Genetic screening for Peutz-Jeghers syndrome

Peutz Jeghers syndrome is a genetic disorder characterized by benign tumors, known as hamartomatous polyps, in the gastrointestinal tract, and pigmentation of the mucous membranes (especially around the mouth).

People with this disorder are at an increased risk of developing cancer. This is a rare disorder; its prevalence is around 1 in 100,000 individuals. The disease occurs in both women and men, in all ethnic populations.

Signs and symptoms

The three main symptoms of this disorder are hamartomatous polyps in the gastrointestinal tract, hyperpigmentation of the mucous membranes, and an increased risk for malignant tumors.

Hyperpigmentation spots, also known as melanocytic macules, are caused by pigment-laden macrophages. These appear as flat, blue spots several millimeters in diameter. 

The spots most commonly develop on the lips and around the mouth, on the hands and feet, and buccal mucosa. They may also occur around the genitals and anus and in the nose. The spots do not affect the patient’s health and only rarely become cancerous.

Hamartomatous polyps are tissue remnants that do not belong in their current location. In Peutz-Jeghers syndrome, they are composed of muscle cells that invade other tissue areas. They tend to occur in the small intestine, large intestine, and stomach. 

Multiple polyps start developing during childhood, in the first decade of life. Polyp overgrowth can cause various symptoms such as bowel obstructions, intussusception of the small bowel, intestinal bleeding, abdominal pain, and more.

People with this disorder are at a greatly increased risk for developing cancer, especially gastrointestinal tract cancer. The risk for cancer is estimated at around 50-90% (based on reports in medical literature). Cancer tends to develop at an earlier age than general population, around 40 years of age. Tumors commonly develop in the colon, pancreas, and breast (in women).

Genetic basis

The disorder was first reported in one family by Dutch physician Doctor Jan Peutz. it was discovered that this disease runs in families and has an autosomal dominant inheritance pattern. This means that one defected gene inherited from one of the parents is enough for develop this condition. The disease has increased penetrance, which means that gene mutation carriers have a high probability of developing the disease.

Genetic analysis has revealed the disease is caused by a mutation of a gene on chromosome 19 (19q13.3). this gene is coded to a protein called LKB1, a serine/threonine kinase protein that transfers phosphorus to various amino acids.

Genetic damage in this disorder is estimated to be both acquired and inherited. In cases of an inherited gene mutation from one of the parents, an additional damage occurs in the parent’s germ cells that disrupts the activity of the gene’s other allele.

This can help explain why Peutz Jeghers disorder is an autosomal dominant disease. The role of the affected protein is unknown, and it is still unknown why disruptions to its function lead to Peutz Jegher disorder.

Certain researchers suggest this protein may belong to the tumor suppressor genes, due to the high prevalence of cancer among Peutz Jegher patients. This theory has yet to be proven. It should be noted that the LKB1 gene is defected in some patients, but not all. 


How is the disorder diagnosed?

Peutz Jeghers syndrome can be diagnosed using a genetic screening test. Unfortunately, since people with this disorder carry many different gene mutations, all relevant variations have yet to be discovered.

Today, only around half of the possible mutations can be detected. It is estimated that there is another gene mutation responsible for this disorder.

In several documented cases, families with Peutz Jeghers did not how the original gene mutation 19q13.3.

For this reason, genetic screening can confirm this condition, but certainly not rule it out. This screening test maps the gene and compares it to a healthy genetic sequence based on known data.

Modern diagnosis of Peutz Jeghers syndrome is based on clinical criteria. It is accepted that diagnosis is clinical, and not a laboratory diagnosis. Criteria include pathological evidence of hamartomatous polyps in the gastrointestinal tract, and two of the following criteria: family history of this disorder, hyperpigmentation in the mucous membranes, multiple polyps in the small intestine.

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