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1.
Br J Haematol ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710708

RESUMO

GATA2 deficiency, first described in 2011, is a bone marrow failure disorder resulting in a complex haematological and immunodeficiency syndrome characterised by cytopenias, severe infections, myelodysplasia and leukaemia. The only curative treatment is allogeneic haematopoietic stem cell transplantation (HSCT). Although knowledge on this syndrome has greatly expanded, in clinical practice many challenges remain. In particular, guidelines on optimal donor and stem cell source and conditioning regimens regarding HSCT are lacking. Additionally, genetic analysis of GATA2 is technically cumbersome and could easily result in false-negative results. With this report, we wish to raise awareness of these pitfalls amongst physicians dealing with haematological malignancies and primary immunodeficiencies.

2.
Biol Blood Marrow Transplant ; 25(9): 1786-1791, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31082473

RESUMO

Gonadal impairment is an important late effect with a significant impact on quality of life of transplanted patients. The aim of this study was to compare gonadal function after busulfan (Bu) or treosulfan (Treo) conditioning regimens in pre- and postpubertal children. This retrospective, multicenter study included children transplanted in pediatric European Society for Blood and Marrow Transplantation (EBMT) centers between 1992 and 2012 who did not receive gonadotoxic chemoradiotherapy before the transplant. We evaluated 137 patients transplanted in 25 pediatric EBMT centers. Median age at transplant was 11.04 years (range, 5 to 18); 89 patients were boys and 48 girls. Eighty-nine patients were prepubertal at transplant and 48 postpubertal. One hundred eighteen children received Bu and 19 Treo. A higher proportion of girls treated with Treo in the prepubertal stage reached spontaneous puberty compared with those treated with Bu (P = .02). Spontaneous menarche was more frequent after Treo than after Bu (P < .001). Postpubertal boys and girls treated with Treo had significantly lower luteinizing hormone levels (P = .03 and P = .04, respectively) compared with the Bu group. Frequency of gonadal damage associated with Treo was significantly lower than that observed after Bu. These results need to be confirmed in a larger population.

4.
J Allergy Clin Immunol ; 143(6): 2238-2253, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30660643

RESUMO

BACKGROUND: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT). OBJECTIVE: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics. METHODS: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure. RESULTS: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%. CONCLUSION: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy.

5.
Pediatr Blood Cancer ; 66(1): e27499, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30318730

RESUMO

BACKGROUND: Physical fitness is an important determinant of quality of life (QOL) after hematopoietic stem cell transplantation. Cardiac function can influence exercise performance. The aim of this study was to assess these factors and their interrelationship. PROCEDURE: Children underwent cardiopulmonary exercise testing (CPET) at least 1 year after hematopoietic stem cell transplantation (HSCT) and were compared with healthy controls. Systolic and diastolic heart function and left ventricle (LV) wall dimensions were measured. Health-related QOL (HR-QOL) was evaluated using PedsQL questionnaires. RESULTS: Forty-three patients performed CPET (26 boys, 13.6 ± 3.4 years, weight 45.5 ± 13.3 kg, length 152.9 ± 17.5 cm, body surface area 1.35 ± 0.28). HSCT patients had lower maximal oxygen consumption (VO2peak/kg, 34.7 ± 8.4 vs 46.3 ± 7.1 mL/kg/min, P < 0.001), shorter exercise duration (9.1 ± 2.5 vs 12.9 ± 2.6 min, P < 0.001), and lower maximal load (%Ppeak 70.8 ± 19.7 vs 102.4% ± 15.9%, P < 0.001). Echocardiography demonstrated decreased interventricular septal wall thickness (interventricular septum in diastole [IVSd] Z-value -0.64 ± 0.69, P < 0.001), and more systolic (11% of patients) and diastolic dysfunction (high E/E' Z-value 1.06 ± 1.13, P < 0.001). LV dilatation correlates with VO2max/kg (r = -0.364, P = 0.017). HR-QOL showed lower overall and emotional functioning scores (respectively, P = 0.016 and P = 0.001). Patients after anthracycline therapy have the lowest maximal exercise performance, but have no difference in QOL. Diminished exercise performance is not encountered as a QOL limitation. Total body irradiation influences the domain of psychosocial functioning. CONCLUSIONS: LV (systolic and diastolic) and right ventricle dysfunctions justify the need for thorough cardiac follow-up in children after HSCT. Lower physical fitness levels and lower HR-QOL emphasize the importance of CPET and fitness programs.


