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Juvenile Polyposis Syndrome

, MS, CGC and , MD.

Author Information
Humphrey Cancer Center
North Memorial Hospital
Robbinsdale, Minnesota
, MD
Department of Surgery
University of Iowa Hospitals and Clinics
Iowa City, Iowa

Initial Posting: ; Last Update: May 22, 2014.


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 a hundred. 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 in families with JPS ranges from 9% to 50%. 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) (termed JPS/HHT) is present in most individuals with an SMAD4 pathogenic variant.


JPS is clinically diagnosed if any one of the three following findings is present:

  • More than five juvenile polyps of the colorectum
  • Multiple juvenile polyps throughout the GI tract
  • Any number of juvenile polyps and a family history of juvenile polyps

Juvenile polyps are hamartomas with a distinct histology that differs from that of adenomas. The genes known to be associated with JPS are BMPR1A and SMAD4. Approximately 20% of individuals with JPS have pathogenic variants in BMPR1A; approximately 20% have pathogenic variants in SMAD4.


Treatment of manifestations: Routine colonoscopy with endoscopic polypectomy to reduce the risk of bleeding, intestinal obstruction, and colon cancer. When the number of polyps is large, removal of all or part of the colon or stomach may be necessary. Treatment as needed for manifestations of HHT.

Prevention of primary manifestations: Cancer prevention/risk reduction through cancer screening.

Surveillance: For individuals at risk: monitoring for rectal bleeding and/or anemia, abdominal pain, constipation, and diarrhea; screening by complete blood count (CBC), colonoscopy, and upper endoscopy starting in the mid-teens (age 15 years) or earlier when symptoms occur. In families with the combined JPS/HHT syndrome and/or a known SMAD4 pathogenic variant, predictive molecular genetic testing may be appropriate before age 15 years as surveillance for potential complications of HHT begins in early childhood.

Evaluation of relatives at risk: When the family-specific pathogenic variant 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.

Genetic counseling.

JPS is inherited in an autosomal dominant manner. Approximately 75% of individuals with JPS have an affected parent; approximately 25% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of de novo mutation. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing JPS. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known. Requests for prenatal testing for conditions which (like JPS) are treatable and do not affect intellect are not common.

GeneReview Scope

Juvenile Polyposis Syndrome: Included Disorders
  • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

For synonyms and outdated names see Nomenclature.


Clinical Diagnosis

Juvenile* polyposis syndrome (JPS) is diagnosed if any one of the following findings is present:

  • More than five juvenile polyps of the colorectum
  • Multiple juvenile polyps of the upper and lower GI tract
  • Any 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.


Histology. 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 Characteristics) [Aretz et al 2007].

Molecular Genetic Testing

Genes. The two genes in which pathogenic variants are known to cause JPS are BMPR1A and SMAD4 (see Table 1).

Evidence for further locus heterogeneity

  • ENG. To date, two young individuals with early-onset JPS have been found to have ENG pathogenic variants. Neither had clinical symptoms of hereditary hemorrhagic telangiectasia (HHT), which is known to be associated with ENG pathogenic variants; however, neither had yet reached the age at which symptoms of HHT commonly manifest. Subsequent studies have not identified deleterious ENG allelic variants among persons with JPS who did not have identifiable SMAD4 and BMPR1A pathogenic variants. Thus, the data are too preliminary to suggest that mutation of ENG predisposes to JPS [Sweet et al 2005, Howe et al 2007].
  • Other. While it has been suggested that pathogenic variants 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 testing

Table 1.

Summary of Molecular Genetic Testing Used in Juvenile Polyposis Syndrome

Gene 1Proportion of JPS Attributed to Pathogenic Variants in This GeneTest MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
BMPR1A20%-25% 2, 3Sequence analysis of coding region and flanking introns 413/65 5
3/27 6
22/102 7
Sequencing of promoter region6/65 8
Deletion/duplication analysis 93/65 5
3/27 6
2/102 7
SMAD420%Sequence analysis 417/65 5
6/27 6
20/102 7
Deletion/duplication analysis 96/65 5
1/27 6
2/102 7

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies exon or whole-gene deletions/duplications not 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.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • Pathologic 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 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).

