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1.
Blood ; 134(3): 277-290, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31151987

RESUMO

Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.

2.
Ann Biol Clin (Paris) ; 76(4): 435-438, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078780

RESUMO

Shwachman-Diamond syndrome is a constitutional disorder characterized by exocrine pancreatic failure and neutropenia with dysgranulopoiesis. It is a rare disease, with less than 100 cases reported in France. Here we report the case of a 23-year-old woman with this syndrome. The clinical feature and the diagnostic steps are described, as well as the evolution and management in medical and laboratory medicine practice.


Assuntos
Doenças da Medula Óssea/diagnóstico , Insuficiência Pancreática Exócrina/diagnóstico , Lipomatose/diagnóstico , Doenças da Medula Óssea/terapia , Técnicas de Laboratório Clínico , Diagnóstico Diferencial , Insuficiência Pancreática Exócrina/terapia , Feminino , Humanos , Lipomatose/terapia , Adulto Jovem
3.
Blood ; 132(12): 1318-1331, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-29914977

RESUMO

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

4.
Oncotarget ; 9(5): 6478-6489, 2018 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-29464086

RESUMO

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. ZBTB7A mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. FOXP1 focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried FOXP1 truncating mutations. Finally, CCDC26 disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.

6.
J Pediatr Hematol Oncol ; 40(1): 43-47, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29189507

RESUMO

Central nervous system (CNS) involvement at diagnosis of pediatric acute myeloid leukemia (AML) is not considered as an independent prognostic factor. This study describes the prognostic value of pediatric AML with CNS involvement at diagnosis. Pediatric patients were treated for de novo AML in the French multicenter trial ELAM02. Lumbar puncture was carried out in the first week, and the treatment was adapted to the CNS status. No patient received CNS radiotherapy. The patients were classified into 2 groups: CNS+ and CNS-. Of the 438 patients, 16% (n=70) had CNS involvement at diagnosis, and 29% showed clinical signs. The patients with CNS disease were younger (40% were below 2 y old), had a higher white blood cell count (median of 45 vs. 13 G/L), and had M4 and M5 morphologies. The complete remission rate was similar at 92.8% for CNS+ and 88.5% for CNS-. There was no significant difference between the CNS+ and the CNS- group in overall survival (76% and 71%, respectively) and event-free survival (57% and 52%, respectively). Regarding the occurrence of first relapse, the CNS+ group had a higher combined relapse rate of 26.1% compared with 10% for the CNS- group. The results indicate that CNS involvement at diagnosis of pediatric AML is not an independent prognostic factor. Triple intrathecal chemotherapy combined with high-dose intravenous cytarabine should be the first-line treatment for CNS disease.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Leucemia Mieloide Aguda/diagnóstico , Prognóstico , Adolescente , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Casos e Controles , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/mortalidade , Criança , Pré-Escolar , Citarabina/administração & dosagem , França , Humanos , Lactente , Leucemia Monocítica Aguda , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mielomonocítica Aguda , Contagem de Leucócitos , Recidiva , Análise de Sobrevida
7.
Br J Haematol ; 179(4): 557-574, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28875503

RESUMO

This review focuses on the classification, diagnosis and natural history of congenital neutropenia (CN). CN encompasses a number of genetic disorders with chronic neutropenia and, for some, affecting other organ systems, such as the pancreas, central nervous system, heart, bone and skin. To date, 24 distinct genes have been associated with CN. The number of genes involved makes gene screening difficult. This can be solved by next-generation sequencing (NGS) of targeted gene panels. One of the major complications of CN is spontaneous leukaemia, which is preceded by clonal somatic evolution, and can be screened by a targeted NGS panel focused on somatic events.


Assuntos
Genômica/métodos , Neutropenia/congênito , Transformação Celular Neoplásica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia/etiologia , Neutropenia/classificação , Neutropenia/complicações , Neutropenia/diagnóstico
8.
Ann Biol Clin (Paris) ; 75(5): 562-568, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28958966

