FaCD Online Syndrome Fact Sheet

Last updated: 13 Mar 2013

Name: Cowden syndrome

Synonym: CS, Cowden disease, Multiple Hamartoma Syndrome, incl.: Lhermitte-Duclos; part of PTEN hamartoma tumour syndrome (PHTS) / PTEN-MATCHS, Cowden-like syndrome

Mode of Inheritance: AD

Genes

ATK1, mapped to 14q32.32
KILLIN, mapped to 10q23
PIK3CA, mapped to 3q26.32
PTEN, mapped to 10q23.3
SDHB, mapped to 1p36.1-p35
SDHD, mapped to 11q23

Tumor features

breast cancer
breast cancer, male
cerebellar dysplastic gangliocytoma
colorectal cancer
colorectal hyperplastic polyps
cutaneous hemangioma
endometrial cancer
ganglioneuromatosis, intestinal
gastrointestinal hamartomas
gastrointestinal polyps, juvenile type
intestinal hyperplastic polyps
lipoma
lung hamartoma
oral papules
renal cell cancer
thyroid adenoma
thyroid cancer, follicular
thyroid cancer, papillary
trichilemmoma
urinary tract hamartomas
uterine leiomyoma

Tumor features (possible)

carcinoid, general
cervical cancer
colorectal neuromas
ependymoma
gastric cancer
glioblastoma (multiforme)
hepatocellular cancer (hepatoma)
leukemia, acute myeloid (AML, incl. ANLL)
liposarcoma
melanoma, cutaneous
meningioma
neuroendocrine (Merkel cell) skin carcinoma
non-Hodgkin lymphoma
non-seminoma
osteosarcoma
ovarian cancer (i.e. epithelial origin)
ovarian dysgerminoma
ovarian granulosa cell tumor
ovarian teratoma
pancreatic adenocarcinoma
pancreatic tumor
parathyroid adenoma
pulmonary hamartoma
seminoma
skin cancer, basal cell
tongue cancer
urinary bladder cancer

Non-tumor features

actinic keratosis
arteriovenous malformation
frontal bossing / prominent forehead
glycogenic acanthosis of the esophagus
macrocephaly
palmar pits
palmoplantar hyperkeratosis
plantar pits

Non-tumor features (possible)

immunodeficiency

Comment

This syndrome is characterized by multiple facial trichilemmomas[1] (85-90%, they may become malignant), multiple sclerotic dermal fibromas, oral papules (>80%, giving a cobblestone appearance, including a so-called scrotal tongue), multiple gastrointestinal[2,3,54] and urinary tract hamartomatous polyps (40-60%, which rarely become malignant). Colorectal polyps in this syndrome are most commonly of the hyperplastic type[55]. The esophageal lesions have been characterized as glycogenic acanthosis[51]. These type of lesions of the gingiva have been observed as well[52]. Acral and palmoplantar punctate keratosis[50] and macrocephaly are other characteristic findings. The skin may also show lipomas, fibromas, hemangiomas and neuromas.[4-8,38,49]. A large proportion of Cowden syndrome cases(50-75%?) appear to be isolated[5,54].

Common tumor spectrum
Tumor risks have been reported as follows[5,54]: Fibrocystic breast disease in 76% of patients. Many of the women with Cowden syndrome and benign breast disease have a wide range and extensive presence of these lesions which include hamartous lesions[9,35]. The hamartous benign lesions may surround the foci of breast cancer[9]. Breast cancer is found in 25-81% of the female patients (50% of breast cancers are bilateral) at average age of onset 38 years, but has been reported as early as 14 years. Lipomas occurs in 41%, thyroid cancer in 7%, usually of the follicular type, and benign thyroid adenomas or goiter in approximately 50%. The thyroid lesions are usually multifocal, benign and well demarcated[10]). Follicular and papilllary thyroid cancer can occur in children with PTEN mutations and have been reported as early as 12 and 9 years, respectively[53]. Thyroid adenomas have been identified as early as age 6 years in children with Cowden syndrome[53]. Endometrial cancer risk [54], colorectal cancer risk [18,37,54,55] and renal cell cancer risk [20,54] are increased. Colorectal cancer typically occurs before the age of 50 years[55]. Lhermitte-Duclos disease, dysplastic gangliocytoma of the cerebellum, is an additional manifestation of the disease[23-28].

