Cowden syndrome is an autosomal dominant characterised by the development of multiple hamartomas in any organ and an increased risk for certain malignancies.
Description
Cowden syndrome, or multiple hamartoma syndrome, is an autosomal dominant inherited disorder caused by germline mutations in the PTEN gene. It is characterised by multiple hamartomas throughout the body and an increased risk for various malignancies, particularly breast, thyroid, and endometrial cancers.
Pathogenesis
The PTEN gene is a tumour suppressor gene, mutations of which lead to unregulated cell proliferation and survival. In Cowden syndrome, germline mutations of the PTEN gene result in a predisposition to benign and malignant tumour development.
Subtypes
There are no recognised subtypes of Cowden syndrome.
Epidemiology, Risk Factors & Associations
- Cowden syndrome is a rare disorder, affecting approximately 1 in 200,000 individuals.
- The disease equally affects both genders and all ethnic groups.
- A positive family history is the most significant risk factor.
- Lhermitte-Duclose disease (dysplastic cerebellar ganglion) – rare tumour of the cerebellum
Clinical Features
- Characteristic mucocutaneous lesions including trichilemmomas, oral papillomas, and acral keratoses.
- More than 85% of patients may have gastrointestinal involvement with hamartomatous polyps.
- Increased risk of malignancies, especially breast cancer, thyroid cancer, and endometrial cancer.
- Macrocephaly is a common feature.
- Intellectual disability is present in a minority of individuals.
Complications
The most significant complication of Cowden syndrome is the increased risk for certain malignancies. The lifetime risk for breast cancer is up to 85%, for thyroid cancer up to 35%, and for endometrial cancer up to 28%.
Pathological Features
Histopathology
- Macroscopic: Hamartomas can develop in various organs; these are benign, disorganised overgrowths of tissue.
- Microscopic: The hamartomas characteristically demonstrate overgrowth of normal tissue elements in a disorganised fashion.
Serology
No specific serological markers for Cowden syndrome.
Biochemistry
No specific biochemical markers for Cowden syndrome.
Radiological Features
General Features
- Imaging findings are diverse, reflecting the systemic nature of the disease and the variety of potential hamartomas and malignancies.
- Characteristic findings include multiple enhancing intracranial meningiomas and vascular malformations.
CT
- In the brain, CT may show multiple enhancing lesions representing meningiomas.
- In the breast, CT may demonstrate multiple benign-appearing lesions as well as malignant lesions.
MRI
- T1WI: Lesions can be isointense to slightly hyperintense.
- T2WI: Lesions can be hyperintense.
- T1 C+: Lesions usually enhance.
- In the brain, characteristic findings of multiple meningiomas may be seen.
Grading and Staging
There are no specific grading or staging systems for Cowden syndrome itself. Individual malignancies are graded and staged according to their specific systems.
Diagnosis
Diagnosis is typically based on diagnostic clinical criteria established by the International Cowden Syndrome Consortium and can be confirmed with genetic testing for PTEN mutations.
Major Criteria
Patients need to have two major criteria to be diagnosed.
Must include either:
- Lhermitte-Duclos disease
- Macrocephaly
May include:
- Thyroid carcinoma
- Breast cancer
Minor Criteria
Patients with one major and three of the following minor criteria or four minor criteria may be diagnosed with Cowden disease.
- Genitourinary tumours or malformations
- Lipomas
- Fibromas
- Mental retardation
- Fibrocystic disease of the breast
- Gastrointestinal hamartomas
- Other thyroid lesions such as goiter
Mucocutaneous lesions or palmoplantar keratosis can meet the criteria alone if 6 or more are present.
Differential Diagnosis
- Bannayan-Riley-Ruvalcaba syndrome: An autosomal dominant syndrome also caused by PTEN mutation shares clinical features with Cowden syndrome, but is usually associated with macrocephaly, intestinal polyps, and lipomas.
- Proteus syndrome: Characterised by overgrowth of multiple tissues, Proteus syndrome has a similar presentation to Cowden syndrome but does not typically present with the same types of malignancies.
Management
Management is primarily surveillance for malignancies, including regular mammography, thyroid ultrasound, and endometrial biopsy. Genetic counselling is also an important component of management.