Cowden Syndrome

At a glance

A rare syndrome characterized by multiple hamartomas and high risk of breast, thyroid, uterine, and other benign and malignant neoplasias.

Synonym

Multiple Hamartoma Syndrome.

History

Named after Rachel Cowden, the first patient reported.

Incidence

The estimated prevalence is in the range of 1:200,000 for the general population. More than 200 cases have been described in the medical literature. Males and females are equally affected; however, thyroid cancer is the most common cancer in males, whereas breast cancer is the most common in affected women.

Genetic inheritance

Autosomal dominant with wide interfamilial and intrafamilial variance. Based on the underlying genetic defect, seven different types of Cowden Syndrome (CS) can be distinguished and where known, inheritance is autosomal dominant. About 30 to 35% of CS cases are caused by mutations in the PTEN (Phosphatase and Tensin Homologue Tumor Suppressor) gene, which has been mapped to chromosome 10q23. Approximately 30% are caused by mutations in the KLLN (Killin) gene located on chromosome 10q23.31. About 10% are caused by germline variations in the SDHB, SDHC, or SDHD (Succinate Dehydrogenase Complex, Subunit B/C/D, Integral Membrane Protein) gene, which has been mapped to chromosome 1p36.13, 1q23.3, and 11q23.1, respectively (mutations in these three genes may also cause hereditary pheochromocytoma and paraganglioma Syndrome). In another 10%, CS is caused by germline mutations in AKT1S1 (Proline-rich Substrate 1 of AKT) gene on chromosome 19q13.33 and PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha) gene on chromosome 3q26.32. It has been estimated that up to 45% of PTEN-positive CS cases may be due to de novo mutations.

Pathophysiology

The “prototype” of CS results from mutations in the PTEN gene, which encodes a phosphatase that functions as tumor suppressor through its lipid phosphatase activity that regulates the phosphatidylinositol 3-kinase pathway and is involved in regulation of growth, survival, and death of cells. The lack of PTEN functionality appears to be responsible for the uncontrolled proliferation of certain cells and the formation of hamartomas and benign and malignant neoplasias.

Diagnosis

Based on the clinical findings. Usually CS is diagnosed after the first year of life. The “International Cowden Syndrome Consortium” summarized the diagnostic features into major criteria (eg, macrocephaly, thyroid cancer, breast cancer, endometrial cancer, gastrointestinal hamartomas, multiple mucocutaneous lesions, and Lhermitte-Duclos disease, see “Other conditions to be considered”) and minor criteria (colon cancer, renal cancer, thyroid cancer, mental retardation, autism spectrum disorder, nonmalignant thyroid structural lesions, lipomas) (see Pilarski et al 2013 for a complete list). The diagnosis is considered very likely in an individual patient when three or more major criteria (but one must be macrocephaly, Lhermitte-Duclos disease, or gastrointestinal hamartomas), or two major and three minor ...