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1.
Artigo em Inglês | MEDLINE | ID: mdl-33480653

RESUMO

Coronavirus disease-2019 in children has been linked to various clinical presentation, from paucisymptomatic cutaneous eruptions, to multisystemic inflammatory syndrome. We report the case of an 8-year-old boy who presented with persistent fever and pancytopenia, associated to a skin rash. An extensive etiological workup showed a positive serology for severe acute respiratory syndrome coronavirus 2 and Epstein-Barr virus. A few weeks later, type B acute lymphocytic leukemia was diagnosed. This case underlines the polymorphic appearance of coronavirus disease-2019 and the need for critical appraisal.

2.
Br J Haematol ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32700439

RESUMO

The nucleoside analogue, 2-chlorodeoxyadenosine (2CDA), was reported to be an active treatment for childhood Langerhans cell histiocytosis (LCH) without risk organ (RO-) involvement. However, we lack data on long-term effects of 2CDA treatment, including the disease reactivation rate, permanent sequelae and long-term tolerance. This study included 44 children from the French LCH registry, treated for a RO- LCH with 2CDA monotherapy (median number of six courses). The median age at the beginning of 2CDA was 3·6 years (range, 0·3-19·7 years) and the median follow-up after was 5·4 years (range, 0·6-15·1 years). Objective response to 2CDA was observed in 25 patients (56·8%), while six patients (13·6%) had stable disease and 13 patients (29·5%) exhibited progressive disease. Among patients without progression, only two experienced disease reactivation after 2CDA discontinuation. The five-year cumulative incidence of disease progression or reactivation after 2CDA therapy initiation was 34·3%. The lymphopenia reported in all cases [72% below absolute lymphocyte count (ALC) of 0·5 G/l], was addressed with appropriate prophylactic measures. Other toxicities above grade 2 were uncommon, and no second malignant neoplasm or neuropathy was reported. The five-year overall survival was 97·7%. In conclusion, we could confirm that 2CDA monotherapy was a beneficial long-term therapy for treating patients with RO- LCH. Appropriate management of induced immune deficiency is mandatory.

3.
Haematologica ; 104(8): 1554-1564, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30655378

RESUMO

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.


Assuntos
Anemia Hemolítica Congênita/genética , Canalopatias/genética , Hidropisia Fetal/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Canais Iônicos/genética , Anemia Hemolítica Congênita/complicações , Anemia Hemolítica Congênita/cirurgia , Edema/etiologia , Família , Feminino , Hemólise , Humanos , Hidropisia Fetal/cirurgia , Sobrecarga de Ferro , Masculino , Mutação , Mutação de Sentido Incorreto , Gravidez , Estudos Retrospectivos , Esplenectomia/efeitos adversos , Trombose
4.
Pediatr Dermatol ; 35(6): e375-e377, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30189467

RESUMO

Transporter associated with antigen processing (TAP) is essential for the stabilization and surface expression of major histocompatibility complex class I molecules of all nucleated cells. TAP deficiency syndrome, also known as bare lymphocyte syndrome type I, is a rare primary immunodeficiency disorder. We report a case of TAP1 deficiency revealed by skin lesions long before the occurrence of respiratory infectious manifestations.


Assuntos
Membro 2 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Granuloma/patologia , Imunodeficiência Combinada Severa/diagnóstico , Dermatopatias/etiologia , Pré-Escolar , Feminino , Antígenos de Histocompatibilidade Classe I , Humanos , Mutação , Pele/patologia
5.
Haematologica ; 103(8): 1278-1287, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29724903