Other tumors
A wide range of other benign and malignant tumors have been reported in Cowden disease, which include male breast cancer, cervical cancer[11], uterine leiomyomas[11], ovarian teratomas[11], ovarian granulosa cell tumor[17] and dysgerminoma[48], testicular seminoma, mixed germ cell tumor, hamartomas and lipomatosis[33,40,42,43,54], genital cancer (not further specified)[31], AML associated with a deficiency in T-lymphocyte function[12], parathyroid adenoma[13], gastric cancer[13], malignant melanoma[14,54], squamous cell tongue cancer[15], perianal basal cell skin cancer[15], osteosarcoma[16], bladder cancer[5,54], hepatocellular cancer[5,54], pancreatic cancer[5], carcinoid [54], glioblastoma[5], liposarcoma[5], colon cancer[18,37], ganglioneuromas of the colon[19], Merkel cell skin cancer[20], NHL[21], intramedullary ependymoma[36], lung adenocarcinoma[31] and hamartoma[22,44].

Bannayan-Riley-Ruvalcaba syndrome is a variant of Cowden disease and there is clinical overlap with Proteus / Proteus-like syndrome[45,46], Juvenile Polyposis and hyperplastic/mixed polyposis[39]. DiLiberti[30] proposed the name PTEN-MATCHS (Macrocephaly, Autosomal dominant, Thyroid disease, Cancer, Hamartomata, Skin abnormalities) to cover the clinical spectrum associated with germline PTEN mutations. The name PTEN hamartoma tumour syndrome (PHTS) has been coined for the same purpose[49]. Patients with features reminiscent of CS, not meeting the Cowden syndrome diagnostic criteria have been referred to as Cowden-like syndrome[47]

Genes
In 80% of patients with Cowden syndrome a germline PTEN mutation can be identified. Ni et al[47] note that 1% to 5% of SDHB/SDHD mutation carriers have renal cell cancer or papillary thyroid tumors. Therefore, there is an overlap between the familial paraganglioma syndromes and Cowden syndrome. Ni et al performed SDHB/D mutation analysis in CS/CS-like, PTEN mutation negative and indeed detected mutations/variants in these genes. Compared to PTEN mutation patients, carriers of SDH mutations/variants were enriched for carcinomas of the female breast, thyroid and kidney[47]. In more than 40% of Cowden syndrome and 33% of Cowden-like syndrome PTEN mutation negative patients, Bennett et al[56,57] identified hypermethylation of the promotor which regulates PTEN as well as, through a different binding site, the neighbouring KILLIN tumor suppressor gene. Decreased expression of the KILLIN but not of PTEN was detected in these patients. Recently ATK1 and PIK3CA have been suggested as well[60]

Pilarski et[58] al have recently developed an online model to predict the presence of a germline PTEN mutation in a patient. Tan et al[59] have developed an alternative model. The classic criteria for Cowden syndrome are shown below.

International Cowden Consortium operational criteria (2006)[47]:

• Pathognomonic criteria:
• - facial trichilemmoma
• - acral keratosis
• - papillomatous papules
• - mucosal lesions
• - Lhermitte-Duclos disease
• Major criteria:
• - breast cancer
• - epithelial thyroid cancer
• - macrocephaly (megalencephaly) (head circumference equal or greater than 97th centile)
• - endometrial cancer
• Minor criteria:
• - other anatomic thyroid lesions (e.g. adenoma, multinodular goiter)
• - mental retardation (IQ equal or lower than 75)
• - gastrointestinal hamartomas
• - fibrocystic breast disease
• - lipomas
• - fibromas
• - genito-urinary tumors (e.g. renal cell cancer, uterine fibroids) or malformation

• 1) in case only mucocutaneous lesions are present:
• a) at least 6 facial papules (at least 3 of which are trichilemmomas);
• or
• b) cutaneous facial papules + oral mucosal papillomatosis;
• or
• c) oral mucosal papillomatosis + acral keratoses;
• or
• d) at least 6 palmoplantar keratoses
• 2) 2 major criteria (should include macrocephaly and/or Lhermitte-Duclos disease)
• 3) 1 major + 3 minor criteria
• 4) 4 minor criteria

• 1) the pathognomonic criterion/ia
• 2) any 1 major criterion
• 3) 2 minor criteria

Links

booklet by Virtual Children's Hospital 18 1 08
OHIO PTEN mutation prediction model 28 7 2011

