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Pracoviště: Department of Pediatrics McGill University Mont...

2 záznamů v Medvik Filtry

Článek

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C

Pelletier, Félixe
Autor Pelletier, Félixe Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Department of Pediatrics, McGill University, Montreal, QC, Canada Department of Human Genetics, McGill University, Montreal, QC, Canada Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada Division of Child Neurology, Department of Pediatrics, CHU Sainte-Justine, Université de Montréal, Montreal, QC, Canada
Perrier, Stefanie
Autor Perrier, Stefanie Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
Cayami, Ferdy K
Autor Cayami, Ferdy K Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Center of Biomedical Research, Faculty of Medicine, Diponegoro University, Semarang, Indonesia
Mirchi, Amytice
Autor Mirchi, Amytice Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Department of Pediatrics, McGill University, Montreal, QC, Canada Department of Human Genetics, McGill University, Montreal, QC, Canada Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada
Saikali, Stephan
Autor Saikali, Stephan Department of Pathology, Centre Hospitalier Universitaire de Québec, Québec City, QC, Canada
Tran, Luan T
Autor Tran, Luan T Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Department of Pediatrics, McGill University, Montreal, QC, Canada Department of Human Genetics, McGill University, Montreal, QC, Canada Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
Ulrick, Nicole
Autor Ulrick, Nicole Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
Guerrero, Kether
Autor Guerrero, Kether Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada Department of Pediatrics, McGill University, Montreal, QC, Canada Department of Human Genetics, McGill University, Montreal, QC, Canada Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
Rampakakis, Emmanouil
Autor Rampakakis, Emmanouil Department of Pediatrics, McGill University, Montreal, QC, Canada
van Spaendonk, Rosalina M L
Autor van Spaendonk, Rosalina M L Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

The Journal of clinical endocrinology and metabolism. 2021 ; 106 (2) : e660-e674. [pub] 20210123

J Clin Endocrinol Metab
ISSN 1945-7197
Medvik
Zdroj

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.

Článek

Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort

Lancet oncology. 2018 ; 19 (6) : 785-798. [pub] 20180509

Lancet Oncol.
ISSN 1474-5488
Medvik
Zdroj

BACKGROUND: Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. METHODS: In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. FINDINGS: We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. INTERPRETATION: Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. FUNDING: German Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

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