Peutz-Jeghers syndrome affects the digestive tract and skin most prominently, though its cancer risk extends to several other organs. Doctors look for a specific combination of clinical findings to establish the diagnosis.

• Gastrointestinal polyps: a distinctive type of polyp, called a hamartomatous polyp, occurs most often in the small intestine, particularly the segment nearest the stomach, but can also appear in the stomach, large bowel, and occasionally outside the digestive tract altogether. These polyps can cause chronic bleeding, anemia, and, especially in children and young adults, a serious folding-in of the bowel called intussusception, which may require emergency surgery.
• Skin and mucous membrane pigmentation: dark blue to dark brown spots typically appear in early childhood around the mouth, eyes, and nostrils, inside the cheeks, on the fingers, and around the anus. These spots often fade during the teenage years and adulthood, so their presence is most useful for diagnosis in children.
• Family history: any number of the characteristic polyps or the characteristic skin spots occurring in a person with a close relative who has confirmed Peutz-Jeghers syndrome supports the diagnosis.

A clinical diagnosis can be made when a person has two or more of the characteristic polyps confirmed on tissue examination, any number of these polyps together with a family history of the condition, characteristic skin spots together with a family history, or both the polyps and the skin spots together. Because the skin spots may be subtle and the polyps may cause no symptoms for years, genetic testing of the STK11 gene, usually starting with sequencing followed by testing for larger deletions or duplications if needed, is used to confirm the diagnosis and to allow testing of at-risk relatives.