Clinical Characteristics

Clinical Description

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. “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 have only 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; cancers of the stomach, upper GI tract, and pancreas have also 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.
  • The relative risk for colorectal cancer was 34.0 in individuals with JPS. The mean age of diagnosis of colorectal cancer was 43.9 years, with a cumulative lifetime risk of 38.7% [Brosens et al 2007].

In one large family with germline SMAD4 pathogenic variant (i.e., a pathogenic variant in the germline), the risk for colon cancer was approximately 40%, and the risk for 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 SMAD4 germline pathogenic variants [Gallione et al 2004]. Although recent studies suggest that 15%-22% of individuals with an SMAD4 pathogenic variant 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. More recently it has been suggested that most individuals with JPS who have an SMAD4 germline pathogenic variant have HHT [O’Malley et al 2012, Schwenter et al 2012].

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 pathogenic variant 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.

A recent study by Nishida et al [2012] reviewed the frequency of HHT symptoms by associated gene with a focus on intracranial AVMs. The number of affected individuals with SMAD4 pathogenic variants in this cohort was small; however the authors did not find a significant difference in the age of onset of intracranial AVMs by gene (22 years, range 11 years ±7, for those with SMAD4 pathogenic variants).

O’Malley et al [2012] reported the following frequency of symptoms in those with SMAD4 pathogenic variants: epistaxis in 15/21 (71%); telangiectasias in 12/21 (57%); visceral AVM in 18/21 (86%); and pulmonary AVM in 17/21 (81%). None of the individuals with pathogenic variants in BMPR1A in this study demonstrated features of HHT.

Wain et al [2014] reported the frequency of HHT-related symptoms in a cohort of 34 individuals with SMAD4 pathogenic variants. Frequencies in their cohort were as follows: epistaxis (61%), mucocutaneous telangiectasia (48%), liver AVMs (38%), brain AVMs (4%), pulmonary AVMs (53%), and intrapulmonary shunting on echocardiogram bubble study (61%). In addition, other symptoms of HHT were noted in 50% of affected individuals who did not have pulmonary or visceral AVMs. These symptoms included migraine headaches, exercise intolerance, and/or digital clubbing. Not all of the individuals with SMAD4 pathogenic variants noted in these studies met the Curaçao criteria for the clinical diagnosis of HHT [Wain et al 2014].

It is clear from these studies that while features may be variable in frequency, HHT is an important medical concern for individuals with SMAD4 pathogenic variants. Such individuals would benefit from surveillance for both the gastrointestinal and the HHT-related complications.

Genotype-Phenotype Correlations

Genotype-phenotype correlations in general are poor; some members of families with JPS and the same pathogenic variant 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 pathogenic variant are more likely to have a personal or family history of upper GI polyps than individuals with pathogenic variants in BMPR1A or those with no known pathogenic variants.
  • Individuals with either an SMAD4 or BMPR1A pathogenic variant are more likely than those without pathogenic variants 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 pathogenic variants that are primarily within the MH2 domain (exons 8-11) [Gallione et al 2004, Gallione et al 2006, Pyatt et al 2006]; however, pathogenic variants in other exons have also been observed [Gallione et al 2010].


No studies have examined the proportion of individuals with known germline pathogenic variants for JPS who develop polyps. It is expected to be higher than 90%; however, some family members may not develop polyps until middle age. In some instances, HHT-related symptoms in individuals with SMAD4 pathogenic variants may be present prior to the onset of polyps [Author, personal observations].


Anticipation (earlier age of onset and increased severity of symptoms with each successive generation) has been observed in some families with JPS. This observation may be partially accounted for by increased awareness of the disorder and better surveillance of young at-risk relatives.