RESUMO

We report the case of a 5 year old, initially followed for congenital sideroblastic anemia, whose explorations reveal a complex family hemoglobinopathy. Myelogram performed in children, reveals dystrophic mature erythroblasts with hemoglobinization defect and basophil punctuations. These abnormalities point towards an abnormal synthesis of heme or globin chains. Iterative transfusions in child do not allow interpreting a search for abnormal hemoglobin. However, the analysis carried out in his parents, with increased HBA2 rate and microcytosis concluded in beta-thalassemia trait for father and mother. Knowing that beta-thalassemia syndrome is a genetic condition, usually recessive, the presence of beta-thalassemia trait in parents is in favor of a beta-thalassemia syndrome in child. This diagnostic hypothesis is confirmed by molecular study of globin genes that will reveal a complex hemoglobinopathie for all family's members. The parents are carriers for heterozygous mutation of ß+ thalassemia that the sick child presents in homozygous state supporting the diagnosis of beta-thalassemia syndrome. Moreover, a triple α globin gene is present respectively at heterozygous state for mother and at homozygous state for father and child. The triple α globin gene is a known factor of aggravation of beta-thalassemia and this clinical case with continuum observed, perfectly illustrates the intricacies between α and ß globin genes.


Assuntos
Transfusão de Sangue , Talassemia beta/diagnóstico , Talassemia beta/terapia , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Mielografia , Pais , Recidiva , Síndrome , Globinas beta/genética , Talassemia beta/genética
9.
Ann Biol Clin (Paris) ; 75(5): 503-512, 2017 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-28853417

RESUMO

Cytological identification of blasts in cerebrospinal fluid in acute leukemia, lymphoid or myeloid, in adult and child, at diagnosis or during follow up lead to the diagnosis of leukemic meningitidis. Suitable CNS therapy based on a defined "CNS status" following an international standardized classification, lead to decrease cerebrospinal relapses. Established in 1993, this classification allows to treat patients based on their CNS status. Based on the red blood cells count, nucleated cells count and presence of blasts, it requires a standard technical procedure that guarantees the comparability of results coming from different medical laboratory. To improve the quality of cerebrospinal fluid analysis, in acute leukemias, preanalytical guidelines (turn around time), analytical guidelines (cytocentrifugation, adding serum protein, speed and duration of cytocentrifugation) and postanalytical guidelines (duration of conservation) are set by the Groupe francophone d'hématologie cellulaire.


Assuntos
Líquido Cefalorraquidiano/química , Líquido Cefalorraquidiano/citologia , Hematologia/normas , Leucemia/líquido cefalorraquidiano , Leucemia/diagnóstico , Doença Aguda , Humanos , Oncologia/normas
10.
Eur J Paediatr Neurol ; 21(6): 907-911, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28801223

RESUMO

Acid sphingomyelinase (ASM) deficient Niemann-Pick disease is a lysosomal storage disorder resulting from mutations in the SMPD1 gene. The clinical spectrum distinguishes a severe infantile neurological form (type A), a non-neurological visceral form (type B) and a rare intermediate neurovisceral form. We report the first case of presymptomatic cord blood transplantation in a child with the intermediate type of ASM deficiency due to a homozygous Tyr369Cys mutation, whose affected elder brother had developed neurodevelopmental delay from 19 months of age, and had died from severe visceral complications at the age of 3. In the transplanted propositus, neurological deterioration became evident by 4 years of age; the child was alive at age 8, although severely disabled. Whereas the transplant prevented visceral progression and early death, it could only delay neurocognitive deterioration.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Doenças de Niemann-Pick/terapia , Criança , Feminino , Homozigoto , Humanos , Masculino , Mutação , Linhagem , Irmãos , Esfingomielina Fosfodiesterase/deficiência , Resultado do Tratamento
11.
Pediatr Hematol Oncol ; 34(8): 425-427, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29303660

RESUMO

We report the outcome of 27 children with de novo acute megakaryoblastic leukemia (AMKL) (excluding Down syndrome) enrolled in the French multicenter prospective study ELAM02 (2005-2011). There was no difference in gender, initial leukocyte count, CNS involvement, and complete remission rate (88.9%), as compared to other acute myeloid leukemia (AML) subtypes. AMKL patients had a significantly poorer outcome (5-year overall survival 54% [CI 95% 33%-71%] than children with other AML subtypes (5-year overall survival 73% [CI 95% 68%-77%] p = 0.02). Gender, age, CNS leukemia, hyperleukocytosis, complete remission or cytogenetic subgroups were not significant prognostic factors of disease-free survival. AMKL (excluding Down syndrom) remains an AML subgroup with inferior outcome.


