Journal of Genetic Counseling

, Volume 18, Issue 1, pp 13–27 | Cite as

Cowden Syndrome: A Critical Review of the Clinical Literature

  • Robert PilarskiEmail author


Cowden syndrome (CS) is a multi-system disease involving hamartomatous overgrowth of tissues of all three embryonic origins and increased risks for thyroid, breast and possibly other cancers. Benign breast, thyroid, uterine and skin lesions are also common. Approximately 80% of patients with CS have an identifiable germline mutation in the PTEN gene. The majority of the existing data on the frequencies of component clinical features have been obtained from compilations of case reports in the literature, many of which predate the establishment in 1996 of consensus diagnostic criteria. Many of these reports also suffer from ascertainment bias which emphasized the dermatologic features of the disease. This paper presents an overview of Cowden syndrome focusing on a critical evaluation of the major literature on the component cancers, benign features, and molecular findings in CS, noting the limitations of the published data.


Cowden syndrome PTEN PTEN hamartoma tumor syndrome PHTS 


  1. Ambler, M., Pogacar, S., & Sidman, R. (1969). Lhermitte–Duclos disease (granule cell hypertrophy of the cerebellum) pathological analysis of the first familial cases. Journal of Neuropathology and Experimental Neurology, 28(4), 622–647. doi: 10.1097/00005072-196910000-00005.PubMedCrossRefGoogle Scholar
  2. Bagan, J. V., Penarrocha, M., & Vera-Sempere, F. (1989). Cowden syndrome: Clinical and pathological considerations in two new cases. Journal of Oral and Maxillofacial Surgery, 47(3), 291–294. doi: 10.1016/0278-2391(89)90234-6.PubMedCrossRefGoogle Scholar
  3. Bancroft, L. W., Kransdorf, M. J., Peterson, J. J., & O’Connor, M. I. (2006). Benign fatty tumors: Classification, clinical course, imaging appearance, and treatment. Skeletal Radiology, 35(10), 719–733. doi: 10.1007/s00256-006-0189-y.PubMedCrossRefGoogle Scholar
  4. Biesecker, L. G., Happle, R., Mulliken, J. B., Weksberg, R., Graham, J. M., Viljoen, D. L., et al. (1999). Proteus syndrome: Diagnostic criteria, differential diagnosis and patient evaluation. American Journal of Medical Genetics, 84, 389–395. doi:10.1002/(SICI)1096-8628(19990611)84:5"<389::AID-AJMG1>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
  5. Black, D., Bogomolniy, F., Robson, M. E., Offit, K., Barakat, R. R., & Boyd, J. (2005). Evaluation of germline PTEN mutations in endometrial cancer patients. Gynecologic Oncology, 96(1), 21–24. doi: 10.1016/j.ygyno.2004.09.024.PubMedCrossRefGoogle Scholar
  6. Borgfeldt, C., & Andolf, E. (1999). Transvaginal sonographic ovarian findings in a random sample of women 25–40 years old. Ultrasound in Obstetrics & Gynecology, 13(5), 345–350. doi: 10.1046/j.1469-0705.1999.13050345.x.CrossRefGoogle Scholar
  7. Bosserhoff, A. K., Grussendorf-Conen, E. I., Rubben, A., Rudnik-Schoneborn, S., Zerres, K., Buettner, R., et al. (2006). Multiple colon carcinomas in a patient with Cowden syndrome. International Journal of Molecular Medicine, 18(4), 643–647.PubMedGoogle Scholar
  8. Boyle, K. J., & Torrealday, S. (2008). Benign gynecologic conditions. The Surgical Clinics of North America, 88(2), 245–264. doi: 10.1016/j.suc.2007.12.001.PubMedCrossRefGoogle Scholar
  9. Brownstein, M. H., Mehregan, A. H., & Bilowski, J. B. (1977). Trichilemmomas in Cowden’s disease. Journal of the American Medical Association, 238(1), 26. doi: 10.1001/jama.238.1.26.PubMedCrossRefGoogle Scholar
