DiagnosisClinical DiagnosisJuvenile* polyposis syndrome (JPS) is diagnosed if any one of the following findings is present:More than five juvenile polyps of the colorectumMultiple juvenile polyps of the upper and lower GI tractAny number of juvenile polyps and a family history of juvenile polyps*The term "juvenile" refers to the type of polyp (see Testing, Histology), not the age of onset of polyps.TestingHistology. Juvenile polyps are hamartomas that develop from an abnormal collection of tissue elements normally present at this site. Juvenile polyps show a normal epithelium with a dense stroma, an inflammatory infiltrate, and a smooth surface with dilated, mucus-filled cystic glands in the lamina propria. Muscle fibers and the proliferative characteristics of adenomas are typically not seen in juvenile polyps. Note: Variability has been reported with the polyp type associated with the combined JPS/HHT syndrome (see Clinical Description) [Aretz et al 2007].Molecular Genetic TestingGenes. The two genes in which mutations are known to cause JPS are BMPR1A and SMAD4 (see Table 1).Evidence for further locus heterogeneityENG. To date, two young individuals with early-onset JPS have been found to have ENG mutations. Neither had clinical symptoms of hereditary hemorrhagic telangiectasia (HHT), which is known to be associated with ENG mutations; however, neither had yet reached the age at which symptoms of HHT commonly manifest. Subsequent studies have not identified deleterious ENG mutations among persons with JPS who did not have identifiable SMAD4 and BMPR1A mutations. Thus, the data are too preliminary to suggest that mutations in ENG predispose to JPS [Sweet et al 2005, Howe et al 2007].Other. While it has been suggested that mutations in PTEN are a cause of JPS, individuals thought to have JPS and changes in this gene probably have either Cowden syndrome or Bannayan-Riley-Ruvalcaba syndrome, phenotypes of the PTEN hamartoma tumor syndrome (PHTS) [Eng & Ji 1998].Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Juvenile Polyposis SyndromeView in own windowGene SymbolProportion of all JPS Attributed to Mutations in This GeneTest MethodMutations DetectedMutation Detection Frequency by Gene and Test Method ^{1Test AvailabilityBMPR1A20% 2, 3Sequence analysisSequence variants 413/65 53/27 622/102 7 ClinicalDuplication / deletion analysis 8Exonic, multiexonic, or whole-gene deletions3/65 53/27 62/102 7SMAD420% 3Sequence analysisSequence variants 417/65 56/27 620/102 7ClinicalDuplication/ deletion analysis 8Exonic, multiexonic, or whole-gene deletions6/65 51/27 62/102 71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sayed et al [2002] 3. Howe et al [2004]4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.5. Aretz et al [2007]6. van Hattem et al [2008]7. Calva-Cerqueira et al [2009]3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm/establish the diagnosis in a probandPathologic confirmation of the type of polyp is essential in order to apply the clinical diagnostic criteria.In individuals meeting the diagnostic criteria for JPS, molecular genetic testing of BMPR1A and SMAD4 is performed.Note: If no mutation is found, molecular genetic testing of PTEN is appropriate to determine if the individual has PTEN hamartoma tumor syndrome rather than JPS (see also Genetically Related Disorders).Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersBMPR1A. No phenotypes other than JPS are known to be caused by germline mutations in BMPR1A, with the exception of several families with features of hereditary mixed polyposis syndrome (HMPS). (See Differential Diagnosis, HMPS.)10q22-q23 microdeletions:Hamartomatous polyposis and 10q22-q23 deletions have been reviewed by Dahdaleh et al [2011].10q22-q23 microdeletions that include both PTEN and BMPR1A have been reported:Four individuals with a severe early-onset form of JPS (previously called juvenile polyposis of infancy) [Delnatte et al 2006] One individual with a milder phenotype with multiple colonic polyps diagnosed initially at age six years, who did not have juvenile polyposis of infancy [Salviati et al 2006] Two individuals both with typical juvenile polyps, one of whom had thyroid cancer, raising the question of Cowden syndrome [Van Hattem et al 2008]. See PTEN Hamartoma Tumor Syndrome. One individual diagnosed at age 20 years with features suggestive of Bannayan-Riley-Ruvalcaba syndrome (BRRS) (i.e., macrocephaly, trichilemmoma, hernias) [Calva-Cerqueira et al 2009]. See PTEN Hamartoma Tumor Syndrome.One child diagnosed at age 3 years; no other clinical details were given [Aretz et al 2007]. A small subset of individuals with BMPR1A mutations who were initially diagnosed with Cowden syndrome/Bannayan-Riley-Ruvalcaba or Cowden syndrome/Bannayan-Riley-Ruvalcaba-like phenotypes, but who did not meet the diagnostic criteria set forth by the International Cowden Consortium, likely should be reclassified as having the diagnosis of JPS [Zhou et al 2001, Zbuk & Eng 2007].SMAD4. No phenotypes other than JPS and the combined JPS/HHT syndrome are known to be caused by germline mutations in SMAD4.}

