[go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Hamartomatous polyposis syndromes

Nature Clinical Practice Gastroenterology & Hepatology volume 4, pages 492–502 (2007)Cite this article

Abstract

The hamartomatous polyposis syndromes are a heterogeneous group of disorders that share an autosomal-dominant pattern of inheritance and are characterized by hamartomatous polyps of the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz–Jeghers syndrome and the PTEN hamartoma tumor syndrome. The frequency and location of the polyps vary considerably among syndromes, as does the affected patient's predisposition to the development of gastrointestinal and other malignancies. Although the syndromes are uncommon, it is important for the clinician to recognize these disorders because they are associated with considerable morbidity and mortality, not only from malignancy but also from nonmalignant manifestations such as bleeding, intussusception, and bowel obstruction. Each hamartomatous polyposis syndrome has its own distinctive organ-specific manifestations and each requires a different surveillance strategy, which makes accurate diagnosis crucial for appropriate patient management. The availability of clinical genetic testing for these disorders means that appropriate recognition allows for timely referral for cancer genetic counseling, and often allows for predicative testing in at-risk family members. Promisingly, an understanding of the molecular pathogenesis of these disorders offers insights into the mechanisms underlying the development of sporadic malignancy, and enables rational selection of targeted therapies that warrant further investigation.

Key Points

  • Hamartomatous polyposis syndromes are inherited autosomal-dominant syndromes that confer predisposition to cancers and have divergent clinical features, but often involve interconnected molecular pathways

  • Juvenile polyposis syndrome is caused by germline mutations of SMAD4, BMPR1A and ENG, and it predisposes individuals to colon cancer, and, to a lesser extent, upper gastrointestinal malignancies

  • Cowden syndrome, the most common PTEN hamartoma tumor syndrome, is caused by germline PTEN mutations and is characterized by benign and malignant breast, thyroid and endometrial manifestations, in addition to macrocephaly and characteristic mucocutaneous findings

  • Peutz–Jeghers syndrome is caused by germline STK11 mutations and is associated with a markedly increased risk of gastrointestinal, breast and gynecologic malignancies

  • Timely diagnosis of hamartomatous polyposis syndromes allows for appropriate surveillance and management, which varies considerably between syndromes

  • Clinical testing for germline mutations should occur in the setting of appropriate genetic counseling and offer predictive testing for family members

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A typical Peutz–Jeghers syndrome polyp demonstrating the arborizing pattern of smooth-muscle proliferation
Figure 2: The suggested age-range-specific surveillance recommendations for patients with Peutz–Jeghers syndrome
Figure 3: Signaling pathways dysregulated in patients with Peutz–Jeghers syndrome or PTEN hamartoma tumor syndrome
Figure 4: A typical juvenile polyp demonstrating gland dilatation, inflammatory cell infiltrate and absence of smooth-muscle proliferation

Similar content being viewed by others

References

  1. Nagy R et al. (2004) Highly penetrant hereditary cancer syndromes. Oncogene 23: 6445–6470

    Article  CAS  Google Scholar 

  2. Wang ZJ et al. (1999) Allelic imbalance at the LKB1 (STK11) locus in tumours from patients with Peutz–Jeghers' syndrome provides evidence for a hamartoma-(adenoma)-carcinoma sequence. J Pathol 188: 9–13

    Article  CAS  Google Scholar 

  3. Kutscher AH et al. (1960) Incidence of Peutz–Jeghers syndrome. Am J Dig Dis 5: 576–577

    Article  CAS  Google Scholar 

  4. Utsunomiya J et al. (1975) Peutz–Jeghers syndrome: its natural course and management. Johns Hopkins Med J 136: 71–82

    CAS  Google Scholar 

  5. McGarrity TJ and Amos C (2006) Peutz–Jeghers syndrome: clinicopathology and molecular alterations. Cell Mol Life Sci 63: 2135–2144

    Article  CAS  Google Scholar 

  6. Giardiello FM and Trimbath JD (2006) Peutz–Jeghers syndrome and management recommendations. Clin Gastroenterol Hepatol 4: 408–415

    Article  Google Scholar 

  7. Giardiello FM et al. (1987) Increased risk of cancer in the Peutz–Jeghers syndrome. N Engl J Med 316: 1511–1514

    Article  CAS  Google Scholar 

  8. Estrada R and Spjut HJ (1983) Hamartomatous polyps in Peutz–Jeghers syndrome. A light-, histochemical, and electron-microscopic study. Am J Surg Pathol 7: 747–754

