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Progress report: Peutz–Jeghers syndrome

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Abstract

Peutz–Jeghers syndrome is a rare, autosomal dominant polyposis syndrome. Presenting with a remarkable phenotype including development of characteristic gastrointestinal polyps, mucocutaneous pigmentations, and an increased risk of cancer, the syndrome has been subject to many studies concerning the natural course of disease. In most patients, pathogenic germline variants are detected in the STK11 gene including cases of mosaicism and structural variants. Yet, studies assessing the effect of surveillance, understanding of cancer development, as well as clinical studies evaluating chemoprevention are lacking. In addition, the impact of Peutz–Jeghers syndrome on mental health, education, and family planning are insufficiently addressed. In this progress report, we describe current knowledge, clinical phenotype, surveillance strategies, and future areas of research.

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References

  1. Jelsig AM, van Overeem Hansen T, Gede LB, Qvist N, Christensen LL, Lautrup CK et al (2023) Survival, surveillance, and genetics in patients with Peutz–Jeghers syndrome: a nationwide study. Clin Genet 104(1):81–89

    Article  CAS  PubMed  Google Scholar 

  2. Utsunomiya J, Gocho H, Miyanaga T, Hamaguchi E, Kashimure A (1975) Peutz–Jeghers syndrome: its natural course and management. Johns Hopkins Med J 136:71–82

    CAS  PubMed  Google Scholar 

  3. Jelsig AM, van Overeem Hansen T, Gede LB, Qvist N, Christensen LL, Lautrup CK et al (2023) Survival, surveillance, and genetics in patients with Peutz–Jeghers syndrome: a nationwide study. Clin Genet. https://doi.org/10.1111/cge.14337

    Article  PubMed  Google Scholar 

  4. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ et al (2006) Frequency and spectrum of cancers in the Peutz–Jeghers syndrome. Clin cancer Research: Official J Am Association Cancer Res 12:3209–3215

    Article  CAS  Google Scholar 

  5. Amos CI, Keitheri-Cheteri MB, Sabripour M, Wei C, McGarrity TJ, Seldin MF et al (2004) Genotype-phenotype correlations in Peutz–Jeghers syndrome. J Med Genet 41:327–333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hearle N, Schumacher V, Menko FH, Olschwang S, Boardman LA, Gille JJ et al (2006) STK11 status and intussusception risk in Peutz–Jeghers syndrome. J Med Genet 43:e41

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vogel T, Schumacher V, Saleh A, Trojan J, Möslein G (2000) Extraintestinal polyps in Peutz–Jeghers syndrome: presentation of four cases and review of the literature. Deutsche Peutz–Jeghers-Studiengruppe. Int J Colorectal Dis 15(2):118–123

    Article  CAS  PubMed  Google Scholar 

  8. Jelsig AM, Qvist N, Sunde L, Brusgaard K, Hansen T, Wikman FP et al (2016) Disease pattern in Danish patients with Peutz–Jeghers syndrome. Int J Colorectal Dis 31:997–1004

    Article  CAS  PubMed  Google Scholar 

  9. Young RH, Welch WR, Dickersin GR, Scully RE (1982) Ovarian sex cord tumor with annular tubules: review of 74 cases including 27 with Peutz–Jeghers syndrome and four with adenoma malignum of the cervix. Cancer 50:1384–1402

    Article  CAS  PubMed  Google Scholar 

  10. Gourgari E, Saloustros E, Stratakis CA (2012) Large-cell calcifying sertoli cell tumors of the testes in pediatrics. Curr Opin Pediatr 24(4):518–522

    Article  PubMed  PubMed Central  Google Scholar 

  11. Grandone A, del Giudice EM, Cirillo G, Santarpia M, Coppola F, Perrone L (2011) Prepubertal gynecomastia in two monozygotic twins with Peutz–Jeghers syndrome: two years’ treatment with anastrozole and genetic study. Horm Res Paediatr 75(5):374–379

    Article  CAS  PubMed  Google Scholar 

  12. Wagner A, Aretz S, Auranen A, Bruno MJ, Cavestro GM, Crosbie EJ et al (2021) The management of Peutz–Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline. J Clin Med 10(3):473

