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• W2598346119 abstract "The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease. The US Multi-Society Task Force on Colorectal Cancer, with invited experts, developed a consensus statement and recommendations to assist health care providers with appropriate management of patients with biallelic mismatch repair deficiency (BMMRD) syndrome, also called constitutional mismatch repair deficiency syndrome. This position paper outlines what is known about BMMRD, the unique genetic and clinical aspects of the disease, and reviews the current management approaches to this disorder. This article represents a starting point from which diagnostic and management decisions can undergo rigorous testing for efficacy. There is a lack of strong evidence and a requirement for further research. Nevertheless, providers need direction on how to recognize and care for BMMRD patients today. In addition to identifying areas of research, this article provides guidance for surveillance and management. The major challenge is that BMMRD is rare, limiting the ability to accumulate unbiased data and develop controlled prospective trials. The formation of effective international consortia that collaborate and share data is proposed to accelerate our understanding of this disease. The US Multi-Society Task Force on Colorectal Cancer has produced a series of consensus statements, guidelines, and recommendations on topics related to the diagnosis and management of colorectal cancer (CRC).1Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2014; 147: 502-526Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar Traditionally, the guidelines use the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) system to evaluate the strength of evidence in the development of guidelines and recommendations.2Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar Prior guidelines addressed issues such as the optimal approaches to screening for CRC, management of patients with adenomatous polyps of the colon, guidelines for the performance of colonoscopy, and the optimal approach to bowel preparation for colonoscopy.3Johnson D.A. Barkun A.N. Cohen L.B. et al.Optimizing adequacy of bowel cleansing for colonoscopy: recommendations from the US multi-society task force on colorectal cancer.Gastroenterology. 2014; 147: 903-924Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 4Lieberman D.A. Rex D.K. Winawer S.J. et al.Guidelines for colonoscopy surveillance after screening and polypectomy: a consensus update by the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2012; 143: 844-857Abstract Full Text Full Text PDF PubMed Scopus (1425) Google Scholar In each instance, prospective controlled clinical trials were considered the gold standard for high-quality evidence. Recently, the Task Force published guidelines for the evaluation and management of Lynch syndrome (LS), some of which were drawn from high-quality evidence, but others were developed from expert opinions because of the absence of optimal prospective clinical trials.1Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2014; 147: 502-526Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar The strength of evidence is based on the science at any point in time, but clinical decisions must be made at all times in the context of the available studies. High-quality studies and evidence require the availability of a large number of research subjects. A computer-aided search of MEDLINE from 1999 to March 2016 was performed focusing on biallelic mismatch repair deficiency (BMMRD) syndrome and constitutional mismatch repair deficiency (CMMRD) syndrome. The search was restricted to English language articles. In addition, a search was conducted using references from accessed articles. Publications were retrieved, and the authors synthesized and assessed the available data. There were no controlled trials in BMMRD. Experts pooled their collective experiences to develop consensus guidelines as an initial attempt to produce more uniform approaches to patient management, and prioritize areas in greatest need of research. The Multi-Society Task Force is composed of gastroenterology specialists with a special interest in CRC, representing the following major gastroenterology professional organizations: American College of Gastroenterology, the American Gastroenterological Association Institute, and the American Society for Gastrointestinal Endoscopy. The North American Society of Pediatric Gastroenterology, Hepatology and Nutrition, and representatives of the Collaborative Group of the Americas on Inherited Colorectal Cancer also reviewed this article. This document was approved by the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition. LS is the autosomal-dominant disease caused by a monoallelic germline mutation in a DNA mismatch repair (MMR) or EPCAM gene, and is the most common cause of inherited CRC.5Boland C.R. Evolution of the nomenclature for the hereditary colorectal cancer syndromes.Fam Cancer. 