  10. Brownstein, M. H., Mehregan, A. H., Bikowski, J. B., Lupulescu, A., & Patterson, J. C. (1979). The dermatopathology of Cowden’s syndrome. The British Journal of Dermatology, 100(6), 667–673. doi: 10.1111/j.1365-2133.1979.tb08070.x.PubMedCrossRefGoogle Scholar
  11. Brownstein, M. H., Wolf, M., & Bikowski, J. B. (1978). Cowden’s disease: A cutaneous marker of breast cancer. Cancer, 41(6), 2393. –2398. doi:10.1002/1097-0142(197806)41:6"<2393::AID-CNCR2820410644>3.0.CO;2-K.PubMedCrossRefGoogle Scholar
  12. Butler, M. G., Dasouki, M. J., Zhou, X. P., Talebizadeh, Z., Brown, M., Takahashi, T. N., et al. (2005). Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. Journal of Medical Genetics, 42(4), 318–321. doi: 10.1136/jmg.2004.024646.PubMedCrossRefGoogle Scholar
  13. Buxbaum, J. D., Cai, G., Chaste, P., Nygren, G., Goldsmith, J., Reichert, J., et al. (2007). Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(4), 484–491. doi: 10.1002/ajmg.b.30493.CrossRefGoogle Scholar
  14. Carlson, G. J., Nivatvongs, S., & Snover, D. C. (1984). Colorectal polyps in Cowden’s disease (multiple hamartoma syndrome). The American Journal of Surgical Pathology, 8(10), 763–770. doi: 10.1097/00000478-198410000-00005.PubMedCrossRefGoogle Scholar
  15. Carroll, B. T., Couch, F. J., Rebbeck, T. R., & Weber, B. L. (1999). Polymorphisms in PTEN in breast cancer families. Journal of Medical Genetics, 36(2), 94–96.PubMedGoogle Scholar
  16. Chan, O. T., & Haghighi, P. (2006). Hamartomatous polyps of the colon: Ganglioneuromatous, stromal, and lipomatous. Archives of Pathology & Laboratory Medicine, 130(10), 1561–1566.Google Scholar
  17. Chen, Y. M., Ott, D. J., Wu, W. C., & Gelfand, D. W. (1987). Cowden’s disease: A case report and literature review. Gastrointestinal Radiology, 12(4), 325–329. doi: 10.1007/BF01885173.PubMedCrossRefGoogle Scholar
  18. Chibon, F., Primois, C., Bressieux, J. M., Lacombe, D., Lok, C., Mauriac, L., et al. (2008). Contribution of PTEN large rearrangements in Cowden disease: A MAPH screening approach. Journal of Medical Genetics. doi:10.1136/jmg.2008.058131. Retrieved May 2 from
  19. Cohen Jr, M. M., Turner, J. T., & Biesecker, L. G. (2003). Proteus syndrome: Misdiagnosis with PTEN mutations. American Journal of Medical Genetics. Part A, 122A(4), 323–324. doi: 10.1002/ajmg.a.20474.PubMedCrossRefGoogle Scholar
  20. Day Baird, D., Dunson, D. B., Hill, M. C., Cousins, D., & Schectman, J. M. (2003). High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence. American Journal of Obstetrics and Gynecology, 188(1), 100–107. doi: 10.1067/mob.2003.99.PubMedCrossRefGoogle Scholar
  21. Devi, M., Leonard, N., Silverman, S., Al-Qahtani, M., & Girgis, R. (2007). Testicular mixed germ cell tumor in an adolescent with Cowden disease. Oncology, 72(3–4), 194–196. doi: 10.1159/000112825.PubMedCrossRefGoogle Scholar
  22. De Vivo, I., Gertig, D. M., Nagase, S., Hankinson, S. E., O’Brien, R., Speizer, F. E., et al. (2000). Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers. Journal of Medical Genetics, 37(5), 336–341. doi: 10.1136/jmg.37.5.336.PubMedCrossRefGoogle Scholar
  23. Drolet, B. A., Esterly, N. B., & Frieden, I. J. (1999). Hemangiomas in children. The New England Journal of Medicine, 341(3), 173–181. doi: 10.1056/NEJM199907153410307.PubMedCrossRefGoogle Scholar
  24. Eng, C. (1997). Cowden syndrome. Journal of Genetic Counseling, 6, 181–191. doi: 10.1023/A:1025664119494.CrossRefGoogle Scholar