    Article  PubMed  PubMed Central  Google Scholar 

  13. Latchford A, Cohen S, Auth M, Scaillon M, Viala J, Daniels R et al (2019) Management of Peutz–Jeghers Syndrome in Children and adolescents: a position paper from the ESPGHAN polyposis Working Group. J Pediatr Gastroenterol Nutr 68:442–452

    Article  PubMed  Google Scholar 

  14. Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV et al (2000) Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119:1447–1453

    Article  CAS  PubMed  Google Scholar 

  15. Resta N, Pierannunzio D, Lenato GM, Stella A, Capocaccia R, Bagnulo R et al (2013) Cancer risk associated with STK11/LKB1 germline mutations in Peutz–Jeghers syndrome patients: results of an Italian multicenter study. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the study of the liver. 45:606–611

  16. Lim W, Hearle N, Shah B, Murday V, Hodgson SV, Lucassen A et al (2003) Further observations on LKB1/STK11 status and cancer risk in Peutz–Jeghers syndrome. Br J Cancer 89(2):308–313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mehenni H, Resta N, Park JG, Miyaki M, Guanti G, Costanza MC (2006) Cancer risks in LKB1 germline mutation carriers. Gut 55:984–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. van Lier MG, Westerman AM, Wagner A, Looman CW, Wilson JH, de Rooij FW et al (2011) High cancer risk and increased mortality in patients with Peutz–Jeghers syndrome. Gut 60:141–147

    Article  PubMed  Google Scholar 

  19. Jelsig AM, Wullum L, Kuhlmann TP, Ousager LB, Burisch J, Karstensen JG (2023) Risk of cancer and mortality in Peutz–Jeghers syndrome and Juvenile polyposis syndrome-a Nationwide cohort study with matched control individuals. Gastroenterology. 165(6):1565–1567

    Article  PubMed  Google Scholar 

  20. van Lier MG, Westerman AM, Wagner A, Looman CW, Wilson JH, de Rooij FW et al (2011) High cancer risk and increased mortality in patients with Peutz–Jeghers syndrome. Gut 60(2):141–147

    Article  PubMed  Google Scholar 

  21. Xu ZX, Jiang LX, Chen YR, Zhang YH, Zhang Z, Yu PF et al (2023) Clinical features, diagnosis, and treatment of Peutz–Jeghers syndrome: experience with 566 Chinese cases. World J Gastroenterol 29(10):1627–1637

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hendricks LAJ, Hoogerbrugge N, Schuurs-Hoeijmakers JHM, Vos JR (2021) A review on age-related cancer risks in PTEN hamartoma tumor syndrome. Clin Genet 99(2):219–225

    Article  CAS  PubMed  Google Scholar 

  23. Boland CR, Idos GE, Durno C, Giardiello FM, Anderson JC, Burke CA et al (2022) Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-society Task Force on Colorectal Cancer. Gastrointest Endosc 95(6):1025–1047

    Article  PubMed  Google Scholar 

  24. Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P et al (2005) Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294:2465–2473

    Article  CAS  PubMed  Google Scholar 

  25. Stanich PP, Pearlman R, Hinton A, Gutierrez S, LaDuca H, Hampel H et al (2019) Prevalence of germline mutations in polyposis and Colorectal Cancer-Associated genes in patients with multiple colorectal polyps. Clin Gastroenterol Hepatol 17(10):2008–15e3

    Article  CAS  PubMed  Google Scholar 

  26. Rosner G, Petel-Galil Y, Laish I, Levi Z, Kariv R, Strul H et al (2022) Adenomatous polyposis phenotype in BMPR1A and SMAD4 variant carriers. Clin Translational Gastroenterol 13(10):e00527

    Article  Google Scholar 

  27. Hemminki A, Tomlinson I, Markie D, Jarvinen H, Sistonen P, Bjorkqvist AM et al (1997) Localization of a susceptibility locus for Peutz–Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 15:87–90

    Article  CAS  PubMed  Google Scholar 

  28. Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R et al (1998) Peutz–Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43

    Article  CAS  PubMed  Google Scholar 

  29. Jelsig AM, Bertelsen B, Forss I, Karstensen JG (2020) Two cases of somatic STK11 mosaicism in Danish patients with Peutz–Jeghers syndrome. Fam Cancer 22:50–59

