What is Peutz-Jeghers Syndrome?

Peutz–Jeghers syndrome is an autosomal dominant genetic disorder which causes benign polyps in the gastrointestinal tract, an increase in red pigment around the lips and melanosis (browning) of the colon. The disorder was first discovered by British surgeon Sir Jonathan Hutchinson in 1894 and classified by Dutch physician Jan Peutz in 1921 when he observed the combination of gastrointestinal polyps and melanin spots in three siblings. Further observation of the family found that many family members were afflicted with the same symptoms along with abdominal pain and rectal blood loss. The syndrome stems from 4 mutations located on the STK11 (also known as LKB1) gene. Peutz-Jeghers syndrome is rare in the United States with a frequency between 1 case per 60,000 people and 1 case per 300,000 people.

Portrait of Sir Jonathan Hutchinson, year unknown.

Symptoms and Prognosis

Symptoms

Gastrointestinal Polyps (leads to abdominal pain, GI bleeding, anemia, and intestinal blockages.
Discoloration of the skin on the gums, lips, inner lining of the mouth and the skin surrounding the mouth.
Clubbed finger and toes.
Cramps in the abdominal region.
Dark freckles located around the mouth or lips (typically seen in newbowns.)
Blood in stool.
Acute vomiting.

Prognosis

Top Left: Example of PJS induced discoloration of patient's gums.

Top Right: Example of PJS induced discoloration around patient's mouth.

Bottom Left: Stained biopsy of PJS gastrointestinal polyps.

Bottom Right: Example of patient exhibiting clubbed toes.

While most symptoms caused by Peutz-Jeghers Syndrome are relatively benign the syndrome can lead to a drastic increase in the development of cancer. Notably the polyps that develop in the gastrointestinal tract have a low risk of cancer (less than 3%) however a patient that has been diagnosed with this disorder has a large risk of developing cancer in other parts of the body: notably in the pancreas, liver, lungs, breast, ovaries, uterus, and testicles. The cancer risk increases as the patient ages:

The overall risk for cancer is greater in females than in males and has the highest likelihood of developing in the gastrointestinal, pancreatic, and gynecologic-cervical systems of the body.

Genetic Cause

The over expression of TSC 1/2 stems from 4 mutations located on the STK11 gene. These four mutations include three frameshift mutations (125-137del; 474-480del; 516-517insT) and one nonsense mutation (Q220X). A more recent study has also linked the increased cancer risk associated with Peutz-Jeghers syndrome with ten different mutations on the STK11 gene. Nine of the discovered mutations appeared to be novel with no apparent affect on the pathway while ten mutations were associated with an increase in cancer risk. The onset of the syndrome has been linked to an error in the regulation of the TSC pathway by STK11, which is a pathway responsible for tumor suppression. Specifically, the risk of cancer increase develops due to a dysregulation of the TSC2/mTOR pathway. The onset of the hallmark polyps associated may also be caused by a separate pathway dysregulation in the Wnt cell signaling pathway. This may be caused by a dysregulation in ß-catenin and IFITM1 levels in the body coupled with the known STK11 error.

Affected Signaling Pathway

Diagram of affected RTK pathway. Peutz-Jeghers Syndrome occurs in individuals with an error/mutation in the expression of LKB1 (also known as STK11) leading to the over expression of the TSC 1/2 pathway. The affected pathway is highlighted in yellow.

Current and Future Treatments

Currently treatment of Peutz-Jeghers syndrome is limited to pharmaceutical control and surgeries to maintain the growth of the gastrointestinal polyps. Laparotomies and laparoscopies are the most common surgeries performed for both gastrointestinal and extraintestinal complications. Once cancer has developed in a patient the treatment typically consists of chemotherapy and anticancer drug treatments. While still in its infancy CRISPR/Cas9 has shown some promise in genome editing and may be a treatment used regularly in the future. CRISPR/Cas9 could be utilized to repair the errors located on the STK11 gene, removing or greatly reducing the genetic defects and cancer risk that typically accompanies them.

References

Vahidnezhad et al., Molecular Genetics of the PI3K-AKT-mTOR Pathway in Genodermatoses: Diagnostic Implications and Treatment Opportunities. Journal of Investigative Dermatology, Volume 136, Issue 1, 2016, Pages 15-23.

Nicholas et al., Frequency and Spectrum of Cancers in the Peutz-Jeghers Syndrome. Clin Cancer, 12(10), 3209-3215.

Kruse et al., Peutz-jeghers syndrome: Four novel inactivating germline mutations in the STK11 gene. Human Mutation, 13(3), 257.

Ma et al., Wnt signaling may be activated in a subset of Peutz-Jeghers syndrome polyps closely correlating to LKB1 expression. Oncology Reports, 23, 1569-1576.

Mcgarrity, T. J., & Amos, C., Peutz-jeghers syndrome: Clinicopathology and molecular alterations. Cellular and Molecular Life Sciences, 63(18), 2135-44.

Dienstmann et al., Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors. Mol Cancer Ther, May 1 2014, 1021-1031.

Schumacher et al., STK11 genotyping and cancer risk in Peutz-Jeghers Syndrome. Journal of Medical Genetics, 42(5), 428.

Peutz-Jeghers Syndrome

Reported by Jacob Steele