Assuntos
Aptidão Cardiorrespiratória , Ecocardiografia/métodos , Teste de Esforço/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Neoplasias/terapia , Qualidade de Vida , Função Ventricular Esquerda , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Neoplasias/patologia , Prognóstico , Estudos Prospectivos , Transplante Homólogo
6.
Front Immunol ; 9: 2544, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443258

RESUMO

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited disorders affecting one or multiple components of the innate and/or adaptive immune system. Currently, over 300 underlying genetic defects have been discovered. The most common clinical findings in patients with PIDs are infections, autoimmunity, and malignancies. Despite international efforts, the cancer risk associated with PIDs, given the heterogeneous character of this group of diseases, is difficult to estimate. The diverse underlying mechanisms of cancer in PID add another layer of complexity. Treatment of cancer within a context of PID is complicated by serious toxicities and long-term effects, including second malignancies. This review will focus on the little-known crossroad between PID and cancer genes and the value thereof for directing future research on our understanding of cancer in PID and for the identification of early cancer biomarkers in PID patients.

7.
Blood Adv ; 2(1): 49-60, 2018 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-29344584

RESUMO

Leukodystrophies (LD) are devastating inherited disorders leading to rapid neurological deterioration and premature death. Hematopoietic stem cell transplantation (HSCT) can halt disease progression for selected LD. Cord blood is a common donor source for transplantation of these patients because it is rapidly available and can be used without full HLA matching. However, precise recommendations allowing care providers to identify patients who benefit from HSCT are lacking. In this study, we define risk factors and describe the early and late outcomes of 169 patients with globoid cell leukodystrophy, X-linked adrenoleukodystrophy, and metachromatic leukodystrophy undergoing cord blood transplantation (CBT) at an European Society for Blood and Marrow Transplantation center or at Duke University Medical Center from 1996 to 2013. Factors associated with higher overall survival (OS) included presymptomatic status (77% vs 49%; P = .006), well-matched (≤1 HLA mismatch) CB units (71% vs 54%; P = .009), and performance status (PS) of >80 vs <60 or 60 to 80 (69% vs 32% and 55%, respectively; P = .003). For patients with PS≤60 (n = 20) or 60 to 80 (n = 24) pre-CBT, only 4 (9%) showed improvement. Of the survivors with PS >80 pre-CBT, 50% remained stable, 20% declined to 60 to 80, and 30% to <60. Overall, an encouraging OS was found for LD patients after CBT, especially for those who are presymptomatic before CBT and received adequately dosed grafts. Early identification and fast referral to a specialized center may lead to earlier treatment and, subsequently, to improved outcomes.

8.
J Oncol Pharm Pract ; 24(7): 537-539, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28682150

RESUMO

Pipamperon is a potent neuroleptic drug with many side effects, including prolongation of the QT interval. We report a case of a child treated for leukemia in which prolongation of the QT interval was observed. Physicians and pharmacists should be cautious for drug-drug interactions when pipamperon is prescribed, especially in combination with other QT-prolongating agents. Alternative strategies should be used whenever possible.


Assuntos
Butirofenonas/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Ondansetron/efeitos adversos , Butirofenonas/administração & dosagem , Criança , Interações de Medicamentos , Eletrocardiografia/efeitos dos fármacos , Humanos , Leucemia/tratamento farmacológico , Masculino , Ondansetron/administração & dosagem
10.
Blood Adv ; 1(24): 2236-2242, 2017 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-29296871

RESUMO

Hurler syndrome (HS) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Hematopoietic stem cell transplantation (HSCT) results in long-term survival, although with significant residual disease burden. How this residual disease affects the health-related quality of life is unknown. Therefore, we conducted a multicenter cohort study on functional and psychosocial health and compared the outcomes to normative data using the Child Health Questionnaire and Pediatric Outcomes Data Collection Instrument. Perception of care was evaluated by the Measure of Processes of Care questionnaire. Sixty-three HS patients receiving HSCT with at least 3 years of follow-up after HSCT were included. The influence of potential predictors was analyzed using linear regression analysis, and correlation analysis was performed using Spearman rank correlation. Functional health of transplanted HS patients was significantly diminished compared with normative data (median physical summary z score, -2.4 [range, -3.5 to -1.6]; median global functioning z score, -3.2 [range, -4.8 to -1.8]). Psychosocial health was comparable or only slightly reduced compared with healthy peers (median psychosocial summary z score, 0.15 [range, -0.7 to 0.8]). A higher obtained lysosomal enzyme level post-HSCT predicted for superior functional health. Overall, parents were satisfied with the care received. Functional health of transplanted HS patients appeared significantly more affected than psychosocial health. To improve functional health, the use of only noncarrier donors and striving to achieve full-donor chimerism, both resulting in higher enzyme levels, is advised. Assessing the health-related quality of life could play an important role in evaluating outcomes of HS patients receiving novel (cell) therapies, including autologous gene-transduced HSCT.

