Abstract
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.
Similar content being viewed by others
References
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Chan, O. T., & Haghighi, P. (2006). Hamartomatous polyps of the colon: Ganglioneuromatous, stromal, and lipomatous. Archives of Pathology & Laboratory Medicine, 130(10), 1561–1566.
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.
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 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=18456716.
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.
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.
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.
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.
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.
Eng, C. (1997). Cowden syndrome. Journal of Genetic Counseling, 6, 181–191. doi:10.1023/A:1025664119494.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Hanssen, A. M. N., & Fryns, J. P. (1995). Cowden syndrome. Journal of Medical Genetics, 32, 117–119.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:10.1097/01.md.0000158792.24888.d2.
Longy, M., & Lacombe, D. (1996). Cowden disease. Report of a family and review. Annales de Genetique, 39, 35–42.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 http://www.nccn.org.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 http://seer.cancer.gov/csr/1975_2005/
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.
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.
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.
Santen, R. J., & Mansel, R. (2005). Benign breast disorders. The New England Journal of Medicine, 353(3), 275–285. doi:10.1056/NEJMra035692.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Tamguney, T., & Stokoe, D. (2007). New insights into PTEN. Journal of Cell Science, 120(Pt 23), 4071–4079. doi:10.1242/jcs.015230.
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.
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.
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.
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.
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.
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.
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.
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 http://www.genetests.org.
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.
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.
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.
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.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Pilarski, R. Cowden Syndrome: A Critical Review of the Clinical Literature. J Genet Counsel 18, 13–27 (2009). https://doi.org/10.1007/s10897-008-9187-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10897-008-9187-7