Terms used in the past for JPS:

  • Familial juvenile polyposis (an older term used to distinguish between simplex and familial cases; a simplex case is a single affected individual in a family)
  • Generalized juvenile polyposis (to designate upper and lower GI tract involvement)
  • Juvenile polyposis of infancy (a particularly severe form of the syndrome with early onset)


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

Differential Diagnosis

Juvenile 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 for 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 hamartomatous polyposis, lipomas, and pigmented macules of the glans penis. PTEN is the only gene in which mutation is known to cause PHTS. Up to 85% of individuals who meet the diagnostic criteria for Cowden syndrome and 65% of individuals with a clinical diagnosis of Bannayan-Riley-Ruvalcaba syndrome have a detectable PTEN pathogenic variant. Inheritance is autosomal dominant.
  • Nevoid basal cell carcinoma syndrome (NBCCS), 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. PTCH1 is the only gene in which mutation is known to cause NBCCS. Inheritance is autosomal dominant.
  • Peutz-Jeghers syndrome (PJS), characterized by the association of GI polyposis, mucocutaneous pigmentation, and cancer predisposition. 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. These polyps differ from juvenile polyps by having smooth muscle hyperplasia as a prominent feature. STK11 is the only gene in which mutation is known to cause PJS. Inheritance is autosomal dominant.
  • Hereditary mixed polyposis syndrome (HMPS) (OMIM 601228), 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], and a recent study found that Ashkenazi Jewish families with HMPS had a 40-kb duplication of the last four exons of SCG5, just upstream from GREM1. It was suggested that enhancer elements drive increased expression of GREM1, which causes reduced bone morphogenetic protein activity [Jaeger et al 2012]. 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 [2009] identified a germline BMPR1A pathogenic variant in four of eight Singapore Chinese families with HMPS, and O’Riordan et al [2010] detected a BMPR1A pathogenic nonsense variant in a multi-generational Irish family with HMPS

Other syndromes characterized by the presence of polyps which do not share features with JPS include the following:

  • Familial adenomatous polyposis, 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 familial adenomatous polyposis (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.
  • Lynch syndrome. 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 differentiating the two diagnoses. Lynch syndrome 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. Lynch syndrome is known to be associated with germline pathogenic variants in one of four mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) and germline deletions in EPCAM (not a mismatch repair gene). Inheritance is autosomal dominant.
  • Hereditary hemorrhagic telangiectasia (HHT). Persons with HHT who do not have an identifiable pathogenic variant in ENG or ALK1, the two genes most commonly associated with HHT, should be evaluated for pathogenic variants in SMAD4, and those with an SMAD4 pathogenic variant 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.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 color
  • Complete blood count (CBC), colonoscopy, and upper endoscopy in the mid-teens (age 15 years) or at the time of initial symptoms, whichever is earlier
  • Medical genetics consultation

Expert opinion also suggests that all individuals with an SMAD4 pathogenic variant be evaluated for complications related to hereditary hemorrhagic telangiectasia (HHT) [Gallione et al 2004].

Treatment of Manifestations

JPS. The most effective management is routine colonoscopy with endoscopic polypectomy. Early endoscopic polypectomy may reduce morbidity by reducing the risk for 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. Treat as needed for manifestations of HHT (see HHT).

Prevention of Primary Manifestations

Increased awareness, education, and screening have helped successive generations benefit from early detection of JPS and cancer prevention/risk reduction.

Prevention of Secondary Complications

When present, anemia may be improved by polypectomy or surgery.


For 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 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 [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 pathogenic variant, 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 pathogenic variant.

Precautionary screening recommendations for individuals at risk for JPS who do not have the family-specific pathogenic variant [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 and screening 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.

For surveillance recommendations for individuals with HHT, see Hereditary Hemorrhagic Telangiectasia.

Evaluation of Relatives at Risk

When the family-specific pathogenic variant 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 pathogenic variant 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 Investigation

Search 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.


No known chemoprevention options are effective for juvenile polyps.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

  • Approximately 75% of individuals with JPS have an affected parent.
  • Approximately 25% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of de novo mutation.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing of the parents if a pathogenic variant has been identified in the proband. If a pathogenic variant has not been identified in the proband, both parents should be screened (see Surveillance) to determine if other relatives are also at risk for this condition.

Note: Although 75% of individuals diagnosed with JPS have an affected parent, the family history may appear to be negative because of the failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

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 or has the pathogenic variant, the risk to the sibs is 50%.
  • If molecular genetic testing and/or surveillance measures have demonstrated that the parents are not likely to be affected, the risk to the sibs is negligible, as germline mosaicism has not been documented in individuals with JPS.