  25. Eng, C. (2000). Will the real Cowden syndrome please stand up: Revised diagnostic criteria. Journal of Medical Genetics, 37, 828–830. doi: 10.1136/jmg.37.11.828.PubMedCrossRefGoogle Scholar
  26. Fackenthal, J. D., Marsh, D. J., Richardson, A. L., Cummings, S. A., Eng, C., Robinson, B. G., et al. (2001). Male breast cancer in Cowden syndrome patients with germline PTEN mutations. Journal of Medical Genetics, 38(3), 159–164. doi: 10.1136/jmg.38.3.159.PubMedCrossRefGoogle Scholar
  27. FitzGerald, M. G., Marsh, D. J., Wahrer, D., Bell, D., Caron, S., Shannon, K. E., et al. (1998). Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene, 17(6), 727–731. doi: 10.1038/sj.onc.1201984.PubMedCrossRefGoogle Scholar
  28. Gorlin, R. J., Cohen, M. M., Condon, L. M., & Burke, B. A. (1992). Bannayan-Riley-Ruvalcaba syndrome. American Journal of Medical Genetics, 44(3), 307–314. doi: 10.1002/ajmg.1320440309.PubMedCrossRefGoogle Scholar
  29. Greene, S. L., Thomas, J. R., & Doyle, J. A. (1984). Cowden’s disease with associated malignant melanoma. International Journal of Dermatology, 23(7), 466–467.PubMedGoogle Scholar
  30. Guenard, F., Labrie, Y., Ouellette, G., Beauparlant, C. J., Bessette, P., Chiquette, J., et al. (2007). Germline mutations in the breast cancer susceptibility gene PTEN are rare in high-risk non-BRCA1/2 French Canadian breast cancer families. Familial Cancer, 6(4), 483–490. doi: 10.1007/s10689-007-9151-y.PubMedCrossRefGoogle Scholar
  31. Guldberg, P., thor Straten, P., Birck, A., Ahrenkiel, V., Kirkin, A. F., & Zeuthen, J. (1997). Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Research, 57(17), 3660–3663.PubMedGoogle Scholar
  32. Haibach, H., Burns, T. W., Carlson, H. E., Burman, K. D., & Deftos, L. J. (1992). Multiple hamartoma syndrome (Cowden’s disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). American Journal of Clinical Pathology, 97(5), 705–712.PubMedGoogle Scholar
  33. Haiman, C. A., Stram, D. O., Cheng, I., Giorgi, E. E., Pooler, L., Penney, K., et al. (2006). Common genetic variation at PTEN and risk of sporadic breast and prostate cancer. Cancer Epidemiology, Biomarkers & Prevention, 15(5), 1021–1025. doi: 10.1158/1055-9965.EPI-05-0896.CrossRefGoogle Scholar
  34. Hanssen, A. M. N., & Fryns, J. P. (1995). Cowden syndrome. Journal of Medical Genetics, 32, 117–119.PubMedCrossRefGoogle Scholar
  35. Hanssen, A. M., Werquin, H., Suys, E., & Fryns, J. P. (1993). Cowden syndrome: Report of a large family with macrocephaly and increased severity of signs in subsequent generations. Clinical Genetics, 44(6), 281–286.PubMedCrossRefGoogle Scholar
  36. Harach, H. R., Soubeyran, I., Brown, A., Bonneau, D., & Longy, M. (1999). Thyroid pathologic findings in patients with Cowden disease. Annals of Diagnostic Pathology, 3(6), 331–340. doi: 10.1016/S1092-9134(99)80011-2.PubMedCrossRefGoogle Scholar
  37. Herman, G. E., Butter, E., Enrile, B., Pastore, M., Prior, T. W., & Sommer, A. (2007). Increasing knowledge of PTEN germline mutations: Two additional patients with autism and macrocephaly. American Journal of Medical Genetics. Part A, 143(6), 589–593. doi: 10.1002/ajmg.a.31619.PubMedCrossRefGoogle Scholar
  38. Hover, A. R., Cawthern, T., & McDanial, W. (1986). Cowden disease. A hereditary polyposis syndrome diagnosable by mucocutaneous inspection. Journal of Clinical Gastroenterology, 8(5), 576–579. doi: 10.1097/00004836-198610000-00019.PubMedCrossRefGoogle Scholar