References

[1] Starink TM, Hausman R. The cutaneous pathology of facial lesions in Cowden's disease. J Cutan Pathol 1984; 11:331-337.
[2] Marra G, Armelao F, Vecchio FM, Percesepe A, Anti M. Cowden's disease with extensive gastrointestinal polyposis. J Clin Gastroenterol 1994; 18(1):42-47.
[3] Hizawa K, Iida M, Matsumoto T, Kohrogi N, Suekane H, Yao T, Fujishima M. Gastrointestinal manifestations of Cowden's disease. Report of four cases. J Clin Gastroenterol 1994; 18(1):13-18.
[4] Hanssen AMN, Fryns JP. Cowden syndrome. J Med Genet 1995; 32(2):117-119.
[5] Eng C. Genetics of Cowden syndrome: Through the looking glass of oncology (Review). Int J Oncol 12[3], 701-710. 1998.
[6] Takenoshita Y, Kubo S, Takeuchi T, Iida M. Oral and facial lesions in Cowden's disease: report of two cases and a review of the literature. J Oral Maxillofac Surg 1993; 51(6):682-687.
[7] Starink TM, van der Veen JPW, Arwert F, de Waal LP, de Lange GG, Gille JJP, Eriksson AW. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet 1986; 29(3):222-233.
[8] Starink TM, Hausman R. The cutaneous pathology of extrafacial lesions in Cowden's disease. J Cutan Pathol 1984; 11(5):338-344.
[9] Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M. Clinical and pathological features of breast disease in Cowden's syndrome: An underrecognized syndrome with an increased risk of breast cancer. Hum Pathol 29[1], 47-53. 1998.
[10] Harach HR, Soubeyran I, Brown A, Bonneau D, Longy M. Thyroid pathologic findings in patients with Cowden disease. Ann Diagn Pathol 1999; 3(6):331-340.
[11] Guerin V, Bene MC, Judlin P, Beurey J, Landes P, Faure G. Cowden disease in a young girl: gynecologic and immunologic overview in a case and in the literature. Obstet Gynecol 1989; 73(5 Pt 2):890-892.
[12] Ruschak PJ, Kauh YC, Luscombe HA. Cowden's disease associated with immunodeficiency. Arch Dermatol 1981; 117(9):573-575.
[13] Hamby LS, Lee EY, Schwartz RW. Parathyroid adenoma and gastric carcinoma as manifestations of Cowden's disease. Surgery 1995; 118:115-117.
[14] Greene SL, Thomas JR, Doyle JA. Cowden's disease with associated malignant melanoma. Int J Dermatol 1984; 23(7):466-467.
[15] Camisa C, Bikowski JB, McDonald SG. Cowden's disease. Association with squamous cell carcinoma of the tongue and perianal basal cell carcinoma. Arch Dermatol 1984; 120(5):677-678.
[16] Yen BC, Kahn H, Schiller AL, Klein MJ, Phelps RG, Lebwohl MG. Multiple hamartoma syndrome with osteosarcoma. Arch Pathol Lab Med 1993; 117(12):1252-1254.
[17] Neumann S. [Cowden syndrome with an ovarian tumor (multiple hamartoma syndrome]. Chirurg 1991; 62(8):629-630.
[18] Hover AR, Cawthern T, McDanial W. Cowden disease. A hereditary polyposis syndrome diagnosable by mucocutaneous inspection. J Clin Gastroenterol 1986; 8(5):576-579.
[19] Lashner BA, Riddell RH, Winans CS. Ganglioneuromatosis of the colon and extensive glycogenic acanthosis in Cowden's disease. Dig Dis Sci 1986; 31(2):213-216.
[20] Haibach H, Burns TW, Carlson HE, Burman KD, Deftos LJ. Multiple hamartoma syndrome (Cowden's disease) associated with renal cell carcinoma and primary neuroendocrine carcinoma of the skin (Merkel cell carcinoma). Am J Clin Pathol 1992; 97(5):705-712.
[21] Elston DM, James WD, Rodman OG, Graham GF. Multiple hamartoma syndrome (Cowden's disease) associated with non-Hodgkin's lymphoma. Arch Dermatol 1986; 122(5):572-575.
[22] Sasaki M, Hakozaki H, Ishihara T. Cowden's disease with pulmonary hamartoma. Intern Med 1993; 32(1):39-41.
[23] Milbouw G, Born JD, Martin D, Collignon J, Hans P, Reznik M, Bonnal J. Clinical and radiological aspects of dysplastic gangliocytoma (Lhermitte-Duclos disease): a report of two cases with review of the literature. Neurosurgery 1988; 22(1):124-128.
