Hereditary mixed polyposis syndrome
Hereditary mixed polyposis syndrome (HMPS) is an autosomal dominant inherited condition that significantly increases the risk of developing polyps in the digestive tract and colorectal cancer. Characterized by a mixed histology of polyps, HMPS often presents at an early age and is marked by a family history of the disease. The syndrome is considered rare, and not all colorectal cancers are hereditary; however, individuals with HMPS face heightened risks due to genetic factors. Polyps associated with HMPS can include atypical juvenile polyps, hyperplastic polyps, and adenomatous polyps, with the latter being associated with malignancy. Genetic studies have identified potential links to specific chromosomes and mutations, particularly in the BMPR1A and BMPR2 genes. Symptoms may include rectal bleeding, changes in bowel habits, and abdominal pain, necessitating medical evaluation and possibly colonoscopy for diagnosis and treatment. Early detection through family history and genetic counseling is crucial, as timely intervention can significantly improve outcomes and survival rates for colorectal cancer linked to HMPS.
Hereditary mixed polyposis syndrome
ALSO KNOWN AS: HMPS
DEFINITION Hereditary mixed polyposis syndrome (HMPS) is a distinct, autosomal dominant inherited condition that causes an increased risk for polyps, groups of normal cells that clump together in the digestive tract, and an increased risk of colorectal cancer. The polyps that develop are of mixed histology and eventually lead to colorectal cancer. HMPS is defined by a positive family history, onset at an early age, number and location of polyps, and histologic features. Not all colorectal cancers are hereditary, however, and in fact, HMPS is considered relatively rare.
Risk Factors
An autosomal dominant inheritance pattern occurs when one gene mutation occurs in either the mother or father and is passed to the child, increasing the risk for a disease caused by the mutation. Cells normally have two copies of each gene; one from the mother and one from the father. When one parent has a mutation of a gene known to trigger HMPS, there is a 50-percent chance of passing the normal gene and a 50-percent chance of passing the mutated gene to the child, meaning that the child of a parent with a mutated gene for HMPS has a 50-percent chance of developing HMPS.
Etiology and Genetics
Hereditary mixed polyposis syndrome may cause different types of colorectal tumors. Atypical juvenile polyps (initially not malignant but may become malignant over time), hyperplastic polyps (rarely malignant), and adenomatous polyps (almost all malignant polyps are this type) characterize the syndrome.
The genetic mechanisms of HMPS are continually being studied and no single, specific gene has been identified as causative. Family clusters continue to be studied to determine genetic mechanisms.
A large family of Ashkenazi Jewish descent was mapped to 6q and then revised to 6q16-q21, and additional study demonstrated that a HMPS/CRAC1 locus on 15q13-q14 is important in the Ashkenazim population. A study of fifteen family members with a three-generation history of HMPS identified a 7 cM putative linkage interval on chromosome 10q23. Mutations in the bone morphogenetic protein receptor Type 1A (BMPR1A) are implicated in the genetic basis of the disease in some family clusters.
In 2023, researchers from the Galician Public Foundation of Genomic Medicine and the Health Research Institute of Santiago de Compostela colloborated on a study that up to two percent of polyposis syndrome patients have loss-of-function variants in the BMPR2 gene. This gene helps stem cells differentiate into their final cell type. When these genes malfunction, stem cells can produce too many of one type of cell; in this case, too many cells produce polyps. Understanding the genetic origin of conditions can help researchers develop better ways to treat hereditary conditions like polyposis syndrome.
Symptoms
If early recognition of HMPS based on family history does not occur, symptoms from colon polyps may develop. Rectal bleeding noticed on toilet tissue, blood in the stool (feces) with bowel movements, changes in bowel patterns such as diarrhea, constipation or ribbonlike stools, and pain or abdominal cramps may be indicative of colon polyps. If any symptoms are present, then a visit to the physician is indicated. The physician may order a fecal occult blood test, which takes a sample of the stool and tests it for hidden blood. It does not screen for polyps, but presence of blood indicates a need for further testing. Research continues on stool DNA testing that can detect cancer cells and genetic mutations for precancerous and malignant polyps in feces. A colonoscopy uses a video camera to allow the physician to view the entire colon and rectum. If polyps are seen on colonoscopy, they can be immediately removed and sent for pathological examination, including genetic markers.
Screening and Diagnosis
Individuals with HMPS have a genetic predisposition to colorectal cancer, with an increased risk of developing a malignancy in their lifetime. The amount of risk has not been confirmed. Determining family history (cancer pedigree), or parents, siblings, or children with a history of polyps, is the first step in assessing individuals at risk. If the cancer pedigree indicates that colon polyps occurred in family members, then a referral for a comprehensive genetic evaluation may be indicated. If genetic evidence of HMPS is uncovered, then early and frequent colonoscopy is indicated. There is no current blood test for HMPS, but research on screening tests is ongoing. When a family history of polyps is determined, it is suggested that the individual should begin colonoscopy approximately five to ten years before the earliest age of diagnosis of polyps in family members or by age twenty-five.
Treatment
At present, the only treatment for HMPS is surgical unless colon cancer develops. Removal of polyps during colonoscopy is the initial treatment. If polyps begin early in the teen years, the surgeon may recommend the removal of the entire colon.
Prevention and Outcomes
Understanding the family history of disease is important in order to recognize early risks of inherited or familial diseases. Talking with family members early may lead to timely genetic counseling or medical intervention if the risks for diseases are determined. Early intervention is the key to preventing the development of colorectal cancer in HMPS. Early polyp removal decreases the likelihood that a polyp will become malignant. If the polyp is malignant and the disease is early stage, then five-year survival rates for colon cancer approach 90 percent. Research is continuing to determine more specific genetic mutations, genetic tests, and potential treatments for the syndrome.
Bibliography
Cao, X., et al. “Mapping of Hereditary Mixed Polyposis Syndrome (HMPS) to Chromosome 10q23 by Genomewide High-Density Single Nucleotide Polymorphism (SNP) Scan and Identification of BMPR1A Loss of Function.” Journal of Medical Genetics 43.3 (2006): e13. Print.
Cheah, Peh Yean, et al. "The Classification of Intestinal Polyposis." Nature Genetics 45.1 (2013): 2. Print.
Jaeger, Emma, et al. “Common Genetic Variants at the CRAC1 (HMPS) Locus on Chromosome 15q13.3 Influence Colorectal Cancer Risk.” Nature Genetics 40.1 (2008): 26–28. Print.
Jaeger, Emma, et al. "Hereditary Mixed Polyposis Syndrome Is Caused by a 40-kb Upstream Duplication That Leads to Increased and Ectopic Expression of the BMP Antagonist GREM1." Nature Genetics 44.6 (2012): 699–703. Print.
O’Riordan, J., et al. “Hereditary Mixed Polyposis Syndrome Due to a BMTR1A Mutation.” Colorectal Disease 12.6 (2010): 570–73. Print.
Pachler, Frederik Rønne et al. “Hereditary polyposis Syndromes Remain a Challenging Disease Entity: Old Dilemmas and New Insights.” World Journal of Gastrointestinal Surgery, vol. 15, no. 10, 27 Jan. 2023, doi:10.4240/wjgs.v15.i1.1. Accessed 9 Sept. 2024.