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.
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.
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.
Le médulloblastome de l’enfant Yazigi-Rivard, L.; Masserot, C.; Lachenaud, J. ...
Archives de pédiatrie : organe officiel de la Société française de pédiatrie,
12/2008, Letnik:
15, Številka:
12
Journal Article
Recenzirano
Le médulloblastome est l’une des tumeurs cérébrales les plus fréquentes de l’enfant : il s’agit d’une tumeur neuroectodermique primitive localisée au niveau du cervelet et du 4
e ventricule. Elle est ...le plus souvent sporadique, mais certains syndromes, comme le syndrome de Gorlin ou les mutations du gène
SUFU, prédisposent au développement de cette tumeur. Les circonstances du diagnostic sont habituellement liées à l’hypertension intracrânienne, dont la présentation souvent atypique ne doit pas faire retarder les explorations neuroradiologiques. L’IRM cérébrale et spinale permet de faire le diagnostic de tumeur de la fosse postérieure et d’évaluer son extension. L’examen histologique confirme le diagnostic de médulloblastome. L’étude cytologique du LCR, prélevé par ponction lombaire en postopératoire, complète le bilan d’extension. Les patients peuvent alors être séparés en 2 groupes : groupe à risque standard (tumeur localisée ayant pu faire l’objet d’une exérèse totale ou subtotale) et groupe à haut risque (métastases ou présence d’un résidu tumoral). Les caractéristiques biologiques de la tumeur permettent d’identifier des facteurs pronostiques nouveaux et pourraient dans le futur être la base du développement de thérapeutiques ciblées. Chez les grands enfants, le traitement comprend habituellement une exérèse chirurgicale suivie d’une radiothérapie et d’une chimiothérapie. Le progrès des connaissances de ces dernières années a permis de diminuer les doses d’irradiation crâniospinale chez les grands enfants et d’éviter autant que possible la radiothérapie chez les plus jeunes en cas de risque standard. Cependant, les séquelles à long terme restent fréquentes. Leur détection et leur prise en charge sont indispensables dans le suivi de ces patients.
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.
Childhood medulloblastoma Yazigi-Rivard, L; Masserot, C; Lachenaud, J ...
Archives de pédiatrie : organe officiel de la Société française de pédiatrie
15, Številka:
12
Journal Article
Recenzirano
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.
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