Disease 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 of 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 been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) may be present in 15%-22% of individuals with an SMAD4 mutation.
Diagnosis/testing. 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 mutations in BMPR1A; approximately 20% have mutations in SMAD4. Molecular genetic testing of both genes is available on a clinical basis.
Management. 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 mutation, predictive molecular genetic testing may be appropriate before age 15 years as surveillance for potential complications of HHT begins in early childhood. Testing relatives at risk: When 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.
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 a new gene mutation. Each child of an affected individual has a 50% chance of inheriting the mutation and developing JPS. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in the family is known. Requests for prenatal testing for treatable conditions such as JPS that do not affect intellect are not common.
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 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 Description) [Aretz et al 2007].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genes. Two genes are known to be associated with JPS:
BMPR1A. Approximately 20% of individuals affected with JPS have mutations in BMPR1A [Sayed et al 2002, Howe et al 2004].
SMAD4. Approximately 20% of individuals affected with JPS have mutations in SMAD4 [Howe et al 2004].
Other genes/loci
ENG
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 testing
Sequence analysis of SMAD4 and BMPR1A is available on a clinical basis.
Duplication/deletion testing. Recent studies suggest that multiplex ligation-dependent probe amplification (MLPA) identified an additional 9%-14% of mutations in SMAD4 [Aretz et al 2007; van Hattem et al 2008; Calva et al, submitted].
Table 1 summarizes molecular genetic testing for this disorder.
Gene Symbol | Proportion of all JPS Attributed to Mutations in This Gene 1 | Test Method | Mutations Detected | Mutation Detection Frequency by Gene and Test Method | Test Availability |
BMPR1A | 20% | Sequence analysis | Sequence variants | 18% 3 | Clinical |
Duplication/ deletion testing 2 | Exonic, multiexonic, or whole-gene deletions | 6% 3 | |||
SMAD4 | 20% | Sequence analysis | Sequence variants | 21% 3 | Clinical |
Duplication/ deletion testing 2 | Exonic, multiexonic, or whole-gene deletions | 7% 3 |
1. Of all individuals with JPS [Howe et al 2004]
2. Using a variety of methods including quantitative PCR (qPCR)/real-time PCR (rt-PCR), and MLPA
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To confirm 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 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.
BMPR1A. No phenotypes other than JPS are known to be caused by germline mutations in BMPR1A, with the exception of two families with features of hereditary mixed polyposis syndrome (HMPS) [Cao et al 2006].
Note: (1) Contiguous gene deletions of chromosome 10q22-q23 that include both PTEN and BMPR1A have been reported in (a) four individuals with a severe early-onset form of JPS (previously called juvenile polyposis of infancy) [Delnatte et al 2006] and in (b) one individual with a milder phenotype with multiple colonic polyps diagnosed initially at age six years, but not juvenile polyposis of infancy [Salviati et al 2006]. The role of deletion of each gene in contributing to the phenotype is unknown. (2) 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.
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 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 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.
No studies have examined the percentage of individuals with germline JPS mutations who develop polyps. It is expected to be higher than 90%; however, some family members may not develop polyps until middle age [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 accounted for in part 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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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 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 known to be associated with 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 gene 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 known to be associated with 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. LKB1 (STK11) is the only gene known to be associated with 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).
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 known to be associated with 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 of 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.
To establish the extent of disease in an individual diagnosed with juvenile polyposis syndrome (JPS), the following evaluations are recommended:
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
Expert opinion suggests that all individuals with an SMAD4 mutation be evaluated for complications related to hereditary hemorrhagic telangiectasia (HHT) [Gallione et al 2004].
JPS. 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 is 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).
Increased awareness, education, and screening have helped successive generations benefit from early detection of JPS and cancer prevention/risk reduction.
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 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.
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.
Note: These screening recommendations are precautionary as molecular genetic testing for JPS is still new and efforts are underway to learn about the functions of these genes and the significance of the mutations that occur.
When 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.
Search 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.
No known chemoprevention options are effective for juvenile polyps.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Juvenile polyposis syndrome (JPS) is inherited in an autosomal dominant manner.
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 a de novo gene mutation.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include molecular genetic testing of the parents if a mutation has been identified in the proband. If a mutation has not been identified in the proband, both parents should be screened (see Testing of Relatives at Risk) 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 disease-causing mutation, 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 mutation 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.
See Management, Testing of Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.
Genetic cancer risk assessment and counseling. For comprehensive descriptions of the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without molecular genetic testing, see:
Elements of Cancer Genetics Risk Assessment and Counseling (part of PDQ®, National Cancer Institute)
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made 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 mutation 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 mutation 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. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for an SMAD4 or a BMPR1A mutation is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions such as JPS that 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 available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
---|---|---|---|
SMAD4 | 18q21.1 | Mothers against decapentaplegic homolog 4 | SMAD4 |
BMPR1A | 10q22.3 | Bone morphogenetic protein receptor type-1A | BMPR1A |
174900 | JUVENILE POLYPOSIS SYNDROME; JPS |
600993 | MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4 |
601299 | BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IA; BMPR1A |
How 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.
Normal allelic variants. There is a common normal allelic variant in nucleotide 4 of BMPR1A [Howe et al 2001].
Pathologic allelic variants. Thirty-one pathologic variants, including insertions, deletions, missense, nonsense, and splice-site alterations, have been described [Howe et al 2004].
Normal gene product. BMPR1A comprises 11 coding exons. 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].
Normal allelic variants. SMAD4 has 13 exons.
Pathologic allelic variants. See Table 2. Germline pathologic variants have been described in six of eleven coding exons. Changes include small deletions, insertions, and missense and nonsense mutations. No splice-site variants are known. 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] for a comprehensive list of the pathologic variants reported in SMAD4 (previously known as MADH4).
DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
---|---|---|
c.1081C>T | p.Arg361Cys | NM_005359.5NP_005350.1 |
c.1162C>T | p.Glu388X | |
c.1244_1247delACAG | p.Asp415GlufsX20 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://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.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
Dr. Howe is a 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.
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