    Google Scholar 

  30. McKay V, Cairns D, Gokhale D, Mountford R, Greenhalgh L (2016) First report of somatic mosaicism for mutations in STK11 in four patients with Peutz–Jeghers syndrome. Fam Cancer 15:57–61

    Article  CAS  PubMed  Google Scholar 

  31. Butel-Simoes GI, Spigelman AD, Scott RJ, Vilain RE (2019) Low-level parental mosaicism in an apparent de novo case of Peutz–Jeghers syndrome. Fam Cancer 18:109–112

    Article  CAS  PubMed  Google Scholar 

  32. Kariv R, Dahary D, Yaron Y, Petel-Galil Y, Malcov M, Rosner G (2022) Whole genome sequencing applied in Familial Hamartomatous Polyposis identifies novel structural variations. Genes 13(8):1408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jiang LX, Chen YR, Xu ZX, Zhang YH, Zhang Z, Yu PF et al (2023) Peutz–Jeghers syndrome without STK11 mutation may correlate with less severe clinical manifestations in Chinese patients. World J Gastroenterol 29(21):3302–3317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Buchet-Poyau K, Mehenni H, Radhakrishna U, Antonarakis SE (2002) Search for the second Peutz–Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2. Cytogenet Genome Res 97:171–178

    Article  CAS  PubMed  Google Scholar 

  35. Mehenni H, Blouin JL, Radhakrishna U, Bhardwaj SS, Bhardwaj K, Dixit VB et al (1997) Peutz–Jeghers syndrome: confirmation of linkage to chromosome 19p13.3 and identification of a potential second locus, on 19q13.4. Am J Hum Genet 61:1327–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jelsig AM, Qvist N, Brusgaard K, Nielsen CB, Hansen TP, Ousager LB (2014) Hamartomatous polyposis syndromes: a review. Orphanet J Rare Dis 9:101

    Article  PubMed  PubMed Central  Google Scholar 

  37. Woo A, Sadana A, Mauger DT, Baker MJ, Berk T, McGarrity TJ (2009) Psychosocial impact of Peutz–Jeghers Syndrome. Fam Cancer 8(1):59–65

    Article  PubMed  Google Scholar 

  38. van Lier MG, Korsse SE, Mathus-Vliegen EM, Kuipers EJ, van den Ouweland AM, Vanheusden K et al (2012) Peutz–Jeghers syndrome and family planning: the attitude towards prenatal diagnosis and pre-implantation genetic diagnosis. Eur J Hum Genet 20(2):236–239

    Article  PubMed  Google Scholar 

  39. Byrjalsen A, Roos L, Diemer T, Karstensen JG, Løssl K, Jelsig AM (2022) Preimplantation genetic testing in two Danish couples affected by Peutz–Jeghers syndrome. Scand J Gastroenterol. 58(3):314–318

    Article  PubMed  Google Scholar 

  40. Xu X, Song R, Hu K, Li Y, Jin H, Chen B et al (2022) Multidisciplinary management for Peutz–Jeghers syndrome and prevention of vertical transmission to offspring using preimplantation genetic testing. Orphanet J Rare Dis 17(1):64

    Article  PubMed  PubMed Central  Google Scholar 

  41. Latchford AR, Neale K, Phillips RK, Clark SK (2011) Peutz–Jeghers syndrome: intriguing suggestion of gastrointestinal cancer prevention from surveillance. Dis Colon Rectum 54(12):1547–1551

    Article  CAS  PubMed  Google Scholar 

  42. Paiella S, Salvia R, De Pastena M, Pollini T, Casetti L, Landoni L et al (2018) Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: a systematic review and proportion meta-analysis of screening results. Pancreatology 18(4):420–428

    Article  PubMed  Google Scholar 

  43. Kuwano H, Takano H, Sugimachi K (1989) Solitary Peutz–Jeghers type polyp of the stomach in the absence of familial polyposis coli in a teenage boy. Endoscopy 21(4):188–190

    Article  CAS  PubMed  Google Scholar 

  44. Bott SJ, Hanks JB, Stone DD (1986) Solitary hamartomatous polyp of the duodenum in the absence of familial polyposis. Am J Gastroenterol 81(10):993–994