    Article  CAS  Google Scholar 

  9. Giardiello FM et al. (2000) Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119: 1447–1453

    Article  CAS  Google Scholar 

  10. Lim W et al. (2004) Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology 126: 1788–1794

    Article  CAS  Google Scholar 

  11. Srivatsa PJ et al. (1994) Disseminated cervical adenoma malignum and bilateral ovarian sex cord tumors with annular tubules associated with Peutz–Jeghers syndrome. Gynecol Oncol 53: 256–264

    Article  CAS  Google Scholar 

  12. Scully RE et al. (1970) Sex cord tumor with annular tubules a distinctive ovarian tumor of the Peutz–Jeghers syndrome. Cancer 25: 1107–1121

    Article  CAS  Google Scholar 

  13. Terauchi S et al. (2006) Double-balloon endoscopy and Peutz–Jeghers syndrome: a new look at an old disease. Proc (Bayl Univ Med Cent) 19: 335–337

    Article  Google Scholar 

  14. Volikos E et al. (2006) LKB1 exonic and whole gene deletions are a common cause of Peutz–Jeghers syndrome. J Med Genet 43: e18

    Article  CAS  Google Scholar 

  15. Sweet K et al. (2005) Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA 294: 2465–2473

    Article  CAS  Google Scholar 

  16. Alessi DR et al. (2006) LKB1-dependent signaling pathways. Annu Rev Biochem 75: 137–163

    Article  CAS  Google Scholar 

  17. Corradetti MN et al. (2004) Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz–Jeghers syndrome. Genes Dev 18: 1533–1538

    Article  CAS  Google Scholar 

  18. Amos CI et al. (2004) Genotype-phenotype correlations in Peutz–Jeghers syndrome. J Med Genet 41: 327–333

    Article  CAS  Google Scholar 

  19. Miyoshi H et al. (2002) Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res 62: 2261–2266

    CAS  PubMed  Google Scholar 

  20. Zbuk KM and Eng C (2007) Cancer phenomics: RET and PTEN as illustrative models. Nat Rev Cancer 7: 35–45

    Article  CAS  Google Scholar 

  21. Nelen MR et al. (1997) Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6: 1383–1387

    Article  CAS  Google Scholar 

  22. The NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian Guideline (V.1.2007) © 2006 National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the guideline, go online to www.nccn.org (accessed July 1 2007)

  23. Gorlin RJ et al. (1992) Bannayan–Riley–Ruvalcaba syndrome. Am J Med Genet 44: 307–314

    Article  CAS  Google Scholar 

  24. Wiedemann HR et al. (1983) The proteus syndrome. Partial gigantism of the hands and/or feet, nevi, hemihypertrophy, subcutaneous tumors, macrocephaly or other skull anomalies and possible accelerated growth and visceral affections. Eur J Pediatr 140: 5–12

    Article  CAS  Google Scholar 

  25. Starink TM et al. (1986) The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 29: 222–233

    Article  CAS  Google Scholar 

  26. Weber HC et al. (1998) Germline PTEN/MMAC1/TEP1 mutations and association with gastrointestinal manifestations in Cowden disease. Gastroenterology 114: 2902

    Google Scholar 

  27. Marra G et al. (1994) Cowden's disease with extensive gastrointestinal polyposis. J Clin Gastroenterol 18: 42–47

    Article  CAS  Google Scholar 

  28. McGarrity TJ et al. (2003) GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol 98: 1429–1434

    Article  Google Scholar 

  29. Eng C (2000) Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 37: 828–830

    Article  CAS  Google Scholar 

  30. Marsh DJ et al. (1998) Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7: 507–515

    Article  CAS  Google Scholar 

  31. Bosserhoff AK et al. (2006) Multiple colon carcinomas in a patient with Cowden syndrome. Int J Mol Med 18: 643–647

    CAS  PubMed  Google Scholar 

  32. Carethers JM et al. (1998) Absence of PTEN/MMAC1 germ-line mutations in sporadic Bannayan–Riley–Ruvalcaba syndrome. Cancer Res 58: 2724–2726

    CAS  PubMed  Google Scholar 

  33. Zigman AF et al. (1997) Localization of the Bannayan–Riley–Ruvalcaba syndrome gene to chromosome 10q23. Gastroenterology 113: 1433–1437