[24] Padberg GW, Schot JDL, Vielvoye GJ, Bots GTAM, de Beer FC. Lhermitte-Duclos disease and Cowden disease: a single phakomatosis [see comments]. Ann Neurol 1991; 29(5):517-523.
[25] Rimbau J, Isamat F. Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease) and its relation to the multiple hamartoma syndrome (Cowden disease). J Neurooncol 1994; 18(3):191-197.
[26] Vital A, Vital C, Martin-Negrier ML, Mc Grogan G, Bioulac P, Trojani M, Loiseau H, Rougier A. Lhermitte-Duclos type cerebellum hamartoma and Cowden disease. Clin Neuropathol 1994; 13(4):229-231.
[27] Wells GB, Lasner TM, Yousem DM, Zager EL. Lhermitte-Duclos disease and Cowden's syndrome in an adolescent patient - Case report. J Neurosurg 1994; 81:133-136.
[28] Iida S, Tanaka Y, Fujii H, Hayashi S, Kimura M, Nagareda T, Moriwaki K. A heterozygous frameshift mutation of the PTEN/MMAC1 gene in a patient with Lhermitte-Duclos disease - Only the mutated allele was expressed in the cerebellar tumor. Int J Mol Med 1[6], 925-929. 1998.
[29] Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PLM, Zheng ZM, Liaw D, Caron S, Duboue B, Lin AY, Richardson AL, Bonnetblanc JM, Bressieux JM, Cabarrot-Moreau A, Chompret A, Demange L, Eeles RA, Yahanda AM, Fearon ER, Fricker JP, Gorlin RJ, Hodgson SV, Huson S, Lacombe D, LePrat F, Odent S, Toulouse C, Olopade OI, Sobol H, Tishler S, Woods CG, Robinson BG, Weber HC, Parsons R, Peacocke M, Longy M, Eng C. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7[3], 507-515. 1998.
[30] DiLiberti JH. Inherited macrocephaly-hamartoma syndromes. Am J Med Genet 79[4], 284-290. 1998.
[31] De Vivo I, Gertig DM, Nagase S, Hankinson SE, O'Brien R, Speizer FE, Parsons R, Hunter DJ. Novel germline mutations in the PTEN tumour suppressor gene found in women with multiple cancers. J Med Genet 2000; 37:336-341.
[32] Eng C. Will the real cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000; 37:828-830.
[33] Devi M, Leonard N, Silverman S, Al-Qahtani M, Girgis R. Testicular mixed germ cell tumor in an adolescent with cowden disease. Oncology 2007; 72(3-4):194-6.
[34] Fackenthal JD, Marsh DJ, Richardson AL, Cummings SA, Eng C, Robinson BG, Olopade OI. Male breast cancer in Cowden syndrome patients with germline PTEN mutations. Journal of medical genetics 2001; 38(3):159-64.
[35] Sabaté JM, Gómez A, Torrubia S, Blancas C, Sánchez G, Alonso MC, Lerma E. Evaluation of breast involvement in relation to Cowden syndrome: a radiological and clinicopathological study of patients with PTEN germ-line mutations. European radiology 2006; 16(3):702-6.
[36] Farhadi MR, Rittierodt M, Stan A, Capelle HH, Tham-Mücke B, Krauss JK. Intramedullary ependymoma associated with Lhermitte-Duclos disease and Cowden syndrome. Clinical neurology and neurosurgery 2007; 109(8):692-7.
[37] Bosserhoff AK, Grussendorf-Conen EI, Rübben A, Rudnik-Schöneborn S, Zerres K, Buettner R, Merkelbach-Bruse S. Multiple colon carcinomas in a patient with Cowden syndrome. International journal of molecular medicine 2006; 18(4):643-7.
[38] Schaffer JV, Kamino H, Witkiewicz A, McNiff JM, Orlow SJ. Mucocutaneous neuromas: an underrecognized manifestation of PTEN hamartoma-tumor syndrome. Archives of dermatology 2006; 142(5):625-32.
[39] Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA : the journal of the American Medical Association 2005; 294(19):2465-73.
[40] Woodhouse JB, Delahunt B, English SF, Fraser HH, Ferguson MM. Testicular lipomatosis in Cowden's syndrome. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2005; 18(9):1151-6.
[41] Pilarski R, Eng C. Will the real Cowden syndrome please stand up (again)? Expanding mutational and clinical spectra of the PTEN hamartoma tumour syndrome. Journal of medical genetics 2004; 41(5):323-6.