RESUMO

Heterozygous germline GATA2 mutations strongly predispose to leukemia, immunodeficiency, and/or lymphoedema. We describe a series of 79 patients (53 families) diagnosed since 2011, made up of all patients in France and Belgium, with a follow up of 2249 patients/years. Median age at first clinical symptoms was 18.6 years (range, 0-61 years). Severe infectious diseases (mycobacteria, fungus, and human papilloma virus) and hematologic malignancies were the most common first manifestations. The probability of remaining symptom-free was 8% at 40 years old. Among the 53 probands, 24 had missense mutations including 4 recurrent alleles, 21 had nonsense or frameshift mutations, 4 had a whole-gene deletion, 2 had splice defects, and 2 patients had complex mutations. There were significantly more cases of leukemia in patients with missense mutations (n=14 of 34) than in patients with nonsense or frameshift mutations (n=2 of 28). We also identify new features of the disease: acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, fatal progressive multifocal leukoencephalopathy related to the JC virus, and immune/inflammatory diseases. A revised International Prognostic Scoring System (IPSS) score allowed a distinction to be made between a stable disease and hematologic transformation. Chemotherapy is of limited efficacy, and has a high toxicity with severe infectious complications. As the mortality rate is high in our cohort (up to 35% at the age of 40), hematopoietic stem cell transplantation (HSCT) remains the best choice of treatment to avoid severe infectious and/or hematologic complications. The timing of HSCT remains difficult to determine, but the earlier it is performed, the better the outcome.


Assuntos
Deficiência de GATA2/epidemiologia , Mutação em Linhagem Germinativa , Adulto Jovem , Adolescente , Adulto , Bélgica , Criança , Pré-Escolar , França , Deficiência de GATA2/complicações , Deficiência de GATA2/genética , Deficiência de GATA2/terapia , Neoplasias Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Pessoa de Meia-Idade , Mortalidade , Prognóstico , Inquéritos e Questionários
6.
Blood Cells Mol Dis ; 66: 11-18, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28772256

RESUMO

The most frequent germline mutations responsible for non syndromic congenital sideroblastic anemia are identified in ALAS2 and SLC25A38 genes. Iron overload is a key issue and optimal chelation therapy should be used to limit its adverse effects on the development of children. Our multicentre retrospective descriptive study compared the strategies for diagnosis and management of congenital sideroblastic anemia during the follow-up of six patients with an ALAS2 mutation and seven patients with an SLC25A38 mutation. We described in depth the clinical, biological and radiological phenotype of these patients at diagnosis and during follow-up and highlighted our results with a review of available evidence and data on the management strategies for congenital sideroblastic anemia. This report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications. The use of an international registry would certainly help defining recommendations for the management of these rare disorders to improve patient outcome.


Assuntos
5-Aminolevulinato Sintetase/genética , Anemia Sideroblástica/congênito , Proteínas de Transporte da Membrana Mitocondrial/genética , Anemia Sideroblástica/genética , Criança , Humanos , Sobrecarga de Ferro , Fenótipo , Estudos Retrospectivos
7.
Forensic Sci Int ; 245: e15-7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25459275

RESUMO

We report the case of a 2-month-old infant with a single apparently ecchymotic lesion on the shoulder that raised suspicions of abuse. The medicolegal examination concluded that the appearance of the lesion was only mildly suggestive of an ecchymosis. A second, temporally remote examination confirmed this doubt. The evolution of the lesion, notably an increase in its volume, allowed us to rule out a traumatic lesion and was suggestive of a vascular tumor. The histological type of the tumor was a tufted angioma. There was thrombocytopenia and consumptive coagulopathy. All these data confirmed the diagnosis of Kasabach-Merritt syndrome. In contrast to benign infantile hemangiomas, which are frequent and well-known in clinical practice, vascular tumors complicated by Kasabach-Merritt syndrome are rare. They deserve to be widely known because they mandate rapid medical management and because they are one of the only differential diagnoses of ecchymosis, especially in children. When there is doubt about the traumatic nature of a cutaneous lesion, a temporally remote examination is essential. The evolution of the lesion may then suggest a dermatologic origin.


Assuntos
Hemangioma/diagnóstico , Síndrome de Kasabach-Merritt/diagnóstico , Neoplasias Cutâneas/diagnóstico , Maus-Tratos Infantis/diagnóstico , Diagnóstico Diferencial , Equimose/etiologia , Humanos , Lactente , Masculino
8.
Nat Commun ; 4: 1884, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23695678