  39. Howe, J. R., Bair, J. L., Sayed, M. G., Anderson, M. E., Mitros, F. A., Petersen, G. M., et al. (2001). Germline mutations of the gene encoding bone morphogenetic protein receptor 1A in juvenile polyposis. Nature Genetics, 28(2), 184–187. doi: 10.1038/88919.PubMedCrossRefGoogle Scholar
  40. Howe, J. R., Roth, S., Ringold, J. C., Summers, R. W., Jarvinen, H. J., Sistonen, P., et al. (1998). Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science, 280(5366), 1086–1088. doi: 10.1126/science.280.5366.1086.PubMedCrossRefGoogle Scholar
  41. Huang, J., & Kontos, C. D. (2002). PTEN modulates vascular endothelial growth factor-mediated signaling and angiogenic effects. The Journal of Biological Chemistry, 277(13), 10760–10766. doi: 10.1074/jbc.M110219200.PubMedCrossRefGoogle Scholar
  42. Huang, S. C., Chen, C. R., Lavine, J. E., Taylor, S. F., Newbury, R. O., Pham, T. T., et al. (2000). Genetic heterogeneity in familial juvenile polyposis. Cancer Research, 60(24), 6882–6885.PubMedGoogle Scholar
  43. Kay, P. S., Soetikno, R. M., Mindelzun, R., & Young, H. S. (1997). Diffuse esophageal glycogenic acanthosis: An endoscopic marker of Cowden’s disease. The American Journal of Gastroenterology, 92(6), 1038–1040.PubMedGoogle Scholar
  44. Kimura, T., Suzuki, A., Fujita, Y., Yomogida, K., Lomeli, H., Asada, N., et al. (2003). Conditional loss of PTEN leads to testicular teratoma and enhances embryonic germ cell production. Development, 130(8), 1691–1700. doi: 10.1242/dev.00392.PubMedCrossRefGoogle Scholar
  45. Koul, D., Shen, R., Garyali, A., Ke, L. D., Liu, T. J., & Yung, W. K. (2002). MMAC/PTEN tumor suppressor gene regulates vascular endothelial growth factor-mediated angiogenesis in prostate cancer. International Journal of Oncology, 21(3), 469–475.PubMedGoogle Scholar
  46. Kurose, K., Araki, T., Matsunaka, T., Takada, Y., & Emi, M. (1999). Variant manifestation of Cowden disease in Japan: Hamartomatous polyposis of the digestive tract with mutation of the PTEN gene. American Journal of Human Genetics, 64(1), 308–310. doi: 10.1086/302207.PubMedCrossRefGoogle Scholar
  47. Lachlan, K. L., Lucassen, A. M., Bunyan, D., & Temple, I. K. (2007). Cowden syndrome and Bannayan Riley Ruvalcaba syndrome represent one condition with variable expression and age-related penetrance: Results of a clinical study of PTEN mutation carriers. Journal of Medical Genetics, 44(9), 579–585. doi: 10.1136/jmg.2007.049981.PubMedCrossRefGoogle Scholar
  48. Lashner, B. A., Riddell, R. H., & Winans, C. S. (1986). Ganglioneuromatosis of the colon and extensive glycogenic acanthosis in Cowden’s disease. Digestive Diseases and Sciences, 31(2), 213–216. doi: 10.1007/BF01300711.PubMedCrossRefGoogle Scholar
  49. Lauge, A., Lefebvre, C., Laurent-Puig, P., Caux, V., Gad, S., Eng, C., et al. (1999). No evidence for germline PTEN mutations in families with breast and brain tumours. International Journal of Cancer, 84(3), 216–219. doi:10.1002/(SICI)1097-0215(19990621)84:3"<216::AID-IJC3>3.0.CO;2-E.CrossRefGoogle Scholar
  50. Liaw, D., Marsh, D. J., Li, J., Dahia, P. L. M., Wang, S. I., Zheng, Z., et al. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genetics, 16, 64–67. doi: 10.1038/ng0597-64.PubMedCrossRefGoogle Scholar
  51. Lindsay, C., Boardman, L., & Farrell, M. (2003). Testicular hamartomas in Cowden disease. Journal of Clinical Ultrasound, 31(9), 481–483. doi: 10.1002/jcu.10209.PubMedCrossRefGoogle Scholar
