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Cowden Disease (Multiple Hamartoma Syndrome)

  • Author: Katherine H Fiala, MD; Chief Editor: William D James, MD  more...
 
Updated: Feb 07, 2014
 

Background

Cowden disease, also termed Cowden syndrome and multiple hamartoma syndrome, is an autosomal dominant condition with variable expression that can be associated with a mutation in the PTEN gene on arm 10q, as reported by Liaw et al.[1] Originally described in 1963 by Lloyd and Dennis, Cowden disease (multiple hamartoma syndrome) was named after the family in which it was first reported.[2] A broader category, PTEN (phosphatase and tensin homolog) hamartoma tumor syndrome includes Cowden disease (multiple hamartoma syndrome), Bannayan-Riley-Ruvulcaba syndrome (BRRS), Proteus syndrome, and Proteus-like syndrome, which all have PTEN mutations.

Cowden disease (multiple hamartoma syndrome) causes hamartomatous neoplasms of the skin and mucosa, GI tract, bones, CNS, eyes, and genitourinary tract. Skin is involved in 90-100% of cases, and the thyroid is involved in 66% of cases.

Mucocutaneous features of Cowden disease (multiple hamartoma syndrome) include trichilemmomas, oral mucosal papillomatosis, acral keratoses, and palmoplantar keratoses. Cowden disease (multiple hamartoma syndrome) is associated with the development of several types of malignancy, which is why recognition of individuals with the syndrome is important. In particular, a marked increase is seen in the incidence of breast carcinoma in women and of thyroid carcinoma in both men and women. Reports also exist of several other types of malignancies, such as colon cancer and renal cell carcinoma, in patients with Cowden disease (multiple hamartoma syndrome).

Note the clinical image below.

A patient with trichilemmoma papules on the face. A patient with trichilemmoma papules on the face.
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Pathophysiology

Traditionally, Cowden disease (multiple hamartoma syndrome) is caused by a mutation in the PTEN tumor suppressor gene (also termed MMAC1 or TEP1) on band 10q23.3. The protein product of the gene is a phosphatase that negatively controls the phosphoinositide 3-kinase–signaling pathway for regulating cell growth and survival by dephosphorylating the 3 position of phosphoinositide.

The original reports of families studied at tertiary referral centers found PTEN mutations in 80% of patients clinically diagnosed with Cowden disease.[1] However, newer prospective reports of unrelated individuals identified PTEN mutations in approximately 25% of individuals studied.[3] The relationship between Cowden disease and PTEN mutations is under investigation. Deep sequencing techniques have identified PTEN mosaicism not detected by traditional techniques.[4] Another study discovered germline mutations downstream in the phosphoinositide 3-kinase–signaling pathway.[5] Additional mutations related to the Cowden disease phenotype have been reported.[6, 7]

The PTEN protein is believed to promote cell death. A mutation that causes loss of the protein's function may result in overproliferation of cells, resulting in hamartomatous growths. Part of this overproliferation may be due to some interaction between the PTEN tumor suppressor gene and a more widely known tumor suppressor gene, TP53.PTEN mutations have been found to occur most frequently in association with endometrial cancer, glioblastomas, and prostate cancer.[8]

Identical mutations in PTEN have been described in Bannayan-Ruvulcaba-Riley syndrome (BRRS). Alternate names for BRRS include Bannayan-Zonana syndrome, Riley-Smith syndrome, and Ruvulcaba-Myhre-Smith syndrome.[9] Patients with BRRS have a much lower predisposition to cancer, which suggests that a mutation in the PTEN gene is not the only factor responsible for the clinical features of the disease.

A percentage of patients with Proteuslike syndromes, adult Lhermitte-Duclos disease (LDD), and autismlike disorders associated with macrocephaly have also demonstrated PTEN mutations.

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Epidemiology

Frequency

International

Internationally, more than 300 cases have been published, including separate studies of several generations of affected family members, as reported by Tok Celebri et al.[10] The prevalence of Cowden disease (multiple hamartoma syndrome) is estimated to be approximately 1 case per 200,000 population; however, it is likely more prevalent because many features of Cowden disease (multiple hamartoma syndrome) are found in the general population and the diagnosis may be overlooked, which leads to underdiagnosis. Penetrance is thought to be nearly complete; it approaches 90% by age 20 years.[11]

Mortality/Morbidity

Morbidity and mortality from Cowden disease (multiple hamartoma syndrome) primarily is associated with increased frequency of malignant tumors. Benign tumors that develop in Cowden disease (multiple hamartoma syndrome) patients also can cause significant morbidity.