Natural HistoryJuvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. “Generalized juvenile polyposis” refers to polyps of the upper and lower GI tract. “Juvenile polyposis coli” refers to polyps of the colon only.The polyps vary in size and shape: some are flat (sessile), whereas others have a stalk (pedunculated). The number of polyps in individuals with JPS varies. Some individuals may only have four or five polyps over their lifetime; others in the same family may have more than 100.Bleeding may result from sloughing of the polyp or its surface epithelium with the passage of stool. If the polyps are left untreated, they may cause bleeding and anemia.Juvenile polyps develop from infancy through adulthood. Most individuals with JPS have some polyps by age 20 years.In juvenile polyposis of infancy, polyps develop within the first few years of life and are accompanied by hypoproteinemia, protein-losing enteropathy, diarrhea, anemia, anasarca, and failure to thrive.Cancer risks associated with JPS. Most juvenile polyps are benign; however, malignant transformation can occur. Lifetime estimates of developing GI cancers in families with JPS range from 9% to 50% [Howe et al 1998b]. Most of the increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have been reported:The incidence of colorectal cancer is 17%-22% by age 35 years and approaches 68% by age 60 years. The median age is 42 years.The incidence of gastric cancer is 21% in those with gastric polyps.In one large family with a germline SMAD4 mutation, the risk of colon cancer was approximately 40%, and the risk of upper GI cancers was 20% [Howe et al 1998b]. However, these cancer rates may change over time with the implementation of screening of young at-risk individuals and the removal of polyps before cancer develops.Combined JPS/HHT syndrome. The combined syndrome of JPS and HHT, initially reported in the 1980s [Cox et al 1980, Conte et al 1982], has now been attributed to causative SMAD4 germline mutations [Gallione et al 2004]. Although recent studies suggest that 15%-22% of individuals with an SMAD4 mutation are likely to have the combined JPS/HHT syndrome [Gallione et al 2004, Aretz et al 2007], this may be an underestimate as practitioners may not routinely investigate individuals with JPS for signs and symptoms of HHT.Individuals with the combined JPS/HHT syndrome have variable findings of juvenile polyposis (GI bleeding, gastric and colorectal polyps) and HHT (mucocutaneous telangiectases, pulmonary arteriovenous malformations [AVMs], hepatic AVMs, cerebral AVMs, GI AVMs, and telangiectases, epistaxis, and intracranial bleeding). Findings of HHT may manifest in early childhood. Although the frequency of each HHT complication in individuals with an SMAD4 mutation is not well established, a high frequency of pulmonary AVMs (and digital clubbing) has been consistently noted. Conversely, nosebleeds and telangiectases do not appear to be a constant feature.

Genotype-Phenotype CorrelationsGenotype-phenotype correlations in general are poor; some members of families with JPS and the same mutation have a few polyps, whereas others have 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:Individuals with JPS and an SMAD4 mutation are more likely to have a family history of upper-GI polyps than individuals with mutations in BMPR1A or those with no known mutations.Individuals with either an SMAD4 or BMPR1A mutation are more likely than those without mutations identified in these genes to have more than ten lower GI polyps and a family history of GI cancer [Burger et al 2002, Friedl et al 2002, Sayed et al 2002].The combined JPS/HHT syndrome is associated with SMAD4 mutations that are primarily within the MH2 domain (exons 8-11) [Gallione et al 2004, Gallione et al 2006, Pyatt et al 2006]; however, mutations in other exons have also been observed [Gallione et al 2010].