    CAS  PubMed  Google Scholar 

  45. Jelsig AM, Wullum L, Ousager LB, Burish J, Kühlmann TP, Karstensen JG (2023) Cancer risk and mortality in patients with solitary Peutz–Jeghers polyps. Gastroenterol Rep (Oxf) 11:goad056

    Article  PubMed  Google Scholar 

  46. Oncel M, Remzi FH, Church JM, Goldblum JR, Zutshi M, Fazio VW (2003) Course and follow-up of solitary Peutz–Jeghers polyps: a case series. Int J Colorectal Dis 18(1):33–35

    Article  PubMed  Google Scholar 

  47. Iwamuro M, Aoyama Y, Suzuki S, Kobayashi S, Toyokawa T, Moritou Y et al (2019) Long-term outcome in patients with a Solitary Peutz–Jeghers Polyp. Gastroenterol Res Pract 2019:8159072

    Article  PubMed  PubMed Central  Google Scholar 

  48. Miyaki M, Iijima T, Hosono K, Ishii R, Yasuno M, Mori T et al (2000) Somatic mutations of LKB1 and beta-catenin genes in gastrointestinal polyps from patients with Peutz–Jeghers syndrome. Cancer Res 60(22):6311–6313

    CAS  PubMed  Google Scholar 

  49. Katajisto P, Vaahtomeri K, Ekman N, Ventelä E, Ristimäki A, Bardeesy N et al (2008) LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet 40(4):455–459

    Article  CAS  PubMed  Google Scholar 

  50. Poffenberger MC, Metcalfe-Roach A, Aguilar E, Chen J, Hsu BE, Wong AH et al (2018) LKB1 deficiency in T cells promotes the development of gastrointestinal polyposis. Science 361(6400):406–411

    Article  ADS  CAS  PubMed  Google Scholar 

  51. Ollila S, Domènech-Moreno E, Laajanen K, Wong IP, Tripathi S, Pentinmikko N et al (2018) Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway. J Clin Invest 128(1):402–414

    Article  PubMed  Google Scholar 

  52. Wei C, Amos CI, Zhang N, Wang X, Rashid A, Walker CL et al (2008) Suppression of Peutz–Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin cancer Research: Official J Am Association Cancer Res 14(4):1167–1171

    Article  CAS  Google Scholar 

  53. de Brabander J, Eskens F, Korsse SE, Dekker E, Dewint P, van Leerdam ME et al (2018) Chemoprevention in patients with Peutz–Jeghers Syndrome: lessons learned. Oncologist 23(4):399–e33

    Article  PubMed  PubMed Central  Google Scholar 

  54. Wei C, Amos CI, Zhang N, Wang X, Rashid A, Walker CL et al (2008) Suppression of Peutz–Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin cancer Research: Official J Am Association Cancer Res 14:1167–1171

    Article  CAS  Google Scholar 

  55. Wei C, Amos CI, Zhang N, Zhu J, Wang X, Frazier ML (2009) Chemopreventive efficacy of rapamycin on Peutz–Jeghers syndrome in a mouse model. Cancer Lett 277:149–154

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. De Leng WW, Westerman AM, Weterman MA, De Rooij FW, Dekken Hv H, De Goeij AF et al (2003) Cyclooxygenase 2 expression and molecular alterations in Peutz–Jeghers hamartomas and carcinomas. Clin cancer Research: Official J Am Association Cancer Res 9(8):3065–3072

    Google Scholar 

  57. Udd L, Katajisto P, Rossi DJ, Lepistö A, Lahesmaa AM, Ylikorkala A et al (2004) Suppression of Peutz–Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology 127(4):1030–1037

    Article  CAS  PubMed  Google Scholar 

  58. Göransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M et al (2007) Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem 282(45):32549–32560

    Article  PubMed  Google Scholar 

  59. Godara A, Siddiqui NS, Hachem H, Tsichlis PN, Martell RE, Saif MW (2020) Prospective evaluation of Effect of Metformin on activation of AMP-activated protein kinase (AMPK) and Disease Control in a sub-group analysis of patients with GI malignancies. J Cell Signal 1(2):35–41

    PubMed  PubMed Central  Google Scholar 

  60. Wang S, Huang G, Wang JX, Tian L, Zuo XL, Li YQ et al (2022) Altered gut microbiota in patients with Peutz–Jeghers Syndrome. Front Microbiol 13:881508

