Survival Benefit for Individuals with Constitutional Mismatch Repair Deficiency Syndrome and Brain Tumors Who Undergo Surveillance Protocol. A Report from the International Replication Repair Consortium

BACKGROUND Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. METHODS We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. RESULTS Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p\u3c0.004). Similarly, 5-year survival was 82+/-11% and 24+/-6% for surveillance and non-surveillance of brain tumors (p=0.005). Yearly total body and q6 month brain MRI detected asymptomatic cancers in all but 3 symptomatic CNS gliomas. These were tumors uncovered when time between scans was \u3e6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas, which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. CONCLUSION These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival for patients with CNS tumors

Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

PURPOSE: Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS: Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS: A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically (P \u3c .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively (P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance (P \u3c .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION: Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD

Colonic polyps in children and adolescents

Colonic polyps most commonly present with rectal bleeding in children. The isolated juvenile polyp is the most frequent kind of polyp identified in children. ‘Juvenile’ refers to the histological type of polyp and not the age of onset of the polyp. Adolescents and adults with multiple juvenile polyps are at a significant risk of intestinal cancer. The challenge for adult and pediatric gastroenterologists is determining the precise risk of colorectal cancer in patients with juvenile polyposis syndrome. Attenuated familial adenamatous polyposis (AFAP) can occur either by a mutation at the extreme ends of the adenomatous polyposis coli gene or by biallelic mutations in the mutY homologue (MYH) gene. The identification of MYH-associated polyposis as an autosomal recessive condition has important implications for screening and management strategies. Adult and pediatric gastroenterologists need to be aware of the underlying inheritance patterns of polyposis syndromes so that patients and their families can be adequately evaluated and managed. Colonic polyps, including isolated juvenile polyps, juvenile polyposis syndrome, FAP, AFAP and MYH-associated polyposis, are discussed in the present review

Mode of inheritance and demographics of pediatric-onset inflammatory bowel disease

grantor: University of Toronto'Objective'. To describe the occurrence and inheritance pattern of pediatric-onset inflammatory bowel disease in a population of children and adolescents of Jewish and non-Jewish ethnicity. Study design. Prospective clinic based study which approximates a population-based cohort study. Participants and setting. Children and adolescents (n = 974) diagnosed with IBD at the Hospital for Sick Children, Toronto between 1980 and 1996. 'Methods'. Ascertainment of families through probands prospectively registered On the HSC IBD database, family history questionnaire, age-specific prevalence rates and complex segregation analysis. Results. Complex segregation analysis included 974 kindreds with 3921 subjects. All of the genetic models had a significant interaction factor (gene x ethnicity) suggesting that the mode of inheritance of IBD was different for people of Jewish and non-Jewish ethnicity. Among the Jewish kindreds the complex segregation analysis was consistent with a Mendelian gene segregating with dominant inheritance. In the non-Jewish kindreds the recessive model was a better fit. The prevalence of pediatric IBD was 25 cases per 100 000 children in 1991 and 1996. The relative risk estimates of developing IBD for children and adolescents of Jewish compared to non-Jewish ethnicity by age groups ranged from 10 to 20 (95% CL: 8.4, 13.3 and 14.8, 27.0). Lambda s, the relative risk of IBD among siblings of probands compared to the general population, was 54 among individuals of Jewish ethnic origin. 'Conclusions'. Segregation analyses provided strong evidence that the mode of inheritance of IBD was different for children of Jewish and non-Jewish ethnicity. Pediatric-onset IBD among patients of Jewish ethnic origin appears to be the most genetically determined form of IBD. Pediatric patients of Jewish ethnic origin are an ideal population to focus joint segregation and linkage analysis.M.Sc

Management of Juvenile Polyposis Syndromes in Children and Adolescents

International audienceThe European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Polyposis Working Group developed recommendations to assist clinicians and health care providers with appropriate management of patients with juvenile polyposis. This is the first juvenile polyposis Position Paper published by ESPGHAN with invited experts. Many of the published studies were descriptive and/or retrospective in nature, consequently after incorporating a modified version of the GRADE system many of the recommendationsare based on expert opinion. This ESPGHAN Position Paper provides a guide for diagnosis, assessment and management of Juvenile polyposis syndrome (JPS) in children and adolescents, and will be helpful in the appropriate management and timing of procedures in children and adolescents. The formation of international collaboration and consortia is proposed in order to monitor patients prospectively to advance our understanding of juvenile polyposis conditions

SURVIVAL BENEFIT FOR INDIVIDUALS WITH CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME AND BRAIN TUMORS WHO UNDERGO SURVEILLANCE PROTOCOL. A REPORT FROM THE INTERNATIONAL REPLICATION REPAIR CONSORTIUM

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) is a severe cancer predisposition syndrome resulting in early onset central nervous system (CNS) and other cancers. International guidelines for surveillance exist but no study has systematically evaluated the efficacy of this protocol. Methods: We surveyed all confirmed CMMRD patients in the International Replication Repair Deficiency Consortium. A surveillance protocol consisting of frequent biochemical, endoscopic and imaging (CNS and total body MRI) studies were employed. Survival analyses and efficacy of each method were assessed. Results: Surveillance data were collected from 105 CMMRD individuals from 41 countries. Of the 193 malignant tumors, CNS malignancies were the most common (44%). The surveillance protocol uncovered 49 asymptomatic tumors including 16 glioblastomas and medulloblastomas. Five-year overall survival was 89% for tumors discovered by surveillance, and 61% for symptomatic tumors (p6 months as per protocol. Finally, of the low grade tumors identified asymptomatically, 5 were low grade gliomas. All of the low grade gliomas,which were not resected transformed to high grade tumors at a median of 1.6 ± 0.9 years. Conclusion: These data support a survival benefit in CMMRD patients undergoing a surveillance protocol. Adherence to protocol and resection of lower grade lesions may improve survival forpatients with CNS tumors