RESUMO

Dehydrated hereditary stomatocytosis is a genetic condition with defective red blood cell membrane properties that causes an imbalance in intracellular cation concentrations. Recently, two missense mutations in the mechanically activated PIEZO1 (FAM38A) ion channel were associated with dehydrated hereditary stomatocytosis. However, it is not known how these mutations affect PIEZO1 function. Here, by combining linkage analysis and whole-exome sequencing in a large pedigree and Sanger sequencing in two additional kindreds and 11 unrelated dehydrated hereditary stomatocytosis cases, we identify three novel missense mutations and one recurrent duplication in PIEZO1, demonstrating that it is the major gene for dehydrated hereditary stomatocytosis. All the dehydrated hereditary stomatocytosis-associated mutations locate at C-terminal half of PIEZO1. Remarkably, we find that all PIEZO1 mutations give rise to mechanically activated currents that inactivate more slowly than wild-type currents. This gain-of-function PIEZO1 phenotype provides insight that helps to explain the increased permeability of cations in red blood cells of dehydrated hereditary stomatocytosis patients. Our findings also suggest a new role for mechanotransduction in red blood cell biology and pathophysiology.


Assuntos
Anemia Hemolítica Congênita/genética , Hidropisia Fetal/genética , Ativação do Canal Iônico/genética , Canais Iônicos/genética , Canais Iônicos/metabolismo , Mutação/genética , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Fenômenos Biomecânicos , Criança , Análise Mutacional de DNA , Feminino , Humanos , Interações Hidrofóbicas e Hidrofílicas , Canais Iônicos/química , Cinética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Proteínas Recombinantes/metabolismo , Adulto Jovem
9.
Blood ; 113(22): 5605-8, 2009 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-19357398

RESUMO

Matriptase-2 is a transmembrane serine protease that negatively regulates hepcidin expression by cleaving membrane-bound hemojuvelin. Matriptase-2 has a complex ectodomain, including a C-terminal serine protease domain and its activation requires an autocatalytic cleavage. Matriptase-2 mutations have been reported in several patients with iron-refractory iron deficiency anemia. Here we describe a patient with 2 missense mutations in the second class A low-density lipoprotein receptor (LDLRA) domain. Functional studies of these 2 mutations and of a previously reported mutation in the second C1r/C1s, urchin embryonic growth factor and bone morphogenetic protein 1 (CUB) domain were performed. Transfection of mutant cDNAs showed that membrane targeting of the 2 LDLRA mutants was impaired, with Golgi retention of the variants. The activating cleavage was absent for the LDLRA mutants and reduced for the CUB mutant. All 3 mutated proteins were still able to physically interact with hemojuvelin but only partially repressed hepcidin expression compared with wild-type matriptase-2. Our results underline the importance of LDLRA and CUB domains of matriptase-2.


Assuntos
Anemia Ferropriva/genética , Peptídeos Catiônicos Antimicrobianos/antagonistas & inibidores , Proteínas de Membrana/genética , Serina Endopeptidases/genética , Anemia Ferropriva/tratamento farmacológico , Criança , Células HeLa , Hepcidinas , Humanos , Ferro/uso terapêutico , Masculino , Modelos Biológicos , Mutação/fisiologia , Transdução de Sinais/genética , Falha de Tratamento
10.
Joint Bone Spine ; 70(2): 149-53, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12713862

RESUMO

Hyperuricemia is a well-known consequence of glucose-6-phosphatase (G6Pase) deficiency, the enzymatic abnormality that characterizes glycogen storage disease (GSD) Type Ia. However, acute gout as the presenting manifestation of GSD Type Ia has been reported in only a few patients. We report a new case in a 17-year-old male evaluated for acute gouty tendinitis in the right Achilles tendon. Blood tests showed chronic acidosis with high levels of uric acid, lactic acid, and cholesterol. A liver enzyme study confirmed the diagnosis of GSD Type Ia. A genetic study showed that the index patient and his sister were composite heterozygotes for the known mutation R83C and the previously unreported mutation M5R. Acute gout in an adolescent with liver enlargement and high blood levels of uric acid and cholesterol should suggest GSD. Demonstration by molecular biology techniques of a mutation in both alleles of the G6Pase gene establishes the diagnosis of GSD Type Ia, obviating the need for a liver biopsy.


Assuntos
Doença de Depósito de Glicogênio Tipo I/diagnóstico , Gota/complicações , Tendinopatia/etiologia , Adolescente , Feminino , Doença de Depósito de Glicogênio Tipo I/complicações , Doença de Depósito de Glicogênio Tipo I/genética , Heterozigoto , Humanos , Masculino , Mutação
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