2005; 4: 211-218Crossref PubMed Scopus (108) Google Scholar LS is caused by a large number of heterozygous germline mutations in MLH1, MSH2, MSH6, PMS2, and EPCAM, and the tumor DNA is characterized by microsatellite instability (microsatellite instability–high [MSI-H], or, by convention, MSI). Penetrance for cancer is incomplete in LS; the cumulative lifetime risk of CRC is variable depending on the gene mutated and sex, and ranges from 40% to 70% for women and men, respectively, for the genes MSH2, MLH1, and MSH6.5Boland C.R. Evolution of the nomenclature for the hereditary colorectal cancer syndromes.Fam Cancer. 2005; 4: 211-218Crossref PubMed Scopus (108) Google Scholar Penetrance for CRC is reduced substantially for LS associated with mutations in PMS2, ranging from 10% to 20%.6ten Broeke S.W. Brohet R.M. Tops C.M. et al.Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.J Clin Oncol. 2015; 33: 319-325Crossref PubMed Scopus (144) Google Scholar, 7Antelo M. Milito D. Rhees J. et al.Pitfalls in the diagnosis of biallelic PMS2 mutations.Fam Cancer. 2015; 14: 411-414Crossref PubMed Scopus (9) Google Scholar, 8Goodenberger M.L. Thomas B.C. Riegert-Johnson D. et al.PMS2 monoallelic mutation carriers: the known unknown.Genet Med. 2016; 18: 13-19Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Patients with LS also are predisposed to extracolonic malignancies, primarily endometrial cancer (40% in women with mutations in MSH2 and MLH1), and, to a lesser extent, other gastrointestinal and genitourinary cancers. These syndromes can be managed adequately by annual colonoscopy and appropriate gynecologic surgery.1Giardiello F.M. Allen J.I. Axilbund J.E. et al.Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer.Gastroenterology. 2014; 147: 502-526Abstract Full Text Full Text PDF PubMed Scopus (314) Google Scholar A rare and far more virulent cancer syndrome occurs in the setting of biallelic MMR gene mutations (biallelic MMR deficiency [BMMRD]) (OMIM database accession no. 2763000). This disorder also is called constitutional MMR deficiency (CMMRD), because those born with biallelic inactivation of any one of the MMR genes have no DNA MMR activity in any tissue. In contrast, in LS, gene expression from the one wild-type allele is sufficient for adequate DNA MMR activity until a second hit inactivates the wild-type allele from the unaffected parent. The consequent tumor tissue is DNA-MMR deficient, which permits MSI to ensue. BMMRD is characterized by the absence of DNA-MMR activity from birth, and results in brain tumors, colonic polyposis, colorectal and small-bowel cancers, leukemias, and lymphomas (Table 1). Patients often have café-au-lait macules and other stigmata that can be mistaken for neurofibromatosis type 1.9Stark Z. Campbell L.J. Mitchell C. et al.Clinical problem-solving. Spot diagnosis.N Engl J Med. 2014; 370: 2229-2236Crossref PubMed Scopus (7) Google Scholar, 10Urganci N. Genc D.B. Kose G. et al.Colorectal cancer due to constitutional mismatch repair deficiency mimicking neurofibromatosis I.Pediatrics. 2015; 136: e1047-e1050Crossref PubMed Scopus (12) Google Scholar Somatic mutations in the NF1 gene as a consequence of constitutional absence of MMR activity are the presumed explanation for this occurrence.11Wang Q. Montmain G. Ruano E. et al.Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type.Hum Genet. 2003; 112: 117-123Crossref PubMed Scopus (84) Google ScholarTable 1Estimated Penetrance and Age of Onset of Neoplasms in BMMRDOrganEstimated penetrance, %Age at diagnosis, median (range), yReferencesSmall-bowel adenomasaLow- and high-grade adenomas with probable rapid progression.5012 (10–20)12Aronson M. Gallinger S. Cohen Z. et al.Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium.Am J Gastroenterol. 