Juvenile Polyposis Syndrome

Clinical characteristics.

Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than 100. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers ranges from 11% to 86%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) is present in most individuals with an SMAD4 pathogenic variant.

Diagnosis/testing.

The diagnosis of JPS is established in a proband with any of the following: more than five juvenile polyps of the colorectum; multiple juvenile polyps throughout the GI tract; or any number of juvenile polyps and a family history of juvenile polyposis. Identification of a heterozygous pathogenic variant in SMAD4 or BMPR1A confirms the diagnosis if clinical features are inconclusive.

Management.

Treatment of manifestations: Colonoscopy with endoscopic polypectomy to reduce the risk of cancer, bleeding, and intestinal obstruction. When a large number of polyps are present, removal of all or part of the colon or stomach may be necessary. Iron replacement and red blood cell transfusion as needed for anemia; treatment as needed for manifestations of HHT, arteriovenous malformations, aortopathy, and/or valvular disease per cardiologist and cardiothoracic surgeon.

Surveillance: Assess for rectal bleeding, anemia, abdominal pain, constipation, diarrhea, or change in stool size, shape, and/or color at each visit; complete blood count as needed based on symptoms; colonoscopy and upper endoscopy every three years beginning at age 15 years or earlier if symptomatic or if polyps were present on the prior colonoscopy. For individuals following surgical resection: endoscopic evaluation of the remaining colon, rectum, and ileal pouch. In individuals with (or at risk for) SMAD4-related JPS, follow HHT surveillance guidelines and consider transthoracic echocardiogram.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early surveillance and intervention. Evaluations include molecular genetic testing (if the pathogenic variant in the family is known) and gastrointestinal and hematologic evaluations if the pathogenic variant in the family is not known.

Genetic counseling.

JPS is inherited in an autosomal dominant manner. Up to half of individuals with JPS have an affected parent; approximately 50% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing JPS. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.

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

Note: "Juvenile" refers to the polyp histopathology, not the age of onset of polyps.

Histopathologic features. 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 in histopathology has been reported in polyps associated with juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) (see Clinical Characteristics) [Aretz et al 2007].

Establishing the Diagnosis

The diagnosis of JPS is established in a proband with any one of the following features:

• More than five juvenile polyps of the colon or rectum
• Multiple juvenile polyps of the upper and lower gastrointestinal tract
• Any number of juvenile polyps and a family history of juvenile polyposis
• Identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include BMPR1A and SMAD4 concurrent testing, serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

• BMPR1A and SMAD4 concurrent testing can be considered in individuals with clinical features suggestive of JPS. Sequence analysis including analysis of promoter regions as well as gene-targeted deletion/duplication analysis of BMPR1A and SMAD4 is performed first. If no pathogenic variant is found, consider use of a multigene panel that includes PTEN and other genes of interest (see Differential Diagnosis, Table 3).
• Serial single-gene testing can be considered in individuals with clinical features suggestive of JPS/HHT (see Table 2 and HHT).

  1.

  Sequence analysis and deletion/duplication analysis of SMAD4 is performed first.

  2.

  Sequence analysis and deletion/duplication analysis of BMPR1A should be considered next if no SMAD4 pathogenic variant is identified.

  3.

  Consider molecular genetic testing of additional HHT-related genes if an SMAD4 or BMPR1A pathogenic variant has not been identified.

• A multigene panel that includes BMPR1A, SMAD4, and other genes of interest (see Differential Diagnosis) – in particular PTEN (see *) – may be considered in individuals with JPS. Note: (1) The genes included and the sensitivity of multigene panels vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) Understanding the limitations of the panel is critical for interpreting a negative test result and determining if additional testing is required. It is important to ensure that the panel provides the best coverage for those genes with the highest clinical suspicion, and includes analysis of the promoter regions.
  Deletions of 10q22-q23 detectable by chromosomal microarray analysis including either BMPR1A or both BMPR1A and PTEN may be associated with additional clinical features with or without juvenile polyposis or with severe early-onset JPS [Delnatte et al 2006, Salviati et al 2006, van Hattem et al 2008, Calva-Cerqueira et al 2009, Breckpot et al 2012, Oliveira et al 2013, Alimi et al 2015]. Hamartomatous polyposis and 10q22-q23 deletions have been reviewed by Dahdaleh et al [2012].
  * If no pathogenic variant 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).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Juvenile Polyposis Syndrome