  52. Lloyd, K. M., & Denis, M. (1963). Cowden’s disease: A possible new symptom complex with multiple system involvement. Annals of Internal Medicine, 58, 136–142.PubMedGoogle Scholar
  53. Lok, C., Viseux, V., Avril, M. F., Richard, M. A., Gondry-Jouet, C., Deramond, H., et al. (2005). Brain magnetic resonance imaging in patients with Cowden syndrome. Medicine; Analytical Reviews of General Medicine, Neurology, Psychiatry, Dermatology, and Pediatries, 84(2), 129–136. doi: 10.1097/ Scholar
  54. Longy, M., & Lacombe, D. (1996). Cowden disease. Report of a family and review. Annales de Genetique, 39, 35–42.PubMedGoogle Scholar
  55. Love, S. M., Gelman, R. S., & Silen, W. (1982). Sounding board. Fibrocystic “disease” of the breast—a nondisease? The New England Journal of Medicine, 307(16), 1010–1014.PubMedGoogle Scholar
  56. Lynch, E. D., Ostermeyer, E. A., Lee, M. K., Arena, J. F., Ji, H., Dann, J., et al. (1997). Inherited mutations in PTEN that are associated with breast cancer, Cowden syndrome and juvenile polyposis. American Journal of Human Genetics, 61, 1254–1260. doi: 10.1086/301639.PubMedCrossRefGoogle Scholar
  57. Marra, G., Armelao, F., Vecchio, F. M., Percesepe, A., & Anti, M. (1994). Cowden’s disease with extensive gastrointestinal polyposis. Journal of Clinical Gastroenterology, 18(1), 42–47. doi: 10.1097/00004836-199401000-00011.PubMedCrossRefGoogle Scholar
  58. Marsh, D. J., Caron, S., Dahia, P. L. M., Kum, J. B., Frayling, I. M., Tomlinson, I. P. M., et al. (1998a). Germline PTEN mutations in Cowden syndrome-like families. Journal of Medical Genetics, 35, 881–885.PubMedCrossRefGoogle Scholar
  59. Marsh, D. J., Coulon, V., Lunetta, K. L., Rocca-Serra, P., Dahia, P. L. M., Zheng, Z., et al. (1998b). Mutation spectrum and genotype–phenotype analyses in Cowden disease and Bannayan–Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Human Molecular Genetics, 7, 507–515. doi: 10.1093/hmg/7.3.507.PubMedCrossRefGoogle Scholar
  60. Marsh, D. J., Kum, J. B., Lunetta, K. L., Bennett, M. J., Gorlin, R. J., Ahmed, S. F., et al. (1999). PTEN mutation spectrum and genotype-phenotype correlations in Bannayan–Riley–Ruvalcaba syndrome suggest a single entity with Cowden syndrome. Human Molecular Genetics, 8, 1461–1472. doi: 10.1093/hmg/8.8.1461.PubMedCrossRefGoogle Scholar
  61. Mazereeuw-Hautier, J., Assouere, M. N., Moreau-Cabarrot, A., Longy, M., & Bonafe, J. L. (2004). Cowden’s syndrome: Possible association with testicular seminoma. The British Journal of Dermatology, 150(2), 378–379. doi: 10.1111/j.1365–2133.2003.05770.x.PubMedCrossRefGoogle Scholar
  62. McGarrity, T. J., Wagner Baker, M. J., Ruggiero, F. M., Thiboutot, D. M., Hampel, H., Zhou, X. P., et al. (2003). GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. The American Journal of Gastroenterology, 98(6), 1429–1434. doi: 10.1111/j.1572-0241.2003.07496.x.PubMedCrossRefGoogle Scholar
  63. Merg, A., & Howe, J. R. (2004). Genetic conditions associated with intestinal juvenile polyps. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics, 129C(1), 44–55. doi: 10.1002/ajmg.c.30020.PubMedCrossRefGoogle Scholar
  64. Mignogna, M. D., Lo Muzio, L., Ruocco, V., & Bucci, E. (1995). Early diagnosis of multiple hamartoma and neoplasia syndrome (Cowden disease). The role of the dentist. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics, 79(3), 295–299. doi: 10.1016/S1079-2104(05)80222-7.PubMedCrossRefGoogle Scholar
