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Juvenile Polyposis Syndrome

, MS, CGC and , MD.

Author Information

Initial Posting: ; Last Update: March 9, 2017.

Summary

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 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 (JPS/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; 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: Routine 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. Treatment as needed for manifestations of HHT.

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

Prevention of secondary complications: Anemia may be improved by polypectomy or surgery.

Surveillance: For individuals following surgical resection: endoscopic evaluation of the rectum and pouch is required. 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 if symptoms occur. In families with JPS/HHT syndrome and/or a known SMAD4 pathogenic variant: it may be appropriate to follow the HHT surveillance guidelines.

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 33% of individuals with JPS have an affected parent; approximately 67% 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 pregnancies at increased risk is possible if the pathogenic variant in the family is known.

GeneReview Scope

Juvenile Polyposis Syndrome: Included Phenotypes
  • Juvenile polyposis syndrome (JPS)
  • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JPS/HHT syndrome)

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Juvenile polyposis syndrome (JPS) should be suspected in a proband with the following clinical and histopathology 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.

Histopathology 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 JPS/HHT syndrome (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 clinical features:

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

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 and gene-targeted deletion/duplication analysis of BMPR1A and SMAD4 is performed first. If no pathogenic variant is found reflex to a multigene panel that includes PTEN and other genes of interest (see Differential Diagnosis, Table 3 and Table 4).

Serial single-gene testing can be considered in individuals with clinical features suggestive of JPS/HHT (see Table 2 and hereditary hemorrhagic telangiectasia).

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 at the most reasonable cost 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 the genes with the highest clinical suspicion and includes analysis of the promoter regions.

* 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

Gene 1Proportion of Juvenile Polyposis Syndrome Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detectable by This Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
BMPR1A28% 569%-85% 5, 615% 5
SMAD427% 583% 517% 5
Unknown 745%NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.

Sequence analysis of the BMPR1A promoter region identified a pathogenic variant in 6/65 individuals with JPS who did not have a BMPR1A or SMAD4 pathogenic variant identified on sequencing of the coding regions or deletion/duplication testing [Calva-Cerqueira et al 2010]. Sequence analysis that includes the promoter region increases the proportion of pathogenic variants detected by sequencing.

7.

Two 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 [Sweet et al 2005, Howe et al 2007].

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, Brosens et al 2007, Latchford et al 2012]; of individuals treated surgically and followed with surveillance, four of 27 individuals with SMAD4 pathogenic variants and 0 of 8 individuals with BMPR1A pathogenic variants developed cancer [Aytac et al 2015]. 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 at diagnosis 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 a germline SMAD4 pathogenic variant, 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.

Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT syndrome). Individuals with JPS/HHT syndrome have variable findings of juvenile polyposis and hereditary hemorrhagic telangiectasia (epistaxis, telangiectases, arteriovenous malformations, and digital clubbing). Most individuals with JPS who have an SMAD4 germline pathogenic variant have one or more clinical features of HHT (see Table 2) [O’Malley et al 2012, Schwenter et al 2012, Jelsig et al 2016]. The findings of HHT may manifest in early childhood. A high frequency of pulmonary AVMs (and digital clubbing) and epistaxis has been consistently noted. 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 Hereditary Hemorrhagic Telangiectasia Reported in Individuals with an SMAD4 Pathogenic Variant

Clinical FeatureProportion of Individuals with this Clinical FeatureAge of Onset
Epistaxis61%-71% 1, 2Childhood 3
Telangiectases57% 2Often after 30 years 4
Mucocutaneous telangiectases48% 35-65 years 3
Pulmonary AVM53%-81% 2, 3Birth - 52 years 3
Visceral AVM86% 2
Hepatic AVM38% 321-52 years 3
Intracranial AVM4% 322 years, range 11 years ±7 1
Aortopathy38% 424 years, range 21-48 years 5, 6
Intrapulmonary shunting on echocardiogram61% 35-59 years 3

HHT = hereditary hemorrhagic telangiectasia

AVM = arteriovenous malformation

1.
2.
3.
4.
5.
6.