Assuntos
Leucemia Megacarioblástica Aguda/mortalidade , Criança , Pré-Escolar , Intervalo Livre de Doença , Síndrome de Down , Feminino , França/epidemiologia , Humanos , Lactente , Leucemia Megacarioblástica Aguda/sangue , Leucemia Megacarioblástica Aguda/terapia , Masculino , Estudos Prospectivos , Taxa de Sobrevida
12.
Ann Biol Clin (Paris) ; 74(3): 317-22, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27108925

RESUMO

We report the identification of a new case of familial non syndromic severe thrombocytopenia. Bleeding was mild and no extra-haematological symptoms were found. Platelet morphology was normal as well as the quantitative expression of platelet membrane glycoproteins. Platelet functions could not be studied due to the intensity of the thrombocytopenia. Molecular analysis identified a mutation located in the promoter of the ankyrin repeat domain 26 (ANKRD26) gene, c.-127A>T, recently reported to be responsible of normocytic thrombocytopenia, but also of a possible increased risk of leukemia/myelodysplasia. Actual knowledge on this new type of inherited thrombocytopenia is also presented.


Assuntos
Proteínas Nucleares/genética , Trombocitopenia/genética , Criança , Análise Mutacional de DNA , Família , Humanos , Masculino , Mutação de Sentido Incorreto , Linhagem , Trombocitopenia/diagnóstico
13.
Ann Biol Clin (Paris) ; 74(3): 299-305, 2016 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-27101632

RESUMO

We report the case of a 2 year-old boy hospitalized into the emergency room for influenza pneumonia infection. The evolution was marked by a respiratory distress syndrome, a severe hemolytic anemia, associated with thrombocytopenia and kidney failure. First, a diagnosis of hemolytic uremic syndrome (HUS) has been judiciously suggested due to the classical triad: kidney failure, hemolytic anemia and thrombocytopenia. But, strikingly, blood smears do not exhibit schizocytes, but instead ghosts and hemighosts, some characteristic features of a glucose-6-phosphate dehydrogenase deficiency. Our hypothesis has been confirmed by enzymatic dosage and molecular biology. The unusual initial aplastic feature of this anemia could be the result of a transient erythroblastopenia due to the viral agent, at the origin of the G6PD crisis on a background of a major erythrocyte anti-oxydant enzyme defect. This case of G6PD defect points out the continuously importance of the cytology, which was able to redirect the diagnosis by the hemighost and ghost detection.


Assuntos
Citodiagnóstico , Deficiência de Glucosefosfato Desidrogenase/diagnóstico , Pré-Escolar , Citodiagnóstico/métodos , Membrana Eritrocítica/patologia , Eritrócitos/patologia , Deficiência de Glucosefosfato Desidrogenase/patologia , Humanos , Masculino , Valor Preditivo dos Testes
14.
Eur J Hum Genet ; 24(8): 1124-31, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26757980

RESUMO

Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.


Assuntos
Leucemia Mielomonocítica Juvenil/genética , Mutação , Síndrome de Noonan/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas ras/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Leucemia Mielomonocítica Juvenil/patologia , Masculino , Síndrome de Noonan/patologia , Linhagem , Fenótipo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia
15.
Blood Cells Mol Dis ; 56(1): 9-22, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26603718

RESUMO

Inherited red blood cell (RBC) membrane disorders, such as hereditary spherocytosis, elliptocytosis and hereditary ovalocytosis, result from mutations in genes encoding various RBC membrane and skeletal proteins. The RBC membrane, a composite structure composed of a lipid bilayer linked to a spectrin/actin-based membrane skeleton, confers upon the RBC unique features of deformability and mechanical stability. The disease severity is primarily dependent on the extent of membrane surface area loss. RBC membrane disorders can be readily diagnosed by various laboratory approaches that include RBC cytology, flow cytometry, ektacytometry, electrophoresis of RBC membrane proteins and genetics. The reference technique for diagnosis of RBC membrane disorders is the osmotic gradient ektacytometry. However, in spite of its recognition as the reference technique, this technique is rarely used as a routine diagnosis tool for RBC membrane disorders due to its limited availability. This may soon change as a new generation of ektacytometer has been recently engineered. In this review, we describe the workflow of the samples shipped to our Hematology laboratory for RBC membrane disorder analysis and the data obtained for a large cohort of French patients presenting with RBC membrane disorders using a newly available version of the ektacytomer.


