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1.
Am J Hum Genet ; 108(7): 1301-1317, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34038740

RESUMEN

Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.


Asunto(s)
Encefalitis/genética , Enfermedades Mitocondriales/genética , Animales , Evolución Biológica , Sistemas CRISPR-Cas , Línea Celular , Encefalitis/mortalidad , Femenino , Genes Recesivos , Glucógeno/metabolismo , Humanos , Inflamación/genética , Masculino , Proteínas de la Membrana/genética , Enfermedades Mitocondriales/mortalidad , Linaje , Convulsiones/genética , Convulsiones/mortalidad , Pez Cebra/genética
2.
Lupus ; 30(12): 1983-1990, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34459313

RESUMEN

Introduction: Systemic lupus erythematosus (SLE) may present with features of several systems, including hematological manifestations. In this study, we aimed to evaluate the characteristics of hematological involvement and assess possible associations and correlations in pediatric SLE patients. Method: This is a retrospective multi-center study. The medical records of pediatric SLE patients followed between January 2000 and June 2020 were analyzed. All children fulfilled the criteria of the Systemic Lupus International Collaborating Clinics. Results: The study included 215 children with SLE, 118 of whom had hematological manifestations. Concomitant renal involvement and low C3 levels were significantly more frequent in patients with hematological involvement (p = 0.04, p = 0.008, respectively). Also, anti-cardiolipin, anti-beta-2-glycoprotein I (anti-ß2 GP1), and anti-Sm antibody positivity, and the presence of lupus anticoagulant were more common in the group with hematological findings (p = 0.001 for anti-cardiolipin antibody positivity and p < 0.001 for the positivity of anti-ß2 GP1 antibody, anti-Sm antibody, and lupus anticoagulant). The most common hematologic abnormality was anemia (n = 88, 74.5%), with autoimmune hemolytic anemia constituting the majority (n = 40). Corticosteroids followed by IVIG were the mainstay of treatment. In patients resistant to corticosteroid and IVIG treatments, the most preferred drug was rituximab. Low levels of C3, high SLEDAI score, high incidence of renal involvement, and positive antiphospholipid antibodies were associated with hematological involvement in the univariate analysis. The presence of antiphospholipid antibodies and high SLEDAI score were independently associated with hematological involvement in multivariate analysis (OR: 4.021; 95% CI: 2.041-7.921; p < 0.001 and OR: 1.136; 95% CI: 1.065-1.212; p < 0.001). Conclusion: Hematological abnormalities are frequently encountered in pediatric SLE. Positive antiphospholipid antibodies and high SLEDAI scores were associated with hematological involvement.


Asunto(s)
Anemia Hemolítica Autoinmune/epidemiología , Lupus Eritematoso Sistémico/complicaciones , Administración Oral , Adolescente , Corticoesteroides/administración & dosificación , Corticoesteroides/uso terapéutico , Anemia Hemolítica Autoinmune/tratamiento farmacológico , Anticuerpos Antifosfolípidos , Niño , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Inmunoglobulinas Intravenosas , Inhibidor de Coagulación del Lupus , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/epidemiología , Masculino , Estudios Retrospectivos
3.
Proc Natl Acad Sci U S A ; 115(20): 5241-5246, 2018 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-29712865

RESUMEN

BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for BRCA1 truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for BRCA1 truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in BRCA1 exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5' of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame BRCA1 message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N- and C-terminal sequences. These patients extend the range of BRCA1-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene.


Asunto(s)
Empalme Alternativo , Proteína BRCA1/genética , Neoplasias de la Mama/genética , Codón sin Sentido , Homocigoto , Neoplasias Ováricas/genética , Adolescente , Adulto , Neoplasias de la Mama/patología , Niño , Preescolar , Femenino , Humanos , Neoplasias Ováricas/patología , Linaje
4.
Pediatr Blood Cancer ; 67(12): e28722, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32970355

