Description
Peutz-Jeghers syndrome (PJS) is a rare genetic disorder characterised by the development of characteristic hamartomatous polyps in the gastrointestinal tract and a distinct pattern of pigmented mucocutaenous lesions. The disease significantly increases the risk of various cancers, particularly gastrointestinal, but also lung, breast, and gynaecological malignancies.
Pathogenesis
Peutz-Jeghers syndrome is caused by an autosomal dominant mutation in the STK11/LKB1 gene on chromosome 19p13.3. This gene encodes a tumour suppressor protein involved in regulating cell cycle, apoptosis, and polarity of epithelial cells. Loss of function of this protein leads to increased cellular proliferation and hamartomatous polyp formation. The disease is typically inherited in an autosomal dominant fashion, although de novo mutations are not uncommon.
Epidemiology, Risk Factors & Associations
- The syndrome is rare with an estimated prevalence of 1 in 8,300 to 200,000 individuals worldwide.
- It affects males and females equally and shows no racial or ethnic predilection.
- There are no known risk factors aside from having a family history of PJS.
- The cumulative cancer risk by age 70 is estimated to be 85-93%.
- The syndrome is associated with an increased risk of cancers, particularly gastrointestinal cancers. Additionally, women with PJS have an increased risk of breast and gynaecological cancers:
- Gastric (29 times higher risk)
- Colorectal cancer (39 times higher risk)
- Small bowel cancer (520 times higher risk)
- Breast, ovarian, testicular, and pancreatic cancers.
Clinical Features
- Presence of numerous hamartomatous pedunculated polyps in the gastrointestinal tract, most commonly in the small bowel but also in the stomach and colon.
- Mucocutaneous pigmentation: Dark blue to dark brown macules, often present around the mouth, eyes, nostrils, and also on the hands and feet. These usually appear in infancy or early childhood and may fade after puberty.
- Patients may also present with recurrent abdominal pain, gastrointestinal bleeding, or bowel obstruction secondary to intussusception.
- Extraintestinal manifestations: Increased risk of developing several extraintestinal malignancies (e.g., breast, lung, ovarian, and uterine).
Complications
The main complications of Peutz-Jeghers syndrome relate to the presence of polyps and the increased risk of malignancies:
- Intestinal obstruction or intussusception due to large polyps.
- Chronic bleeding leading to anaemia.
- High risk of gastrointestinal and extraintestinal malignancies.
Pathological Features
Histopathological
The polyps in PJS are characterised as hamartomatous polyps, which are benign, non-cancerous growths. These polyps typically have a distinctive arborising (branching) pattern of smooth muscle derived from the muscularis mucosae, extending into the lamina propria with branching fronds covered by normal colonic epithelium.
Radiological Features
General Features
- Numerous polyps throughout the gastrointestinal tract, particularly the jejunum.
- Potential signs of complications such as bowel obstruction or intussusception.
CT/MRI
- Polyps appear as well-defined, non-enhancing, intraluminal filling defects. They may show a ‘ball-on-a-string’ appearance due to central umbilication.
- Mural thickening and enhancement may be seen if there is associated bowel obstruction or intussusception.
- Useful in surveillance for associated malignancies, such as ovarian and pancreatic cancers.
Fluoroscopy
- Barium swallow and follow-through studies can delineate the polyps throughout the gastrointestinal tract.
- Show filling defects corresponding to the polyps. The classic “coin on a string” sign may be seen, representing the central umbilication of the polyp by the radiolucent muscular band.
Differential Diagnosis
- Familial Adenomatous Polyposis (FAP): This condition also presents with multiple polyps in the gastrointestinal tract, similar to PJS. Key differentiating factors include:
- The polyps in FAP are typically adenomas (arise from glandular tissue), while PJS presents with hamartomatous (arise from disorganised or overgrowth of normal tissue) polyps.
- FAP often leads to hundreds to thousands of polyps, mainly located in the colon, usually developing in the teenage years.
- FAP is caused by mutations in the APC gene, whereas PJS is linked to mutations in the STK11/LKB1 gene.
- The presence of mucocutaneous pigmentation is unique to PJS and is not seen in FAP.
- Juvenile Polyposis Syndrome: Characterised by multiple juvenile polyps in the gastrointestinal tract, the condition may resemble PJS. However, it doesn’t feature the mucocutaneous pigmentation seen in PJS.
- Cowden Syndrome (PTEN Hamartoma Tumour Syndrome): This condition presents with multiple hamartomas and an increased risk of certain types of cancer, similar to PJS. However, the distribution of polyps, specific associated cancers, and presence of mucocutaneous lesions differ.
Cronkhite-Canada Syndrome: This non-hereditary syndrome also involves the formation of polyps throughout the digestive tract. However, it typically begins later in life and involves additional symptoms like alopecia and nail abnormalities.
Management
- Regular surveillance with endoscopy and imaging to monitor for polyp growth, potential complications, and malignancies.
- Polyp removal as necessary, usually during surveillance endoscopy.
- Genetic counseling for patients and families.