Differential DiagnosisJuvenile polyposis syndrome (JPS) may account for as many as 10% of cases of GI polyposis.Juvenile polyps can result from genetic predisposition or chance. It should be noted that 1% to 2% of individuals in the general population develop solitary juvenile polyps and do not meet diagnostic criteria for JPS.Several syndromes characterized by the presence of polyps have additional characteristics that are not associated with JPS. These include the following:PTEN hamartoma tumor syndrome (PHTS). Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, the two most common phenotypes of PHTS, can be associated with juvenile polyps. Cowden syndrome is a multiple hamartoma syndrome with a high risk of benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s. Bannayan-Riley-Ruvalcaba syndrome is characterized by macrocephaly, intestinal polyposis, lipomas, and pigmented macules of the glans penis. PTEN is the only gene in which mutation is known to cause PHTS. Approximately 80% of individuals who meet the diagnostic criteria for Cowden syndrome and 60% of individuals with a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome have a detectable PTEN mutation. Inheritance is autosomal dominant.Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas usually from the third decade onwards. Approximately 60% of individuals have a recognizable appearance with macrocephaly, bossing of the forehead, coarse facial features, and facial milia. Hamartomatous gastric polyps can occur. PTCH is the only gene in which mutation is known to cause NBCCS. Inheritance is autosomal dominant.Peutz-Jeghers syndrome (PJS) is characterized by the association of GI polyposis and mucocutaneous pigmentation. Peutz-Jeghers type hamartomatous polyps are most prevalent in the small intestine (jejunum, ileum, and duodenum, respectively), but also occur in the stomach and large bowel in the majority of affected individuals. STK11 is the only gene in which mutation is known to cause PJS. Inheritance is autosomal dominant.Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228) is characterized by atypical juvenile polyps, with mixed features of hamartomas and adenomas and a predisposition to cancer. The HMPS locus has been mapped to 15q13-q14 [Jaeger et al 2003]. Recently, one three-generation family with HMPS showed linkage to chromosome 10q23, and affected members had an 11-bp deletion in BMPR1A. The clinical history and polyp histology of these individuals was similar to that described for HMPS, with individuals having juvenile, hyperplastic, and/or mixed polyps [Cao et al 2006] (see also Genetically Related Disorders). Cheah et al identified a germline BMPR1A mutation in four of eight Singapore Chinese families with HMPS [Cheah et al 2009], and O’Riordan et al [2010] detected a BMPR1A nonsense mutation in a multi-generational Irish family with HMPS. Other syndromes characterized by the presence of polyps do not share features with JPS. These include the following:Familial adenomatous polyposis (FAP) is a colon cancer predisposition syndrome characterized by hundreds to thousands of precancerous adenomatous colonic polyps, beginning at a mean age of 16 years (range 7-36 years). The adenomatous polyps of FAP and juvenile polyps of JPS are histologically distinct. Extracolonic manifestations that are variably present include polyps of the gastric fundus and duodenum, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium (CHRPE), soft-tissue tumors, desmoid tumors, and associated cancers. APC is the only gene in which mutation is known to cause FAP. Inheritance is autosomal dominant.Hereditary non-polyposis colon cancer (HNPCC). This diagnosis enters the differential of JPS as a result of the distribution of the polyps and the variable number of polyps found. However, the pathology of the polyps should be useful in distinguishing the two diagnoses. HNPCC is characterized by an increased risk for colon cancer and cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. HNPCC is known to be associated with mutations in five genes involved in mismatch repair: MSH2, MLH1, PMS1, PMS2, and MSH6. Inheritance is autosomal dominant.Hereditary hemorrhagic telangiectasia (HHT). Persons with HHT who do not have an identifiable mutation in ENG or ALK1, the two genes known to be associated with HHT, should be evaluated for mutations in SMAD4, and those with an SMAD4 mutation should be screened for gastric and colonic polyposis [Gallione et al 2006]. Young persons with HHT who have GI bleeding or anemia not explained by epistaxis or bleeding from telangiectasias should also be evaluated for polyposis.