11.
Haematologica ; 102(1): 192-202, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27634199

RESUMO

The etiology of primary antibody deficiencies is largely unknown. Beside rare monogenic forms, the majority of cases seem to have a more complex genetic basis. Whereas common variable immunodeficiency has been investigated in depth, there are only a few reports on milder primary antibody deficiencies such as idiopathic primary hypogammaglobulinemia and IgG subclass deficiency. We performed flow cytometric immunophenotyping in 33 patients with common variable immunodeficiency, 23 with idiopathic primary hypogammaglobulinemia and 21 with IgG subclass deficiency, as well as in 47 asymptomatic first-degree family members of patients and 101 unrelated healthy controls. All three groups of patients showed decreased memory B- and naïve T-cell subsets and decreased B-cell activating factor receptor expression. In contrast, circulating follicular helper T-cell frequency and expression of inducible T-cell co-stimulator and chemokine receptors were only significantly altered in patients with common variable immunodeficiency. Asymptomatic first-degree family members of patients demonstrated similar, albeit intermediate, alterations in naïve and memory B- and T-cell subsets. About 13% of asymptomatic relatives had an abnormal peripheral B-cell composition. Furthermore, asymptomatic relatives showed decreased levels of CD4+ recent thymic emigrants and increased central memory T cells. Serum IgG and IgM levels were also significantly lower in asymptomatic relatives than in healthy controls. We conclude that, in our cohort, the immunophenotypic landscape of primary antibody deficiencies comprises a spectrum, in which some alterations are shared between all primary antibody deficiencies whereas others are only associated with common variable immunodeficiency. Importantly, asymptomatic first-degree family members of patients were found to have an intermediate phenotype for peripheral B- and T-cell subsets.


Assuntos
Agamaglobulinemia/diagnóstico , Doenças Assintomáticas , Imunodeficiência de Variável Comum/diagnóstico , Família , Deficiência de IgG/diagnóstico , Imunofenotipagem , Adolescente , Adulto , Agamaglobulinemia/sangue , Idoso , Idoso de 80 Anos ou mais , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise por Conglomerados , Imunodeficiência de Variável Comum/sangue , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Humanos , Deficiência de IgG/sangue , Imunoglobulinas/sangue , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Fenótipo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem
12.
Biol Blood Marrow Transplant ; 22(11): 1997-2002, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27470286

RESUMO

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for most children with osteopetrosis (OP). Timing of HSCT is critical; therefore, umbilical cord blood transplantation (UCBT) is an attractive option. We analyzed outcomes after UCBT in 51 OP children. Median age at UCBT was 6 months. Seventy-seven percent of the cord blood grafts had 0 or 1 HLA disparity with the recipient. Conditioning regimen was myeloablative (mostly busulfan-based in 84% and treosulfan-based in 10%). Antithymocyte globulin was given to 90% of patients. Median number of total nucleated and CD34+ cells infused was 14 × 107/kg and 3.4 × 105/kg, respectively. Median follow-up for survivors was 74 months. Cumulative incidence (CI) of neutrophil recovery was 67% with a median time to recovery of 23 days; 33% of patients had graft failure, 81% of engrafted patients had full donor engraftment, and 19% had mixed donor chimerism. Day 100 CI of acute graft-versus-host disease (grades II to IV) was 31% and 6-year CI of chronic graft-versus-host disease was 21%. Mechanical ventilation was required in 28%, and veno-occlusive disease was diagnosed in 16% of cases. Six-year overall survival rate was 46%. Comparative studies with other alternative donors should be performed to evaluate whether UCBT remains a valid alternative for children with OP without an HLA-matched donor.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Osteopetrose/terapia , Doadores não Relacionados , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro , Humanos , Lactente , Recém-Nascido , Masculino , Neutrófilos , Osteopetrose/mortalidade , Recuperação de Função Fisiológica , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
14.
Pediatr Allergy Immunol ; 27(1): 93-6, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26248889
15.
Blood ; 127(11): 1387-97; quiz 1518, 2016 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-26702063

RESUMO

Germline GATA2 mutations cause cellular deficiencies with high propensity for myeloid disease. We investigated 426 children and adolescents with primary myelodysplastic syndrome (MDS) and 82 cases with secondary MDS enrolled in 2 consecutive prospective studies of the European Working Group of MDS in Childhood (EWOG-MDS) conducted in Germany over a period of 15 years. Germline GATA2 mutations accounted for 15% of advanced and 7% of all primary MDS cases, but were absent in children with MDS secondary to therapy or acquired aplastic anemia. Mutation carriers were older at diagnosis and more likely to present with monosomy 7 and advanced disease compared with wild-type cases. For stratified analysis according to karyotype, 108 additional primary MDS patients registered with EWOG-MDS were studied. Overall, we identified 57 MDS patients with germline GATA2 mutations. GATA2 mutations were highly prevalent among patients with monosomy 7 (37%, all ages) reaching its peak in adolescence (72% of adolescents with monosomy 7). Unexpectedly, monocytosis was more frequent in GATA2-mutated patients. However, when adjusted for the selection bias from monosomy 7, mutational status had no effect on the hematologic phenotype. Finally, overall survival and outcome of hematopoietic stem cell transplantation (HSCT) were not influenced by mutational status. This study identifies GATA2 mutations as the most common germline defect predisposing to pediatric MDS with a very high prevalence in adolescents with monosomy 7. GATA2 mutations do not confer poor prognosis in childhood MDS. However, the high risk for progression to advanced disease must guide decision-making toward timely HSCT.


