Peutz-Jeghers Syndrome

ABSTRACT

• The typical features of Peutz-Jeghers syndrome (PJS) are mucocutaneous melanin pigmentation and gastrointestinal polyposis.

• Peutz-Jeghers polyps are hamartomas characterized by a stromal tree-like pattern of smooth muscle tissue.

• PJS patients are predisposed to cancer. An excess of gastrointestinal as well as extraintestinal cancers has been reported in PJS families. The cancer predisposition is less focused than in many other cancer-susceptibility syndromes.

• The major predisposing gene is LKB1. LKB1 mutations are found in most but not all PJS patients. At present it is unclear whether more predisposing loci exist.

• LKB1 is a serine/threonine kinase, and it has been proposed to function as an upstream regulator of AMP-activated protein kinase. The germ-line mutations associated with tumorigenesis are usually of an inactivating nature, suggesting a role as a tumor suppressor.

INTRODUCTION

The syndrome is named after Peutz and Jeghers, the discoverers of the disease. The first report was by Peutz in 1921, followed by work by Jeghers and colleagues in 1949. The major hallmarks of Peutz-Jeghers syndrome (PJS) are mucocutaneous melanin pigmentation and intestinal hamartomatous polyposis (Phillips et al,²⁷). PJS patients appear to be at increased risk of cancer (Table 45-1). Especially malignant tumors of the gastrointestinal tract, breast, uterine cervix, and ovary may be associated with the disease (Boardman et al,⁵; Giardiello et al,¹¹; Hemminki,¹³). Benign ovarian (such as granulosa cell tumor, sex cord tumor with annular tubules) and testicular (Sertoli cell tumor) lesions are relatively frequently found in PJS (Phillips et al,²⁷). Since PJS is a rare disorder, considerably more rare than, for example, familial adenomatous polyposis, it has been difficult to evaluate the cancer spectrum and risk levels typical for PJS. Giardiello and colleagues¹¹ reported an 18-fold lifetime risk of malignancy in PJS. Boardman and colleagues⁵ reported a similar relative risk for women, but in their study the risk for men was only 6.2. Gastrointestinal cancer and gynecologic malignancies in particular, as well as breast cancer, were associated with PJS in this study.

Germ-line mutations in a serine/threonine kinase gene LKB1 (also called STK11) located on chromosome 19p 13.3 recently have been shown to underlie a major proportion of PJS cases (Hemminki et al,¹³). LKB1 is believed to act as a tumor suppressor gene (Hemminki et al,¹⁴; ...