What is the cause of Peutz-Jeghers syndrome?

From the Guidelines

Peutz-Jeghers syndrome is caused by mutations in the STK11 gene, which is a tumor suppressor gene located on chromosome 19p13.3, as supported by the most recent and highest quality study 1. This genetic disorder is inherited in an autosomal dominant pattern, meaning that a person needs only one copy of the altered gene to develop the condition. The STK11 gene normally produces a protein that helps regulate cell growth and division, and when mutated, this regulation is disrupted, leading to the formation of hamartomatous polyps in the gastrointestinal tract and the characteristic mucocutaneous pigmentation (dark spots on the lips, mouth, and fingers). These genetic mutations can be detected through genetic testing, which is recommended for individuals with clinical features of the syndrome or those with a family history of the condition, as stated in 1 and 1. Some key points to consider in the management of Peutz-Jeghers syndrome include:

• The condition is associated with an increased risk of various cancers, particularly in the gastrointestinal tract, breast, and reproductive organs, as noted in 1 and 1.
• Early diagnosis is crucial to prevent and manage these complications, as emphasized in 1 and 1.
• Genetic testing and surveillance are essential for individuals with Peutz-Jeghers syndrome, as recommended in 1, 1, and 1.
• The syndrome can be diagnosed with any one of the following: two or more PJS polyps, any number of PJS polyps and a history of PJS in a close relative, characteristic mucocutaneous pigmentation in an individual with a history of PJS in a close relative, or any number of PJS polyps with characteristic mucocutaneous pigmentation, as stated in 1. It is essential to prioritize the single most recent and highest quality study, which in this case is 1, to ensure that the recommendation is based on the most up-to-date and reliable evidence.

From the Research

Cause of Peutz-Jeghers Syndrome

The cause of Peutz-Jeghers syndrome (PJS) is attributed to mutations in the tumor suppressor gene, STK11.

• Mutations in the STK11 gene lead to the development of gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer 2, 3, 4, 5, 6.
• The STK11 gene plays a crucial role in cell polarization, regulation of apoptosis, and DNA damage response 5.
• Truncating variants in STK11 are thought to predispose to a more severe phenotype, while missense variants are generally considered less severe than truncating variants 4.
• The location of variants in the STK11 gene can impact protein structure and overall severity of the PJS phenotype, but a consensus on phenotype severity based on variant location is yet to be established 4.

Types of Mutations

• Various types of mutations in the STK11 gene have been identified, including novel mutations such as c.904C > T 2, c.A527G 3, and a novel stop codon mutation 5.
• These mutations can lead to changes in the amino acid sequence of the STK11 protein, resulting in its partial or complete loss of function 2, 3, 5.
• The identification of novel mutations in the STK11 gene highlights the need for further research into the genetic basis of PJS and its associated cancer risk 3, 5, 6.

Cancer Risk

• PJS is associated with an increased risk of developing various types of cancer, including gastrointestinal, breast, and other cancers 4, 6.
• The risk of cancer in PJS patients is thought to be related to the type and location of the mutation in the STK11 gene 4.
• Early screening and surveillance are essential for PJS patients to detect and manage cancer risk 3, 4, 6.