    Article  PubMed  PubMed Central  Google Scholar 

  61. Wang YX, Huang HB, Dong YH, Li ZS, Liu F, Du YQ (2023) Alterations and clinical relevance of gut microbiota in patients with Peutz–Jeghers syndrome: a prospective study. J Dig Dis 24(3):203–212

    Article  ADS  CAS  PubMed  Google Scholar 

  62. Wang Z, Liang L, Liu L, Wang Z, Wang Y, Yu Z et al (2023) Changes in the Gut Microbiome Associated with Intussusception in patients with Peutz–Jeghers Syndrome. Microbiol Spectr 11(2):e0281922

    Article  PubMed  Google Scholar 

  63. Andrews L, Mireskandari S, Jessen J, Thewes B, Solomon M, Macrae F et al (2007) Impact of familial adenomatous polyposis on young adults: quality of life outcomes. Dis Colon Rectum 50(9):1306–1315

    Article  CAS  PubMed  Google Scholar 

  64. Mireskandari S, Sangster J, Meiser B, Thewes B, Groombridge C, Spigelman A et al (2009) Psychosocial impact of familial adenomatous polyposis on young adults: a qualitative study. J Genet Couns 18(5):409–417

    Article  PubMed  Google Scholar 

  65. Douma KF, Aaronson NK, Vasen HF, Gerritsma MA, Gundy CM, Janssen EP et al (2010) Psychological distress and use of psychosocial support in familial adenomatous polyposis. Psychooncology 19(3):289–298

    Article  PubMed  Google Scholar 

  66. Gjone H, Diseth TH, Fausa O, Nøvik TS, Heiberg A (2011) Familial adenomatous polyposis: mental health, psychosocial functioning and reactions to genetic risk in adolescents. Clin Genet 79(1):35–43

    Article  CAS  PubMed  Google Scholar 

  67. Karstensen JG, Bülow S, Højen H, Jelsig AM, Jespersen N, Andersen KK et al (2023) Cancer in patients with familial adenomatous polyposis: a Nationwide Danish cohort study with matched controls. Gastroenterology 165(3):573–581

    Article  PubMed  Google Scholar 

  68. Petersen GM, Slack J, Nakamura Y (1991) Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology 100(6):1658–64

    Article  CAS  PubMed  Google Scholar 

  69. Win AK, Dowty JG, Cleary SP, Kim H, Buchanan DD, Young JP et al (2014) Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146:1208–1211

    Article  CAS  PubMed  Google Scholar 

  70. Thomas LE, Hurley JJ, Sanchez AA, Aznárez MR, Backman AS, Bjork J et al (2021) Duodenal Adenomas and Cancer in MUTYH-associated Polyposis: an International cohort study. Gastroenterology 160(3):952–954

    Article  CAS  PubMed  Google Scholar 

  71. Jelsig AM, Gede LB, Qvist N, Christensen LL, Lautrup CK et al (2023) Whole genome sequencing and disease pattern in patients with juvenile polyposis syndrome: a nationwide study. Fam Cancer 22(4):429–436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Buchanan DD, Stewart JR, Clendenning M, Rosty C, Mahmood K, Pope BJ, et al. Risk of colorectal cancer for carriers of a germ-line mutation in POLE or POLD1. Genetics in medicine : official journal of the American College of Medical Genetics. 2018;20:890-5

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Authors and Affiliations

  1. Department of Clinical Genetics, University Hospital of Copenhagen – Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Anne Marie Jelsig

  2. The Danish Polyposis Register, Gastro Unit and Department of Clinical Medicine, Amager and Hvidovre, Copenhagen University Hospital and University of Copenhagen-, Copenhagen, Denmark

    John Gásdal Karstensen

  3. Department of Clinical Genetics and Department of Clinical Medicine, University Hospital of Copenhagen, Rigshospitalet and Copenhagen University, Copenhagen, Denmark

    Thomas V. Overeem Hansen

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AMJ drafted the manuscript. TovM and JGK critically reviewed the genetic and clinical sections. All authors critically reviewed the manuscript.

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Jelsig, A.M., Karstensen, J.G. & Overeem Hansen, T.V. Progress report: Peutz–Jeghers syndrome. Familial Cancer (2024). https://doi.org/10.1007/s10689-024-00362-7

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