    Article  CAS  Google Scholar 

  34. Zhou XP et al. (2003) Germline PTEN promoter mutations and deletions in Cowden/Bannayan–Riley–Ruvalcaba syndrome result in aberrant PTEN protein and dysregulation of the phosphoinositol-3-kinase/Akt pathway. Am J Hum Genet 73: 404–411

    Article  CAS  Google Scholar 

  35. Suzuki A et al. (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8: 1169–1178

    Article  CAS  Google Scholar 

  36. Waite KA and Eng C (2002) Protean PTEN: form and function. Am J Hum Genet 70: 829–844

    Article  CAS  Google Scholar 

  37. Chow LM and Baker SJ (2006) PTEN function in normal and neoplastic growth. Cancer Lett 241: 184–196

    Article  CAS  Google Scholar 

  38. Di Cristofano A et al. (1998) Pten is essential for embryonic development and tumour suppression. Nat Genet 19: 348–355

    Article  CAS  Google Scholar 

  39. Toccalino H et al. (1973) Juvenile polyps of the rectum and colon. Acta Paediatr Scand 62: 337–340

    Article  CAS  Google Scholar 

  40. Doxey BW et al. (2005) Inherited polyposis syndromes: molecular mechanisms, clinicopathology, and genetic testing. Clin Gastroenterol Hepatol 3: 633–641

    Article  CAS  Google Scholar 

  41. Jass JR et al. (1988) Juvenile polyposis—a precancerous condition. Histopathology 13: 619–630

    Article  CAS  Google Scholar 

  42. Giardiello FM et al. (1991) Colorectal neoplasia in juvenile polyposis or juvenile polyps. Arch Dis Child 66: 971–975

    Article  CAS  Google Scholar 

  43. Howe JR et al. (1998) The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann Surg Oncol 5: 751–756

    Article  CAS  Google Scholar 

  44. Sayed MG et al. (2002) Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol 9: 901–906

    Article  CAS  Google Scholar 

  45. Friedl W et al. (2002) Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet 111: 108–111

    Article  CAS  Google Scholar 

  46. Coburn MC et al. (1995) Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol 2: 386–391

    Article  CAS  Google Scholar 

  47. Schreibman IR et al. (2005) The hamartomatous polyposis syndromes: a clinical and molecular review. Am J Gastroenterol 100: 476–490

    Article  Google Scholar 

  48. Brosens LA et al. (2007) Risk of colorectal cancer in juvenile polyposis. Gut 56: 965–967

    Article  Google Scholar 

  49. Cao X et al. (2006) Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J Med Genet 43: e13

    Article  CAS  Google Scholar 

  50. Gallione CJ et al. (2004) A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet 363: 852–859

    Article  CAS  Google Scholar 

  51. Waite KA and Eng C (2003) From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family. Nat Rev Genet 4: 763–773

    Article  CAS  Google Scholar 

  52. Wang J et al. (1995) Demonstration that mutation of the type II transforming growth factor beta receptor inactivates its tumor suppressor activity in replication error-positive colon carcinoma cells. J Biol Chem 270: 22044–22049

    Article  CAS  Google Scholar 

  53. Grady WM et al. (1999) Mutational inactivation of transforming growth factor beta receptor type II in microsatellite stable colon cancers. Cancer Res 59: 320–324

    CAS  PubMed  Google Scholar 

  54. Grady WM and Markowitz SD (2002) Genetic and epigenetic alterations in colon cancer. Annu Rev Genomics Hum Genet 3: 101–128

    Article  CAS  Google Scholar 

  55. Howe JR et al. (2004) The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet 41: 484–491

    Article  CAS  Google Scholar 

  56. Howe J et al. (2007) ENG mutations in MADH4/BMPR1A mutation negative patients with juvenile polyposis. Clin Genet 71: 91–92

    Article  CAS  Google Scholar 

  57. Delnatte C et al. (2006) Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet 78: 1066–1074

    Article  CAS  Google Scholar 

  58. Tsuchiya KD et al. (1998) Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome. Genes Chromosomes Cancer 21: 113–118

    Article  CAS  Google Scholar 

  59. Jacoby RF et al. (1997) Del(10)(q22.3q24.1) associated with juvenile polyposis. Am J Med Genet 70: 361–364

    Article  CAS  Google Scholar 

  60. Eng C and Ji H (1998) Molecular classification of the inherited hamartoma polyposis syndromes: clearing the muddied waters. Am J Hum Genet 62: 1020–1022

