Cowden syndrome is a rare genetic disorder characterized by the development of multiple noncancerous, tumor-like growths (hamartomas) on various parts of the body. This condition is associated with an increased risk of certain cancers, particularly breast, thyroid, and endometrial cancers. Cowden syndrome is a rare multisystem disease that is part of the group of pathologies called PTHS (PTEN tumor hamartoma syndrome).
Cowden syndrome genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximetaly 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Cowden syndrome include:
Genetic Basis: Cowden syndrome is caused by PTEN (phosphatase and tensin homolog) gene mutations. The PTEN gene typically helps regulate cell growth and division. Mutations in this gene lead to uncontrolled cell growth and the formation of hamartomas.
Clinical Features
- Skin Abnormalities: Individuals with Cowden syndrome often develop skin abnormalities, such as trichilemmomas (benign tumors of the hair follicles), papillomatous papules, and facial papules.
- Oral Mucosa Abnormalities: Benign oral mucosal papillomatosis is a standard feature.
- Breast Abnormalities: Women with Cowden syndrome have an increased risk of developing breast cancer. Breast fibrocystic disease is also common.
- Thyroid Abnormalities: Thyroid disorders, including goiter and thyroid nodules, are frequently observed.
- Gastrointestinal Hamartomas: Hamartomatous gastrointestinal polyps may occur, leading to gastrointestinal symptoms.
- Cancer Risk: Individuals with Cowden syndrome have an elevated risk of certain cancers, especially breast, thyroid, and endometrial cancers. Regular cancer screening and surveillance are essential for early detection.
Management of Cowden syndrome involves regular surveillance and screening for cancer, especially breast cancer in females. Surgical removal or treatment of hamartomas may be considered based on symptoms and location. Genetic counseling is crucial for individuals and families affected by Cowden syndrome to understand the inheritance pattern and potential risks for family members. It's important to note that Cowden syndrome is a complex disorder with variable expressivity, meaning the symptoms and severity can vary among affected individuals. A multidisciplinary approach involving dermatologists, oncologists, and other specialists is often required for comprehensive care and management.
Diagnosis is confirmed through genetic testing to identify mutations in the PTEN gene. Family members of individuals with Cowden syndrome may also undergo testing to determine their risk.
Cowden syndrome causes the growth of hamartomas and increases the risk of several types of cancer. Carrying a PTEN mutation does not indicate the presence of cancer but increases the risk of cancer compared to the risk in the general population.
The most common malignancy in patients with Cowden syndrome is breast cancer. In addition, patients with Cowden syndrome may also develop, to a lesser extent, endometrial, thyroid, gastrointestinal, and renal neoplasms. Benign lesions may appear in the skin (cutaneous fibromas), brain, thyroid gland (multinodular goiter), and bowel (colonic polyps).
Cowden syndrome is frequently inherited following an autosomal dominant pattern but can also occur by de novo (or "new") mutations in PTEN. If it is a de novo mutation, the carrier`s parents are unaffected, but the patient may have affected children. Although pathogenic germline PTEN variants have been detected in the majority of Cowden syndrome patients, somatic PTEN mutations can also occur, resulting in a wide range of sporadic-type tumors.
The PTEN or phosphatase and tensin homolog gene produces a lipid and protein phosphatase enzyme involved in cell cycle regulation and apoptosis. The most relevant function of PTEN is its ability to dephosphorylate PI(3,4,5)P3 or PIP3, which is the main product of the PI3K/AKT signaling pathway that promotes cell survival and proliferation.
Most of the pathogenic variants in the PTEN gene, causing more severe forms of the disease, are those that inactivate the PTEN protein. As PTEN mutations have been identified, they have been increasingly associated with phenotypes typical of Cowden disease and the spectrum of PTEN hamartoma tumor syndrome (PHTS). PTEN mutations have even been found in patients with autism and macrocephaly. To date, it has not been possible to perform extensive studies on patients with PHTS to define all possible associated phenotypes clearly.
The genetic test of Cowden syndrome analyzes the 82 most frequent pathogenic mutations of the PTEN gene.
With the technique used for genetic testing, only the gene's specific mutations, which are the most important and frequent in the literature, are analyzed. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested, which cannot be identified with this method. Different analysis techniques can be used for these cases, such as, e.g., next-generation sequencing (NGS).