RESUMEN

BACKGROUND: Brain atrophy, abnormal pituitary morphology, corpus callosum, and posterior fossa abnormalities have been described in patients with Fanconi anemia (FA). We aimed to provide an overview of cranial neuroimaging findings and to evaluate the clinical implications in FA patients. PROCEDURE: Cranial magnetic resonance imaging (MRI) studies of 34 patients with FA were retrospectively evaluated, and patients' clinical data were correlated with the imaging findings. RESULTS: The patients' median age was 17.6 (range, 3.9-28) years. At least one pathological brain imaging finding was demonstrated in 22 (65%) patients. These findings included corpus callosum abnormalities and other related supratentorial malformations in nine, pituitary abnormalities in eight, craniovertebral junction and posterior fossa abnormalities in eight, vascular lesions in six, and intracerebral calcifications in two patients. Among the 22 patients who had abnormal cranial MRI findings, six (27%) had mild to moderate intellectual disability (ID), three (14%) had epilepsy, one (5%) had mild hearing loss, and one patient (5%) had hemiplegia. Among these 34 patients, 14 (41%) were transfusion dependent. There was no significant difference between patients with congenital and acquired neuroimaging findings and patients with normal neuroimaging regarding transfusion dependency. CONCLUSIONS: Acquired abnormalities in brain tissue, such as white matter intensity changes, white matter T2 hyperintense discrete foci, or infarcts along with congenital abnormalities, were identified in this study. Variable abnormal brain imaging findings in FA patients, although some were not associated with clinical neurological manifestations, suggest that brain imaging could be part of screening in FA.


Asunto(s)
Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/etiología , Anemia de Fanconi/complicaciones , Neuroimagen/métodos , Adolescente , Adulto , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pronóstico , Estudios Retrospectivos , Adulto Joven
5.
J Pediatr Hematol Oncol ; 42(6): e434-e439, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32324696

RESUMEN

Hemophagocytic lymphohistiocytosis (HLH) is characterized by uncontrolled and excessive immune responses with high mortality. We aimed to define mortality-related parameters in HLH secondary to primary immunodeficiency (PID). A total of 28 patients with HLH between the years 2013 and 2017 were enrolled in the study. The patients were evaluated in 2 groups including PID with hypopigmentation (n=7) (Chédiak-Higashi syndrome [CHS] and Griscelli syndrome type 2 [GS2]) and other PIDs (n=21). The median age of the study population was 23 (4.3 to 117.0) months at the time of the diagnosis of HLH. Central nervous system involvement was recorded in 7 (GS2/CHS patients [n=4], other PIDs [n=3], P=0.026), and death was observed in 9 patients (GS2/CHS patients [n=1], other PIDs [n=8], P=0.371). Five patients (3 GS2/CHS and 2 other PID patients) underwent hematopoietic stem cell transplantation. Low serum albumin level was the only variable associated with the mortality and albumin levels less than the cut-off value of 3.07 g/dL increased mortality 5.8 times in patients with HLH secondary to PID. We presented a single-center experience consisting of patients with HLH secondary to PID with a mortality rate of 32.1%. Hypoalbuminemia was the only risk factor to increase the overall mortality rate of HLH.


Asunto(s)
Síndrome de Chediak-Higashi/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Linfohistiocitosis Hemofagocítica/mortalidad , Piebaldismo/mortalidad , Enfermedades de Inmunodeficiencia Primaria/mortalidad , Síndrome de Chediak-Higashi/complicaciones , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/etiología , Linfohistiocitosis Hemofagocítica/patología , Linfohistiocitosis Hemofagocítica/terapia , Masculino , Piebaldismo/complicaciones , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Pronóstico , Factores de Riesgo , Tasa de Supervivencia
6.
Hemoglobin ; 44(2): 137-138, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32400222

RESUMEN

Hb H disease is a moderate to severe form of α-thalassemia (α-thal). Patients with Hb H disease may become symptomatic, especially during infections and pregnancy, and may require transfusions. Herein, we present a 16-year-old female with Hb H disease who was initially diagnosed during adolescent pregnancy and was found to carry the -α3.7/-(α)20.5 deletions. The relatively mild presentation of this case highlights the milder phenotypic consequences of deletional α mutations. The case describes the screening and management of pregnancy with Hb H disease. Additionally, this case demonstrates that screening of some undiagnosed inherited blood disorders is important during pregnancy.


Asunto(s)
Hemoglobina H/análisis , Complicaciones Hematológicas del Embarazo/diagnóstico , Talasemia alfa/diagnóstico , Adolescente , Femenino , Eliminación de Gen , Hemoglobina H/genética , Humanos , Embarazo , Complicaciones Hematológicas del Embarazo/sangre , Complicaciones Hematológicas del Embarazo/genética , Globinas alfa/análisis , Globinas alfa/genética , Talasemia alfa/sangre , Talasemia alfa/genética
8.
J Clin Immunol ; 39(7): 726-738, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31432443