Assuntos
Fator de Transcrição GATA2/deficiência , Síndromes Mielodisplásicas/genética , Adolescente , Idade de Início , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 7/genética , Cromossomos Humanos Par 8/genética , Ensaios Clínicos Fase III como Assunto , Análise Mutacional de DNA , Surdez/genética , Feminino , Fator de Transcrição GATA2/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Síndromes de Imunodeficiência/genética , Estimativa de Kaplan-Meier , Masculino , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/patologia , Fenótipo , Prevalência , Prognóstico , Estudos Prospectivos , Viés de Seleção , Adulto Jovem
16.
Am J Med Genet A ; 167A(12): 3214-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26358756

RESUMO

VPS45 mutations cause severe congenital neutropenia (SCN). We report on a girl with SCN and neurological impairment harboring a homozygous p.E238K mutation in VPS45 (vacuolar sorting protein 45). She successfully underwent hematopoietic stem cell transplantation. Our findings delineate the phenotype and indicate a possible genotype-phenotype correlation for neurological involvement.


Assuntos
Homozigoto , Mutação/genética , Doenças do Sistema Nervoso/etiologia , Neutropenia/congênito , Proteínas de Transporte Vesicular/genética , Pré-Escolar , Feminino , Genótipo , Humanos , Doenças do Sistema Nervoso/patologia , Neutropenia/complicações , Neutropenia/genética , Neutropenia/patologia , Fenótipo , Prognóstico
17.
Blood ; 125(13): 2164-72, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25624320

RESUMO

Mucopolysaccharidosis type I-Hurler syndrome (MPS-IH) is a lysosomal storage disease characterized by multisystem morbidity and death in early childhood. Although hematopoietic cell transplantation (HCT) has been performed in these patients for more than 30 years, large studies on the long-term outcome of patients with MPS-IH after HCT are lacking. The goal of this international study was to identify predictors of the long-term outcome of patients with MPS-IH after successful HCT. Two hundred seventeen patients with MPS-IH successfully engrafted with a median follow-up age of 9.2 years were included in this retrospective analysis. Primary endpoints were neurodevelopmental outcomes and growth. Secondary endpoints included neurologic, orthopedic, cardiac, respiratory, ophthalmologic, audiologic, and endocrinologic outcomes. Considerable residual disease burden was observed in the majority of the transplanted patients with MPS-IH, with high variability between patients. Preservation of cognitive function at HCT and a younger age at transplantation were major predictors for superior cognitive development posttransplant. A normal α-l-iduronidase enzyme level obtained post-HCT was another highly significant predictor for superior long-term outcome in most organ systems. The long-term prognosis of patients with MPS-IH receiving HCT can be improved by reducing the age at HCT through earlier diagnosis, as well as using exclusively noncarrier donors and achieving complete donor chimerism.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mucopolissacaridose I/terapia , Adolescente , Adulto , Criança , Desenvolvimento Infantil , Pré-Escolar , Cognição , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Lactente , Recém-Nascido , Masculino , Mucopolissacaridose I/epidemiologia , Mucopolissacaridose I/fisiopatologia , Mucopolissacaridose I/psicologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Blood ; 124(18): 2867-71, 2014 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-25193871

RESUMO

Mutations in genes encoding proteins that are involved in mitochondrial heme synthesis, iron-sulfur cluster biogenesis, and mitochondrial protein synthesis have previously been implicated in the pathogenesis of the congenital sideroblastic anemias (CSAs). We recently described a syndromic form of CSA associated with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Here we demonstrate that SIFD is caused by biallelic mutations in TRNT1, the gene encoding the CCA-adding enzyme essential for maturation of both nuclear and mitochondrial transfer RNAs. Using budding yeast lacking the TRNT1 homolog, CCA1, we confirm that the patient-associated TRNT1 mutations result in partial loss of function of TRNT1 and lead to metabolic defects in both the mitochondria and cytosol, which can account for the phenotypic pleiotropy.


Assuntos
Anemia Sideroblástica/congênito , Anemia Sideroblástica/genética , Deficiências do Desenvolvimento/complicações , Febre/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Síndromes de Imunodeficiência/complicações , Mutação/genética , RNA Nucleotidiltransferases/genética , Alelos , Anemia Sideroblástica/complicações , Anemia Sideroblástica/enzimologia , Deficiências do Desenvolvimento/genética , Febre/genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/enzimologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética
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