Clinical Diagnosis

The sine qua non of the diagnosis of Peutz-Jeghers syndrome (PJS) is the hamartomatous gastrointestinal polyp characterized histopathologically by the unique finding of mucosa with interdigitating smooth muscle bundles in a characteristic branching tree appearance [Buck et al 1992]. Epithelial misplacement that can occur in PJS small-bowel polyps 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].

A working definition of PJS was suggested by Giardiello et al [1987] and further defined in a recent consensus meeting [Beggs et al 2010]:

In a single individual, a clinical diagnosis of PJS may be made when any ONE of the following is present:

• Two or more histologically confirmed PJ polyps

• Any number of PJ polyps detected in one individual who has a family history of PJS in close relative(s)

• Characteristic mucocutaneous pigmentation in an individual who has a family history of PJS in close relative(s)

• Any number of PJ polyps in an individual who also has characteristic mucocutaneous pigmentation.

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.

Molecular Genetic Testing

Gene. Currently only mutations in STK11 (LKB1) have been identified as a cause for Peutz-Jeghers syndrome (PJS) [Hemminki et al 1998, Jenne et al 1998].

Other loci. 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.

• Although one child with a PJS hamartoma had a translocation of 19q13.4, no mutations in candidate genes mapping to this breakpoint were identified [Hearle et al 2004].

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

Clinical testing

Sequence analysis and deletion/duplication studies. In a study of 56 individuals with a clinical diagnosis of PJS in which a combination of sequence analysis to detect point mutations and multiplex ligation-dependent probe amplification (MLPA) to detect large STK11 deletions was used, STK11 mutation detection rate was 94% [Aretz et al 2005]. In that study,

• 100% of persons with familial PJS had a mutation identified by either sequence analysis or MLPA

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

• None of the samples (0/12) from persons who did not meet diagnostic criteria for PJS had an identifiable mutation.

• One third of samples in which the PJS status was unknown had a mutation detected by sequence analysis.

A wide variety of mutations have been detected including missense, splicing, and small deletions or insertion deletions.

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 about 15% of individuals with PJS. Intragenic homologous recombination has been noted as a mechanism that can lead to deletion of exons 4-7 of STK11. One patient 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].

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

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1, 2		Test Availability
			Positive Family History	Negative Family History
STK11	Sequence analysis	Sequence variants 3	55%	70%	Clinical
	Deletion/duplication analysis 4	Exon(s) and whole-gene deletion	45%	21%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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

2. From Aretz et al [2005]: 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

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

Interpretation of test results

• For issues to consider in interpretation of sequence analysis results, click here.

• 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 genetic testing of anyone with a PJS polyp or typical perioral pigmentation.

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.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

One individual with a nonsense mutation of STK11 was diagnosed with gonadotropin-independent precocious puberty and one with a large insertion was diagnosed with juvenile polyposis coli (see Juvenile Polyposis Syndrome). These findings could reflect clinical heterogeneity or incomplete diagnosis of Peutz-Jeghers syndrome, in which a wide range in the numbers and types of polyps can be seen.

Natural History

Peutz-Jeghers syndrome (PJS) is characterized by the association of gastrointestinal polyposis and mucocutaneous pigmentation. The risk for gastrointestinal and extra-intestinal malignancies is 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, 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, and have also been reported in the renal pelvis, urinary bladder, lungs, and nares [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]. In a 78-year follow up study of the original family reported with PJS, 16 of 22 affected members had undergone 33 laparotomies necessitated by bowel obstruction [Westerman et al 1999]

The age of onset of symptoms from polyps is variable, with some children developing symptoms within the first few years of life. 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]. In a review of 32 kindreds with PJS, laparotomy for bowel obstruction was performed in 30% of individuals by age ten years and in 68% by age 18 years [Hinds et al 2004].

Mucocutaneous pigmentation. Hyperpigmented macules 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.

Histologically, increased melanocytes are observed at the epidermal-dermal junction, with increased melanin in the basal cells.

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. SCTATs in PJS are bilateral, multifocal, small tumors with a typically benign course [Young 2005]. In contrast, in the general population SCTATs are large, unilateral, and associated with a 20% cancer risk.

Males occasionally develop calcifying Sertoli cell tumors of the testes that secrete estrogen and can lead to gynecomastia.

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 of 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. Similar figures were reported in a series of 419 individuals with PJS of whom 297 had documented STK11 mutations [Hearle et al 2006a].

Hearle et al [2006a] found cumulative risks for any cancer to be 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. 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.

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, although data describing the age-specific risks for these cancers are not available. 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. Lim et al [2004] reported that 8% of women with PJS developed breast cancer by age 40 years and 32% by age 60 years; Hearle et al [2006a] found very similar risks.

Females can also present with adenoma malignum of the cervix.

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, Hearle et al 2006a]. 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.

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 surgical gastrointestinal surgeries, a higher polyp count, and an earlier age at first polypectomy than persons with non-truncating mutations.

The risk of 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Peutz-Jeghers syndrome (PJS), the following evaluations are recommended:

• Upper endoscopy plus small bowel examination (MR or CT enterography, wireless capsule endoscopy) beginning at age eight years or when symptoms occur

• Colonoscopy beginning age 18 years

• Women. Gynecologic and breast examinations and (after age 20 years) mammogram

• Men. Testicular examination and testicular ultrasound examination, if clinically indicated

Treatment of Manifestations

Polyps. Routine endoscopic and intraoperative enteroscopy with polypectomy decreases the frequency of emergency laparotomy and bowel loss resulting from intussusception [Pennazio & Rossini 2000, Edwards et al 2003, Oncel et al 2004].

Laparotomy and intraoperative endoscopy are appropriate for removal of polyps larger than 1.5 cm.

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, two 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:

• Wireless capsule endoscopy 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].

• Double-balloon, or "push and pull," enteroscopy can remove distal small-bowel polyps with or without laparotomy [Ohmiya et al 2005, Ross et al 2006, Gao et al 2010].

• Magnetic resonance enterography is a reliable procedure for the detection of small bowel polyps and avoids the radiation exposure of CT enterography [Caspari et al 2004, Gupta et al 2010].

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 hysterectomy and bilateral salpingo-oophrectomy to prevent gynecologic malignancy in women after age 35 years or after child-bearing has been completed should be considered. In other high-risk disorders, such as 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.

Agents/Circumstances to Avoid

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

Testing 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 with STK11 haploinsufficiency. 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 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, although two studies are being conducted: an open-label Phase II clinical trial of everolimus (a derivative of rapamycin) at the University of Utah (clinicaltrials.gov) and an open-label study by the University of Amsterdam for treatment of malignancies in patients with Peutz-Jeghers syndrome (clinicaltrialsfeeds.org).

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

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• About 50% of probands have an affected parent and about 50% 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 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

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. Testing of at-risk asymptomatic adults for Peutz-Jeghers syndrome is available after 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 STK11 mutation.

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 during childhood. Testing of at-risk individuals during childhood for Peutz-Jeghers syndrome is available after 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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must be identified in the family before prenatal testing can be performed.

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 such as Peutz-Jeghers syndrome that 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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 normal structure 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 [HGMD, 8-23-2010]. 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.

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 kinase-deficient mutants predominantly display nuclear immunostaining, suggesting aberrant signal transduction for such mutants. 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 to lead to 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].

Published Guidelines/Consensus Statements

1. American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. Available at jco.ascopubs.org. 2003. Accessed 10-28-10.

Literature Cited

1. Alhopuro P, Phichith D, Tuupanen S, Sammalkorpi H, Nybondas M, Saharinen J, Robinson JP, Yang Z, Chen LQ, Orntoft T, Mecklin JP, Järvinen H, Eng C, Moeslein G, Shibata D, Houlston RS, Lucassen A, Tomlinson IP, Launonen V, Ristimäki A, Arango D, Karhu A, Sweeney HL, Aaltonen LA. Unregulated smooth-muscle myosin in human intestinal neoplasia. Proc Natl Acad Sci U S A. 2008;105(14):5513–8. [PMC free article: PMC2291082] [PubMed: 18391202]
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Suggested Reading

1. Alhopuro P, Parker AR, Lehtonen R, Enholm S, Järvinen HJ, Mecklin JP, Karhu A, Eshleman JR, Aaltonen LA. A novel functionally deficient MYH variant in individuals with colorectal adenomatous polyposis. Hum Mutat. 2005;26:393. [PubMed: 16134146]
2. McGarrity TJ, Amos C. Less common colorectal cancer predisposition syndromes. Surg Oncol Clin N Am. 2009;18(4):647–61. [PubMed: 19793572]
3. 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(1):97–107. [PubMed: 19727776]

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

• 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