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with juvenile polyposis syndrome (JPS), the following evaluations are recommended [Howe et al 1998a]:History for abdominal pain, rectal bleeding, constipation, diarrhea, or change in stool size, shape, and/or colorComplete blood count (CBC), colonoscopy, and upper endoscopy in the mid-teens (age 15 years) or at the time of initial symptoms, whichever is earlierExpert opinion also suggests that all individuals with an SMAD4 mutation be evaluated for complications related to hereditary hemorrhagic telangiectasia (HHT) [Gallione et al 2004].Treatment of ManifestationsJPS. The most effective management is routine colonoscopy with endoscopic polypectomy. Early endoscopic polypectomy may reduce morbidity by reducing the risk of the cancer, bleeding, or intestinal obstruction.In some cases, removal of all or part of the colon or stomach may be necessary to alleviate symptoms and/or reduce cancer risk when a large number of polyps are present. The preferred procedure is debated: Some experts prefer subtotal colectomy with ileorectal anastomosis, whereas others prefer proctocolectomy with an ileoanal pouch. The number of colonic or rectal polyps does not appear to correlate with the need for proctectomy [Oncel et al 2005].JPS/HHT. Treatment as needed for manifestations of HHT (see HHT).Prevention of Primary ManifestationsIncreased awareness, education, and screening have helped successive generations benefit from early detection of JPS and cancer prevention/risk reduction.Prevention of Secondary ComplicationsWhen present, anemia may be improved by polypectomy or surgery.SurveillanceFor individuals with JPS who have undergone surgical resection of bowel, endoscopic follow up is required regardless of the surgical procedure because of the high rate of subsequent development of polyps in the rectum and the pouch [Oncel et al 2005].For individuals with an SMAD4 or BMPR1A mutation 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 [Howe et al 1998a]:Monitoring for rectal bleeding and/or anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape, and/or color. These symptoms may warrant additional screening.CBC, colonoscopy, and upper endoscopy screening should begin in the mid-teens (age 15 years) or at the time of initial symptoms, whichever is earlier.If negative, screening should be repeated in three years.If only one or a few polyps are identified, the polyps should be removed. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.If many polyps are identified, removal of most of the colon or stomach may be necessary. Subsequently, screening should be done annually until no additional polyps are found, at which time screening every three years may resume.In families in which findings suggest the combined JPS/HHT syndrome or families with a known SMAD4 mutation, predictive molecular genetic testing may be appropriate before age 15 years because surveillance for potential complications of HHT begins in early childhood [Gallione et al 2004]. Until the frequency and spectrum of HHT complications in the combined JPS/HHT syndrome are known, it may be appropriate to follow the HHT surveillance guidelines for individuals with combined JPS/HHT syndrome or a known SMAD4 mutation.Precautionary screening recommendations for individuals at risk for JPS who do not have the family-specific mutation [Howe et al 1998a]:CBC and lower intestinal endoscopy should be performed at age 15 years as a baseline screening.If negative, repeat screening every ten years until age 45 years, after which the standard American Cancer Society recommendations for colon cancer screening should be followed.If polyps are identified, they need to be removed.If polyps are identified, screening should be repeated in one year.It is appropriate to consider repeating the molecular genetic testing or testing a different gene if the polyps identified are indeed juvenile polyps.Evaluation of Relatives at RiskWhen the family-specific mutation is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention. Note: Molecular genetic testing before age 15 years for children at risk for an SMAD4 mutation may be warranted because the surveillance for HHT-related findings begins earlier in childhood than the surveillance for polyps.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.OtherNo known chemoprevention options are effective for juvenile polyps.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Juvenile Polyposis Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSMAD418q21​.2Mothers against decapentaplegic homolog 4SMAD4 Database
