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Cowden disease

Written2000-06Michel Longy
Unite de Genetique Oncologique, Institut Bergonie, 180, rue de Saint-Genes, 33076 Bordeaux, France

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Other namesMultiple hamartoma syndrome
Atlas_Id 10018
Genes implicated inPTEN   SDHB   SDHD  
Inheritance autosomal dominant; high penetrance (close to 100% by the age of 30 yrs); highly variable expressivity (between and within families)


Phenotype and clinics clinical manifestations usually occur during the 2nd and 3rd decade; they are dystrophic, hamartomatous or tumoral lesions including the following to variable extend:
- mucocutaneous papillomatous lesions (facial papules, sometimes related to trichilemmoma; oral papillomatosis with cobblestone gingiva; acral keratoses)
- both dystrophic and adenomatous multinodular goiter
- intestinal tract polyps with variable histologies
- adenosis and fibrocystic disease of the breast
- macrocephaly
- lipomas
- genito-urinary abnormalities
Overlapping syndromes
  • Bannayan-Riley-Ruvalcaba syndrome including precocious stigmata of Cowden disease (macrocephaly, lipomas, genital pigmented macules, hamartomatous intestinal tract polyps) is considered as a pediatric form of Cowden disease
  • Lhermitte Duclos syndrome or dysplastic gangliocytoma of the cerebelum is a rare and complex hamartomatous condition of the cerebellum which can occur alone but also in association with Cowden disease
  • juvenile polyposis and Peutz Jeghers syndrome : Cowden disease, by its intestinal tract lesions can be linked to the scope of hereditary hamartomatous polyposis; molecular diagnosis can be useful in distinguishing juvenile polyposis, Peutz Jeghers syndrome or Cowden disease/Bannayan
  • Neoplastic risk
  • the main neoplastic risks arethyroid carcinoma (follicular type) and breast carcinoma of various histological types which are reported in respectively 15% of the patients and 30% of the affected women.
  • other tumor types occur rarely but more frequently than expected in the general population: renal cell carcinoma, neuroendocrine cell carcinoma, germ cell tumor, malignant melanoma, endometrial carcinoma
  • Genes involved and Proteins

    Gene NamePTEN (Phosphatase and Tensin homolog deleted on chromosome Ten)
    Location 10q23.31
    Expression 403 amino-acids, phosphatase with tumor suppressive effects, negative regulator of the PI3K/Akt signal cell pathway by dephosphorylating PIP3
    Germinal to date, at least 110 mutations have been described; they are observed along the various exons of the gene except the 9th (never described) and the 1st (very few reports); a mutational hot spot is observed in exon 5 in relation with the catalytic core motif; in the great majority of cases, inactivating mutations are observed, either by protein truncation, or by misense mutation within the phosphatase domain
    Somatic a lot of somatic mutations (more than 300) have been described in several tumor types but mainly in glioblastoma and in endometrial carcinoma; they lead to a biallelic inactivation of the gene more often by a combination of point mutation and large deletion of the second allele


    Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 24-1987. A 56-year-old man with a substernal goiter, multiple cutaneous and mucosal lesions, and a positive stool test for occult blood.
    The New England journal of medicine. 1987 ; 316 (24) : 1531-1540.
    PMID 3587282
    Cowden's disease: a cutaneous marker of breast cancer.
    Brownstein MH, Wolf M, Bikowski JB
    Cancer. 1978 ; 41 (6) : 2393-2398.
    PMID 657103
    Cowden's disease. A possible new symptom complex with multiple system involvement.
    Annals of internal medicine. 1963 ; 58 : 136-142.
    PMID 13931122
    Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
    Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R
    Nature genetics. 1997 ; 16 (1) : 64-67.
    PMID 9140396
    Cowden disease. Report of a family and review.
    Longy M, Lacombe D
    Annales de genetique. 1996 ; 39 (1) : 35-42.
    PMID 9297442
    Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
    Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, Liaw D, Caron S, Duboué 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, Eng C
    Human molecular genetics. 1998 ; 7 (3) : 507-515.
    PMID 9467011
    Localization of the gene for Cowden disease to chromosome 10q22-23.
    Nelen MR, Padberg GW, Peeters EA, Lin AY, van den Helm B, Frants RR, Coulon V, Goldstein AM, van Reen MM, Easton DF, Eeles RA, Hodgsen S, Mulvihill JJ, Murday VA, Tucker MA, Mariman EC, Starink TM, Ponder BA, Ropers HH, Kremer H, Longy M, Eng C
    Nature genetics. 1996 ; 13 (1) : 114-116.
    PMID 8673088
    Lhermitte-Duclos disease and Cowden disease: a single phakomatosis.
    Padberg GW, Schot JD, Vielvoye GJ, Bots GT, de Beer FC
    Annals of neurology. 1991 ; 29 (5) : 517-523.
    PMID 1859181
    Cowden's disease (multiple hamartoma and neoplasia syndrome). A case report and review of the English literature.
    Salem OS, Steck WD
    Journal of the American Academy of Dermatology. 1983 ; 8 (5) : 686-696.
    PMID 6863628
    The Cowden syndrome: a clinical and genetic study in 21 patients.
    Starink TM, van der Veen JP, Arwert F, de Waal LP, de Lange GG, Gille JJ, Eriksson AW
    Clinical genetics. 1986 ; 29 (3) : 222-233.
    PMID 3698331


    This paper should be referenced as such :
    Longy, M
    Cowden disease
    Atlas Genet Cytogenet Oncol Haematol. 2000;4(3):153-154.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 5 ]


    External links

    OrphanetCowden syndrome
    Other databaseCowden syndrome (GARD)
    Other databasePediatric Database
    Genes implicated inPTEN   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inSDHB   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  
    Genes implicated inSDHD   [ Atlas ]   [ Entrez ]  [ LOVD ]  [ GeneReviews ]  

    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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