Juvenile polyposis syndrome

Juvenile polyposis syndrome (JPS) is an autosomal dominant condition characterised by predisposition to hamartomatous polyps in the GI tract. The prevalence is between 1/100,000 and 1/160,000. The polyps in JPS have the potential for malignant transformation and lifelong surveillance is required, with a lifetime cancer risk of between 38% and 68%.

Polyps and cancer risk

People with JPS have an increased lifetime risk of colorectal cancer, and lifelong colonoscopic surveillance is recommended. Those with confirmed constitutional (germline) pathogenic variants in SMAD4 and BMPR1A should also undergo upper GI surveillance as gastric cancer risk is increased.

Although histologically distinct from polyps associated with Peutz-Jeghers syndrome, hamartomas similar to those seen in JPS can also be seen in PTEN hamartoma tumour syndrome (PHTS) and are a characteristic of hereditary mixed polyposis syndrome. The GI tract phenotype is variable and extraintestinal manifestations can occur in patients with JPS.

Juvenile polyps are hamartomatous polyps with normal epithelium, an inflammatory infiltrate with dilated, mucus-filled cystic glands in the lamina propria. The term ‘‘juvenile’’ refers to the histopathology of the polyp and not the age of onset of polyps.

Hereditary haemorrhagic telangiectasia (HHT)

Up to 76% of patients with JPS due to SMAD4 variants have features of HHT. Thoracic aortic disease and mitral valve dysfunction have also been reported. Aortopathy has been described in 38% of patients with a constitutional SMAD4 variant, irrespective of the JPS phenotype. Patients may lack overt clinical symptoms of HHT but are at risk of asymptomatic arteriovenous malformation (AVM), which can result in life-threatening complications.

JPS may be a clinical and/or genetic diagnosis. A diagnosis can be made if an individual has any one of the following diagnostic criteria:

• More than five juvenile polyps in the colon or rectum.
• Multiple juvenile polyps of the upper and lower GI tract.
• Any number of juvenile polyps and a positive family history of JPS.
• Confirmation of a constitutional pathogenic variant in SMAD4 or BMPR1A.

About 40% of families with JPS have constitutional variants in SMAD4 and a further 40% in BMPR1A. Large chromosomal deletions encompassing both PTEN and BMPR1A genes (contiguous gene deletion) have been reported as a cause of JPS, and have been associated with very early onset disease, including juvenile polyposis of infancy, which presents as a hypoproteinaemia, protein-losing enteropathy and failure to thrive. Carriers of a contiguous deletion involving these genes also have features associated with PHTS.

Constitutional (germline) testing for SMAD4 and BMPR1A may be offered to a patient with adenomatous polyposis alongside other genes associated with overlapping phenotypes such hereditary mixed polyposis syndrome (GREM1) or PHTS (PTEN) as part of a multigene panel for polyposis predisposition (R211).

Genetic testing is available via the National Genomic Test Directory (R211 Inherited polyposis and early onset colorectal cancer panel). The clinical indication for this panel can be used if a living affected individual (proband) with colorectal polyps, +/- family history, meets one of the following criteria:

• any colorectal cancer or endometrial cancer diagnosis under 40 years;
• five or more adenomatous polyps and colorectal cancer; or
• five or more adenomatous polyps ( diagnosed before 40 years of age); or
• ten or more adenomatous polyps (diagnosed before 60 years of age); or
• twenty or more adenomatous polyps (diagnosed after age 60); or
• five or more adenomatous polyps (diagnosed before age 60 years) and at least one first-degree relative with five or more adenomatous polyps or colorectal cancer (diagnosed before age 60); or
• a clinical diagnosis of serrated polyposis syndrome (SPS) (as per WHO criteria); if
  • patient aged younger than 50 years; or
  • family history of one or more affected first-degree relative with SPS, or
  • evidence of dysplasia within any polyp.
• hamartomatous polyposis syndromes; if
  • five or more hamartomatous polyps of the colorectum; or
  • two or more hamartomatous polyps throughout the GI tract; or
  • one or more hamartomatous polyp and a first-/second-degree relative has hamartomatous polyp.

Note: The majority of polyps are histologically confirmed.

Genetic testing may occasionally be appropriate outside these criteria following discussion at a specialist MDT with a cancer geneticist present.

Individuals with JPS may harbour constitutional (germline) variants in the SMAD4 (18q21.1) or BMPR1A (10q23.2) genes . A genetic variant (SMAD4 or BMPR1A) will be identified in 40% to 60% of patients with JPS. Approximately 25% of patients have de novo variants.

Patients with JPS and a microdeletion involving BMPR1A and PTEN are at risk of the clinical manifestations of both JPS and PTEN-hamartoma tumour syndrome (PHTS). PTEN, is also located on 10q22–23, 1Mb telomeric to BMPR1A.

Genotype-phenotype correlations are inconsistent, with variable age of presentation and number of polyps, even in the same family with JPS. Some correlations have been established, however, for example, JPS caused by constitutional SMAD4 variants appears to be associated with more aggressive gastric polyps and to have a higher risk for gastric cancer.

• JPS is inherited in an autosomal dominant pattern. This means that first-degree relatives of an individual with an inherited variant in SMAD4 or BMPR1A have a 50% chance of having the familial variant themselves.
• Predictive testing can be offered to children from three years of age to enable interpretation of any gastrointestinal symptoms that might indicate intussusception.
• There is significant inter- and intra-familial variability.
• Referral to clinical genetics should be arranged for newly identified individuals with pathogenic or likely pathogenic variants in SMAD4 or BMPR1A to discuss onward management, family planning implications and cascade testing of at-risk relatives.

• People with JPS should be managed in expert centres who manage lifelong surveillance.
• Colonoscopic surveillance should commence from the age of 15 years or earlier if symptomatic. The surveillance interval should be 1–3 yearly, personalised according to colorectal phenotype.
• For those with a confirmed clinical or genetic diagnosis, upper GI endoscopic surveillance should start at the age of 18 years for SMAD4 variant carriers and 25 years for BMPR1A variant carriers and those with a clinical diagnosis without an identified constitutional variant. The surveillance interval should be 1–3 yearly, personalised according to upper GI tract phenotype.
• For those with a first-degree relative (parent, sibling or child) with a clinical diagnosis of JPS and in whom a variant has not been identified, screening of the upper GI tract is not required routinely but should be initiated if/when a clinical diagnosis is made on the basis of colonic phenotype. It may, however, be considered if there is a family history suggestive of hereditary haemorrhagic telangiectasia (HHT), even in the absence of colonic polyps.
• Patients with SMAD4 pathogenic variant should be evaluated for HHT; those at risk of, or with a confirmed diagnosis of, HHT are best managed in conjunction with a specialist HHT centre.
• Patients with JPS and a microdeletion involving BMPR1A and PTEN are at risk of the clinical manifestations of both JPS and PTEN-hamartoma tumour syndrome (PHTS). We suggest that they should be referred to their local genetics centre for further advice and to co-ordinate their surveillance needs.

For clinicians

References:

• Monahan K, Bradshaw N, Dolwani S and others. ‘Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG)‘. Gut 2020: volume 69, issue 3, pages 411–444. DOI: 10.1136/gutjnl-2019-319915
• Cohen S, Hyer W, Mas E and others. ‘Management of Juvenile Polyposis Syndrome in Children and Adolescents‘. Journal of Pediatric Gastroenterology and Nutrition 2019: issue 68, pages 453–462. DOI: 10.1097/MPG.0000000000002246