Peutz-Jeghers syndrome is an autosomal dominant disorder characterized by melanocytic macules of the lips, buccal mucosa, and digits; multiple gastrointestinal hamartomatous polyps; and an increased risk of various neoplasms.
In the syndrome named for Peutz (1921) and Jeghers (Jeghers et al., 1949), polyps may occur in any part of the gastrointestinal tract but jejunal polyps are a consistent feature. Intussusception and bleeding are the usual symptoms. Melanin ... In the syndrome named for Peutz (1921) and Jeghers (Jeghers et al., 1949), polyps may occur in any part of the gastrointestinal tract but jejunal polyps are a consistent feature. Intussusception and bleeding are the usual symptoms. Melanin spots of the lips, buccal mucosa, and digits represent the second part of the syndrome. Malignant degeneration of the small intestinal polyps is rare. Metastases from a malignant polyp in Peutz-Jeghers syndrome was reported by Williams and Knudsen (1965). Dodds et al. (1972) found 15 cases of gastrointestinal carcinoma in Peutz-Jeghers syndrome: 5 in colon, 4 in duodenum, 4 in stomach, 1 in ileum, and 1 in both jejunum and stomach. In the family reported by Farmer et al. (1963), the father had only polyps, the son apparently only pigmentation, and the daughter both polyps and pigmentation. Kieselstein et al. (1969), who found polycystic kidney disease in the same family, also noted a dissociation of signs. Brigg et al. (1976) observed a case of presumed Peutz-Jeghers syndrome without spots or positive family history. Hamartomatous polyps were limited to the jejunum and caused bleeding. Griffith and Bisset (1980) reported 3 cases. In 2 of them, the family history was negative; in the third, the father and a paternal uncle had melanin spots of the lips but no history of intestinal disorder. Sommerhaug and Mason (1970) added the ureter to the sites of polyps described in the Peutz-Jeghers syndrome. Previously described extraintestinal sites include esophagus, bladder, renal pelvis, bronchus and nose. Burdick and Prior (1982) reported nonresectable adenocarcinoma of the jejunum arising in a Peutz-Jeghers polyp and accompanied by metastases in mesenteric lymph nodes. Two developed breast carcinoma of which 1 arose in a fibroadenoma. Three had benign ovarian tumors, 1 had a benign breast tumor and 1 had a benign colloid thyroid nodule. One of the cases (case 7) reported by Jeghers et al. (1949) died of pancreatic cancer. Bowlby (1986) reported pancreatic cancer in an adolescent boy with PJS. Affected females are prone to develop ovarian tumor, especially granulosa cell tumor (Christian et al., 1964). Wilson et al. (1986) described gynecomastia and multifocal and bilateral testicular tumors in a 6-year-old boy with PJS. The testicular tumors appear to be of Sertoli cell origin and most are calcifying. Two previously reported cases were found. Coen et al. (1991) reported the case of a 4-year-old boy with Peutz-Jeghers syndrome and bilateral sex-cord testicular tumors resulting in gynecomastia. Studies led to the conclusion that increase in aromatase activity (107910) in the gonadal tumors was responsible for estrogen excess and gynecomastia. Three other reported male patients with Peutz-Jeghers syndrome and gonadal tumors had presented with gynecomastia between birth and 6 years of age. They pointed out that multifocal sex-cord tumors were found in palpably normal testes. The occurrence of ovarian tumors far exceeds that of testicular tumors in this disorder. The production of estrogen by ovarian tumors is indicated by the reported appearance of isosexual precocity in girls with PJS (Solh et al., 1983). Young et al. (1995) reported 2 boys, aged 3.5 and 5.5 years, who were evaluated for gynecomastia and found to have multicentric Sertoli cell testicular tumors responsible for their feminization. Both had rapid growth and advanced bone age, and serum levels of estradiol were markedly elevated. Bergada et al. (2000) described a 7-year-old boy with Peutz-Jeghers syndrome, gynecomastia, and bilateral neoplastic Sertoli cell proliferation in whom the only abnormal hormonal profile was increased concentration of inhibin-beta (see 147290), which was biologically active, and pro-alpha C of insulin, which was biologically inactive. In a patient with both psoriasis and Peutz-Jeghers syndrome (sine polyps), Banse-Kupin and Douglass (1986) described a peculiar phenomenon: the development of characteristic pigmented macules within preexisting psoriatic plaques in sites highly unusual for PJS, e.g., on the elbow, back of the neck and occipital scalp, buttocks, and legs. Sommerhaug and Mason (1970) suggested that patients with PJS develop polyps in areas of frequent trauma. Banse-Kupin and Douglass (1986) proposed that pigmented macules may likewise be located in areas of frequent trauma or areas of inflammation. Inflammation may induce blockage of pigment transfer from melanocyte to keratinocyte, resulting in a macule. As the inflammation or trauma subsides, so may the blockage and the lesion may fade. Histologically, the oral mucosal lesions resemble lentigo simplex, but the acral lesions are distinctive (Yamada et al., 1981). There is an increased number of melanocytes with long dendrites filled with melanosomes but few melanosomes in keratocytes, suggesting a pigment block. Giardiello et al. (1987) investigated the occurrence of cancer in 31 patients with PJS followed from 1973 to 1985. Gastrointestinal carcinoma developed in 4, nongastrointestinal carcinoma in 10, and multiple myeloma in 1. Adenomatous polyps of the stomach and colon occurred in 3 other patients. There were 4 cases of pancreatic cancer. Foley et al. (1988) provided a 49-year follow-up of the 'Harrisburg family,' 3 affected members of which were reported by Jeghers et al. (1949). The family had also been studied earlier by Bartholomew et al. (1962). In all, 12 affected members have been identified, making this the largest PJS kindred reported. One member of the family had developed a duodenal carcinoma and a hamartoma with adenomatous changes. Another member developed short bowel syndrome. In the follow-up of 72 patients with PJS in the St. Mark's Polyposis Registry, Spigelman et al. (1989) found that malignant tumors had developed in 16 (22%), of whom all but 1 had died. There were 9 gastrointestinal and 7 nongastrointestinal tumors. The chance of dying of cancer by age 57 was 48%. Westerman and Wilson (1999) reviewed the literature on PJS, with particular emphasis on the risks for PJS gene carriers. The risks imposed by polyps included surgical emergencies like small bowel intussusception, and chronic or acute bleeding from the polyps. Many reports, however, suggested an association of PJS with both gastrointestinal and nongastrointestinal malignancies, often at a young age. The frequent occurrence of rare tumors of the ovary, cervix, and testis indicated a general susceptibility for the development of malignancies. The PJS gene was therefore thought to act as a tumor suppressor gene. The authors suggested that a surveillance protocol should be developed for the prevention of cancer in PJS. Unusually early age of onset was observed by Fernandez Seara et al. (1995) in a 15-day-old girl who was found to have generalized gastrointestinal polyposis manifested by abdominal distention, hematemesis, bloody diarrhea, and edema. At 15 days of age, ileocecal intussusception causing intestinal obstruction was diagnosed radiologically and reduced by hydrostatic enema; ileocecal surgical resection was required, however. Rectal prolapse due to a large polyp occurred at one month of age. Esophagogastroscopy showed polyps in the stomach; one in the antrum partially obstructed the lumen. No hyperpigmentation of the lips or oral mucosa was observed at any time and none was present in her relatives. The histologic appearance of the polyps removed during life and at autopsy was consistent with Peutz-Jeghers syndrome. Gruber et al. (1998) noted that the histopathologic appearance of hamartomas in PJS is distinct from that of other types of gastrointestinal polyps and likely reflects a different pathogenetic sequence for their development. PJS hamartomas show an elongated, frond-like epithelium with cystic dilatation of glands overlying an arborizing network of smooth muscle bundles. Hypermucinous goblet cells are often prominent. In addition, pseudoinvasion by histopathologically benign epithelium is common in PJS hamartomas. These characteristic features are easily distinguished from the cytologic atypia and lack of differentiation seen in typical adenomas, and it is not surprising that PJS tumors seem to share few of the earliest genetic events observed in the transition of normal epithelium to dysplastic adenomas. Hamartomatous polyps arising in the juvenile polyposis syndrome (174900) originate through yet another mechanism as a consequence of germline mutations in the SMAD4/DPC4 gene (600993). The hamartomas of juvenile polyposis are histologically distinct from those of PJS, and the risk of malignancy also differs in these 2 syndromes. Some patients with PJS may be disturbed by the appearance of lentigines. Kato et al. (1998) described ruby laser therapy of labial lentigines in 2 children with this disorder. They stated that the response to treatment was excellent, with no sequelae or recurrence of the lesions. Boardman et al. (2000) pointed out that diagnosing PJS, even in an individual from a known PJS kindred, can be difficult. Oral pigmentation tends to fade and be forgotten with time, and polyps can often be asymptomatic. Additionally, other syndromes may mimic the pigmentation of PJS, occurring in individuals with an occult malignancy (Babin et al., 1978; Eng et al., 1991; Gass and Glatzer, 1991) or in individuals with Laugier-Hunziker syndrome, a condition characterized by oral hyperpigmentation without polyposis (Veraldi et al., 1991). Familial hamartomatous polyps of the small intestine resembling those of PJS were recognized as a feature of Bannayan-Zonana syndrome (BZS; 153480) by DiLiberti et al. (1983) and others. This disorder and Cowden disease (158350) are caused by mutations in the PTEN1 gene. Pigmented spots occur also in BZS but characteristically on the glans penis in males and not on the lips. In connection with the possibility that the melanin spots of the lips represent a benign neoplasm, the observations of Jeghers et al. (1949) may be significant: clinically, some of the spots could be seen to have a somewhat stippled appearance under magnification, which, it was thought, could be explained by a curious histologic pattern observed on biopsy. The pigmentation occurred mainly in vertical bands interrupted by unpigmented areas. The change suggested the possibility of clonality.
In a study of 132 PJS patients with or without cancer who had mutations in the STK11 gene, Schumacher et al. (2005) found that mutations in the part of the gene involved in ATP binding and catalysis were ... In a study of 132 PJS patients with or without cancer who had mutations in the STK11 gene, Schumacher et al. (2005) found that mutations in the part of the gene involved in ATP binding and catalysis were rarely associated with cancer, whereas mutations in the part of the gene involved in substrate recognition were more frequently associated with malignancies. PJS patients with breast cancers had predominantly truncating mutations.
Within a distance of 190 kb proximal to D19S886, the marker with the highest lod score in the study of Hemminki et al. (1997), Jenne et al. (1998) identified and characterized a novel human gene encoding the serine/threonine ... Within a distance of 190 kb proximal to D19S886, the marker with the highest lod score in the study of Hemminki et al. (1997), Jenne et al. (1998) identified and characterized a novel human gene encoding the serine/threonine kinase STK11. In a 3-generation PJS family, they found an STK11 allele with a deletion of exons 4 and 5 and an inversion of exons 6 and 7 (602216.0001) segregating with the disease. Sequence analysis of STK11 exons in 4 unrelated PJS patients identified 3 nonsense mutations (602216.0002, 602216.0003, 602216.0004) and 1 acceptor splice site mutation (602216.0005). All 5 germline mutations were predicted to disrupt the function of the kinase domain. Jenne et al. (1998) concluded that germline mutations in STK11, probably in conjunction with acquired genetic defects of the second allele in somatic cells, caused the manifestations of PJS. Independently and simultaneously, Hemminki et al. (1998), the group that identified the linkage of PJS to chromosome 19, demonstrated mutations in the serine/threonine kinase gene in 11 of 12 unrelated patients with PJS. Jenne (1998) speculated that cellular context between melanocytes and keratinocytes are regulated by STK11 activity. He pointed to the wide tissue distribution of STK11 and suggested that effects in melanocytes may be observed preferentially at sites of mechanical and physical stress. Gruber et al. (1998) studied 6 families with PJS from the Johns Hopkins Polyposis Registry to identify the molecular basis of PJS and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in these patients. Linkage analysis in the family studied by McKusick, who contributed to the publication of Jeghers et al. (1949), and in 5 other families confirmed linkage to 19p13.3. Germline mutations in STK11 were identified in all 6 families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified LOH of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germline mutation (602216.0012), confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these 2 regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC (611731), or mutations in codons 12 or 13 of the KRAS2 (190070) protooncogene. These data provided evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggested that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutation events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas. Miyaki et al. (2000) presented findings suggesting that gastrointestinal hamartomatous polyps in PJS patients develop through inactivation of the STK11 gene by germline mutation plus somatic mutation or LOH of the unaffected STK11 allele, and that additional mutations of the beta-catenin gene (CTNNB1; 116806) and the p53 gene (TP53; 191170) convert hamartomatous polyps into adenomatous and carcinomatous lesions. Westerman et al. (1999) found novel STK11 mutations in 12 of 19 predominantly Dutch families with PJS. No mutation was found in the remaining 7 families. None of the mutations occurred in more than 1 family, and a number were demonstrated to have arisen de novo. The likelihood of locus heterogeneity was raised. Jiang et al. (1999) conducted a detailed investigation of germline STK11 alterations by protein truncation test and genomic DNA sequence analysis in 10 unrelated PJS families. A novel truncating deletion in a single patient and several known polymorphisms were identified. The results suggested that STK11 mutations account for only some cases of PJS. Boardman et al. (2000) searched for mutations in the STK11 gene in 5 kindreds with more than 2 family members affected by PJS, 5 PJS probands with only 1 other affected family member, and 23 individuals with sporadic PJS. Conformation-sensitive gel electrophoresis was used for the initial screen, followed by direct sequence analysis for characterization. Long-range PCR was used for the detection of larger genetic insertions or deletions. Genetic alterations in the gene were found in 2 probands who had a family history of PJS. Mutations were detected in the gene in only 4 of the 23 patients with sporadic PJS. The authors interpreted these data as suggesting the presence of significant genetic heterogeneity in PJS and the involvement of other loci in this syndrome. They pointed to the report by Mehenni et al. (1997) of a possible second susceptibility locus on 19q in 2 PJS Indian families and to that by Olschwang et al. (1998), in which no evidence of linkage was found in 3 of 20 PJS kindreds. Olschwang et al. (2001) studied 34 families with PJS. Mutations in the STK11 gene were identified in 24 families. In the 10 families in which mutations were not identified, there was a significantly increased risk of proximal biliary adenocarcinoma. Westerman et al. (1999) traced the Dutch family reported by Peutz (1921) and determined that the affected members carried a previously unidentified germline mutation in the STK11 gene (602216.0014). The pedigree, published by Westerman et al. (1999), showed affected individuals in 4 generations and, by inference, in an earlier fifth generation. In total, 22 persons (9 females and 13 males) were affected and 31 were unaffected. Nasal polyposis was present in 2 members of 1 generation and in 4 members of another. Colicky abdominal pain occurred in all 22 affected members, paralytic ileus in 16, chronic anemia in 9, and acute or chronic blood loss in 14. Rectal prolapse due to polyps occurred in 7. In 4 patients, the nasal polyposis was severe, obstructing the nasal cavity and sinuses, requiring repeated surgery. In 1 woman who had had extremely severe nasal polyposis since childhood, a squamous cell carcinoma of the nasal cavity developed. She died of this tumor 4 years later. Three of the 5 cases of gastrointestinal cancer were in the colon, 1 was in the stomach, and 1 was of unknown primary origin. Breast cancer occurred in a female patient at the age of 47 years. Premenopausal breast cancer was diagnosed in a sib at the age of 44; it was not known whether this patient was affected by PJS. No other cancers of the reproductive tract were found in this family. Keller et