Peutz-Jeghers syndrome

2015-11-01   Francesca Clementina Radio , Paola Grammatico 

Medical Genetics Laboratory, Sapienza University of Rome, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense n. 87. 00152 Rome, Italy. ,


Peutz_Jeghers Syndrome (PJS, OMIM 175200) is a rare autosomal dominant disorder characterized by intestinal hamartomatous polyps, mucocutaneous melanotic pigmentation and predisposition to malignancies. The incidence rate of the disease ranges from 1



Peutz-Jeghers syndrome


Hamartomatous Intestinal Polyposis , Polyps-and-Spots Syndrome


Syndrome associating mucocutaneous melanotic pigmentation, intestinal polyposis, and an increased risk of cancers.


Autosomal dominant with a high penetrance; incidence rate of the disease ranges from 1 in 8,300 to 1 in 200,000; 1\/3 to 1\/2 of cases due to de novo mutations.






2869 Peutz-Jeghers syndrome




Phenotype and clinics

  • Skin numerous brown or bleuish mucocutaneous macules (melanin spots) , especially around the orifices (mouth, including the buccal mucosa, eyes, nostrils, anus, genitalia), and digits; the skin hyperpigmentation may disappear with age, in puberty and adulthood. Note: in patients with isolated mucocutaneous melanotic pigmentation (without polyps), the cancer risk is lower, and the genetic defect seems different.
  • Gastrointestinal tract (GI tract): polyps of hamartomatous origin (with a characteristic arborization of nonstriated muscles) may be found in any portion of the GI tract with varying frequencies: from 95% to 15%: (small bowel, jejunum, ileum, large intestin, rectum, stomach, duodenum). Intussusception and bleeding are common symptoms, which may be cause of death. the age of onset is variable from the first year of life onwards (median age of onset 10-25 yrs); polyps have also been reported in other organs (renal pelvis, urinary bladder, ureters, lungs, nares, gallbladder).
  • Neoplastic risk

  • Tumors develop, with a relative risk of 10-20, and a cumulative risk of more than 90% between ages 15 and 64 yrs (Giardiello et al.,2000). The mean interval between the diagnosis of PJS and the diagnosis of cancer is about 20 yrs (the mean age at the first cancer diagnosis about 41 yrs). The overall relative risk (RR) for cancer is greater in females than in males and greatest for gastrointestinal, pancreatic, and gynecologic-cervical cancers (Resta et al.,2013).In particular, the specific RR is:
    small intestin: 520
    stomach: 213
    pancreas: 140
    colon: 84
    esophagus: 57
    cervix: 55.6
    ovary: 30
    benign sex cord tumor with annular tubules in females or Sertoli cell tumors in males: 27
    lung: 17
    uterus: 16
    breast: 15.2 (comparable to that of BRCA1 \/ BRCA2 mutations carriers - Hearle et al.,2006)
  • Treatment

    Surveillance with endoscopic (GI tract) and gynecologic regular screenings, surgery when needed.


    Patients inherit mutations in one allele. The remaining allele is later inactivated generally by LOH or sometimes somatic mutation. This biallelic inactivation of STK11 leads to a loss of tumor suppressor activity, thereby promoting tumorigenesis.


    The prognosis for individuals affected by PJS is thus mainly determined by the risk of malignancy. Although little information on prognosis is available, one report suggests that PJS-associated cancers are particularly aggressive (Spigelman et al.,1989). Several researches show that a diagnosis of PJS has great psychosocial impact, although the physical impact on the patient is not greater than that in the general population (Woo et al.,2009).

    Genes involved and Proteins


    STK11 (LKB1) is the only gene in which mutations has been identified as causative of PJS, to date (Hemminki et al.,1998, Jenne et al.,1998). Evidence for genetic heterogeneity are described but no other locus has been clearly associated.
    One child with a PJS hamartoma show a 19q13.4 translocation, however no pathogenic variants in candidate genes mapping to this breakpoint were identified (Hearle et al.,2004).
    Between 25 patients with PJS without STK11 pathogenic mutations, one had a heterozygous pathogenic variant of MUTYH gene, common cause of autosomal recessive form of adenomatous polyposis (Alhopuro et al.,2008).
    Moreover Wang et colleagues identified 2 germline variants which are represented in all six PJS samples analyzed and are independent of STK11 mutation (Wang et al.,2014).




    A majority of PJS patients shows germline mutations in STK11 gene (around 80%-94%). However, the identification of germline mutations in other genes suggests a genetic heterogeneity of PJS, no definitely known to date.

    Dna description

    9 coding exons, spanning 23 kb. (Additional non-coding exons are described). The gene is transcribed in telomere to centromere direction.


    9 transcripts; 4 protein coding.


    433 amino acids, 48.6 kDa; N-term with a nuclear localization domain and a putative cytoplasmic retention signal, a kinase domain, and a C-terminal CAAX box prenylation motif.


    Ubiquitous, especially high expression in fetal liver and testis where it is required during spermiogenesis (Towler et al.,2008).


    Found in both the nucleus and the cytoplasm. Localization is thought to be dependent on interaction with proteins such as SMARCA4 (BRG1), STK11IP (LIP1), STRADA, CAB39 (MO25).