[42] Mazereeuw-Hautier J, Assouère MN, Moreau-Cabarrot A, Longy M, Bonafé JL. Cowden's syndrome: possible association with testicular seminoma. The British journal of dermatology 2004; 150(2):378-9.
[43] Lindsay C, Boardman L, Farrell M. Testicular hamartomas in Cowden disease. Journal of clinical ultrasound : JCU 2003 Nov-Dec; 31(9):481-3.
[44] Cottin V, Thomas L, Loire R, Chalabreysse L, Gindre D, Cordier JF. Mesenchymal cystic hamartoma of the lung in Cowden's disease. Respiratory medicine 2003; 97(2):188-91.
[45] Zhou X, Hampel H, Thiele H, Gorlin RJ, Hennekam RC, Parisi M, Winter RM, Eng C. Association of germline mutation in the PTEN tumour suppressor gene and Proteus and Proteus-like syndromes. Lancet 2001; 358(9277):210-1.
[46] Barker K, Martinez A, Wang R, Bevan S, Murday V, Shipley J, Houlston R, Harper J. PTEN mutations are uncommon in Proteus syndrome. Journal of medical genetics 2001; 38(7):480-1.
[47] Ni Y, Zbuk KM, Sadler T, Patocs A, Lobo G, Edelman E, Platzer P, Orloff MS, Waite KA, Eng C. Germline Mutations and Variants in the Succinate Dehydrogenase Genes in Cowden and Cowden-like Syndromes. American journal of human genetics 2008; 83(2):261-268.
[48] Cho MY, Kim HS, Eng C, Kim DS, Kang SJ, Eom M, Yi SY, Bronner MP. First report of ovarian dysgerminoma in Cowden syndrome with germline PTEN mutation and PTEN-related 10q loss of tumor heterozygosity. The American journal of surgical pathology 2008; 32(8):1258-64.
[49] Orloff MS, Eng C. Genetic and phenotypic heterogeneity in the PTEN hamartoma tumour syndrome. Oncogene 2008; 27(41):5387-97.
[50] Ferran M, Bussaglia E, Matias-Guiu X, Pujol RM. Bilateral and symmetrical palmoplantar punctate keratoses in childhood: a possible clinical clue for an early diagnosis of PTEN hamartoma-tumour syndrome. Clin Exp Dermatol. 2009 Jul;34(5):e28-30.
[51] McGarrity TJ, Wagner Baker MJ, Ruggiero FM, Thiboutot DM, Hampel H, Zhou XP, Eng C. GI polyposis and glycogenic acanthosis of the esophagus associated with PTEN mutation positive Cowden syndrome in the absence of cutaneous manifestations. Am J Gastroenterol. 2003 Jun;98(6):1429-34.
[52] Nishizawa A, Satoh T, Watanabe R, Takayama K, Nakano H, Sawamura D, Yokozeki H. Cowden syndrome: a novel mutation and overlooked glycogenic acanthosis in gingiva.Br J Dermatol. 2009 May;160(5):1116-8.
[53] Smith JR, Marqusee E, Webb S, Nose V, Fishman SJ, Shamberger RC, Frates MC, Huang SA. Thyroid Nodules and Cancer in Children with PTEN Hamartoma Tumor Syndrome. J Clin Endocrinol Metab. 2010 Oct 20. [Epub ahead of print]
[54] Riegert-Johnson DL, Gleeson FC, Roberts M, Tholen K, Youngborg L, Bullock M, Boardman LA. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010 Jun 17;8(1):6.
[55] Heald B, Mester J, Rybicki L, Orloff MS, Burke CA, Eng C. Frequent Gastrointestinal Polyps and Colorectal Adenocarcinomas in a Prospective Series of PTEN Mutation Carriers. Gastroenterology. 2010 Jun 27. [Epub ahead of print]
[56] Bennett KL, Mester J, Eng C. Germline Epigenetic Regulation of KILLIN in Cowden and Cowden-like Syndrome. JAMA. 2010 Dec 22;304(24):2724-2731.
[57] Jelovac D, Park BH. PTEN Promoter Silencing and Cowden Syndrome: The Role of Epigenetic Regulation of KILLIN. JAMA. 2010 Dec 22;304(24):2744-2745
[58] Pilarski R, Stephens JA, Noss R, Fisher JL, Prior TW. Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features. J Med Genet. 2011 Aug;48(8):505-12.
[59] Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, Milas K, Pederson H, Remzi B, Orloff MS, Eng C. 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.
[60] Orloff MS, He X, Peterson C, Chen F, Chen JL, Mester JL, Eng C. Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. Am J Hum Genet. 2013 Jan 10;92(1):76-80.