INTRODUCTION — This monograph summarizes the interpretation of germline testing of the SMAD4 gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately .
How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Determining the genotype – Identifies variants. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected juvenile polyposis syndrome [JPS] or hereditary hemorrhagic telangiectasia [HHT]).
●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of uncertain significance (VUS).
The table provides a glossary of genetic testing terms (table 2).
Disease associations — Pathogenic and likely pathogenic variants in SMAD4 cause JPS and JP-HHT, an autosomal dominant disorder.
The SMAD4 gene encodes a cytoplasmic mediator of the transforming growth factor-beta (TGF-beta) signaling pathway.
●Intestinal tumors – JPS is characterized by the presence of multiple juvenile polyps in the colorectum. Most patients are symptomatic by age 20 years. Rectal bleeding is the most common presenting symptom. Other symptoms include abdominal pain due to obstruction from intussusception, diarrhea due to protein-losing enteropathy, and rectal prolapse of polyps.
Polyps usually begin to appear in the first decade of life, and patients can develop between five to hundreds of polyps in their lifetime. Polyps occur predominantly in the colorectum but can occur in the stomach, duodenum, jejunum, and ileum.
Individuals with JPS are at increased risk for colorectal, small bowel, and gastric cancer. The cumulative risk of colorectal cancer is 17 to 22 percent by age 35 years and 68 percent by age 60 years [2,3]. The mean age at colorectal cancer diagnosis in patients with JPS is 34 years. Individuals with JPS are also at increased risk for gastric and duodenal cancer, with an estimated lifetime risk of 11 to 20 percent [2,4-6].
Juvenile polyposis of infancy is a rare variant of JPS in which juvenile (hamartomatous) polyps occur in both the upper and lower gastrointestinal tract (including the small bowel) and polyps develop within the first few years of life. In the stomach, juvenile polyps can be more difficult to recognize and often resemble hyperplastic polyps or other hamartomatous gastric polyps. Symptoms include diarrhea, bleeding, and intussusception. Macrocephaly and hypotonia may also occur. Patients often die at an early age due to gastrointestinal complications.
●HHT – Individuals with JPS due to pathogenic variants in SMAD4 are considered to be at risk for HHT. It is estimated that 32 percent of individuals with SMAD4 pathogenic variants will exhibit features of HHT, although the proportion may be considerably higher . JP-HHT is a juvenile polyposis-HHT overlap syndrome that accounts for approximately 1 percent of HHT cases. Individuals with HHT can develop telangiectasia or arteriovenous malformations (AVMs) of the skin, buccal mucosa, gastrointestinal tract, lung, liver, and brain. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)
●Extraintestinal manifestations – Other conditions associated with JPS include cardiac (eg, mitral valve prolapse), vascular (eg, arterial aneurysms), skeletal, and cranial anomalies.
IMPLICATIONS OF A PATHOGENIC OR LIKELY PATHOGENIC VARIANT — We consider all individuals with a pathogenic or likely pathogenic variant in SMAD4 to be at risk for juvenile polyposis syndrome (JPS) and hereditary hemorrhagic telangiectasia (HHT), regardless of the initial reason for testing.
Discussion should include the range of associated risks, possible interventions for surveillance or risk reduction, and implications for family members. (See 'At-risk relatives' below.)
Counseling may require additional visits or referrals. While prompt follow-up is recommended, acting upon genetic test results is rarely an emergency; the individual can be reassured that management decisions can be deferred until questions are answered.
●Cancer – We adhere to National Comprehensive Cancer Network (NCCN) recommendations for cancer surveillance and risk reduction . Findings in family members (type of cancers, age of onset) may also inform surveillance (starting at an earlier age if a family member has an earlier age of onset).
●HHT – We follow consensus guidelines for surveillance and evaluations related to HHT .
In addition to annual physical examination including a cardiovascular examination, we monitor a complete blood count annually to evaluate for iron deficiency anemia secondary to blood loss. Several evaluations and interventions are recommended to reduce the risk of JPS-associated cancers (algorithm 1).
Colorectal polyps and cancer
•Colorectal cancer screening/surveillance:
-Individuals with a pathogenic SMAD4 variant should have a colonoscopy every one to three years, beginning at age 12 years or earlier in patients who present with symptoms. If polyps are found, colonoscopy should be repeated annually; otherwise, colonoscopy intervals can be increased to every one to three years . Polyps can usually be resected endoscopically.