Offspring of a proband. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing JPS.

Other family members. The risk to other family members depends on the status of the proband’s parents. If a parent is affected, his/her relatives are also 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 diagnosis and treatment.

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).

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

Molecular genetic testing of asymptomatic individuals younger than 18 years of age. When a pathogenic variant has been identified in a family, molecular genetic testing can be used to identify family members who would benefit from early screening. Since surveillance for individuals at risk for JPS is recommended beginning at age 15 years, it is appropriate to consider presymptomatic 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 in which there is an SMAD4 pathogenic variant and/or associated symptoms of hereditary hemorrhagic telangiectasia (HHT) may wish to test in early childhood as management for HHT complications would begin in that time frame.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like JPS) do not affect intellect and have treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Because most individuals with JPS will live a relatively normal life with careful screening and removal of polyps, the utility of prenatal screening appears to be outweighed by the risks. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Cancer Institute (NCI)
    6116 Executive Boulevard
    Suite 300
    Bethesda MD 20892-8322
    Phone: 800-422-6237 (toll-free)
  • American Cancer Society (ACS)
    1599 Clifton Road Northeast
    Atlanta GA 30329-4251
    Phone: 800-227-2345 (toll-free 24/7); 866-228-4327 (toll-free 24/7 TTY)

Molecular Genetics

Information 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 Databases

Data 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)


Molecular Genetic Pathogenesis

How juvenile polyps form as a consequence of pathogenic variants in the germline 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.


Gene structure. BMPR1A comprises 11 coding exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. There is a common benign variant in nucleotide 4 of BMPR1A [Howe et al 2001].

Pathogenic allelic variants. Sixty pathogenic variants, including insertions, deletions, and missense, nonsense, and splice-site alterations, have been described [Calva-Cerqueira et al 2009]. Germline deletions or pathogenic missense variants 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 pathogenic DNA variants in the protein kinase domain and occasionally by variants 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 BMPR1A pathogenic missense variants as seen in patients with JP are retained in the cytoplasm and do not traffic to the cell membrane like the wild-type protein [Howe et al 2013].


Gene structure. SMAD4 comprises 11 coding exons.

Pathogenic allelic variants. See Table 2. Germline pathogenic variants have been described in all eleven coding exons. Changes include small deletions, insertions, and missense and nonsense pathogenic variants. Two splice-site variants have been reported. Most pathogenic 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 pathogenic 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 pathogenic missense variants have also been reported in the promoter region [Calva-Cerqueira et al 2010].

Table 2.

Selected SMAD4 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

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. Pathogenic allelic variants in this domain can significantly reduce the DNA binding activity of SMAD4. Most pathogenic allelic variants, including the three recurrent pathogenic variants in Table 2, occur in the MH2 domain, which plays an important role for nuclear localization, interaction with other MAD 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].


Published Guidelines/Consensus Statements

  1. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online; registration or institutional access required. 2010. Accessed 6-11-15.
  2. 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 6-11-15. [PubMed: 23428972]
  3. Joint Test and Technology Transfer Committee Working Group, American College of Medical Genetics. Genetic testing for colon cancer: joint statement of the American College of Medical Genetics and American Society of Human Genetics. Joint Test and Technology Transfer Committee Working Group. Available online. 2000. Accessed 6-11-15. [PMC free article: PMC3111056] [PubMed: 11339660]

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Suggested Reading

  1. Howe JR. Juvenile polyposis syndrome. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 35. New York, NY: McGraw-Hill. Available online. 2013. Accessed 6-11-15.

Chapter Notes

Author Notes

Dr. 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 Medical Center who is actively involved in the development of genetic counseling guidelines with Dr. Howe’s research program.

Revision History

  • 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 to live Web site
  • 20 May 2004 (cd) Revision: Genetic Counseling
  • 27 October 2003 (cd) Revision: Statements and Policies
  • 13 May 2003 (me) Review posted to live Web site
  • 4 January 2003 (jrh) Original submission
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