title: Connections between constitutional mismatch repair deficiency syndrome and neurofibromatosis type 1.
abstract: Constitutional mismatch repair (MMR) deficiency (CMMRD) is a rare childhood cancer susceptibility syndrome resulting from biallelic germline loss-of-function mutations in one of the MMR genes. Individuals with CMMRD have high risk to develop a broad spectrum of malignancies and frequently display features reminiscent of neurofibromatosis type 1 (NF1). Evaluation of the clinical findings of genetically proven CMMRD patients shows that not only multiple café-au-lait macules but also any of the diagnostic features of NF1 may be present in a CMMRD patient. This phenotypic overlap may lead to misdiagnosis of CMMRD patients as having NF1, which impedes adequate management of the patients and their families. The spectrum of CMMRD-associated childhood malignancies includes high-grade glioma, acute myeloid leukaemia or rhabdomyosarcoma, also reported as associated with NF1. Reported associations between NF1 and these malignancies are to a large extent based on studies that neither proved the presence of an NF1 germline mutation nor ruled-out CMMRD in the affected. Hence, these associations are challenged by our current knowledge of the phenotypic overlap between NF1 and CMMRD and should be re-evaluated in future studies. Recent advances in the diagnostics of CMMRD should render it possible to definitely state or refute this diagnosis in these individuals.
authors: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors: K
authors: K
authors: Wimmer
authors: Department of Pediatrics, Sana Kliniken Duisburg, Wedau Kliniken, Duisburg, Germany.
authors: T
authors: T
authors: Rosenbaum
authors: Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors: L
authors: L
authors: Messiaen
mesh_terms: D001932:Brain Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D019080:Cafe-au-Lait Spots / Q000175:diagnosis* / Q000235:genetics / Q000503:physiopathology; D002675:Child, Preschool; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics; D003937:Diagnosis, Differential; D018095:Germ-Line Mutation; D005910:Glioma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D012208:Rhabdomyosarcoma / Q000175:diagnosis / Q000235:genetics / Q000473:pathology
keywords: acute myeloid leukaemia; café-au-lait spot; childhood cancer; constitutional mismatch repair deficiency; germline mutation; high-grade glioma; mismatch repair gene; neurofibromatosis type 1; rhabdomyosarcoma