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Cowden disease

Tuesday 2 November 2004

multiple hamartoma syndrome, Cowden syndrome; PTEN hamartoma tumor syndrome (PHTS).

Definition: Cowden syndrome is a rare autosomal dominant condition named after the Cowden family in which it was initially documented.

Manifestations of the syndrome include gastrointestinal, oral and cutaneous hamartomas, tumors of breast and thyroid, autoimmune thyroiditis, macrocephaly, and mental impairment.

The colorectal polyps have been described variously as hamartomatous, inflammatory, and occasionally adenomatous. Nevertheless, there is little or no risk of colorectal malignancy.

The underlying mechanism is germline mutation of the PTEN gene on chromosome 10q23. PTEN mutations also account for the Bannayan-Riley-Ruvalcaba syndrome, which is phenotypically very similar to Cowden syndrome but is associated with penile speckled pigmentation and presents in infancy.

Cowden polyps

Pathologists frequently fail to suspect a diagnosis of Cowden syndrome. There may be confusion with juvenile polyps, and juvenile polyposis syndrome (JPS) was initially linked with germline mutation of PTEN as a result of such misdiagnoses. Cowden polyps may also be mislabeled as hyperplastic polyps.

Cowden polyps of the colorectum are generally small and nodular, and the expanded lamina propria is more myofibroblastic than edematous.

The crypts may be surrounded by fibroblasts or myofibroblasts in an onion-skin arrangement and may be arranged in lobular clusters.

Stromal ganglion cells have been described on rare occasions, but are in fact seen quite frequently if one searches for them.

Rare reports of juvenile polyposis with ganglioneuromatous features may in fact be examples CS.

One large series of juvenile polyposis syndrome (JPS) cases found no examples of stromal ganglion cells.

Allelic diseases

Autosomal dominant disease allelic with Bannayan-Riley-Ruvalcaba syndrome (PTEN mutations).

Cowden syndrome and Bannayan-Ruvalcaba-Riley syndrome (BRRS; MIM.153480) share clinical characteristics such as hamartomatous polyps of the gastrointestinal tract, mucocutaneous lesions, and increased risk of developing neoplasms.

Furthermore, both conditions and several other distinctive phenotypes are caused by mutations in the PTEN gene.

For this reason, it has been suggested that the spectrum of disorders be referred to as PTEN hamartoma tumor syndrome (PHTS).

Approximately 80% of CS patients have PTEN mutations.

Phenocopies

- Mutations in the SDHB (MIM.185470) and SDHD (MIM.602690) genes have been identified in a subset of PTEN mutation-negative patients with a Cowden-like syndrome (MIM.612359).

Synopsis

- craniofacial anomalies

  • progressive macrocephaly
  • "birdlike" facies
  • hypoplastic mandible
  • hypoplastic maxilla
  • cataract
  • angioid streaks
  • myopia
  • microstomia
  • high-arched palate
  • scrotal tongue
  • oral papillomas

- thyroid aomalies (30%)

- digestive anomalies

  • hamartomatous polyps
  • colon diverticula

- skeletal anomalies

  • scoliosis
  • kyphosis
  • pectus excavatum

- genital anomalies

  • virginal hyperplasia
  • fibrocystic breast disease
  • gynecomastia in males
  • breast fibroadenomas
  • hydrocele
  • varicocele
  • vaginal cysts
  • vulvar cysts
  • ovarian cysts
  • uterine leiomyomas

- cutaneous anomalies

  • multiple facial papules
  • acral keratoses
  • palmoplantar keratoses
  • multiple inverted follicular keratoses
  • multiple skin tags
  • facial trichilemmomas
  • subcutaneous lipomas

- neurocerebral anomalies

  • Lhermitte-Duclos disease
  • cerebellar gangliocytoma (seizure and tremor)

- tumors predisposition

  • breast cancer
  • thyroid follicular carcinoma
  • thyroid medullary carcinoma (17603316)
  • endometrial adenocarcinoma
  • ovarian carcinoma
  • cervical carcinoma
  • transitional cell carcinoma of the bladder
  • colon adenocarcinoma
  • meningioma

Etiology

- germline mutations in PTEN gene (MIM.601728)

- germline mutations in Cowden-like syndrome in genes

Immunochemistry

- Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome. (21921783)

References

- Immunohistochemical staining of thyroidectomy specimens for PTEN can aid in the identification of patients with Cowden syndrome. Barletta JA, Bellizzi AM, Hornick JL. Am J Surg Pathol. 2011 Oct;35(10):1505-11. PMID: 21921783