Download Cancer Prone Disease Section Cowden disease Atlas of Genetics and Cytogenetics

Atlas of Genetics and Cytogenetics
in Oncology and Haematology
OPEN ACCESS JOURNAL AT INIST-CNRS
Cancer Prone Disease Section
Mini Review
Cowden disease
Michel Longy
Unite de Genetique Oncologique, Institut Bergonie, 180, rue de Saint-Genes, 33076 Bordeaux, France (ML)
Published in Atlas Database: June 2000
Online updated version : http://AtlasGeneticsOncology.org/Kprones/CowdenID10018.html
DOI: 10.4267/2042/37655
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence.
© 2000 Atlas of Genetics and Cytogenetics in Oncology and Haematology
polyposis; molecular diagnosis can be useful in
distinguishing juvenile polyposis, Peutz Jeghers
syndrome or Cowden disease/Bannayan.
Identity
Alias: Multiple hamartoma syndrome
Inheritance: Autosomal dominant; high penetrance
(close to 100% by the age of 30 yrs); highly variable
expressivity (between and within families).
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.
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
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(3)
Genes involved and proteins
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.
153
Cowden disease
Longy M
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. Localization of the gene for Cowden
disease to chromosome 10q22-23. Nat Genet. 1996
May;13(1):114-6
References
LLOYD KM 2nd, DENNIS M. Cowden's disease. A possible
new symptom complex with multiple system involvement. Ann
Intern Med. 1963 Jan;58:136-42
Brownstein MH, Wolf M, Bikowski JB. Cowden's disease: a
cutaneous marker of breast cancer. Cancer. 1978
Jun;41(6):2393-8
Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S,
Call KM, Tsou HC, Peacocke M, Eng C, Parsons R. Germline
mutations of the PTEN gene in Cowden disease, an inherited
breast and thyroid cancer syndrome. Nat Genet. 1997
May;16(1):64-7
Salem OS, Steck WD. Cowden's disease (multiple hamartoma
and neoplasia syndrome). A case report and review of the
English literature. J Am Acad Dermatol. 1983 May;8(5):686-96
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.
Mutation spectrum and genotype-phenotype analyses in
Cowden disease and Bannayan-Zonana syndrome, two
hamartoma syndromes with germline PTEN mutation. Hum
Mol Genet. 1998 Mar;7(3):507-15
Starink TM, van der Veen JP, Arwert F, de Waal LP, de Lange
GG, Gille JJ, Eriksson AW. The Cowden syndrome: a clinical
and genetic study in 21 patients. Clin Genet. 1986
Mar;29(3):222-33
. 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. N Engl J
Med. 1987 Jun 11;316(24):1531-40
This article should be referenced as such:
Padberg GW, Schot JD, Vielvoye GJ, Bots GT, de Beer FC.
Lhermitte-Duclos disease and Cowden disease: a single
phakomatosis. Ann Neurol. 1991 May;29(5):517-23
Longy M. Cowden disease. Atlas Genet Cytogenet Oncol
Haematol. 2000; 4(3):153-154.
Longy M, Lacombe D. Cowden disease. Report of a family and
review. Ann Genet. 1996;39(1):35-42
Atlas Genet Cytogenet Oncol Haematol. 2000; 4(3)
154