  65. Mutter, G. L., Lin, M. C., Fitzgerald, J. T., Kum, J. B., Baak, J. P., Lees, J. A., et al. (2000). Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. Journal of the National Cancer Institute, 92(11), 924. –930. doi: 10.1093/jnci/92.11.924.PubMedCrossRefGoogle Scholar
  66. National Comprehensive Cancer Network.I (2008). The NCCN genetic/familial high-risk assessment: Breast and ovarian (version 1.2008). Clinical Practice Guidelines in Oncology. Retrieved June 7 2008, from
  67. Nelen, M. R., Kremer, H., Konings, I. B. M., Schoute, F., van Essen, A. J., Koch, R., et al. (1999). Novel PTEN mutations in patients with Cowden disease: Absence of clear genotype-phenotype correlations. European Journal of Human Genetics, 7, 267–273. doi: 10.1038/sj.ejhg.5200289.PubMedCrossRefGoogle Scholar
  68. Nelen, M. R., Padberg, G. W., Peeters, E. A. J., Lin, A. Y., van den Helm, B., Frants, R. R., et al. (1996). Localization of the gene for Cowden disease to 10q22–23. Nature Genetics, 13, 114–116. doi: 10.1038/ng0596-114.PubMedCrossRefGoogle Scholar
  69. Nelen, M. R., van Staveren, C. G., Peeters, E. A. J., Ben Hassel, M., Gorlin, R. J., Hamm, H., et al. (1997). Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Human Molecular Genetics, 6, 1383–1387. doi: 10.1093/hmg/6.8.1383.PubMedCrossRefGoogle Scholar
  70. Ni, Y., Zbuk, K. M., Sadler, T., Patocs, A., Lobo, G., Edelman, E., et al. (2008). Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. American Journal of Human Genetics, 83(2), 261–268.PubMedCrossRefGoogle Scholar
  71. Olschwang, S., Serova-Sinilnikova, O. M., Lenoir, G. M., & Thomas, G. (1998). PTEN germ-line mutations in juvenile polyposis coli. Nature Genetics, 18(1), 12–14. doi: 10.1038/ng0198-12.PubMedCrossRefGoogle Scholar
  72. Padberg, G. W., Schot, J. D. L., Vielvoye, G. J., Bots, G. T. A. M., & de Beer, F. C. (1991). Lhermitte-Duclos disease and Cowden syndrome: A single phakomatosis. Annals of Neurology, 29, 517–523. doi: 10.1002/ana.410290511.PubMedCrossRefGoogle Scholar
  73. Parisi, M., Dinulos, M. B., Leppid, K. A., Sybert, V. P., Eng, C., & Hudgins, L. (2001). The spectrum and evolution of phenotypic findings in PTEN mutation positive cases of Bannayan-Riley-Ruvalcaba syndrome. Journal of Medical Genetics, 38, 52–57.PubMedCrossRefGoogle Scholar
  74. Pilarski, R., & Eng, C. (2004). Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. Journal of Medical Genetics, 41(5), 323–326. doi: 10.1136/jmg.2004.018036.PubMedCrossRefGoogle Scholar
  75. Reifenberger, J., Rauch, L., Beckmann, M. W., Megahed, M., Ruzicka, T., & Reifenberger, G. (2003). Cowden’s disease: Clinical and molecular genetic findings in a patient with a novel PTEN germline mutation. The British Journal of Dermatology, 148(5), 1040–1046. doi: 10.1046/j.1365-2133.2003.05322.x.PubMedCrossRefGoogle Scholar
  76. Ries, L. A. G., Melbert, D., Krapcho, M, Stinchcomb, D. G., Howlader, N., Horner, M. J., et al. (Eds.) (2008). SEER Cancer Statistics Review, 1975–2005. Retrieved from
  77. Robinson, S., & Cohen, A. R. (2006). Cowden disease and Lhermitte–Duclos disease: An update. Case report and review of the literature. Neurosurgical Focus, 20(1), E6. doi: 10.3171/foc.2006.20.1.7.CrossRefGoogle Scholar
  78. Rosen, J. E., & Stone, M. D. (2006). Contemporary diagnostic approach to the thyroid nodule. Journal of Surgical Oncology, 94(8), 649–661. doi: 10.1002/jso.20701.PubMedCrossRefGoogle Scholar
