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

OMIM number: 158350  

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
Operational diagnosis in an individual:
  • 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
Operational diagnosis for relative of patient(s) already diagnosed with Cowden syndrome: (1,2 or 3 present)
  • 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

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[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.