Clinical Description

Juvenile Polyposis Syndrome / Hereditary Hemorrhagic Telangiectasia (JPS/HHT)

Individuals with JPS/HHT have variable findings of juvenile polyposis and HHT (see Table 2). Most individuals with JPS who have an SMAD4 germline pathogenic variant have one or more clinical features of HHT. The findings of HHT may manifest in early childhood. A high frequency of pulmonary arteriovenous malformations (with digital clubbing) and epistaxis has been consistently noted in individuals with SMAD4-related HHT. Conversely, telangiectases do not appear to be a constant feature. Additional complications reported in individuals with JPS/HHT include anemia, migraine headaches, and exercise intolerance.

Table 2.

Clinical Features of SMAD4-Related Hereditary Hemorrhagic Telangiectasia

Thoracic aortic disease (e.g., aortic root dilatation, aneurysm, and aortic dissection) and mitral valve dysfunction have been reported in individuals with SMAD4 pathogenic variants [Heald et al 2015].

Expanding phenotype. There are reports of individuals with an SMAD4 pathogenic variant who also presented with retinitis pigmentosa, retinal detachment, joint laxity, and/or a marfanoid habitus. Data for these findings is limited and it is unclear if these are features of the SMAD4-related JPS/HHT phenotype. More work is needed to assess the frequency of these findings to determine medical management recommendations. Providers may wish to be aware of these reports and evaluate individuals on a case-by-case basis.

Genotype-Phenotype Correlations

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:

• Individuals with SMAD4-related JPS are more likely to have a personal or family history of upper GI polyps than individuals with a BMPR1A pathogenic variant or those with no known pathogenic variant. The gastric phenotype in individuals with an SMAD4 pathogenic variant tends to be more aggressive with significant polyposis, anemia, and a higher risk for gastric cancer [Aytac et al 2015, Blatter et al 2020, MacFarland et al 2021]. Gastric cancer was reported almost exclusively in individuals with SMAD4-related JPS (27% of SMAD4-associated cancers vs 0% of BMPR1A-associated cancers) [Blatter et al 2020].
• Colorectal cancer occurs more frequently than other cancers in BMPR1A-related JPS (88% of BMPR1A-associated cancers vs 58% of SMAD4-associated cancers) [Blatter et al 2020].
• Individuals with either an SMAD4 or BMPR1A pathogenic variant are more likely than those without a pathogenic variant identified 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, MacFarland et al 2021]. They are also more likely to be older at diagnosis and at higher risk of requiring colectomy [MacFarland et al 2021].
• There is some evidence that in individuals without a germline BMPR1A or SMAD4 pathogenic variant, polyp burden may decrease in adulthood and cancer risk may be lower [MacFarland et al 2021], but this requires further research.
• JPS/HHT is associated with SMAD4 pathogenic variants.

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 [Wain et al 2014]. 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, Aytac et al [2015] 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.

Nomenclature

Familial juvenile polyposis is an older term used to distinguish between simplex (i.e., a single affected individual in a family) and familial cases.

Prevalence

The incidence of JPS has been estimated to range between 1:16,000 and 1:100,000.

BMPR1A

Germline BMPR1A pathogenic variants were identified in affected members of six families with features of hereditary mixed polyposis syndrome. The polyps were reported to be of mixed adenomatous, hyperplastic, and atypical juvenile histology [Cao et al 2006, Cheah et al 2009, O'Riordan et al 2010, Miyahara et al 2020] (see Differential Diagnosis).

Deletions of 10q22-q23 that include PTEN and BMPR1A have been identified in individuals with 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.

One individual with an intragenic BMPR1A deletion was reported to have dysmorphic facies, atrioventricular septal defect, short stature, and delayed puberty [Breckpot et al 2012].

Homozygous BMPR1A missense variants (p.Arg406Lys) were identified in an individual with growth failure, atrial septal defect, airway abnormalities (laryngomalacia, subglottic stenosis), and developmental delay [Russell et al 2019].

