RESUMO
BACKGROUND: CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. METHODS AND RESULTS: CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype. CONCLUSION: A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.
Assuntos
Mutação em Linhagem Germinativa , Transtornos do Crescimento , Leucemia Mielomonocítica Juvenil/genética , Microcefalia , Proteínas Proto-Oncogênicas c-cbl/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Feminino , Predisposição Genética para Doença , Transtornos do Crescimento/complicações , Transtornos do Crescimento/genética , Humanos , Leucemia Mielomonocítica Juvenil/complicações , Masculino , Microcefalia/complicações , Microcefalia/genética , SíndromeAssuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 14/genética , Cadeias Pesadas de Imunoglobulinas/genética , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Translocação Genética/genética , Adulto , Sequência de Bases , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Homologia de Sequência do Ácido NucleicoAssuntos
Doenças do Prematuro/tratamento farmacológico , Josamicina/uso terapêutico , Infecções por Mycoplasma/tratamento farmacológico , Complicações Infecciosas na Gravidez/tratamento farmacológico , Infecções por Ureaplasma/tratamento farmacológico , Antibacterianos/uso terapêutico , Estudos de Casos e Controles , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/microbiologia , Transmissão Vertical de Doenças Infecciosas , Infecções por Mycoplasma/microbiologia , Mycoplasma hominis/crescimento & desenvolvimento , Mycoplasma hominis/patogenicidade , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Resultado do Tratamento , Infecções por Ureaplasma/microbiologia , Ureaplasma urealyticum/crescimento & desenvolvimento , Ureaplasma urealyticum/patogenicidade , Vagina/microbiologiaRESUMO
Medulloblastoma is one of the most common malignant childhood brain tumors. It is a primitive neuroectodermal tumor (PNET) and predominantly arises in the cerebellum and 4th ventricle. Most cases of medulloblastoma are sporadic, but some predisposition syndromes are known, such as SUFU and Gorlin syndromes. Most often intracranial hypertension reveals the disease typically with headache and vomiting. However, the frequent atypical presentation should not delay neuroradiological investigations. Brain and spinal MRI can establish the diagnosis of posterior fossa tumor and define the extent of the disease. CSF study completes the staging. Histologic examination of the tumor confirms the diagnosis of medulloblastoma. Patients are classified into 2 risk groups: standard-risk medulloblastoma, defined by nonmetastatic disease treated by total or subtotal tumor resection; and high-risk patients who have disseminated disease and/or residual disease. Tumor molecular genetic findings allow the use of emerging prognostic factors and may ultimately contribute to the development of targeted therapy. Current treatment in the oldest children combines surgical resection followed by radiotherapy and chemotherapy. The aim of recent studies was to increase survival and decrease sequelae by reducing CSI in older children with standard risk medulloblastoma. Treatment in younger patients is as much as possible restricted to surgery and chemotherapy. However, long-term sequelae after treatment for medulloblastoma remain frequent and the detection and treatment of those sequelae is an essential part of the follow-up of the patients.