2016; 111: 275-284Crossref PubMed Scopus (32) Google Scholar, 33Herkert J.C. Niessen R.C. Olderode-Berends M.J. et al.Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.Eur J Cancer. 2011; 47: 965-982Abstract Full Text Full Text PDF PubMed Scopus (47) Google ScholarColorectal adenomasaLow- and high-grade adenomas with probable rapid progression.>909 (6–15)12Aronson M. Gallinger S. Cohen Z. et al.Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium.Am J Gastroenterol. 2016; 111: 275-284Crossref PubMed Scopus (32) Google Scholar, 33Herkert J.C. Niessen R.C. Olderode-Berends M.J. et al.Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.Eur J Cancer. 2011; 47: 965-982Abstract Full Text Full Text PDF PubMed Scopus (47) Google ScholarSmall-bowel cancer1028 (11–42)12Aronson M. Gallinger S. Cohen Z. et al.Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium.Am J Gastroenterol. 2016; 111: 275-284Crossref PubMed Scopus (32) Google Scholar, 17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarColorectal cancerbPatients undergo subtotal colectomy and ileal–rectal anastomosis, resulting in a decreased risk of colorectal cancer.7016 (8–48)12Aronson M. Gallinger S. Cohen Z. et al.Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium.Am J Gastroenterol. 2016; 111: 275-284Crossref PubMed Scopus (32) Google Scholar, 17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google ScholarLow-grade brain tumorsUnknownUnknownHigh-grade brain tumorscHigh-grade glioma, medulloblastoma, and primitive neuroectodermal tumors.709 (2–40)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarLymphoma20–405 (0.4–30)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarLeukemia10–408 (2–21)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarEndometrial cancer<10(19–44)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarUrinary tract cancer<10(10–22)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google ScholarOther sitesdFewer than 5 cases of each of the following neoplasms have been reported: neuroblastoma, Wilms tumor, rhabdomyosarcoma, osteosarcoma, breast cancer, melanoma, ovarian neuroectodermal tumor, pilomatricoma, and hepatic adenoma.<10(1–35)17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar, 25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google Scholar, 33Herkert J.C. Niessen R.C. Olderode-Berends M.J. et al.Paediatric intestinal cancer and polyposis due to bi-allelic PMS2 mutations: case series, review and follow-up guidelines.Eur J Cancer. 2011; 47: 965-982Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholara Low- and high-grade adenomas with probable rapid progression.b Patients undergo subtotal colectomy and ileal–rectal anastomosis, resulting in a decreased risk of colorectal cancer.c High-grade glioma, medulloblastoma, and primitive neuroectodermal tumors.d Fewer than 5 cases of each of the following neoplasms have been reported: neuroblastoma, Wilms tumor, rhabdomyosarcoma, osteosarcoma, breast cancer, melanoma, ovarian neuroectodermal tumor, pilomatricoma, and hepatic adenoma. Open table in a new tab The lifetime risk of gastrointestinal cancer among BMMRD patients is the highest reported of all gastrointestinal cancer predisposition syndromes as a function of age, with tumors often diagnosed in the first decade of life.12Aronson M. Gallinger S. Cohen Z. et al.Gastrointestinal findings in the largest series of patients with hereditary biallelic mismatch repair deficiency syndrome: report from the International Consortium.Am J Gastroenterol. 2016; 111: 275-284Crossref PubMed Scopus (32) Google Scholar The rate of progression of adenomas among BMMRD patients appears to be accelerated and more rapid than in LS. This may occur because BMMRD tumors acquire early somatic mutations in the polymerase proofreading genes DNA polymerase ε and δ (POLE and POLD1), and together with the underlying DNA-MMR defect, develop ultrahypermutated tumors with a massive number of substitution mutations and an unprecedented rate of progression.13Shlien A. Campbell B.B. de Borja R. et al.Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.Nat Genet. 2015; 47: 257-262Crossref PubMed Scopus (242) Google Scholar This contrasts with the distinctly smaller numbers of mutations seen in most childhood malignancies compared with adult-onset cancers.14Vogelstein B. Papadopoulos N. Velculescu V.E. et al.Cancer genome landscapes.Science. 