SMAD4

Heterozygous gain-of-function SMAD4 pathogenic variants affecting amino acid 496 or 500 are associated with Myhre syndrome. Myhre syndrome is a connective tissue disorder with multisystem involvement including cardiovascular disease, respiratory disease, gastrointestinal disease, thickened skin, proliferative fibrosis and scarring, cognitive impairment, facial dysmorphism, and short stature. To date, no cancers consistent with the typical juvenile polyposis syndrome (JPS) phenotype have been reported in individuals with Myhre syndrome. However, early-onset endometrial cancer and benign brain tumors have been reported in individuals with Myhre syndrome [Lin et al 2020].

Sporadic tumors (including colorectal cancer and pancreatic tumors) occurring as single tumors in the absence of any other findings of JPS frequently harbor a somatic variant in SMAD4 that is not present in the germline [Chen et al 2014]. In these circumstances predisposition to these tumors is not heritable. For more information, see Cancer and Benign Tumors.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with juvenile polyposis syndrome (JPS), the evaluations summarized in Table 4 (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

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with Juvenile Polyposis Syndrome

Surveillance

The surveillance recommended in Table 6 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

Agents/Circumstances to Avoid

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 [Devlin et al 2013].
• 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 [Buscarini et al 2006].

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early surveillance and intervention.

In families in which findings suggest JPS or families with a known BMPR1A pathogenic variant, evaluations can include:

• Molecular genetic testing at or prior to age 15 years if the pathogenic variant in the family is known;
• If the familial pathogenic variant is not known, complete blood count (CBC) and lower intestinal endoscopy in individuals age 15 years an older. Normal results do not rule out a diagnosis of JPS (see Surveillance for additional recommendations).

In families in which findings suggest juvenile polyposis syndrome / hereditary hemorrhagic telangiectasia (JPS/HHT) or families with a known SMAD4 pathogenic variant:

• Molecular genetic testing before age 15 years for children at risk for a known familial SMAD4 pathogenic variant should be offered because the surveillance for HHT-related findings begins earlier in childhood than the surveillance for polyps.
• In families in which findings suggest JPS/HHT but the familial pathogenic variant is not known:
  • CBC and lower intestinal endoscopy in individuals age 15 years an older, or earlier if symptoms of polyposis. Normal results do not rule out a diagnosis of JPS (see Surveillance for additional recommendations).
  • In individuals older than age 40 years, targeted medical history and clinical examination for features of HHT. The absence of mild but recurrent epistaxis and subtle telangiectases in characteristic locations on careful examination is reassuring (see Hereditary Hemorrhagic Telangiectasia).
  • In individuals age 40 years and younger, targeted medical history and clinical examination for features of HHT as well as initial evaluation for brain and pulmonary arteriovenous malformations, as features of HHT may not be identified by medical history and clinical examination in younger individuals

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

See Hereditary Hemorrhagic Telangiectasia, Pregnancy Management.

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 [Busoni et al 2019]. In a small case series, sirolimus therapy reduced symptoms including bleeding and enteropathy, and also reduced rate of colectomy [Taylor et al 2021].

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.

Other

No known chemoprevention options are effective for juvenile polyps.

Mode of Inheritance

Juvenile polyposis syndrome (JPS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Up to half of individuals diagnosed with JPS have an affected parent.
• Approximately 50% of individuals diagnosed with JPS have no previous history of polyps in the family and may have the disorder as the result of a de novo pathogenic variant [Restrepo et al 1978, Coburn et al 1995].
• If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents is recommended in order to clarify their genetic/clinical status and to assess the risk of JPS in sibs and other relatives. Recommendations for the evaluation of parents of a proband include the following:
  • Molecular genetic testing if a causative SMAD4 or BMPR1A pathogenic variant has been identified in the proband
  • Screening/surveillance for JPS (and hereditary hemorrhagic telangiectasia [HHT] if findings in the proband suggest JPS/HHT) if a pathogenic variant has not been identified in the proband
• If the proband has a known pathogenic variant that cannot be identified in either parent and parental identified testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with JPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance and variable expressivity, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or appropriate molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• Intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among family members who are heterozygous for the same SMAD4 or BMPR1A pathogenic variant.
• If the proband has a known JPS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Lamireau et al 2005].
• If the genetic status of the parents is unknown (and/or a molecular diagnosis has not been established in the proband), sibs should be considered at risk for JPS (regardless of whether parents have had manifestations of the disorder) and offered molecular genetic testing and screening/surveillance for JPS (and HHT if findings in the proband suggest JPS/HHT).