    Article  CAS  Google Scholar 

  61. Eng C (2001) To be or not to BMP. Nat Genet 28: 105–107

    Article  CAS  Google Scholar 

  62. Takaku K et al. (1999) Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res 59: 6113–6117

    CAS  PubMed  Google Scholar 

  63. Mishina Y et al. (1995) Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev 9: 3027–3037

    Article  CAS  Google Scholar 

  64. Bourdeau A et al. (1999) A murine model of hereditary hemorrhagic telangiectasia. J Clin Invest 104: 1343–1351

    Article  CAS  Google Scholar 

  65. Chan OT and Haghighi P (2006) Hamartomatous polyps of the colon: ganglioneuromatous, stromal, and lipomatous. Arch Pathol Lab Med 130: 1561–1566

    PubMed  Google Scholar 

  66. Jacob S et al. (1998) Neurofibromatosis of the colon: an unusual manifestation of von Recklinghausen's diseases—a case report. Indian J Pathol Microbiol 41: 113–116

    CAS  PubMed  Google Scholar 

  67. Schwartz RA (1978) Basal-cell-nevus syndrome and gastrointestinal polyposis. N Engl J Med 299 49

    CAS  PubMed  Google Scholar 

  68. Whitelaw SC et al. (1997) Clinical and molecular features of the hereditary mixed polyposis syndrome. Gastroenterology 112: 327–334

    Article  CAS  Google Scholar 

  69. Jaeger EE et al. (2003) An ancestral Ashkenazi haplotype at the HMPS/CRAC1 locus on 15q13-q14 is associated with hereditary mixed polyposis syndrome. Am J Hum Genet 72: 1261–1267

    Article  CAS  Google Scholar 

  70. Fran DN et al. (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59: 490–498

    Article  Google Scholar 

  71. Rubio-Viqueira B and Hidalgo M (2006) Targeting mTOR for cancer treatment. Adv Exp Med Biol 587: 309–327

    Article  CAS  Google Scholar 

  72. Udd L et al. (2004) Suppression of Peutz–Jeghers polyposis by inhibition of cyclooxygenase-2. Gastroenterology 127: 1030–1037

    Article  CAS  Google Scholar 

  73. Brazowski E et al. (2005) Characteristics of familial juvenile polyps expressing cyclooxygenase-2. Am J Gastroenterol 100: 130–138

    Article  CAS  Google Scholar 

  74. Bosman FT (1999) The hamartoma-adenoma-carcinoma sequence. J Pathol 188: 1–2

    Article  CAS  Google Scholar 

  75. Perzin KH and Bridge MF (1982) Adenomatous and carcinomatous changes in hamartomatous polyps of the small intestine (Peutz–Jeghers syndrome): report of a case and review of the literature. Cancer 49: 971–983

    Article  CAS  Google Scholar 

  76. Mills SE and Fechner RE (1982) Unusual adenomatous polyps in juvenile polyposis coli. Am J Surg Pathol 6: 177–183

    Article  CAS  Google Scholar 

  77. Jansen M et al. (2006) Mucosal prolapse in the pathogenesis of Peutz–Jeghers polyposis. Gut 55: 1–5

    Article  CAS  Google Scholar 

  78. Clevers H (2005) Stem cells, asymmetric division and cancer. Nat Genet 37: 1027–1028

    Article  CAS  Google Scholar 

  79. Bronner M (2003) Gastrointestinal inherited polyposis syndromes. Mod Path 16: 359–365

    Article  Google Scholar 

Download references

Acknowledgements

KM Zbuk is a Crile Fellow of the Cleveland Clinic, USA. C Eng is a recipient of the Doris Duke Distinguished Clinical Scientist Award and is supported by grants from the US National Institutes of Health, US National Cancer Institute and the American Cancer Society. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscapeaccredited continuing medical education activity associated with this article.

Author information

Authors and Affiliations

  1. Department of Genetics, KM Zbuk is a Cancer Genomic Medicine Fellow and Crile Fellow at the Genomic Medicine Institute, Cleveland Clinic and C Eng is Chair and Director of the Genomic Medicine Institute and Director of the Center for Personalized Genetic Healthcare, Cleveland Clinic and Professor and Vice Chairman, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,

    Kevin M Zbuk & Charis Eng

Authors
  1. Kevin M Zbuk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Charis Eng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Charis Eng.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zbuk, K., Eng, C. Hamartomatous polyposis syndromes. Nat Rev Gastroenterol Hepatol 4, 492–502 (2007). https://doi.org/10.1038/ncpgasthep0902

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpgasthep0902

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing