Juvenile Polyposis Syndrome

Clinical characteristics.

Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than 100. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers 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.

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.

Deletions of 10q22-q23 detectable by chromosomal microarray analysis including either BMPR1A or both BMPR1A and PTEN may be associated with additional clinical features with or without juvenile polyposis or with severe early-onset JPS [Delnatte et al 2006, Salviati et al 2006, van Hattem et al 2008, Calva-Cerqueira et al 2009, Breckpot et al 2012]. Hamartomatous polyposis and 10q22-q23 deletions have been reviewed by Dahdaleh et al [2012].

* If no pathogenic variant is found, molecular genetic testing of PTEN is appropriate to determine if the individual has PTEN hamartoma tumor syndrome rather than JPS (see also Genetically Related Disorders).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

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.

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.

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