Offspring of a proband. Each child of an individual with JPS has a 50% chance of inheriting the causative pathogenic variant and having an increased risk of developing JPS.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or is known to have the pathogenic variant identified in the proband, the parent's family members may be at risk and may benefit from molecular genetic testing and/or surveillance.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early surveillance and intervention.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Genetic cancer risk assessment and counseling. For a comprehensive description of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see Cancer Genetics Risk Assessment and Counseling – for health professionals (part of PDQ^®, National Cancer Institute).

Molecular genetic testing of asymptomatic individuals younger than age 18 years. If the JPS-causing pathogenic variant has been identified in a family, predictive molecular genetic testing can be used to identify family members who would benefit from early screening.

• Families with a known BMPR1A pathogenic variant. Since surveillance for asymptomatic individuals at risk for JPS is recommended beginning at age 15 years, it is appropriate to consider predictive genetic testing for JPS around this age or earlier. If parents are concerned about their child's ability to cope with the significance of test results, the disclosure of the molecular genetic testing information, but not surveillance, can be delayed.
  If symptoms of JPS appear before age 15 years, surveillance should begin at that time and disclosure of molecular genetic test results may be a reasonable option. It is important to consider the risks and benefits for children of learning this information at a young age and to consider ways to discuss this information with children and to answer their questions.
• Families with a known SMAD4 pathogenic variant. Predictive molecular genetic testing before age 15 years should be offered because the surveillance for HHT-related findings begins earlier in childhood (see Hereditary Hemorrhagic Telangiectasia) than the surveillance for polyps.

See Management, Evaluation of Relatives at Risk for recommended evaluations of at-risk relatives when the familial pathogenic variant is not known.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the JPS-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for JPS are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The mechanism of juvenile polyp formation as a consequence of germline pathogenic variants in SMAD4 or BMPR1A is not known. Although SMAD4 is a tumor suppressor gene, loss of heterozygosity has not been definitively demonstrated to cause polyp development. 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 encodes 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 involving regulatory SMAD proteins, which form protein complexes with SMAD4 that migrate to the nucleus and bind directly to DNA sequences to regulate transcription [Heldin et al 1997, Gómez Pinto et al 2018]. The downstream genes under the control of these signaling pathways are still being actively investigated.

Most BMPR1A pathogenic variants occur in the protein kinase domain and occasionally in the cysteine-rich region of the extracellular domain. No pathogenic variants have been described in the transmembrane domain [Howe et al 2004]. In vitro studies have shown that proteins resulting from JPS-related BMPR1A pathogenic missense variants are retained in the cytoplasm and do not traffic to the cell membrane like the wild type protein [Howe et al 2013].

Most SMAD4 pathogenic variants occur in the MH2 domain, which plays an important role for nuclear localization, interaction with other SMAD proteins, and transcriptional activation. In vitro studies demonstrate that pathogenic nonsense variants lead to significantly reduced bone morphogenetic protein signaling, with less of an effect for missense variants [Carr et al 2012].

Mechanism of disease causation. Unknown

Cancer and Benign Tumors

Somatic SMAD4 variants that are not present in the germline have been reported in colorectal, pancreatic, and prostate cancers occurring as single tumors in the absence of any other findings of juvenile polyposis syndrome [Chen et al 2014, McCarthy & Chetty 2018].

Author Notes

Dr James R Howe is a surgical oncologist and primary researcher in the field of juvenile polyposis syndrome. Joy Larsen Haidle is a genetic counselor with the Cancer Genetics program at North Memorial Health Cancer Center who is actively involved in the development of genetic counseling guidelines with Dr Howe's research program.

