RESUMO
Dysregulated tyrosine kinases in myeloid/lymphoid neoplasms with eosinophilia are rare, but do occur in children. To increase awareness of this diagnosis, we present a child who was diagnosed after a 3-year disease history. The patient was initially treated according to a T-cell lymphoblastic lymphoma protocol, but genetic analyses at recurrence revealed microdeletions resulting in an in-frame fusion of ZMYM2 and FLT3. Treatment with sorafenib, an FLT3 tyrosine kinase inhibitor, rapidly resulted in significant reduction of lymphadenopathy and normalization of white blood cell and eosinophil counts. At 17 months of treatment, he remains in complete hematologic, but not molecular remission.
Assuntos
Antineoplásicos/uso terapêutico , Linfoma/tratamento farmacológico , Proteínas Nucleares/genética , Sorafenibe/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Pré-Escolar , Eosinofilia/complicações , Humanos , Linfoma/complicações , Linfoma/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêuticoRESUMO
Copy number variations (CNVs) are important in relation to diversity and evolution but can sometimes cause disease. The most common genetic cause of the inherited peripheral neuropathy Charcot-Marie-Tooth disease is the PMP22 duplication; otherwise, CNVs have been considered rare. We investigated CNVs in a population-based sample of Charcot-Marie-Tooth (CMT) families. The 81 CMT families had previously been screened for the PMP22 duplication and point mutations in 51 peripheral neuropathy genes, and a genetic cause was identified in 37 CMT families (46%). Index patients from the 44 CMT families with an unknown genetic diagnosis were analysed by whole-genome array comparative genomic hybridization to investigate the entire genome for larger CNVs and multiplex ligation-dependent probe amplification to detect smaller intragenomic CNVs in MFN2 and MPZ. One patient had the pathogenic PMP22 duplication not detected by previous methods. Three patients had potentially pathogenic CNVs in the CNTNAP2, LAMA2, or SEMA5A, that is, genes related to neuromuscular or neurodevelopmental disease. Genotype and phenotype correlation indicated likely pathogenicity for the LAMA2 CNV, whereas the CNTNAP2 and SEMA5A CNVs remained potentially pathogenic. Except the PMP22 duplication, disease causing CNVs are rare but may cause CMT in about 1% (95% CI 0-7%) of the Norwegian CMT families.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Variações do Número de Cópias de DNA/genética , Adulto , Criança , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Laminina/genética , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso Periférico/genética , Fenótipo , Mutação Puntual/genética , SemaforinasRESUMO
INTRODUCTION: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The majority has a duplication of the peripheral myelin protein 22. CMT is otherwise caused by point mutations or small insertions/deletions in one of the 44 known CMT genes. METHODS AND RESULTS: Conventional sequencing of six CMT genes were followed by Multiplex Ligation-dependent Probe Amplification (MLPA), array Comparative Genomic Hybridization (aCGH) and breakpoint analysis in a large Norwegian CMT pedigree. Affected had an extra copy of the myelin protein zero (MPZ) gene. CONCLUSION: To our knowledge this is the first non-peripheral myelin protein 22 copy number variation to cause Charcot-Marie-Tooth disease.