Wain et al [2014] reported the frequency of HHT-related symptoms in a cohort of 34 individuals with SMAD4 pathogenic variants (Table 2). Intrapulmonary shunting on echocardiogram bubble study was identified in 61% of individuals. Other clinical features of HHT noted in 50% of affected individuals who did not have pulmonary or visceral AVMs 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. The Curaçao criteria appear to be less sensitive for identifying individuals with SMAD4-related HHT [Faughnan et al 2011]. The frequency with which aneurysms have been reported in SMAD4-related HHT is important as it suggests a more complex vascular process than classic HHT. Aneurysms may need to be considered as part of the JPS-HHT phenotype; they can affect morbidity and mortality if they are not recognized [Latchford et al 2012].

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. Some of these individuals had features overlapping with thoracic aortic aneurysms and aortic dissections (TAAD) [Teekakirikul et al 2013, Wain et al 2014, Heald et al 2015]. Features overlapping with other syndromes caused by pathogenic variants in the TGFβ pathway, such as Loeys-Dietz syndrome and Marfan syndrome, have also been reported.

  • Wain et al [2014] reported features of a connective tissue disorder in 21% (7/34) of the affected individuals in their cohort. The connective tissue features were defined as: enlarged aortic root (in 2/7), aortic and mitral insufficiency (2/7), fatal aortic dissection (1/7), retinal detachment (1/7), brain aneurysm (1/7), and lax skin and joints (1/7).
  • The SMAD4 pathogenic variants in these individuals were not confined to one region of the gene; this finding is of interest and may suggest that monitoring of the aorta to ensure timely intervention to prevent dissection would be of value [Teekakirikul et al 2013, Wain et al 2014].
  • Heald et al [2015] also reported features of a connective tissue disorder in their cohort of individuals with HHT. The reported individuals did not meet clinical criteria for other known connective tissue disorders and did not have a pathogenic variant identified in other genes in the TGFβR2 pathway.

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. Early data suggest that periodic monitoring of the aorta in individuals with an SMAD4 pathogenic variant may be indicated. Surveillance in individuals with an SMAD4 pathogenic variant may begin earlier (in keeping with HHT surveillance recommendations) than in those with a BMPR1A pathogenic variant (see Surveillance).

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. The gastric phenotype in individuals with an SMAD4 pathogenic variant tends to be more aggressive with significant polyposis and a higher risk for gastric cancer [Aytac et al 2015].
  • 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].
  • JPS/HHT syndrome is associated with SMAD4 pathogenic variants that are primarily within the MH2 domain (exons 8-11) [Gallione et al 2006, Pyatt et al 2006]; however, pathogenic variants in other exons have also been observed [Gallione et al 2010].

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 SMAD4 pathogenic variants may be present prior to the onset of polyps [Author, personal observations]. Similar numbers are not available for individuals with BMPR1A pathogenic variants. 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

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)

Prevalence

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

Differential Diagnosis

A juvenile polyp can result from genetic predisposition or chance. It should be noted that 1% to 2% of individuals in the general population develop a solitary juvenile polyp 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. See Table 3, Table 4.

Table 3.

Disorders to Consider in the Differential Diagnosis of JPS

DisorderGene(s) or RegionMOIClinical Features
Overlapping Clinical FeaturesDistinguishing Clinical Features of Differential Diagnosis Disorder
PTEN hamartoma tumor syndromePTENADHamartomatous polypsBenign & malignant tumors of the thyroid, breast, & endometrium; macrocephaly, trichilemmomas, papillomatous papules, lipomas, pigmented macules of the glans penis
Nevoid basal cell carcinoma syndromePTCH1
SUFU
ADGastric polypsMultiple jaw keratocysts, basal cell carcinoma, macrocephaly, frontal bossing, coarse facial features, facial milia
Peutz-Jeghers syndromeSTK11ADGI polyposisMucocutaneous pigmentation, cancer predisposition; polyps have smooth muscle hyperplasia as prominent feature
Hereditary mixed polyposis syndrome (OMIM 601228)15q13-q14 1ADJuvenile polypsMultiple additional types of polyps: serrated, Peutz-Jeghers polyps, adenomas; significant risk of colorectal cancer
Familial adenomatous polyposis (see APC-Associated Polyposis Conditions)APCADGI polyposisMultiple adenomatous polyps, osteomas, dental anomalies, congenital hypertrophy of the retinal pigment epithelium, soft-tissue tumors, desmoid tumors, additional associated cancers
MUTYH-associated polyposisMUTYHARGI polyposisMultiple colonic adenomatous polyps; duodenal adenomas; additional types of polyps: serrated, hyperplastic/sessile serrated, mixed; significant colorectal cancer risk; cancers of the duodenum, stomach, ovary, & bladder
Lynch syndromeMLH1
MSH2
MSH6
PMS2
EPCAM
ADColorectal polypsFew adenomatous polyps; significant colorectal cancer risk; cancers of the endometrium, ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, & skin

GI = gastrointestinal

1.