Sex

Males and females inherit the mutated gene in equal number; it is autosomal dominant. Cutaneous manifestations of Cowden disease (multiple hamartoma syndrome) are similar in both sexes. However, the incidence of malignancies varies depending on the sex. For example, males are more likely to develop thyroid cancer, while females are at greater risk for breast cancer.

Age

Although the mutant gene is inherited, the onset of clinical manifestations of Cowden disease (multiple hamartoma syndrome) varies in age, ranging from birth to age 46 years.

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Contributor Information and Disclosures
Author

Katherine H Fiala, MD Assistant Professor, Department of Dermatology, Scott and White Northside Clinic

Katherine H Fiala, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Christian Medical and Dental Associations

Disclosure: Nothing to disclose.

Coauthor(s)

Christopher Grant Staples, MD Chief Resident, Department of Dermatology, Texas A&M University Health Science Center, Scott & White

Christopher Grant Staples, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association, Society for Pediatric Dermatology, Texas Dermatological Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Lester F Libow, MD Dermatopathologist, South Texas Dermatopathology Laboratory

Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Texas Medical Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Craig A Elmets, MD Professor and Chair, Department of Dermatology, Director, Chemoprevention Program Director, Comprehensive Cancer Center, UAB Skin Diseases Research Center, University of Alabama at Birmingham School of Medicine

Craig A Elmets, MD is a member of the following medical societies: American Academy of Dermatology, American Association of Immunologists, American College of Physicians, American Federation for Medical Research, Society for Investigative Dermatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: University of Alabama at Birmingham; University of Alabama Health Services Foundation<br/>Serve(d) as a speaker or a member of a speakers bureau for: Ferndale Laboratories<br/>Received research grant from: NIH, Veterans Administration, California Grape Assn<br/>Received consulting fee from Astellas for review panel membership; Received salary from Massachusetts Medical Society for employment; Received salary from UpToDate for employment. for: Astellas.

Acknowledgements

Christopher Grant Staples, MD Resident Physician, Scott and White Dermatology

Disclosure: Nothing to disclose.

Charles Miller, MD Chief, Department of Dermatology, Kaiser Permanente

Charles Miller is a member of the following medical societies: American Academy of Dermatology.

Disclosure: Nothing to disclose.

References
  1. Liaw D, Marsh DJ, Li J, et al. Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet. 1997 May. 16(1):64-7. [Medline].

  2. Lloyd KM II, Dennis M. Cowden's disease. A possible new symptoms complex with multiple system involvement. Ann Intern Med. 1963. 58:136-142.

  3. Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2011 Jan 7. 88(1):42-56. [Medline].

  4. Pritchard CC, Smith C, Marushchak T, Koehler K, Holmes H, Raskind W. A mosaic PTEN mutation causing Cowden syndrome identified by deep sequencing. Genet Med. 2013 Dec. 15(12):1004-7. [Medline].

  5. Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013 Jan 10. 92(1):76-80. [Medline].

  6. Waite KA, Eng C. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet. 2003 Mar 15. 12(6):679-84. [Medline].

  7. Bennett KL, Mester J, Eng C. Germline epigenetic regulation of KILLIN in Cowden and Cowden-like syndrome. JAMA. 2010 Dec 22. 304(24):2724-31. [Medline].

  8. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene. 2008 Sep 18. 27(41):5443-53. [Medline].

  9. Chen H and Fang J. Genetics of the hamartomatous polyposis syndromes: a molecular review. Int J Colorectal Dis. 2009 Aug. 24(8):865-74. [Medline].

  10. Tok Celebi J, Chen FF, Zhang H, Ping XL, Tsou HC, Peacocke M. Identification of PTEN mutations in five families with Bannayan-Zonana syndrome. Exp Dermatol. 1999 Apr. 8(2):134-9. [Medline].

  11. Hobert JA, Eng C. PTEN hamartoma tumor syndrome: an overview. Genet Med. 2009 Oct. 11(10):687-94. [Medline].

  12. Schaffer JV, Kamino H, Witkiewicz A, McNiff JM, Orlow SJ. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Arch Dermatol. 2006 May. 142(5):625-32. [Medline].

  13. Requena L, Gutierrez J, Sanchez Yus E. Multiple sclerotic fibromas of the skin. A cutaneous marker of Cowden's disease. J Cutan Pathol. 1992 Aug. 19(4):346-51. [Medline].

  14. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with cowden syndrome: A meta-analysis. Head Neck. 2012 Mar 20. [Medline].

  15. Fackenthal JD, Marsh DJ, Richardson AL, et al. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. J Med Genet. 2001 Mar. 38(3):159-64. [Medline].

