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Peutz-Jeghers syndrome

Written2002-02Jean-Loup Huret
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Updated2015-11Francesca Clementina Radio, Paola Grammatico
Medical Genetics Laboratory, Sapienza University of Rome, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense n. 87. 00152 Rome, Italy. francesca.clementina.radio@gmail.com , paola.grammatico@uniroma1.it
Abstract 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 in 8,300 to 1 in 200,000 (Boardman,2002; Launonen,2005; Chae and Jeon,2014). Around 55% of affected patients show a family history of the disease. The clinical diagnosis of PJS can be confirmed by molecular genetic testing of STK11 (LKB1) in 80%-94% of affected individuals (Jenne et al.,1998; Hemminki et al.,1998).STK11 gene encodes a tumor suppressor serine/threonine-protein kinase involved in various processes such as cell metabolism, cell polarity, apoptosis and DNA damage response. A genotype-phenotype correlation between STK11 germline mutations and disease manifestations (e.g., the number of polyps, pigmentation pattern, cancer risk) is been proposed (Hemminki et al.,1998; Davidson,2007).
Genetic heterogeneity is suggested by several patients negative at the mutational screening of STK11 gene and multiple causative loci described to date (Alhopuro et al.,2008; Bali et al.,1995; Markie et al.,1996; Mehenni et al.,1997; Schumacher et al.,2005; Wang et al.,2014).

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Identity

Other namesHamartomatous Intestinal Polyposis
Polyps-and-Spots Syndrome
Atlas_Id 10025
Genes implicated inSTK11  
Note Syndrome associating mucocutaneous melanotic pigmentation, intestinal polyposis, and an increased risk of cancers.
Inheritance 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.

Clinics

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.
    Evolution 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.
    Prognosis 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

    Note 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).
    Gene NameSTK11
    Alias LKB1
    Location 19p13.3. Chr19: 1,177,558-1,228,435 (GRCh38).
    Note 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/RNA
    Transcription 9 transcripts; 4 protein coding.
    Protein
    Description 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.
    Expression Ubiquitous, especially high expression in fetal liver and testis where it is required during spermiogenesis (Towler et al.,2008).
    Localisation 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).
    Function 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).
    Homology 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.
    Mutations
    Germinal 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.
    Somatic 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).

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    Citation

    This paper should be referenced as such :
    Radio FC, Grammatico P
    Peutz-Jeghers syndrome;
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Tumors/PeutzJeghersID10025.html
    History of this paper:
    Huret, JL. Peutz-Jeghers syndrome. Atlas Genet Cytogenet Oncol Haematol. 2002;6(2):145-146.
    http://documents.irevues.inist.fr/bitstream/handle/2042/37855/02-2002-PeutzJeghersID10025.pdf


    External links

    OMIM175200
    OrphanetPeutz-Jeghers syndrome
    MeSHD010580  
    MedGenD010580  
    UMLSC0031269  
    ICD-10Q85.8  
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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    indexed on : Fri Jun 30 11:24:33 CEST 2017


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