Duplications of 15q13-q14 lead to overexpression of GREM1.

Table 4.

Disorders to Consider in the Differential Diagnosis of JPS/HHT

DisorderGene(s)MOIClinical Features
Overlapping Clinical FeaturesDistinguishing Clinical Features of Differential Diagnosis Disorder
Hereditary hemorrhagic telangiectasia
(not associated with SMAD4)
ENG
ACVRL1
GDF2
ADGastrointestinal bleeding, anemiaNot associated with polyposis

Management

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 if not already completed:

  • 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
  • Consultation with a clinical geneticist and/or genetic counselor
  • All individuals with an SMAD4 pathogenic variant should be evaluated for complications related to hereditary hemorrhagic telangiectasia (HHT)

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 individuals, 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 manifestations of HHT as needed; see Hereditary Hemorrhagic Telangiectasia.

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.

Surveillance

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]:

  • Monitor 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 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 JPS/HHT syndrome are known, it may be appropriate to follow the HHT surveillance guidelines for individuals with JPS/HHT syndrome or a known SMAD4 pathogenic variant.

Precautionary screening for individuals at risk for JPS who do not have the family-specific pathogenic variant was previously recommended [Howe et al 1998a]; however, this screening is unnecessary if molecular genetic testing was performed in a CLIA-approved laboratory. Family members who do not have the family-specific pathogenic variant can be screened for colon cancer as recommended for the normal U.S. population.

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

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 prompt initiation of treatment and preventive measures.

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

  • Molecular genetic testing in the first to second decade of life if the pathogenic variant in the family is known;
  • If the familial pathogenic variant is not known, 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 JPS/HHT syndrome or families with a known SMAD4 pathogenic variant:

  • Molecular genetic testing before age 15 years for children at risk for an 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 syndrome but the familial pathogenic variant is not known:

  • 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).
  • 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 AVMs, 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.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Other

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 33% of individuals diagnosed with JPS have an affected parent.
  • Most 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. The proportion of individuals with a de novo pathogenic variant is 67% [Calva-Cerqueira et al 2009].
  • 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.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Although 75% of individuals diagnosed with JPS have an affected parent, 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 molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

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%. Inter- and intrafamilial variability (including variable symptoms, ages of onset, and cancer risks) has been reported among individuals with JPS.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent 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. However, parents and sibs should be aware of the symptoms associated with JPS and report them to their physician. Providers should have a low threshold for evaluating symptoms in sibs of a proband with JPS.

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

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 age 18 years. 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 and Preimplantation Genetic Diagnosis

Once the SMAD4 or BMPR1A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for JPS are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

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.

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Juvenile Polyposis Syndrome (View All in OMIM)

174900JUVENILE POLYPOSIS SYNDROME; JPS
600993MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 4; SMAD4
601299BONE MORPHOGENETIC PROTEIN RECEPTOR, TYPE IA; BMPR1A

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.

BMPR1A

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

Pathogenic 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 and be associated with additional or more severe clinical features [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 individuals with JPS are retained in the cytoplasm and do not traffic to the cell membrane like the wild-type protein [Howe et al 2013].

SMAD4

Gene structure. SMAD4 comprises 11 coding exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. See Table 5. 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 5.

Selected SMAD4 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1081C>Tp.Arg361CysNM_005359​.5
NP_005350​.1
c.1162C>Tp.Glu388Ter
c.1244_1247delACAGp.Asp415GlufsTer20

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 (varnomen​.hgvs.org). 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 TGF-β signaling pathway.

Abnormal gene product. The MH1 domain of the SMAD4 protein can directly bind to the DNA of target genes. Pathogenic variants in this domain can significantly reduce the DNA binding activity of SMAD4. Most pathogenic variants, including the three recurrent pathogenic variants in Table 5, 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].

References

Published Guidelines / Consensus Statements

  • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available online. 2010. Accessed 7-3-18.
  • 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 7-3-18. [PubMed: 23428972]
  • Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL., Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. 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. [PubMed: 25394175]
  • 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. Genet Med. 2000;2:362–6. [PMC free article: PMC3111056] [PubMed: 11339660]

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Suggested Reading

  • 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.

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

  • 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
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