Assuntos
Deformação Eritrocítica , Membrana Eritrocítica/patologia , Testes Hematológicos/instrumentação , Esferocitose Hereditária/diagnóstico , Adolescente , Criança , Pré-Escolar , Desenho de Equipamento , Índices de Eritrócitos , Feminino , Humanos , Lactente , Masculino , Esferocitose Hereditária/patologia
16.
Nat Genet ; 47(11): 1334-40, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26457648

RESUMO

Juvenile myelomonocytic leukemia (JMML) is a rare and severe myelodysplastic and myeloproliferative neoplasm of early childhood initiated by germline or somatic RAS-activating mutations. Genetic profiling and whole-exome sequencing of a large JMML cohort (118 and 30 cases, respectively) uncovered additional genetic abnormalities in 56 cases (47%). Somatic events were rare (0.38 events/Mb/case) and restricted to sporadic (49/78; 63%) or neurofibromatosis type 1 (NF1)-associated (8/8; 100%) JMML cases. Multiple concomitant genetic hits targeting the RAS pathway were identified in 13 of 78 cases (17%), disproving the concept of mutually exclusive RAS pathway mutations and defining new pathways activated in JMML involving phosphoinositide 3-kinase (PI3K) and the mTORC2 complex through RAC2 mutation. Furthermore, this study highlights PRC2 loss (26/78; 33% of sporadic JMML cases) that switches the methylation/acetylation status of lysine 27 of histone H3 in JMML cases with altered RAS and PRC2 pathways. Finally, the association between JMML outcome and mutational profile suggests a dose-dependent effect for RAS pathway activation, distinguishing very aggressive JMML rapidly progressing to acute myeloid leukemia.


Assuntos
Redes Reguladoras de Genes/genética , Leucemia Mielomonocítica Juvenil/genética , Mutação , Complexo Repressor Polycomb 2/genética , Transdução de Sinais/genética , Proteínas ras/genética , Acetilação , Doença Aguda , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Progressão da Doença , Feminino , Histonas/metabolismo , Humanos , Lactente , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Leucemia Mielomonocítica Juvenil/metabolismo , Masculino , Metilação , Microscopia Confocal , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Complexo Repressor Polycomb 2/metabolismo , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Análise de Sequência de DNA/métodos , Análise de Sobrevida , Transcriptoma , Proteínas ras/metabolismo
17.
Ann Biol Clin (Paris) ; 73(5): 587-90, 2015 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26489818

RESUMO

A pyrimidine 5'-nucleotidase deficiency in an adult is reported. Interestingly, the P5'N-1 deficiency was associated to a polymalformative syndrome and was characterized by a chronic, pancytopenic evolution with concomitant dyserythropoiesis.


Assuntos
5'-Nucleotidase/deficiência , Anemia Hemolítica/genética , Eritrócitos Anormais/enzimologia , Humanos , Masculino , Pancitopenia/etiologia , Adulto Jovem
18.
Mol Genet Genomic Med ; 2(4): 297-312, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25077172

RESUMO

MYH9-Related Disorders are a group of rare autosomal dominant platelet disorders presenting as nonsyndromic forms characterized by macrothrombocytopenia with giant platelets and leukocyte inclusion bodies or as syndromic forms combining these hematological features with deafness and/or nephropathy and/or cataracts. They are caused by mutations in the MYH9 gene encoding the nonmuscle myosin heavy chain II-A (NMMHC-IIA). Until now, at least 49 MYH9 mutations have been reported in isolated cases or small series but only rarely in large series. We report the results of an 8-year study of a large cohort of 109 patients from 37 sporadic cases and 39 unrelated families. We have identified 43 genetic variants, 21 of which are novel to our patients. A majority, 33 (76.7%), were missense mutations and six exons were preferentially targeted, as previously published. The other alterations were three deletions of one nucleotide, one larger deletion of 21 nucleotides, and one duplication. For the first time, a substitution T>A was found in the donor splice site of intron 40 (c.5765+2T>A). Seven patients, four from the same family, had two genetic variants. The analysis of the genotype-phenotype relationships enabled us to improve the knowledge of this heterogeneous but important rare disease.

19.
J Med Genet ; 51(10): 689-97, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25097206

RESUMO

BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS. METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation. CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.


Assuntos
Leucemia Mielomonocítica Juvenil/complicações , Leucemia Mielomonocítica Juvenil/genética , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Leucemia Mielomonocítica Juvenil/mortalidade , Leucemia Mielomonocítica Juvenil/fisiopatologia , Masculino , Mutação , Síndrome de Noonan/mortalidade , Síndrome de Noonan/fisiopatologia , Estudos Prospectivos , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética
20.
Transfusion ; 54(6): 1459, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24911907
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