Dr Suzanne P MacFarland is a pediatric oncologist and cancer predisposition researcher in the field of juvenile polyposis syndrome. She runs a multidisciplinary polyposis clinic at the Children's Hospital of Philadelphia.

Revision History

• 3 February 2022 (sw) Comprehensive update posted live
• 9 March 2017 (sw) Comprehensive update posted live
• 3 December 2015 (jrh) Revision: corrections to Genetically Related Disorders
• 22 May 2014 (me) Comprehensive update posted live
• 29 September 2011 (me) Comprehensive update posted live
• 9 September 2008 (me) Comprehensive update posted live
• 22 February 2007 (cd) Revision: prenatal diagnosis available for BMPR1A mutations
• 2 November 2006 (cd) Revision: prenatal diagnosis available for SMAD4 mutations
• 13 June 2005 (me) Comprehensive update posted live
• 20 May 2004 (cd) Revision: Genetic Counseling
• 27 October 2003 (cd) Revision: Statements and Policies
• 13 May 2003 (me) Review posted live
• 4 January 2003 (jrh) Original submission

Published Guidelines / Consensus Statements

• Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107-14.
• Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453-62.
• Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 10-14-22.
• Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17:70-87.
• NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available online. Registration required. 2021.

Literature Cited

• Achatz MI, Porter CC, Brugières L, Druker H, Frebourg T, Foulkes WD, Kratz CP, Kuiper RP, Hansford JR, Hernandez HS, Nathanson KL, Kohlmann WK, Doros L, Onel K, Schneider KW, Scollon SR, Tabori U, Tomlinson GE, Evans DGR, Plon SE. Cancer screening recommendations and clinical management of inherited gastrointestinal cancer syndromes in childhood. Clin Cancer Res. 2017;23:e107–e114. [PubMed: 28674119]

• Alimi A, Weeth-Feinstein LA, Stettner A, Caldera F, Weiss JM. Overlap of Juvenile polyposis syndrome and Cowden syndrome due to de novo chromosome 10 deletion involving BMPR1A and PTEN: implications for treatment and surveillance. Am J Med Genet A. 2015;167:1305–8. [PMC free article: PMC4449295] [PubMed: 25846706]

• Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, Siebert R, Vogt S, Spranger S, Holinski-Feder E, Sunde L, Propping P, Friedl W. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44:702–9. [PMC free article: PMC2752176] [PubMed: 17873119]

• Aytac E, Sulu B, Heald B, O'Malley M, LaGuardia L, Remzi FH, Kalady MF, Burke CA, Church JM. Genotype-defined cancer risk in juvenile polyposis syndrome. Br J Surg. 2015;102:114–8. [PubMed: 25389115]

• Blatter R, Tschupp B, Aretz S, Bernstein I, Colas C, Evans DG, Genuardi M, Hes FJ, Hüneburg R, Järvinen H, Lalloo F, Moeslein G, Renkonen-Sinisalo L, Resta N, Spier I, Varvara D, Vasen H, Latchford AR, Heinimann K. Disease expression in juvenile polyposis syndrome: a retrospective survey on a cohort of 221 European patients and comparison with a literature-derived cohort of 473 SMAD4/BMPR1A pathogenic variant carriers. Genet Med. 2020;22:1524–32. [PMC free article: PMC7462743] [PubMed: 32398773]

• Breckpot J, Tranchevent LC, Thienpont B, Bauters M, Troost E, Gewillig M, Vermeesch JR, Moreau Y, Devriendt K, Van Esch H. BMPR1A is a candidate gene for congenital heart defects associated with the recurrent 10q22q23 deletion syndrome. Eur J Med Genet. 2012;55:12–6. [PubMed: 22067610]

• Brosens LA, van Hattem A, Hylind LM, Iacobuzio-Donahue C, Romans KE, Axilbund J, Cruz-Correa M, Tersmette AC, Offerhaus GJ, Giardiello FM. Risk of colorectal cancer in juvenile polyposis. Gut. 2007;56:965–7. [PMC free article: PMC1994351] [PubMed: 17303595]

• Burger B, Uhlhaas S, Mangold E, Propping P, Friedl W, Jenne D, Dockter G, Back W. Novel de novo mutation of MADH4/SMAD4 in a patient with juvenile polyposis. Am J Med Genet. 2002;110:289–91. [PubMed: 12116240]

