Clinical Guidance

Genotype-phenotype correlations in general are weak; family members with JPS and the same pathogenic variant can have a few polyps or more than 100. The age at which polyps develop can vary from the first decade to beyond the fourth decade among affected members of the same family. Some generalizations:

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Penetrance

One study evaluating 34 affected individuals with an SMAD4 pathogenic variant from 20 families revealed that 31/32 (97%) developed colonic polyps (diagnosed between ages 4 and 51 years), 21/31 (68%) developed gastric polyps, and 76% had some feature of HHT . In some instances, HHT-related symptoms in individuals with an SMAD4 pathogenic variant may be present prior to the onset of polyps [Author, personal observations]. Similar information is not available for individuals with a BMPR1A pathogenic variant. However, reported a similar colon and small bowel phenotype among individuals with an SMAD4 or BMPR1A pathogenic variant in the number and location of the polyps and surgical rates.

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Diagnostic Criteria

Suggestive Findings

Juvenile polyposis syndrome (JPS) should be suspected in a proband with the following clinical and histopathologic features.

Clinical features

• Anemia, rectal bleeding, or prolapse of rectal polyp

• More than one juvenile polyp

• One or more juvenile polyps and a family history of JPS

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Differential Diagnosis

A juvenile polyp can result from genetic predisposition or chance. It should be noted that 1% to 2% of individuals in the general population develop a solitary juvenile polyp and do not meet diagnostic criteria for juvenile polyposis syndrome (JPS). Genetic predisposition syndromes characterized by the presence of polyps are summarized in . Table 3. Polyp Predisposition Syndromes in the Differential Diagnosis of Juvenile Polyposis Syndrome

Management Guidelines

Clinical practice guidelines for juvenile polyposis syndrome have been published . Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with juvenile polyposis syndrome (JPS), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with Juvenile Polyposis Syndrome

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Clinical Guidance

SMAD4-related HHT

• Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol.

• Most otolaryngologists with experience treating individuals with HHT advise against electric and chemical cautery and transcatheter embolotherapy for treatment of recurrent nosebleeds.

• Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. In one study, lower-dose agents, particularly anti-platelet agents, were not associated with hemorrhage in a high proportion of affected individuals. The findings support the use of antiplatelet or anticoagulant agents, with caution, if there is a very strong indication for their use .

• Scuba diving should be avoided unless contrast echocardiography performed within the last five years was negative for evidence of a right-to-left shunt.

• Liver biopsy should be avoided .

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Therapies Under Investigation

In individuals with juvenile polyposis of infancy due to deletion of both BMPR1A and PTEN, sirolimus has been investigated as an intervention to decrease polyp burden . In a small case series, sirolimus therapy reduced symptoms including bleeding and enteropathy, and also reduced rate of colectomy . Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Juvenile Polyposis Syndrome"

Surveillance Guidelines

The surveillance recommended in is for individuals with an SMAD4 or BMPR1A pathogenic variant identified by molecular genetic testing, individuals with a clinical diagnosis of JPS, or individuals with a family history of JPS who have not undergone molecular genetic testing or whose molecular genetic test results were uninformative.

Table 6.

Recommended Surveillance for Individuals with Juvenile Polyposis Syndrome

System/Concern | Evaluation | Frequency

Gastrointestinal

| Assess for rectal bleeding, anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape, /or color. | At each visit

Complete blood count | As needed based on symptoms

• Colonoscopy

• Upper endoscopy

• Note: Following surgical bowel resection, continue screening for polyps in remaining colon, rectum, ileal pouch.

| • Every 3 yrs beginning at age 15 yrs or earlier if symptomatic

• If polyps are found: following polyp treatment, annual screening until no polyps are found, then screening every 3 yrs

• In those w/o germline SMAD4 or BMPR1A pathogenic variant: every 5 yrs in adulthood if no polyps are found

Hematologic / Cardiovascular

| • See Hereditary Hemorrhagic Telangiectasia, Surveillance.

• Consider transthoracic echocardiogram.

| Note: To date, frequency of echocardiography monitoring for aortopathy has not been determined.1

1. ,

Source: GeneReviews — "Juvenile Polyposis Syndrome"