2013; 339: 1546-1558Crossref PubMed Scopus (5206) Google Scholar In view of the striking cancer and mortality risk in these patients, close surveillance of affected individuals is important for early cancer detection. Over the past 15 years, BMMRD patients have been followed up with a clinical surveillance protocol15Durno C.A. Aronson M. Tabori U. et al.Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred.Pediatr Blood Cancer. 2012; 59: 652-656Crossref PubMed Scopus (66) Google Scholar designed to diagnose tumors in asymptomatic patients amenable to surgical resection. Gastrointestinal and brain tumors are the most common malignancies described in BMMRD, occurring in more than half of these patients.16Durno C.A. Sherman P.M. Aronson M. et al.Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome.Eur J Cancer. 2015; 51: 977-983Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 17Lavoine N. Colas C. Muleris M. et al.Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.J Med Genet. 2015; 52: 770-778Crossref PubMed Scopus (87) Google Scholar, 18Vasen H.F. Ghorbanoghli Z. Bourdeaut F. et al.Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium “Care for CMMR-D” (C4CMMR-D).J Med Genet. 2014; 51: 283-293Crossref PubMed Scopus (153) Google Scholar Unfortunately, no consensus exists on the optimal screening and surveillance guidelines, which confounds managing physicians, and can lead to inappropriate refusal to pay for reasonable care by insurers. BMMRD will occur in 25% of the offspring of 2 individuals who have LS involving the same gene; consequently, BMMRD is quite rare. The mutations may be homozygous or compound heterozygotes, and the various combinations of mutations can lead to clinical pleiotropy. Patients with colon cancer and café-au-lait macules presumed to have familial adenomatous polyposis with no APC mutation identified should be re-evaluated for BMMRD.19Jerkic S. Rosewich H. Scharf J.G. et al.Colorectal cancer in two pre-teenage siblings with familial adenomatous polyposis.Eur J Pediatr. 2005; 164: 306-310Crossref PubMed Scopus (28) Google Scholar BMMRD probably is under-recognized. Moreover, the rarity of this disease, accompanied by childhood presentation, has led to limited research and the absence of controlled trials in the management of this disorder. Nevertheless, clinicians are confronted with difficult management decisions without guidelines based on data or consensus. Consequently, several experts have pooled collective experiences to develop consensus guidelines as an initial attempt to identify more uniform approaches to patient management, and to prioritize areas in greatest need of research. BMMRD is an under-recognized syndrome with pleiotropic presentations. Clues to guide clinicians to suspect BMMRD and increase recognition of BMMRD are included in Table 2. Patients may be children or young adults diagnosed with early onset CRC, brain tumors, leukemias, lymphomas, or uterine cancer. Any child or young adult with cancer plus parental consanguinity or features of neurofibromatosis not explained by other confirmed germline mutations should be suspected. Raising awareness among gastroenterologists, oncologists, dermatologists, internists, gynecologists, and pediatricians is paramount for improving the characterization of BMMRD patients and outcomes for patients and families with this disorder.Table 2Clinical and Laboratory Features to Raise Suspicion for Possible BMMRDChild or young adult with a Lynch syndrome cancer (colorectal, small bowel, ureter, endometrial, and so forth)Child or young adult with colonic adenomatous polyposis not explained by a known polyposis syndrome mutation (familial adenomatous polyposis, MUTYH-associated polyposis)Any child or young adult with cancer plus parental consanguinity, café-au-lait macules, or features of neurofibromatosis, not explained by other confirmed germline mutation (ie, neurofibromatosis)Any cancer with abnormal immunohistochemistry for the DNA-MMR proteins in normal and tumor tissueHistory of brain cancer, lymphoma, or leukemia without history of radiationAny child or adult with hypermutated tumor Open table in a new tab In contrast to other cancer predisposition syndromes, most patients with BMMRD have no immediate family history of LS-related cancers because their parents are young and not yet phenotypically affected despite harboring a monoallelic mutation in a DNA-MMR gene. In addition, small family sizes will make autosomal-recessive diseases appear to be sporadic.16Durno C.A. Sherman P.M. Aronson M. et al.Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome.Eur J Cancer. 2015; 51: 977-983Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar An important clue in the family history that may suggest BMMRD is parental consanguinity. Therefore, because the family history of cancers often is noncontributory, a high index of suspicion is required. One reason for the negative family history is that biallelic germline mutations in PMS2 are the most common cause of BMMRD. The penetrance for LS-associated cancers is relatively low in monoallelic carriers of mutation in PMS2 (ie, the parents). The combination of the early onset cancer in the proband, later-onset cancer in the parents, and incomplete penetrance for PMS2-LS leads to a family history that often is negative.7Antelo M. Milito D. Rhees J. et al.Pitfalls in the diagnosis of biallelic PMS2 mutations.Fam Cancer. 2015; 14: 411-414Crossref PubMed Scopus (9) Google Scholar, 20De Vos M. Hayward B.E. Charlton R. et al.PMS2 mutations in childhood cancer.J Natl Cancer Inst. 2006; 98: 358-361Crossref PubMed Scopus (71) Google Scholar, 21Kruger S. Kinzel M. Walldorf C. et al.Homozygous PMS2 germline mutations in two families with early-onset haematological malignancy, brain tumours, HNPCC-associated tumours, and signs of neurofibromatosis type 1.Eur J Hum Genet. 2008; 16: 62-72Crossref PubMed Scopus (70) Google Scholar Biallelic germline mutations in MSH6 also are over-represented in BMMRD.22Wimmer K. Kratz C.P. Constitutional mismatch repair-deficiency syndrome.Haematologica. 2010; 95: 699-701Crossref PubMed Scopus (111) Google Scholar In MSH6-LS, the onset of LS-associated tumors occurs at a high frequency, but later in life than with the more common types: MSH2-LS and MLH1-LS. Consequently, the child with biallelic MMR gene mutations most often will develop neoplasia before either parent. As a possibly related observation, when CRC develops in a person younger than age 50 in the absence of a strong family history, again, the PMS2 and MSH6 genes are the most frequently involved.23Goel A. Nagasaka T. Spiegel J. et al.Low frequency of Lynch syndrome among young patients with non-familial colorectal cancer.Clin Gastroenterol Hepatol. 2010; 8: 966-971Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 24Giraldez M.D. Balaguer F. Bujanda L. et al.MSH6 and MUTYH deficiency is a frequent event in early-onset colorectal cancer.Clin Cancer Res. 2010; 16: 5402-5413Crossref PubMed Scopus (68) Google Scholar The phenotypic and genotypic characterization of a patient with BMMRD can be challenging even when the diagnosis is being considered. Diagnostic criteria are proposed for the evaluation of a child or young adult cancer patient based on the phenotypic presentation.25Wimmer K. Kratz C.P. Vasen H.F. et al.Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD).J Med Genet. 2014; 51: 355-365Crossref PubMed Scopus (289) Google Scholar, 26Wimmer K. Etzler J. Constitutional mismatch repair-deficiency syndrome: have we so far seen only the tip of an iceberg?.Hum Genet. 2008; 124: 105-122Crossref PubMed Scopus (208) Google Scholar The diagnosis requires confirmation of biallelic deleterious germline MMR gene mutations. This situation creates constitutional DNA-MMR deficiency, and nonexpression of the MMR protein usually is observed in all normal, non-neoplastic tissues as well as tumor tissues, which can be confusing in the pathologic interpretation of the immunohistochemistry of the tumor tissue and surrounding tissues where the pathologist expects full protein expression in non-neoplastic cells, as was shown in a recent case study.27Biller J.A. Butros S.R. Chan-Smutko G. et al.Case records of the Massachusetts General Hospital. Case 6-2016. A 10-year-old boy with abdominal cramping and fevers.N Engl J Med. 2016; 374: 772-781Crossref PubMed Scopus (5) Google Scholar The family history frequently is negative, and because of the broad implications for the patient and family, it is reasonable to recommend universal testing for immunohistochemistry and MSI on all small- and large-bowel cancers in children. In additio" @default.
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• W2598346119 title "Recommendations on Surveillance and Management of Biallelic Mismatch Repair Deficiency (BMMRD) Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer" @default.
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