• Buscarini E, Plauchu H, Garcia Tsao G, White RI Jr, Sabbà C, Miller F, Saurin JC, Pelage JP, Lesca G, Marion MJ, Perna A, Faughnan ME. Liver involvement in hereditary hemorrhagic telangiectasia: consensus recommendations. Liver Int. 2006;26:1040–6. [PubMed: 17032403]

• Busoni VB, Orsi M, Lobos PA, D'Agostino D, Wagener M, De la Iglesia P, Fox VL. Successful treatment of juvenile polyposis of infancy with sirolimus. Pediatrics. 2019;144:e20182922. [PubMed: 31366686]

• Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009;75:79–85. [PubMed: 18823382]

• Calva-Cerqueira D, Dahdaleh FS, Woodfield G, Chinnathambi S, Nagy PL, Larsen-Haidle J, Weigel RJ, Howe JR. Discovery of the BMPR1A promoter and germline mutations that cause juvenile polyposis. Hum Mol Genet. 2010;19:4654–62. [PMC free article: PMC2972697] [PubMed: 20843829]

• Cao X, Eu KW, Kumarasinghe MP, Li HH, Loi C, Cheah PY. Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. J Med Genet. 2006;43:e13. [PMC free article: PMC2563243] [PubMed: 16525031]

• Carr JC, Dahdaleh FS, Wang D, Howe JR. Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling. J Surg Res. 2012;174:211–4. [PMC free article: PMC3418515] [PubMed: 22316667]

• Cheah PY, Wong YH, Chau YP, Loi C, Lim KH, Lim JF, Koh PK, Eu KW. Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. Am J Gastroenterol. 2009;104:3027–33. [PubMed: 19773747]

• Chen YW, Hsiao PJ, Weng CC, Kuo KK, Kuo TL, Wu DC, Hung WC, Cheng KH. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer. 2014;14:181. [PMC free article: PMC4007528] [PubMed: 24625091]

• Coburn MC, Pricolo VE, DeLuca FG, Bland KI. Malignant potential in intestinal juvenile polyposis syndromes. Ann Surg Oncol. 1995;2:386–91. [PubMed: 7496832]

• Cohen S, Hyer W, Mas E, Auth M, Attard TM, Spalinger J, Latchford A, Durno C. Management of juvenile polyposis syndromes in children and adolescents: a position paper from the ESPGHAN Polyposis Working Group. J Pediatr Gastroenterol Nutr. 2019;68:453–62. [PubMed: 30585890]

• Dahdaleh FS, Carr JC, Calva D, Howe JR. Juvenile polyposis and other intestinal polyposis syndromes with microdeletions of chromosome 10q22-23. Clin Genet. 2012;81:110–6. [PMC free article: PMC3236803] [PubMed: 21834858]

• Delnatte C, Sanlaville D, Mougenot JF, Vermeesch JR, Houdayer C, Blois MC, Genevieve D, Goulet O, Fryns JP, Jaubert F, Vekemans M, Lyonnet S, Romana S, Eng C, Stoppa-Lyonnet D. Contiguous gene deletion within chromosome arm 10q is associated with juvenile polyposis of infancy, reflecting cooperation between the BMPR1A and PTEN tumor-suppressor genes. Am J Hum Genet. 2006;78:1066–74. [PMC free article: PMC1474102] [PubMed: 16685657]

• Devlin HL, Hosman AE, Shovlin CL. Antiplatlet and anticoagulant agents in hereditary hemorrhagic telangiectasia. N Engl J Med. 2013;368:876–8. [PubMed: 23445111]

• Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet. 2002;111:108–11. [PubMed: 12136244]

• Gómez Pinto LI, Rodriguez D, Adamo AM, Mathieu PA. TGF-β pro-oligodendrogenic effects on adult SVZ progenitor cultures and its interaction with the Notch signaling pathway. Glia. 2018;66:396–412. [PubMed: 29076551]

• Heald B, Rigelsky C, Moran R, LaGuardia L, O'Malley M, Burke CA, Zahka K. Prevalence of thoracic aortopathy in patients with juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia due to SMAD4. Am J Med Genet. 2015;167A:1758–62. [PubMed: 25931195]

• Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–71. [PubMed: 9393997]

• Howe JR, Haidle JL, Lal G, Bair J, Song C, Pechman B, Chinnathambi S, Lynch HT. ENG mutations in MADH4.BMPR1A mutation negative patients with juvenile polyposis. Clin Genet. 2007;71:91–2. [PubMed: 17204053]

• Howe JR, Roth S, Ringold JC, Summers RW, Jarvinen HJ, Sistonen P, Tomlinson IP, Houlston RS, Bevan S, Mitros FA, Stone EM, Aaltonen LA. Mutations in the SMAD4/DPC4 gene in juvenile polyposis. Science. 1998;280:1086–8. [PubMed: 9582123]

• Howe JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, Mitros FA, Vaccaro CA, Petersen GM, Giardiello FM, Tinley ST, Aaltonen LA, Lynch HT. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004;41:484–91. [PMC free article: PMC1735829] [PubMed: 15235019]

• Howe JR, Dahdaleh FS, Carr JC, Wang D, Sherman SK, Howe JR. BMPR1A mutations in juvenile polyposis affect cellular localization. J Surg Res. 2013;184:739–45. [PMC free article: PMC3683109] [PubMed: 23433720]

• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]

• Ishida H, Ishibashi K, Iwama T. Malignant tumors associated with juvenile polyposis syndrome in Japan. Surg Today. 2018;48:253–63. [PubMed: 28550623]

• Jelsig AM, Tørring PM, Kjeldsen AD, Qvist N, Bojesen A, Jensen UB, Andersen MK, Gerdes AM, Brusgaard K, Ousager LB. JP-HHT phenotype in Danish patients with SMAD4 mutations. Clin Genet. 2016;90:55–62. [PubMed: 26572829]

• Lamireau T, Olschwang S, Rooryck C, Le Bail B, Chateil JF, Lacombe D. SMAD4 germinal mosaicism in a family with juvenile polyposis and hypertrophic osteoarthropathy. J Pediatr Gastroenterol Nutr. 2005;41:117–20. [PubMed: 15990641]

• Latchford AR, Neale K, Phillips RK, Clark SK. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis Colon Rectum. 2012;55:1038–43. [PubMed: 22965402]

• Lin AE, Alali A, Starr LJ, Shah N, Beavis A, Pereira EM, Lindsay ME, Klugman S. Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome. Am J Med Genet A. 2020;182:328–37. [PubMed: 31837202]

• MacFarland SP, Ebrahimzadeh JE, Zelley K, Begum L, Bass LM, Brand RE, Dudley B, Fishman DS, Ganzak A, Karloski E, Latham A, Llor X, Plon S, Riordan MK, Scollon SR, Stadler ZK, Syngal S, Ukaegbu C, Weiss JM, Yurgelun MB, Brodeur GM, Mamula P, Katona BW. Phenotypic differences in juvenile polyposis syndrome with or without a disease-causing SMAD4/BMPR1A variant. Cancer Prev Res (Phila). 2021;14:215–22. [PMC free article: PMC8557953] [PubMed: 33097490]

• McCarthy AJ, Chetty R. Smad4/DPC4. J Clin Pathol. 2018;71:661–4. [PubMed: 29720405]

• Miyahara Y, Ishida H, Kawabe K, Eto H, Kasai T, Ito T, Kaneko K, Arai M, Kamae N, Momose S, Eguchi H, Okazaki Y. A novel germline BMPR1A variant (c.72_73delGA) in a Japanese family with hereditary mixed polyposis syndrome. Jpn J Clin Oncol. 2020;50:826–9. [PMC free article: PMC7345204] [PubMed: 32378721]

• NCCN. Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines). Version 1.2021 (May 11, 2021). Available online. Registration required. 2021.

