Cowden Disease

Other names	Multiple hamartoma syndrome
Inheritance	autosomal dominant; high penetrance (close to 100% by the age of 30 yrs); highly variable expressivity (between and within families)

Clinics

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 Name	PTEN (or MMAC1 or TEP1)
Location	10q23

Protein
Expression	403 amino-acids, phosphatase with tumor suppressive effects, negative regulator of the PI3K/Akt signal cell pathway by dephosphorylating PIP3

Mutations
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

External links

GeneCards	PTEN
GDB	PTEN
OMIM	158350
Orphanet	Cowden syndrome
HGMD	6022948
Other database	Pediatric Database

Bibliography

Cowden's disease. A possible new symptom complex with multiple system involvement.

LLOYD KM 2nd, DENNIS M

Annals of internal medicine. 1963 ; 58 : 136-142.

PMID 13931122

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 (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

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

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 disease. Report of a family and review.

Longy M, Lacombe D

Annales de genetique. 1996 ; 39 (1) : 35-42.

PMID 9297442

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

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

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, Dubouˆ© 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

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

Contributor(s)

Written	06-2000	Michel Longy
		Unite de Genetique Oncologique, Institut Bergonie, 180, rue de Saint-Genes, 33076 Bordeaux, France

Citation

This paper should be referenced as such :

Longy M . Cowden Disease. Atlas Genet Cytogenet Oncol Haematol. June 2000 . URL : http://AtlasGeneticsOncology.org/Kprones/CowdenID10018.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon May 12 18:13:40 2008

For comments and suggestions or contributions, please contact us