Peutz-Jeghers syndrome is an inherited condition marked by three main features: growths called polyps in the gastrointestinal tract, distinctive dark spots on the skin and inside the mouth, and an increased lifetime risk of several cancers. The severity and combination of features can differ considerably even among members of the same family, a pattern doctors call variable expressivity; some relatives who carry the same genetic change may have only a few skin spots, while others develop extensive polyps requiring repeated procedures.

The condition is caused by changes, known as pathogenic variants, in a single gene called STK11, located on chromosome 19. STK11 provides instructions for a protein that acts as a tumor suppressor, meaning it normally helps control how and when cells divide, and also plays roles in programmed cell death, cell shape and organization, and how cells use energy. When one of the two copies of STK11 that a person carries is altered, this control is disrupted, allowing the characteristic polyps to form and contributing to the elevated cancer risk seen in this condition.

More than three hundred different disease-causing changes have been identified in STK11 to date, ranging from small alterations affecting a single building block of the protein to loss of the entire gene.
A small number of people who clearly show the clinical features of Peutz-Jeghers syndrome do not have a detectable change in STK11 on standard testing. In some of these individuals, the genetic change may be present in only a portion of the body’s cells, a situation called mosaicism, which can be missed by testing a routine blood sample. Testing an alternate tissue source, such as cells from the inside of the cheek, is sometimes considered in this situation.