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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

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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

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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.

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  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.,

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

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