    Tumor suppressor serine\/threonine-protein kinase that controls the activity of AMP-activated protein kinase (AMPK) family members, thereby playing a role in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. Acts by phosphorylating the T-loop of AMPK family proteins, leading to promote their activity: phosphorylates PRKAA1 , PRKAA2 , BRSK1 , BRSK2 , MARK1 , MARK2 , MARK3 , MARK4 , NUAK1 , NUAK2 , SIK1 , SIK2 , SIK3 and SNRK but not MELK. Also phosphorylates non-AMPK family proteins such as STRADA and possibly p53\/TP53. Acts as a key upstream regulator of AMPK by mediating phosphorylation and activation of AMPK catalytic subunits PRKAA1 and PRKAA2: it thereby regulates inhibition of signaling pathways that promote cell growth and proliferation when energy levels are low, glucose homeostasis in liver, activation of autophagy when cells undergo nutrient deprivation, B-cell differentiation in the germinal center in response to DNA damage. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton. Required for cortical neurons polarization by mediating phosphorylation and activation of BRSK1 and BRSK2, leading to axon initiation and specification. Involved in DNA damage response: interacts with p53\/TP53 and recruited to the CDKN1A\/WAF1 promoter to participate in transcription activation. Able to phosphorylate p53\/TP53; the relevance of such result in vivo is however unclear and phosphorylation may be indirect and mediated by downstream STK11\/LKB1 kinase NUAK1 Also acts as a mediator p53\/TP53-dependent apoptosis via interaction with p53\/TP53: translocates to mitochondrion during apoptosis and regulates p53\/TP53-dependent apoptosis pathways (Karuman et al.,2001; Baas et al.,2003; Boudeau et al.,2003; Baas et al.,2004; Lizcano et al.,2004; Jaleel et al.,2005; Zeng et al.,2006; Hou et al.,2011).


    Orthologs found in several species and include: Xenopus laevis egg and embryonic kinase 1(XEEK1), Caenorhabditis elegans partitioning defective gene 4 (PAR4), mouse LKB1 and drosophila LKB1.


    Around 200 pathogenic mutations of STK11 gene has been reported to date, including missense, nonsense, splice site variants, small deletions, small insertions, small indels, large deletions, large insertions and complex rearrangements. Between them more than 90% are associated with PJS. In addition are described: one individual with a nonsense variant and diagnosis of gonadotropin-independent precocious puberty and one patient with a large insertion and diagnosis of juvenile polyposis syndrome.


    Many of the polyps that develop in PJS show loss of heterozygosity or second somatic mutation of SKT11 gene. Somatic mutations rarely occur in sporadic tumors. However, somatic mutations of STK11 gene can be frequent revealed in lung adenocarcinoma (Matsumoto et al.,2007).

    To be noted




    Peutz-Jeghers syndrome


    Pubmed IDLast YearTitleAuthors
    187961642008Somatic mutation analysis of MYH11 in breast and prostate cancer.Alhopuro P et al
    128052202003Activation of the tumour suppressor kinase LKB1 by the STE20-like pseudokinase STRAD.Baas AF et al
    150163792004Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD.Baas AF et al
    124892812002Heritable colorectal cancer syndromes: recognition and preventive management.Boardman LA et al
    145172482003MO25alpha/beta interact with STRADalpha/beta enhancing their ability to bind, activate and localize LKB1 in the cytoplasm.Boudeau J et al
    252526922014Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.Burd CE et al
    246481272014Analysis of patient reports on the referral process to two NSW cancer genetic services.Butel-Simoes GI et al
    266728912015Hamartomatous Tumors in the Gastrointestinal Tract.Cauchin E et al
    249493252014Peutz-Jeghers syndrome with germline mutation of STK11.Chae HD et al
    152870292004Mapping of a translocation breakpoint in a Peutz-Jeghers hamartoma to the putative PJS locus at 19q13.4 and mutation analysis of candidate genes in polyp and STK11-negative PJS cases.Hearle N et al
    168827352006STK11 status and intussusception risk in Peutz-Jeghers syndrome.Hearle N et al
    186003942008Molecular insights into Peutz-Jeghers syndrome: two probands with a germline mutation of LKB1.Hosogi H et al
    213179322011A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation.Hou X et al
    157338512005Identification of the sucrose non-fermenting related kinase SNRK, as a novel LKB1 substrate.Jaleel M et al
    94258971998Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase.Jenne DE et al
    114308322001The Peutz-Jegher gene product LKB1 is a mediator of p53-dependent cell death.Karuman P et al
    221622282012Genetic susceptibility to pancreatic cancer.Klein AP et al
    149765522004LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.Lizcano JM et al
    86983251996A pericentric inversion of chromosome six in a patient with Peutz-Jeghers' syndrome and the use of FISH to localise the breakpoints on a genetic map.Markie D et al
    267560032015Peutz-Jeghers Syndrome With Diffuse Gastrointestinal Polyposis: Three Cases in a Family With Different Manifestations and No Evidence of Malignancy During 14 Years Follow Up.Matini E et al
    173846802007Prevalence and specificity of LKB1 genetic alterations in lung cancers.Matsumoto S et al
    93999021997Peutz-Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4.Mehenni H et al
    234155802013Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study.Resta N et al
    187749452008A novel short splice variant of the tumour suppressor LKB1 is required for spermiogenesis.Towler MC et al
    241546392014Exome sequencing revealed novel germline mutations in Chinese Peutz-Jeghers syndrome patients.Wang HH et al
    171081072006LKB1 is recruited to the p21/WAF1 promoter by p53 to mediate transcriptional activation.Zeng PY et al