Peutz–Jeghers syndrome

Overview

Peutz–Jeghers syndrome (PJS) is a rare inherited disorder characterized by the development of benign polyps in the gastrointestinal (GI) tract and distinctive pigmented spots on the skin and mucous membranes. These polyps, known as hamartomatous polyps, can occur anywhere along the GI tract but are most commonly found in the small intestine. In addition to gastrointestinal manifestations, individuals with PJS have a significantly increased lifetime risk of developing various types of cancer, including those of the pancreas, breast, colon, stomach, ovaries, and cervix. PJS usually presents in childhood or adolescence and requires lifelong surveillance and management to reduce the risk of complications.

Causes

Peutz–Jeghers syndrome is caused by mutations in the STK11 (also known as LKB1) gene, which is located on chromosome 19p13.3. This gene functions as a tumor suppressor and plays a crucial role in regulating cell growth and maintaining cellular polarity. When STK11 is mutated, it leads to abnormal cellular proliferation and the development of polyps and neoplasia.

PJS is inherited in an autosomal dominant manner, meaning a single copy of the mutated gene from an affected parent is sufficient to cause the syndrome. However, around 25% of cases result from new (de novo) mutations without a family history.

Symptoms

The clinical features of Peutz–Jeghers syndrome can vary widely, but the most common signs and symptoms include:

Gastrointestinal Symptoms:

• Hamartomatous polyps: Most often found in the small intestine, but also occur in the stomach, colon, and rectum

• Abdominal pain: Due to polyp growth or complications such as intussusception (telescoping of the intestine)

• GI bleeding: May cause anemia, visible blood in stool, or melena (black, tarry stools)

• Bowel obstruction: Caused by large polyps or intussusception, especially in younger patients

• Vomiting or weight loss: In severe or chronic cases

Mucocutaneous Pigmentation:

• Dark blue to brown freckle-like spots on the lips, inner cheeks, gums, fingers, toes, and around the eyes and nose

• Spots usually appear in early childhood and may fade with age on the skin but often persist in the oral mucosa

Increased Cancer Risk:

Individuals with PJS have an elevated lifetime risk of developing various malignancies, often beginning in early adulthood:

• Gastrointestinal cancers: Colon, stomach, small intestine, and pancreatic cancer

• Gynecological cancers: Cervical adenoma malignum and ovarian sex cord tumors with annular tubules (SCTAT)

• Breast cancer: Particularly in women, with up to 45–50% lifetime risk

• Testicular tumors: Sertoli cell tumors in males

Diagnosis

The diagnosis of Peutz–Jeghers syndrome is based on clinical findings, family history, and genetic testing. Diagnostic criteria typically include the presence of characteristic polyps, mucocutaneous pigmentation, and/or a known STK11 mutation.

Diagnostic Evaluation:

• Clinical examination: Identification of mucocutaneous pigmented lesions

• Endoscopy and colonoscopy: Visualization and biopsy of polyps in the GI tract

• Capsule endoscopy or imaging (e.g., MRI, CT enterography): Useful for detecting small intestine polyps not reachable via traditional endoscopy

• Histopathology: Biopsied polyps showing characteristic hamartomatous architecture

• Genetic testing: Confirmation of STK11 gene mutation in suspected cases or for family screening

Treatment

There is no cure for Peutz–Jeghers syndrome, but management focuses on preventing and treating complications such as intestinal obstruction, bleeding, and cancer. Treatment typically involves regular screening and polyp removal, as well as surveillance for associated malignancies.

Management of Polyps:

• Polypectomy: Endoscopic removal of polyps to prevent complications

• Surgical intervention: Required in cases of large or inaccessible polyps causing obstruction or intussusception

• Iron supplementation or transfusions: To manage anemia from chronic GI bleeding

Cancer Surveillance:

Regular screening protocols are essential and may include:

• Upper endoscopy and colonoscopy: Every 2–3 years starting in late childhood or adolescence

• Pancreatic cancer screening: MRI or endoscopic ultrasound beginning around age 30–35

• Breast exams and imaging: Annual mammography and/or MRI starting at age 25

• Pelvic exams and ultrasound: For gynecologic tumors in females

• Testicular exams: Annual evaluations in males during and after puberty

Genetic Counseling:

• Recommended for affected individuals and their families

• Helps with reproductive planning and early diagnosis of at-risk relatives

Prognosis

The prognosis for individuals with Peutz–Jeghers syndrome depends largely on the success of early detection and management of polyps and malignancies. With diligent surveillance and proactive care, many patients can avoid life-threatening complications and maintain a good quality of life. However, the significantly increased risk of cancer requires lifelong monitoring.

Early diagnosis, regular screenings, and multidisciplinary care (including gastroenterologists, geneticists, oncologists, and surgeons) are key to improving outcomes. With proper management, individuals with PJS can lead active, fulfilling lives, though ongoing vigilance is essential to reduce long-term risks.