  79. Salem, O. S., & Steck, W. D. (1983). Cowden’s disease (multiple hamartoma and neoplasia syndrome). A case report and review of the English literature. Journal of the American Academy of Dermatology, 8(5), 686–696.PubMedCrossRefGoogle Scholar
  80. Santen, R. J., & Mansel, R. (2005). Benign breast disorders. The New England Journal of Medicine, 353(3), 275–285. doi: 10.1056/NEJMra035692.PubMedCrossRefGoogle Scholar
  81. Schaffer, J. V., Kamino, H., Witkiewicz, A., McNiff, J. M., & Orlow, S. J. (2006). Mucocutaneous neuromas: An underrecognized manifestation of PTEN hamartoma-tumor syndrome. Archives of Dermatology, 142(5), 625–632. doi: 10.1001/archderm.142.5.625.PubMedCrossRefGoogle Scholar
  82. Schrager, C. A., Schneider, D., Gruener, A. C., Tsou, H. C., & Peacocke, M. (1997). Clinical and pathological features of breast disease in Cowden’s syndrome: An underrecognised syndrome with an increased risk of breast cancer. Human Pathology, 29, 47–53.CrossRefGoogle Scholar
  83. Shugart, Y. Y., Cour, C., Renard, H., Lenoir, G., Goldgar, D., Teare, D., et al. (1999). Linkage analysis of 56 multiplex families excludes the Cowden disease gene PTEN as a major contributor to familial breast cancer. Journal of Medical Genetics, 36(9), 720–721.PubMedGoogle Scholar
  84. Stambolic, V., Tsao, M. S., Macpherson, D., Suzuki, A., Chapman, W. B., & Mak, T. W. (2000). High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Research, 60(13), 3605–3611.PubMedGoogle Scholar
  85. Starink, T. M. (1984). Cowden’s disease: Analysis of fourteen new cases. Journal of the American Academy of Dermatology, 11(6), 1127–1141. doi: 10.1016/S0190-9622(84)70270-2.PubMedCrossRefGoogle Scholar
  86. Starink, T. M., & Hausman, R. (1984a). The cutaneous pathology of extrafacial lesions in Cowden’s disease. Journal of Cutaneous Pathology, 11(5), 338–344. doi: 10.1111/j.1600-0560.1984.tb00389.x.PubMedCrossRefGoogle Scholar
  87. Starink, T. M., & Hausman, R. (1984b). The cutaneous pathology of facial lesions in Cowden’s disease. Journal of Cutaneous Pathology, 11(5), 331–337. doi: 10.1111/j.1600-0560.1984.tb00388.x.PubMedCrossRefGoogle Scholar
  88. Starink, T. M., Meijer, C. J., & Brownstein, M. H. (1985). The cutaneous pathology of Cowden’s disease: New findings. Journal of Cutaneous Pathology, 12(2), 83–93. doi: 10.1111/j.1600-0560.1985.tb01607.x.PubMedCrossRefGoogle Scholar
  89. Starink, T. M., van der Veen, J. P. W., Arwert, F., de Waal, L. P., de Lange, G. G., Gille, J. J. P., et al. (1986). The Cowden syndrome: A clinical and genetic study in 21 patients. Clinical Genetics, 29, 222–233.PubMedGoogle Scholar
  90. Sweet, K., Willis, J., Zhou, X. P., Gallione, C., Sawada, T., Alhopuro, P., et al. (2005). Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. Journal of the American Medical Association, 294(19), 2465–2473. doi: 10.1001/jama.294.19.2465.PubMedCrossRefGoogle Scholar
  91. Tamguney, T., & Stokoe, D. (2007). New insights into PTEN. Journal of Cell Science, 120(Pt 23), 4071–4079. doi: 10.1242/jcs.015230.PubMedCrossRefGoogle Scholar
  92. Tan, W. H., Baris, H. N., Burrows, P. E., Robson, C. D., Alomari, A. I., Mulliken, J. B., et al. (2007). The spectrum of vascular anomalies in patients with PTEN mutations: Implications for diagnosis and management. Journal of Medical Genetics, 44(9), 594–602. doi: 10.1136/jmg.2007.048934.PubMedCrossRefGoogle Scholar
  93. Taylor, A. J., Dodds, W. J., & Stewart, E. T. (1989). Alimentary tract lesions in Cowden’s disease. The British Journal of Radiology, 62(742), 890–892.PubMedCrossRefGoogle Scholar
