Cancer prone diseases
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Unite de Genetique Oncologique, Institut Bergonie, 180, rue de Saint-Genes, 33076 Bordeaux, France
Multiple hamartoma syndrome
autosomal dominant; high penetrance (close to 100% by the age of 30 yrs); highly variable expressivity (between and within families)
158350 , 612359 , 615106
201 Cowden syndrome
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
- genito-urinary abnormalities
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
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
403 amino-acids, phosphatase with tumor suppressive effects, negative regulator of the PI3K\/Akt signal cell pathway by dephosphorylating PIP3
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
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
To be noted
http:\/\/www.icondata.com\/health\/pedbase\/files\/COWDENS.HTM Pediatric Database
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.
Cowden's disease: a cutaneous marker of breast cancer.
Brownstein MH et al
Cowden's disease. A possible new symptom complex with multiple system involvement.
LLOYD KM 2nd et al
Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome.
Liaw D et al
Cowden disease. Report of a family and review.
Longy M et al
Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation.
Marsh DJ et al
Localization of the gene for Cowden disease to chromosome 10q22-23.
Nelen MR et al
Lhermitte-Duclos disease and Cowden disease: a single phakomatosis.
Padberg GW et al
Cowden's disease (multiple hamartoma and neoplasia syndrome). A case report and review of the English literature.
Salem OS et al
The Cowden syndrome: a clinical and genetic study in 21 patients.
Starink TM et al
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