• Nishida T, Faughnan ME, Krings T, Chakinala M, Gossage JR, Young WL, Kim H, Pourmohamad T, Henderson KJ, Schurm SD, James M, Quinnine N, Bharatha A, Terbrugge KG, White RI Jr. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012;158A:2829–34. [PMC free article: PMC3610331] [PubMed: 22991266]

• Oliveira PH, Cunha C, Almeida S, Ferreira R, Maia S, Saraiva JM, Lopes MF. Juvenile polyposis of infancy in a child with deletion of BMPR1A and PTEN genes: surgical approach. J Pediatr Surg. 2013;48:e33–7. [PubMed: 23331837]

• Oncel M, Church JM, Remzi FH, Fazio VW. Colonic surgery in patients with juvenile polyposis syndrome: a case series. Dis Colon Rectum. 2005;48:49–55. [PubMed: 15690657]

• O'Malley M, LaGuardia L, Kalady MF, Parambil J, Heald B, Eng C, Church J, Burke CA. The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome. Dis Colon Rectum. 2012;55:886–92. [PubMed: 22810475]

• O'Riordan JM, O'Donoghue D, Green A, Keegan D, Hawkes LA, Payne SJ, Sheahan K, Winter DC. Hereditary mixed polyposis syndrome due to a BMPR1A mutation. Colorectal Dis. 2010;12:570–3. [PubMed: 19438883]

• Restrepo C, Moreno J, Duque E, Cuello C, Amsel J, Correa P. Juvenile colonic polyposis in Colombia. Dis Colon Rectum. 1978;21:600–12. [PubMed: 738175]

• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]

• Russell BE, Rigueur D, Weaver KN, Sund K, Basil JS, Hufnagel RB, Prows CA, Oestreich A, Al-Gazali L, Hopkin RJ, Saal HM, Lyons K, Dauber A. Homozygous missense variant in BMPR1A resulting in BMPR signaling disruption and syndromic features. Mol Genet Genomic Med. 2019;7:e969. [PMC free article: PMC6825850] [PubMed: 31493347]

• Salviati L, Patricelli M, Guariso G, Sturniolo GC, Alaggio R, Bernardi F, Zuffardi O, Tenconi R. Deletion of PTEN and BMPR1A on chromosome 10q23 is not always associated with juvenile polyposis of infancy. Am J Hum Genet. 2006;79:593–6. [PMC free article: PMC1559543] [PubMed: 16909400]

• Sayed MG, Ahmed AF, Ringold JR, Anderson ME, Bair JL, Mitros FA, Lynch HT, Tinley ST, Petersen GM, Giardiello FM, Vogelstein B, Howe JR. Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis. Ann Surg Oncol. 2002;9:901–6. [PubMed: 12417513]

• Sweet K, Willis J, Zhou XP, Gallione C, Sawada T, Alhopuro P, Khoo SK, Patocs A, Martin C, Bridgeman S, Heinz J, Pilarski R, Lehtonen R, Prior TW, Frebourg T, Teh BT, Marchuk DA, Aaltonen LA, Eng C. Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis. JAMA. 2005;294:2465–73. [PubMed: 16287957]

• Taylor H, Yerlioglu D, Phen C, Ballauff A, Nedelkopoulou N, Spier I, Loverdos I, Busoni VB, Heise J, Dale P, de Meij T, Sweet K, Cohen MC, Fox VL, Mas E, Aretz S, Eng C, Buderus S, Thomson M, Rojas I, Uhlig HH. mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in patients with juvenile polyposis of infancy with PTEN-BMPR1A deletion. Hum Mol Genet. 2021;30:1273–82. [PMC free article: PMC8804886] [PubMed: 33822054]

• Teekakirikul P, Milewicz DM, Miller DT, Lacro RV, Regalado ES, Rosales AM, Ryan DP, Toler TL, Lin AE. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am J Med Genet A. 2013;161A:185–91. [PMC free article: PMC3535513] [PubMed: 23239472]

• van Hattem WA, Brosens LA, de Leng WW, Morsink FH, Lens S, Carvalho R, Giardiello FM, Offerhaus GJ. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008;57:623–7. [PubMed: 18178612]

• Wain KE, Ellingson MS, McDonald J, Gammon A, Roberts M, Pichurin P, Winship I, Riegert-Johnson DL, Weitzel JN, Lindor NM. Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review. Genet Med. 2014;16:588–93. [PMC free article: PMC4125531] [PubMed: 24525918]