Juvenile polyposis syndrome

The estimated prevalence is 1/16,000-1/100,000.

JPS is inherited in an autosomal dominant manner.1 Each child of an affected individual has a 50% risk of inheriting the familial pathogenic variant. Approximately 50% of individuals diagnosed with JPS have no prior family history of polyps and may have the disorder as the result of a de novo pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is based on histopathologic confirmation of juvenile (hamartomatous) polyps, characterised by normal epithelium, abundant stroma, inflammatory infiltrate, and dilated mucus-filled cystic glands within the lamina propria. Colonoscopy and upper endoscopy allow assessment of polyp distribution in the stomach, small intestine, colon, and rectum. Clinical evaluation also considers the personal and family history of juvenile polyps and gastrointestinal malignancy. In individuals with an SMAD4 pathogenic variant, additional assessment for features of hereditary haemorrhagic telangiectasia, including screening for pulmonary, hepatic, and intracranial arteriovenous malformations, is recommended.

Main differential diagnoses include:

: variable hamartomatous polyps including juvenile polyps but also tubular adenomas, ganglioneuromas and serrated polyps, with extraintestinal features (macrocephaly, trichilemmomas, papillomatous papules, breast/thyroid/endometrial tumour risk, vascular malformations); PTEN

: gastrointestinal hamartomatous polyps with characteristic smooth muscle hyperplasia and mucocutaneous melanin pigmentation, conferring elevated risk of breast, colorectal, pancreatic, ovarian, gastric, lung and small-intestinal cancers; STK11

: multiple adenomatous (not hamartomatous) gastrointestinal polyps with associated osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium, desmoid tumours and increased risk of colorectal, thyroid and other cancers; APC

• Establishing the diagnosis: molecular genetic testing confirms the clinical diagnosis and identifies the causative pathogenic variant, providing a definitive aetiologic basis for clinical decisions.
• Enabling specific and individualised surveillance: identification of the causative variant is the prerequisite for targeted medical care, including organ-specific surveillance for gastrointestinal and, where SMAD4-related, vascular manifestations, as decided by the treating physicians in consultation with the affected individual.
• Family member testing: once the familial pathogenic variant is known, predictive testing of at-risk relatives is technically possible and informs their individual clinical follow-up.

• Larsen Haidle J, MacFarland SP, Howe JR. Juvenile Polyposis Syndrome. 2003 May 13 [Updated 2022 Feb 3]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301642. Available from:
• Jelsig AM, Qvist N, Bertelsen B, Christensen LL, Grossjohan H, Lautrup CK, et al. Distinct gastric phenotype in patients with pathogenic variants in SMAD4: A nationwide cross-sectional study. Endoscopy international open. 2022;10(12):E1537-E1543. doi: 10.1055/a-1954-0522. PMID: . PMCID: PMC9754866.
• Cao K, Plazzer JP, Macrae F. SMAD4 variants and its genotype-phenotype correlations to juvenile polyposis syndrome. Hereditary cancer in clinical practice. 2023;21(1):27. doi: 10.1186/s13053-023-00267-z. PMID: . PMCID: PMC10704831.
• Seppälä TT, Burkhart RA, Katona BW. Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review. BJS open. 2023;7(3). doi: 10.1093/bjsopen/zrad023. PMID: . PMCID: PMC10172688.