SMAD4 homepage - Mendelian genesSMAD4BMPR1A10q23​.2Bone morphogenetic protein receptor type-1ABMPR1A homepage - Mendelian genesBMPR1AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Juvenile Polyposis Syndrome (View All in OMIM) View in own window 174900JUVENILE POLYPOSIS SYNDROME; JPS 600993MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4 601299BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IA; BMPR1AMolecular Genetic PathogenesisHow juvenile polyps form as a consequence of germline mutations in SMAD4 or BMPR1A is not known. Although SMAD4 is a tumor suppressor gene, loss of heterozygosity has not been demonstrated definitively as causal in the development of polyps. Furthermore, whether such changes would affect cells in the epithelium, the lamina propria, or both is also not known. BMPR1A is not known to be a tumor suppressor gene, although few studies have examined it in cancer. SMAD4 is the common intracellular mediator of the TGF-β superfamily signaling pathways. BMPR1A is a type I cell surface receptor for the BMP pathway. Ligands, such as TGF-β or BMP, bind to a receptor and activate signaling pathways leading to protein complexes that migrate to the nucleus and bind directly to DNA sequences to regulate transcription [Heldin et al 1997]. The downstream genes under the control of these signaling pathways are still being actively investigated. Despite the close proximity of BMPR1A to PTEN (both are on 10q22-q23), they do not appear to work together or to be members of the same pathways. A contiguous gene deletion of PTEN and BMPR1A has been associated with a severe form of early-onset JPS (previously called juvenile polyposis of infancy) [Delnatte et al 2006]. Milder phenotypes with a similar deletion of both PTEN and BMPR1A have also been reported [Salviati et al 2006]. The role that each gene contributes to the phenotype is unknown.BMPR1ANormal allelic variants. BMPR1A comprises 11 coding exons. There is a common normal allelic variant in nucleotide 4 of BMPR1A [Howe et al 2001].Pathologic allelic variants. Sixty pathologic variants, including insertions, deletions, missense, nonsense, and splice-site alterations, have been described [Calva-Cerqueira et al 2009]. Germline deletions or missense mutations of the promoter have also been described [Calva-Cerqueira et al 2010]. Large deletions of BMPR1A may also occur in up to 6% of individuals [Aretz et al 2007, van Hattem et al 2008, Calva-Cerqueira et al 2009].Normal gene product. The protein product, BMPR1A, a 533-amino acid protein encoded by 1599 nucleotides, is a type I receptor of the TGF-β super family that mediates the BMP intracellular signaling through SMAD4 [Howe et al 2001].Abnormal gene product. Abnormal BMPR1A proteins frequently result from pathologic DNA variants in the protein kinase domain and occasionally by variants in the cysteine-rich region of the extracellular domain. No pathologic variants have been described in the transmembrane domain [Howe et al 2004].SMAD4Normal allelic variants. SMAD4 comprises 11 coding exons.Pathologic allelic variants. See Table 2. Germline pathologic variants have been described in all eleven coding exons. Changes include small deletions, insertions, and missense and nonsense mutations. Two splice-site variants have been reported. Most pathologic variants are unique, but three have been reported in multiple unrelated families: c.1244_1247delACAG, c.1162C>T, and p.Arg361Cys. See Howe et al [2004] and Calva-Cerqueira et al [2009] for a comprehensive list of the pathologic variants reported in SMAD4 (previously known as MADH4). Larger deletions of SMAD4 may also occur in up to 4% of affected individuals [Aretz et al 2007, van Hattem et al 2008, Calva-Cerqueira et al 2009]. Deletions and missense mutations have also been reported in the promoter region [Calva-Cerqueira et al 2010].Table 2. Selected SMAD4 Pathologic Allelic Variants View in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencec.1081C>Tp.Arg361CysNM_005359​.5
NP_005350​.1c.1162C>Tp.Glu388Xc.1244_1247delACAGp.Asp415Glufs*20See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The protein product, SMAD4, a 552-amino acid protein encoded by 1656 nucleotides, is a critical cytoplasmic mediator in the transforming growth factor-β signaling pathway.Abnormal gene product. The MH1 domain of the SMAD4 protein can directly bind to the DNA of target genes. Pathologic allelic variants in this domain can significantly reduce the DNA binding activity of SMAD4. Most pathologic allelic variants, including the three recurrent mutations in Table 2, occur in the MH2 domain, which plays an important role for nuclear localization, interaction with other MAD proteins, and transcriptional activation.