New Guideline Sheds Light on Diagnosis, Treatment of Rare GI Syndromes

Will Pass

April 29, 2022

A clinical practice guideline for the diagnosis and management of gastrointestinal hamartomatous polyposis syndromes has just been published by the U.S. Multi-Society Task Force on Colorectal Cancer, which is comprised of experts representing the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy.

Gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with intestinal and extraintestinal tumors. Expert consensus statements have previously offered some recommendations for managing these syndromes, but clinical data are scarce, so the present review "is intended to establish a starting point for future research," lead author C. Richard Boland, MD, of the University of California, San Diego, and colleagues reported.

According to the investigators, "there are essentially no long-term prospective controlled studies of comparative effectiveness of management strategies for these syndromes." As a result, their recommendations are based on "low-quality" evidence according to GRADE criteria.

Still, Boland and colleagues highlighted that "there has been tremendous progress in recent years, both in understanding the underlying genetics that underpin these disorders and in elucidating the biology of associated premalignant and malignant conditions."

The guideline was published online in Gastroenterology.

Four Syndromes Reviewed

The investigators gathered these data to provide an overview of genetic and clinical features for each syndrome, as well as management strategies. Four disorders are included: juvenile polyposis syndrome; Peutz-Jeghers syndrome; hereditary mixed polyposis syndrome; and PTEN-hamartoma tumor syndrome, encompassing Bannayan-Riley-Ruvalcaba syndrome and Cowden's syndrome.

Although all gastrointestinal hamartomatous polyposis syndromes are caused by germline alterations, Boland and colleagues pointed out that diagnoses are typically made based on clinical criteria, with germline results serving as confirmatory evidence.

The guideline recommends that any patient with a family history of hamartomatous polyps, or with a history of at least two hamartomatous polyps, should undergo genetic testing. The guideline also provides more nuanced genetic testing algorithms for each syndrome.

Among all the hamartomatous polyp disorders, Peutz-Jeghers syndrome is most understood, according to the investigators. It is caused by aberrations in the STK11 gene, and is characterized by polyps with "branching bands of smooth muscle covered by hyperplastic glandular mucosa" that may occur in the stomach, small intestine, and colon. Patients are also at risk of extraintestinal neoplasia.

For management of Peutz-Jeghers syndrome, the guideline advises frequent endoscopic surveillance to prevent mechanical obstruction and bleeding, as well as multidisciplinary surveillance of the breasts, pancreas, ovaries, testes, and lungs.

Juvenile polyposis syndrome is most often characterized by solitary, sporadic polyps in the colorectum (98% of patients affected), followed distantly by polyps in the stomach (14%), ileum (7%), jejunum (7%), and duodenum (7%). The condition is linked with abnormalities in BMPR1A or SMAD4 genes, with SMAD4 germline abnormalities more often leading to "massive" gastric polyps, gastrointestinal bleeding, protein-losing enteropathy, and a higher incidence of gastric cancer in adulthood. Most patients with SMAD4 mutations also have hereditary hemorrhagic telangiectasia, characterized by gastrointestinal bleeding from mucocutaneous telangiectasias, arteriovenous malformations, and epistaxis.

Management of juvenile polyposis syndrome depends on frequent colonoscopies with polypectomies beginning at 12-15 years.

"The goal of surveillance in juvenile polyposis syndrome is to mitigate symptoms related to the disorder and decrease the risk of complications from the manifestations, including cancer," Boland and colleagues wrote.

PTEN-hamartoma tumor syndrome, which includes both Bannayan-Riley-Ruvalcaba syndrome and Cowden's syndrome, is caused by abnormalities in the eponymous PTEN gene. Patients with the condition have an increased risk of colon cancer and polyposis, as well as extraintestinal cancers.

Diagnosis of PTEN-hamartoma tumor syndrome may be complex, involving "clinical examination, mammography and breast MRI, thyroid ultrasound, transvaginal ultrasound, upper gastrointestinal endoscopy, colonoscopy, and renal ultrasound," according to the guideline.

After diagnosis, frequent colonoscopies are recommended, typically starting at age 35 years, as well as continued surveillance of other organs.

Hereditary mixed polyposis syndrome, which involves attenuated colonic polyposis, is the rarest of the four disorders, having been reported in only "a few families," according to the guideline. The condition has been linked with "large duplications of the promoter region or entire GREM1 gene."

Onset is typically in the late 20s, "which is when colonoscopic surveillance should begin," the investigators wrote. More data are needed to determine appropriate surveillance intervals and if the condition is associated with increased risk of extraintestinal neoplasia.

This call for more research into gastrointestinal hamartomatous polyposis syndromes carried through to the conclusion of the guideline.

"Long-term prospective studies of mutation carriers are still needed to further clarify the risk of cancer and the role of surveillance in these syndromes," Boland and colleagues wrote. "With increases in genetic testing and evaluation, future studies will be conducted with more robust cohorts of genetically characterized, less heterogeneous populations. However, there is also a need to study patients and families with unusual phenotypes where no genotype can be found."

The investigators disclosed no conflicts of interest with the current guideline; however, they provided a list of industry relationships, including Salix Pharmaceuticals, Ferring Pharmaceuticals, and Pfizer, among others.

This article originally appeared on, part of the Medscape Professional Network.


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