al. (2002) reported molecular genetic evidence of an association between nasal polyposis and PJS. They studied 12 nasal polyps from 4 patients with PJS who came from 3 families with known germline mutations in STK11, and 28 sporadic nasal polyps from 28 subjects without evidence of PJS, Kartagener syndrome (244400), cystic fibrosis (CF; 219700), or aspirin sensitivity. In 2 unrelated patients with PJS, 4 of 8 nasal polyps showed loss of heterozygosity at 19p13.3. In contrast, loss of heterozygosity was not found in 23 sporadic nasal polyps. Haplotype analysis showed that loss of heterozygosity comprised deletion of the wildtype allele. Loss of heterozygosity at 19p13.3 in nasal polyps of affected patients corresponded with reports of loss of heterozygosity in gastrointestinal hamartomatous polyps (Entius et al., 2001). In his original publication, Peutz (1921) suggested that nasal polyps represent an extraintestinal manifestation of PJS. Le Meur et al. (2004) reported a family with typical features of PJS, including melanin spots of the oral mucosa, gastrointestinal hamartomatous polyps, and breast and colon cancer. The authors noted that the proband had neurofibromatosis type I (162200) of paternal origin as well as PJS of maternal origin. Using quantitative multiplex PCR of short fluorescent fragments of the 19p13 region, they identified an approximately 250-kb heterozygous deletion that completely removed the STK11 locus. Le Meur et al. (2004) stated that this was the first report of a complete germline deletion of STK11 and suggested that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11. Amos et al. (2004) screened 42 independent probands for mutations in the STK11 gene and detected mutations in 22 of 32 (69%) probands with PJS and 0 of 10 probands referred to rule out PJS. In a total of 51 participants with PJS, the authors found gastric polyps to be very common, with a median age at onset of 16 years. Individuals with missense mutations had a significantly later time to onset of first polypectomy (p = 0.04) and of other symptoms compared with those participants with either truncating mutations or no detectable mutation. Amos et al. (2004) concluded that STK11 mutation analysis should be restricted to individuals who meet PJS criteria or their close relatives, and suggested that mutation characterization might be of value in disease management. They also noted that the common occurrence of gastric polyps might facilitate chemopreventive studies for this disorder. In a 20-year-old female patient with PJS and gastrointestinal hamartomatous polyps, Hernan et al. (2004) identified a de novo heterozygous germline tyr246-to-ter mutation of the STK11 gene (602216.0023). Comparison of melting curve profiles obtained from DNA from the patient's lymphocytes and hamartomatous polyps showed no differences, indicative of a heterozygous mutation rather than loss of heterozygosity in the polyps. Hernan et al. (2004) suggested that biallelic inactivation of STK11 is not necessarily required for hamartoma formation in PJS patients. In a patient with PJS and a primary gastric cancer (137215), Shinmura et al. (2005) identified heterozygosity for a deletion mutation of the STK11 gene (602216.0022), resulting in a truncated protein. No inactivation of the wildtype allele by somatic mutation, chromosomal deletion, or hypermethylation at the 5-prime CpG site of STK11 was detected in the gastric carcinoma. The patient's sister also had PJS and died of gastric carcinoma in her twenties. Shinmura et al. (2005) stated that this was the first report of an STK11 germline mutation in a PJS patient with gastric carcinoma. - Genetic Heterogeneity Alhopuro et al. (2008) identified a heterozygous germline mutation in the MYH11 gene (160745) in 1 of 33 PJS patients who did not have STK11 mutations, and the mutation was not identified in 1,015 controls. The patient had a cystic astrocytoma at age 13 years. At age 23 years, he developed intussusception and was diagnosed with typical PJS. His unaffected father also carried the mutation; there was no family history of the disorder. The authors postulated autosomal recessive inheritance and the presence of a second unidentified MYH11 mutation. In an unrelated patient with colorectal tumor showing microsatellite instability, Alhopuro et al. (2008) identified the same mutation in the somatic state.
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]. ...