  16. Chen YM, Ott DJ, Wu WC, Gelfand DW. Cowden's disease: a case report and literature review. Gastrointest Radiol. 1987. 12(4):325-9. [Medline].

  17. Nishizawa A, Satoh T, Watanabe R, et al. Cowden syndrome: a novel mutation and overlooked glycogenic acanthosis in gingiva. Br J Dermatol. 2009 May. 160(5):1116-8. [Medline].

  18. Schmeler KM, Daniels MS, Brandt AC, Lu KH. Endometrial cancer in an adolescent: a possible manifestation of Cowden syndrome. Obstet Gynecol. 2009 Aug. 114(2 Pt 2):477-9. [Medline].

  19. Woodhouse J, Ferguson MM. Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. Br J Radiol. 2006 Oct. 79(946):801-3. [Medline].

  20. Yen BC, Kahn H, Schiller AL, Klein MJ, Phelps RG, Lebwohl MG. Multiple hamartoma syndrome with osteosarcoma. Arch Pathol Lab Med. 1993 Dec. 117(12):1252-4. [Medline].

  21. Walsh S, Carter M, Tubridy N, McDermott EW. Lhermitte-Duclos and Cowden diseases: breast cancer as an unusual initial presentation of these overlapping conditions. BMJ Case Rep. 2011 Oct 20. 2011:[Medline].

  22. Lok C, Viseux V, Avril MF, et al. Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine (Baltimore). 2005 Mar. 84(2):129-36. [Medline].

  23. Pilarski R, Burt R, Kohlman W, Pho L, Shannon KM, Swisher E. Cowden syndrome and the PTEN hamartoma tumor syndrome: systematic review and revised diagnostic criteria. J Natl Cancer Inst. 2013 Nov 6. 105(21):1607-16. [Medline].

  24. Loffeld A, McLellan NJ, Cole T, Payne SJ, Fricker D, Moss C. Epidermal naevus in Proteus syndrome showing loss of heterozygosity for an inherited PTEN mutation. Br J Dermatol. 2006 Jun. 154(6):1194-8. [Medline].

  25. Milas M, Mester J, Metzger R, Shin J, Mitchell J, Berber E. Should patients with Cowden syndrome undergo prophylactic thyroidectomy?. Surgery. 2012 Dec. 152(6):1201-10. [Medline].

  26. Van Calenbergh F, Vantomme N, Flamen P, et al. Lhermitte-Duclos disease: 11C-methionine positron emission tomography data in 4 patients. Surg Neurol. 2006 Mar. 65(3):293-6; discussion 296-7. [Medline].

  27. Bosserhoff AK, Grussendorf-Conen EI, Rubben A, et al. Multiple colon carcinomas in a patient with Cowden syndrome. Int J Mol Med. 2006 Oct. 18(4):643-7. [Medline].

  28. Pilarski R. Cowden syndrome: a critical review of the clinical literature. J Genet Couns. 2009 Feb. 18(1):13-27. [Medline].

  29. O'Hare AM, Cooper PH, Parlette HL 3rd. Trichilemmomal carcinoma in a patient with Cowden's disease (multiple hamartoma syndrome). J Am Acad Dermatol. 1997 Jun. 36(6 Pt 1):1021-3. [Medline].

  30. Cnudde F, Boulard F, Muller P, Chevallier J, Teron-Abou B. [Cowden disease: treatment with acitretine]. Ann Dermatol Venereol. 1996. 123(11):739-41. [Medline].

  31. Walton BJ, Morain WD, Baughman RD, Jordan A, Crichlow RW. Cowden's disease: a further indication for prophylactic mastectomy. Surgery. 1986 Jan. 99(1):82-6. [Medline].

  32. Squarize CH, Castilho RM, Gutkind JS. Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin. Cancer Res. 2008 Sep 1. 68(17):7066-72. [Medline].

  33. Tan MH, Mester JL, Ngeow J, Rybicki LA, Orloff MS, Eng C. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012 Jan 15. 18(2):400-7. [Medline].

  34. Diggelmann HR, Van Daele DJ, O'Dorisio TM, Hoffman HT. Insular thyroid carcinoma in a patient with Cowden syndrome. Laryngoscope. 2010 Mar. 120(3):454-7. [Medline].

  35. Blumenthal GM, Dennis PA. PTEN hamartoma tumor syndromes. Eur J Hum Genet. 2008 Nov. 16(11):1289-300. [Medline].

 
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A patient with trichilemmoma papules on the face.
Multiple benign oral fibromas.
Multiple trichilemmomas in patient with Cowden disease.
 
 
 
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