Cowden syndrome
Cowden syndrome (CS), also known as PTEN hamartoma tumor syndrome, is a rare genetic disorder characterized by a predisposition to various tumors and hamartomas. Individuals with CS may exhibit features such as macrocephaly, trichilemmomas, and papillomatous papules. The condition is linked to mutations in the PTEN gene, which plays a critical role in regulating cell growth and preventing tumor formation. CS is associated with an increased risk of several cancers, particularly benign and malignant forms of breast, thyroid, and endometrial cancers.
Screening for CS typically involves a detailed clinical evaluation and genetic testing for PTEN mutations. Those diagnosed may display symptoms by their late twenties, often not unique to CS but related to the cancers and conditions that accompany the syndrome. Preventive measures and surveillance strategies are crucial for managing the increased cancer risks, with recommendations for regular screenings beginning at specific ages based on individual risk factors. Genetic counseling is also advised for affected individuals and their families to better understand inheritance patterns and to guide preventive care. Overall, early diagnosis and proactive management can significantly influence health outcomes for individuals with Cowden syndrome.
Cowden syndrome
ALSO KNOWN AS: CS; Cowden disease; PTEN hamartoma tumor syndrome; multiple hamartoma syndrome
DEFINITION: Cowden syndrome (CS), one of the syndromes making up the PTEN hamartoma tumor syndrome, is a hamartoma syndrome with cancer predisposition. Persons with CS may have macrocephaly, trichilemmomas, and papillomatous papules. Cancers most frequently seen with CS include benign and malignant forms of thyroid, breast, and endometrial cancers. According to the Cleveland Clinic, CS affects approximately 1 in 200,000 people.
Risk Factors
Persons at risk for CS are identified through personal and/or family history of clinical manifestations of mucocutaneous lesions, macrocephaly, intellectual disability, and benign and malignant cancers. A mutation in the PTEN gene can be identified in the majority of persons meeting the diagnostic criteria for CS.
Etiology and Genetics
Although thought to be underdiagnosed, CS is a rare syndrome. Most disease is associated with a mutation in the PTEN gene, located on chromosome 10. No other gene has been associated with CS.
The PTEN gene encodes for a major lipid phosphatase, which can cause cell arrest and apoptosis, thereby suppressing tumor formation. The protein phosphatase may also inhibit cell migration and spreading.
When the PTEN gene is mutated, there is less ability to activate arrest and apoptosis, with abnormal cell survival. While some recurrent mutations associated with CS have been identified, more than one hundred unique mutations in the PTEN gene have been reported. The described mutations in the PTEN gene associated with CS may be inherited or arise de novo. The inherited mutations are transmitted by autosomal dominant inheritance. The mutation may be passed from either the maternal or paternal lineage, with a 50 percent chance of transmission with each offspring. However, many people with CS are simplex cases, meaning that there is no obvious family history of the syndrome. Simplex cases may be related to underdiagnosis in the family, early death of family members before the clinical onset of the syndrome, late-onset disease in family members, or de novo mutations.
Symptoms
CS is a predisposition syndrome, yet nearly all persons with CS will have some clinical manifestation by their late twenties. Those who do develop disease have symptoms respective of the sporadic forms—that is, the symptoms of the diseases associated with CS are not unique to CS.
Screening and Diagnosis
Screening for CS includes clinical examination and evaluation of family history, with genetic testing for PTEN mutations to confirm the diagnosis. The criteria for testing for CS diagnosis include the following: presence of any single pathognomonic criterion, two or more major criteria, one major and three or more minor criteria, or four or more minor criteria. Patognomonic criteria include adult Lermitte-Duclos disease or mucocutaneous lesions. Major criteria include breast cancer, nonmedullary thyroid cancer, macrocephaly, and endometrial cancer. Minor criteria include other thyroid lesions, intellectual disability, gastrointestinal (GI) harmartomas, fibrocystic disease of the breast, lipomas, fibromas, genitourinary tumors or structural manifestations, or uterine fibroids.
While sequencing the PTEN gene with attention to large deletions and rearrangements is performed to confirm the diagnosis of CS, such testing will not identify a mutation in all persons meeting the criteria of CS. Failure to identify a mutation, however, does not exclude a clinical diagnosis of CS.
Treatment and Therapy
For individuals with CS who are affected by disease, treatment and therapy will be similar to the clinical management of the respective disease—that is, the diseases associated with CS also occur sporadically, and there is no special treatment based on an accompanying diagnosis of CS
Prevention and Outcomes
Medically, the most serious outcomes of CS relate to the increased cancer risks. The associated breast cancer is of early onset, generally before the age of fifty, with a lifetime risk of 25 to 50 percent. The lifetime risk for thyroid cancer is 10 percent and for endometrial cancer is 5 to 10 percent. Skin cancer, renal cell carcinoma, and brain tumors may also be seen in CS. Although hamartomatous polyps of the GI tract may occur, the risk of colorectal cancer is not thought to be increased.
For breast cancer surveillance, mastectomy or intensified surveillance may be indicated. The later may include semiannual or annual clinical breast examinations beginning at age twenty-five years with annual mammography and breast MRI beginning at age thirty to thirty-five years, or five to ten years earlier than the youngest age at diagnosis of breast cancer in the family, in addition to monthly self-examinations. Surveillance for thyroid cancer may include a baseline thyroid ultrasound examination at age eighteen years and an annual thyroid examination. Endometrial cancer surveillance may include annual suction biopsies beginning at age thirty-five to forty years for premenopausal women and annual transvaginal ultrasound examination for postmenopausal women. However, all cancer surveillance needs to be individualized and account for current research findings.
Other general surveillance for persons with CS may include annual physical examination starting at age eighteen, annual urinalysis, annual dermatologic examination, general cancer screening such as colonoscopy starting at age fifty, and a heightened awareness of the signs and symptoms of CS disease.
For persons with CS, genetic counseling and possible PTEN testing of other family members, including those who are asymptomatic, may be indicated to guide cancer prevention and improve outcomes.
Bibliography
"Cowden Syndrome." Cleveland Clinic, 14 Mar. 2023, my.clevelandclinic.org/health/diseases/24815-cowden-syndrome. Accessed 9 Sept. 2024.
Kelly, Evelyn B. Encyclopedia of Human Genetics and Disease. 2 vols. Santa Barbara: Greenwood, 2013. Print.
Niederhuber, John E., et al. Abeloff's Clinical Oncology. 5th ed. Philadelphia: Elsevier, 2013. Print.
Offit, Kenneth. Clinical Cancer Genetics. New York: Wiley-Liss, 1998. Print.
Rimoin, David L., Reed E. Pyeritz, and Bruce R. Korf. Emery and Rimoin's Principles and Practice of Medical Genetics. 6th ed. San Diego: Elsevier, 2013. Print.
Schottenfeld, David, and Joseph F. Fraumeni, Jr. Cancer Epidemiology and Prevention. 2nd ed. New York: Oxford UP, 1996. Print.
Vogel, Victor G. Management of Patients at High Risk for Breast Cancer. Malden: Blackwell Science, 2001. Print.