DiagnosisClinical DiagnosisThe 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 polypsAny 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 TestingGene. 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 testingSequence 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 View in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1, 2Test AvailabilityPositive Family HistoryNegative Family HistorySTK11Sequence analysisSequence variants 355%70%Clinical Deletion/duplication analysis 4Exon(s) and whole-gene deletion45%21%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 mutation3. 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.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 StrategyTo 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.Genetically Related (Allelic) DisordersOne 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.
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....
Natural HistoryPeutz-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 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....
Genotype-Phenotype CorrelationsGenotype-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].
Table 2 summarizes the differential diagnosis of Peutz-Jeghers syndrome (PJS)....
Differential DiagnosisTable 2 summarizes the differential diagnosis of Peutz-Jeghers syndrome (PJS).One individual diagnosed with PJS who did not have mutation in STK11 was found to be heterozygous for a mutation of the DNA repair gene MYH [Alhopuro et al 2008].Juvenile polyposis syndrome (JPS) is characterized by predisposition for 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 25% have mutations in BMPR1A. JPS is inherited in an autosomal dominant manner. Mixed hereditary polyposis syndrome. Individuals with mixed hereditary polyposis syndrome have polyps with the morphologic characteristics of both juvenile polyposis coli and adenomas and are at increased risk for colon cancer [Heiss et al 1993]. 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 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 40%-50% 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 PJSView in own windowSyndromeGene Symbol PigmentationGI Tumors Sertoli Cell Tumors CancersOtherPJSSTK11 Facial++ Mucosal+++Adenoma+ Hamartoma++++/-Colon, gastric, cervical, ovarian, breast, pancreatic, lungHyper-estrogenismJPS 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 heartFAP APC -Adenoma+++-Colon, brainDesmoid tumors, osteomas, CHRPEHNPCC MLH1, MSH2, MSH3, MSH6, PMS1, PMS2 Adenoma+-Endometrial, gastric, renal pelvis and ureter, ovarianSebaceous adenoma+ indicates presence of symptom with number of +'s indicating relative frequency of sign or symptom for the condition +/- indicates an occasional or rare symptom ? indicates anecdotal associationJPS=juvenile polyposis syndrome FAP=familial adenomatous polyposis CHRPE=congenital hypertrophy of the retinal pigment epithelium HNPCC=hereditary non-polyposis colorectal cancerThe differential diagnosis of oral pigmented lesions includes the following:The Langier-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 cancers 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Peutz-Jeghers syndrome (PJS), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 yearsWomen. Gynecologic and breast examinations and (after age 20 years) mammogram Men. Testicular examination and testicular ultrasound examination, if clinically indicated Treatment of ManifestationsPolyps. 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 ManifestationsAlthough 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]. SurveillanceThe 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 SyndromeView in own windowSiteProcedureOnset (yr)Interval (yr)StomachUpper endoscopy 182-3 Small intestineCapsule endoscopy or MR enterography 282-3Large intestineColonoscopy182-3BreastBreast examination25 3MonthlyMammography or MRI25 31OvaryTransvaginal ultrasound and serum CA 125 3181Cervix and uterusPelvic exam with pap smear 4181PancreasMRI-MRCP or endoscopic ultrasound and CA 19-9251-2 TestesTesticular exam; Ultrasound if symptomatic or abnormality on examBirth11. Extended upper endoscopy beginning at age 18 years2. CT enterography as alternative3. Discuss prophylactic mastectomy.4. Discuss prophylactic hysterectomy and oophorectomy.Agents/Circumstances to Avoid No agents that increase the risk for polyp development or for cancers have been described. Evaluatioin of Relatives at RiskFamily 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 InvestigationSearch 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.OtherSeveral 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSTK1119p13.3Serine/threonine-protein kinase 11Catalogue of Somatic Mutations in Cancer (COSMIC) STK11 homepage - Mendelian genesSTK11Data 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) View in own window 175200PEUTZ-JEGHERS SYNDROME; PJS 602216SERINE/THREONINE PROTEIN KINASE 11; STK11Molecular Genetic PathogenesisDysregulation 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].