  94. Tsou, H. C., Teng, D. H., Ping, X. L., Brancolini, V., Davis, T., Hu, R., et al. (1997). The role of MMAC1 mutations in early-onset breast cancer: Causative in association with Cowden syndrome and excluded in BRCA1-negative cases. American Journal of Human Genetics, 61(5), 1036–1043. doi: 10.1086/301607.PubMedCrossRefGoogle Scholar
  95. Turnbull, M. M., Humeniuk, V., Stein, B., & Suthers, G. K. (2005). Arteriovenous malformations in Cowden syndrome. Journal of Medical Genetics, 42(8), 50. doi: 10.1136/jmg.2004.030569.CrossRefGoogle Scholar
  96. Weary, P. E., Gorlin, R. J., Gentry, W. C., Comer, J. E., & Greer, K. E. (1972). Multiple hamartoma syndrome (Cowden’s disease). Archives of Dermatology, 106(5), 682–690. doi: 10.1001/archderm.106.5.682.PubMedCrossRefGoogle Scholar
  97. Woodhouse, J. B., Delahunt, B., English, S. F., Fraser, H. H., & Ferguson, M. M. (2005). Testicular lipomatosis in Cowden’s syndrome. Modern Pathology, 18(9), 1151–1156. doi: 10.1038/modpathol.3800448.PubMedCrossRefGoogle Scholar
  98. Woodhouse, J., & Ferguson, M. M. (2006). Multiple hyperechoic testicular lesions are a common finding on ultrasound in Cowden disease and represent lipomatosis of the testis. The British Journal of Radiology, 79(946), 801–803. doi: 10.1259/bjr/50628431.PubMedCrossRefGoogle Scholar
  99. Zbuk, K. M., Stein, J. L., & Eng, C.(2006). PTEN Hamartoma Tumor Syndrome (PHTS). GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Retrieved from
  100. Zhou, X., Hampel, H., Thiele, H., Gorlin, R. J., Hennekam, R. C., Parisi, M., et al. (2001a). Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet, 358(9277), 210–211. doi: 10.1016/S0140-6736(01)05412-5.PubMedCrossRefGoogle Scholar
  101. Zhou, X. P., Marsh, D. J., Hampel, H., Mulliken, J. B., Gimm, O., & Eng, C. (2000). Germline and germline mosaic mutations associated with a Proteus-like syndrome of hemihypertrophy, lower limb asymmetry, arterio-venous malformations and lipomatosis. Human Molecular Genetics, 9, 765–768. doi: 10.1093/hmg/9.5.765.PubMedCrossRefGoogle Scholar
  102. Zhou, X. P., Marsh, D. J., Morrison, C. D., Chaudhury, A. R., Maxwell, M., Reifenberger, G., et al. (2003a). Germline inactivation of PTEN and dysregulation of the phosphoinositol-3-kinase/Akt pathway cause human Lhermitte–Duclos disease in adults. American Journal of Human Genetics, 73(5), 1191–1198. doi: 10.1086/379382.PubMedCrossRefGoogle Scholar
  103. Zhou, X. P., Waite, K. A., Pilarski, R., Hampel, H., Fernandez, M. J., Bos, C., et al. (2003b). 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. American Journal of Human Genetics, 73(2), 404–411. doi: 10.1086/377109.PubMedCrossRefGoogle Scholar
  104. Zhou, X. P., Woodford-Richens, K., Lehtonen, R., Kurose, K., Aldred, M., Hampel, H., et al. (2001b). Germline mutations in BMPR1A/ALK3 cause a subset of cases of juvenile polyposis syndrome and of Cowden and Bannayan–Riley–Ruvalcaba syndromes. American Journal of Human Genetics, 69(4), 704–711. doi: 10.1086/323703.PubMedCrossRefGoogle Scholar

Copyright information

© National Society of Genetic Counselors, Inc. 2008

Authors and Affiliations

  1. 1.Division of Human Genetics, Department of Internal Medicine and Clinical Cancer Genetics Program, Comprehensive Cancer Center, James Cancer Hospital and Solove Research InstituteOhio State UniversityColumbusUSA
  2. 2.Clinical Cancer Genetics ProgramOhio State UniversityColumbusUSA

Personalised recommendations