•Indications for colectomy and ileorectal anastomosis (IRA) or proctocolectomy and ileal pouch anal anastomosis include:
-Severe symptoms related to colonic polyps (eg, severe gastrointestinal bleeding)
-Colorectal cancer, adenoma with high-grade dysplasia, or multiple adenomas >6 mm
-Marked increases in polyp number on consecutive examinations
-Inability to adequately survey the colon because of multiple polyps
•Following colectomy, continued endoscopic evaluation of the rectum and ileal pouch every 12 months.
Upper gastrointestinal tract polyps and cancer
●Upper endoscopy starting at the age of 12 years. If polyps are detected, upper endoscopy is repeated annually. In the absence of upper gastrointestinal tract polyps, upper endoscopy can be performed every two to three years .
●Baseline examination of the small bowel starting in the teenage years and then repeated periodically based upon the presence of small bowel polyps or symptoms, including anemia or protein-losing enteropathy. The small bowel can be evaluated using wireless capsule endoscopy, small bowel imaging (eg, computed tomography [CT] enterography), or small bowel enteroscopy (eg, double balloon enteroscopy).
●In patients with advanced dysplasia, gastric cancer, or massive gastric polyposis that cannot be effectively managed endoscopically, complete or partial gastrectomy is warranted.
Additional details and supporting evidence are discussed separately. (See "Juvenile polyposis syndrome", section on 'Management'.)
Hereditary hemorrhagic telangiectasia — Pathogenic variants in SMAD4 can cause HHT, although HHT is more commonly caused by variants in other genes.
Individuals with pathogenic variants in SMAD4 should have an assessment of family history and personal history for clinical manifestations and complications of HHT, including epistaxis, gastrointestinal bleeding, and others. (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)
All symptoms attributable to telangiectasia, arteriovenous malformations (AVMs), or bleeding should be thoroughly evaluated. Decisions regarding screening of asymptomatic individuals, including the specific tests and age at which to initiate them, are best done in consultation with an HHT center and/or facilitated by a clinician with expertise in HHT management. (See "Hereditary hemorrhagic telangiectasia (HHT): Evaluation and therapy for specific vascular lesions" and "Hereditary hemorrhagic telangiectasia (HHT): Routine care including screening for asymptomatic AVMs".)
IMPLICATIONS OF A NEGATIVE TEST — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes (eg, BMPR1A).
●If a familial SMAD4 variant is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for juvenile polyposis syndrome (JPS) or hereditary hemorrhagic telangiectasia (HHT), with caveats outlined above (see 'How to read the report' above). However, it is important to provide an individualized risk assessment based on family history and other risk factors.
●If a familial SMAD4 variant is not known and the results of genetic testing of the presenting (or consulting) patient are negative, the extent of additional testing depends on the personal and family history. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of gastrointestinal polyposis or telangiectasia. (See 'Locating an expert' below.)
IMPLICATIONS OF A VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).
New information may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually).
The implications of genetic test results should be discussed with the individual's gastroenterologist, oncologist, or surgeon; in some cases, referral to a specialist in hereditary colorectal cancer syndromes may be appropriate.
CONSIDERATIONS FOR FAMILY MEMBERS
Reproductive counseling — Family planning is appropriate for individuals with a pathogenic or likely pathogenic variant in SMAD4 who are considering childbearing.
Some may elect assisted reproduction (including donor gametes or in vitro fertilization [IVF] with preimplantation genetic testing [PGT]) or prenatal diagnosis. (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
At-risk relatives — Individuals with a pathogenic variant or likely pathogenic variant in SMAD4 should inform their at-risk relatives about the importance of genetic counseling and possible testing.
●The risk of inheriting or having the variant is typically 50 percent for first-degree relatives. Others at risk may include aunts, uncles, nieces, nephews, and cousins.
●Usually, the variant segregates on the side of the family with a history of polyposis or gastrointestinal cancer; however, if possible, it is recommended to test a parent or other relative with cancer.
●Genetic testing of at-risk relatives may be considered as early as 12 years. Age of polyposis onset for relatives may help guide the timing.
●Families facing decisions to test minors should meet with a genetic counselor or other health care provider with genetics expertise. If genetic testing is deferred in a child at 50 percent risk, juvenile polyposis syndrome (JPS) screening is recommended until genetic testing is obtained. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications of a pathogenic or likely pathogenic variant' above.)
●Juvenile polyposis syndrome (JPS) – (See "Juvenile polyposis syndrome".)
●Hereditary hemorrhagic telangiectasia (HHT) – (See "Clinical manifestations and diagnosis of hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)
•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Genetic testing – (See "Genetic testing".)
•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Locating an expert
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
●National Institutes of Health (NIH) Cancer Genetics Services Directory
●HHT Centers of Excellence – Cure HHT
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