults for PJS is possible once the disease-causing STK11 mutation has been identified in an affected family member. Such testing may provide some insight concerning age of onset, as Amos et al [2004] found that onset was later in individuals with missense mutations than in those with protein-truncating mutations. However, only six different missense mutations were present in individuals in the Amos et al [2004] study; therefore, there may be heterogeneity in presentation of disease, depending on the effect of the missense mutation on the STK11 protein structure or function. Lim et al [2003] showed higher risks for cancer among individuals with PJS who have a mutation in STK11.

Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. At-risk asymptomatic adult family members may seek molecular genetic testing in order to make personal decisions regarding medical surveillance, reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of Peutz-Jeghers syndrome, and the possible impact of positive and negative test results are discussed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow up and evaluations.

Testing of at-risk individuals younger than age 18 years for Peutz-Jeghers syndrome is possible once the disease-causing STK11 mutation has been identified in an affected family member.

Because early detection of at-risk individuals who have an STK11 mutation 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 mutations of STK11 had a later onset than individuals with truncating mutations [Amos et al 2004]; however, the age of onset distribution is highly variable among individuals.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal diagnosis for conditions which (like Peutz-Jeghers syndrome) do not affect intellect and have some treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

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.

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

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
STK1119p13​.3Serine/threonine-protein kinase 11STK11 homepage - Mendelian genesSTK11

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

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

175200PEUTZ-JEGHERS SYNDROME; PJS
602216SERINE/THREONINE PROTEIN KINASE 11; STK11

Molecular Genetic 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 mutations in either TSC1 or TSC2 [Cheadle et al 2000]. 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.

Normal allelic variants. The gene structure (NM_000455.4) includes ten exons, of which nine are translated.

Pathologic allelic variants. The Human Gene Mutation Database for STK11 reported 212 unique mutations, of which 66 were point mutations (missense or nonsense), 26 were splicing, 53 were small deletions, 32 were small insertions, seven were small indels, 22 were large deletions, three were large insertions, and three were complex rearrangements (see Table A, HGMD). Of these reported variants, 205 were in persons with Peutz-Jeghers syndrome, five were in individuals with a presumed but not confirmed diagnosis of Peutz-Jeghers syndrome, one individual with a nonsense mutation was diagnosed with gonadotropin-independent precocious puberty (see Genetically Related Disorders), and one with a large insertion was diagnosed with juvenile polyposis syndrome.

Intragenic homologous recombination has been noted as a mechanism that can lead to deletion of exons 4-7 of STK11. One individual with both Peutz-Jeghers syndrome and schizophrenia was found to have a large deletion encompassing exons 2-7 and part of exon 8 [Kam et al 2006].

Normal gene product. This serine/threonine-protein kinase has a prenylation motif suggesting that it is involved in protein-protein interactions and membrane binding [Collins et al 2000]. The predicted protein structure also shows an autophosphorylation domain [Mehenni et al 1998], along with a cyclic AMP-dependent protein kinase phosphorylation site. STK11 expression was shown to cause apoptosis in epithelial cells [Karuman et al 2001]. The transport of STK11 to the mitochondria appears to be an early step in apoptosis. STK11 co-localizes 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 [Lizcano et al 2004]. Mutations in the C-terminal non-catalytic region decreased mediation of AMP-activated kinase and cell polarity [Boudeau et al 2003, Spicer & Ashworth 2004, Forcet et al 2005]. AMPK is an evolutionally conserved Ser/Thr kinase that functions as a key regulator of cellular energy metabolism [Kahn et al 2005, Sanders et al 2007]. Through activation of AMPK by phosphorylation, LKB1 plays a role in energy metabolism [Hawley et al 2003]. In summary, LKB1 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 mutations resulting in deletion of amino acids 1-310 abrogate the kinase activity of STK11. Tiainen et al [2002] demonstrated that expression of mutant 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 mutations may have on the protein structure. Hemminki et al [1998] found nonsense mutations 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 mutations in the C-terminal non-catalytic region have been identified [Forcet et al 2005].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available online. 2003. Accessed 9-17-13.

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Suggested Reading

  1. Gaude H, Aznar N, Delay A, Bres A, Buchet-Poyau K, Caillat C, Vigouroux A, Rogon C, Woods A, Vanacker JM, Höhfeld J, Perret C, Meyer P, Billaud M, Forcet C. Molecular chaperone complexes with antagonizing activities regulate stability and activity of the tumpr suppressor LKB1. Oncogene. 2012;31:1582–91. [PubMed: 21860411]
  2. Korsse SE, Harnick F, van Lier MGF, Biermann K, Offerhaus GJA, Krak N, Looman CWN, van Veelan W, Kuipers EJ, Wagner A, Dekker E, Mathus-Vliegen EMH, Fockens P, van Leerdam ME, Bruno M. Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance. J Med Genet. 2013;50:59–64. [PubMed: 23240097]
  3. Reigert-Johnson D, Roberts M, Gleeson FC, Krishna M, Boardman L. Case studies in the diagnosis and management of Peutz-Jeghers syndrome. Fam Cancer. 2011;10:463–8. [PubMed: 21503748]
  4. Salloch H, Reinacher-Schick A, Schulmann K, Pox C, Willert J, Tannapfel A, Heringlake S, Goecke TO, Aretz S, Stemmler S, Schmiegel W. Truncating mutations in Peutz-Jeghers syndrome are associated with more polyps, surgical interventions and cancers. Int J Colorectal Dis. 2010;25:97–107. [PubMed: 19727776]
  5. Tanwar PS, Kaneko-Taruil T, Zhang L, Teixeira JM. Altered LKB1/AMPK/TSC1/TSC2/mTOR signaling causes disruption of Sertoli cell polarity and spermatogenesis. Hum Mol Genet. 2012;21:4394–405. [PMC free article: PMC3459463] [PubMed: 22791749]
  6. Udd L, Mäkelä TP. LKB1 signaling in advancing cell differentiation. Fam Cancer. 2011;10:425–35. [PubMed: 21519908]
  7. van Lier MG, Mathus-Vliegen EM, Wagner A, van Leerdam ME, Kuipers EJ. High cumulative risk of intussusceptions in patients with Peutz-Jeghers syndrome: Time to update surveillance guidelines? Am J Gastroenterol. 2011;106:940–45. [PubMed: 21157440]

Chapter Notes

Author Notes

Drs. Amos and Frazier hold 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.

Revision History

  • 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 to live Web site
  • 19 May 2004 (ca) Revision: Genetic Counseling
  • 26 November 2003 (me) Comprehensive update posted to live Web site
  • 23 February 2001 (me) Review posted to live Web site
  • 11 July 2000 (ca) Original submission
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