RESUMEN

INTRODUCTION: Autosomal recessively inherited lipopolysaccharide-responsive beige-like anchor (LRBA) protein deficiency was shown to be responsible for different types of inborn errors of immunity, such as common variable immunodeficiency (CVID) and autoimmune lymphoproliferative syndrome (ALPS). The aim of this study was to compare patients with LRBA-related ALPS and LRBA-related CVID, to describe their clinical and laboratory phenotypes, and to prepare an algorithm for their diagnosis and management. METHODS: Fifteen LRBA-deficient patients were identified among 31 CVID and 14 possible ALPS patients with Western blotting (WB), primary immunodeficiency disease (PIDD) gene, next-generation panel screening (NGS), and whole exome sequencing (WES). RESULTS: The median age on admission and age of diagnosis were 7 years (0.3-16.5) and 11 years (5-44), respectively. Splenomegaly was seen in 93.3% (14/15) of the patients on admission. Splenectomy was performed to 1/5. Recurrent upper respiratory tract infections (93.3% (14/15)), autoimmune cytopenia (80% (12/15)), chronic diarrhea (53.3% (8/15)), lower respiratory tract infections (53.3% (8/15)), lymphoma (26.6% (4/15)), Evans syndrome (26.6% (4/15)), and autoimmune thyroiditis (20% (3/15)) were common clinical findings and diseases. Lymphopenia (5/15), intermittant neutropenia (4/15), eosinophilia (4/15), and progressive hypogammaglobulinemia are recorded in given number of patients. Double negative T cells (TCRαß+CD4-CD8-) were increased in 80% (8/10) of the patients. B cell percentage/numbers were low in 60% (9/15) of the patients on admission. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Thelper (Th) cells, markedly increased effector memory/effector memory RA+ (TEMRA) Th were documented. Large PD1+ population, increased memory, and enlarged follicular helper T cell population in the CD4+ T cell compartment was seen in one of the patients. Most of the deleterious missense mutations were located in the DUF1088 and BEACH domains. Interestingly, one of the two siblings with the same homozygous LRBA defect did not have any clinical symptom. Hematopoietic stem cell transplantation (HSCT) was performed to 7/15 (46.6%) of the patients. Transplanted patients are alive and well after a median of 2 years (1-3). In total, one patient died from sepsis during adulthood before HSCT. CONCLUSION: Patients with LRBA deficiency may initially be diagnosed as CVID or ALPS in the clinical practice. Progressive decrease in B cells as well as IgG in ALPS-like patients and addition of IBD symptoms in the follow-up should raise the suspicion for LRBA deficiency. Decreased switched memory B cells, decreased naive and recent thymic emigrant (RTE) Th cells, and markedly increased effector memory/effector memory RA+ Th cells (TEMRA Th) cells are important for the diagnosis of the patients in addition to clinical features. Analysis of protein by either WB or flow cytometry is required when the clinicians come across especially with missense LRBA variants of uncertain significance. High rate of malignancy shows the regulatory T cell's important role of immune surveillance. HSCT is curative and succesful in patients with HLA-matched family donor.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/deficiencia , Síndrome Linfoproliferativo Autoinmune/diagnóstico , Síndrome Linfoproliferativo Autoinmune/etiología , Inmunodeficiencia Variable Común/diagnóstico , Inmunodeficiencia Variable Común/etiología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adolescente , Adulto , Síndrome Linfoproliferativo Autoinmune/complicaciones , Síndrome Linfoproliferativo Autoinmune/terapia , Biomarcadores , Niño , Preescolar , Terapia Combinada , Inmunodeficiencia Variable Común/complicaciones , Inmunodeficiencia Variable Común/terapia , Enfermedades Transmisibles/etiología , Femenino , Estudios de Asociación Genética/métodos , Sitios Genéticos , Trasplante de Células Madre Hematopoyéticas , Humanos , Inmunofenotipificación , Masculino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Resultado del Tratamiento , Secuenciación del Exoma , Adulto Joven
9.
Eur J Haematol ; 102(2): 123-130, 2019 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-30300449

RESUMEN

OBJECTIVES: To evaluate the long-term efficacy and safety of deferasirox therapy in a large observational cohort of children with transfusion-dependent thalassemia (TDT) and sickle cell anemia (SCA) in Turkey. METHODS: This was a multicenter, prospective cohort study including TDT and SCA patients aged 2-18 years with iron overload (≥100 mL/kg of pRBC or a serum ferritin [SF] level >1000 µg/L) receiving deferasirox. Patients were followed for up to 3 years according to standard practice. RESULTS: A total of 439 patients were evaluated (415 [94.5%] TDT, 143 [32.6%] between 2 and 6 years). Serum ferritin levels consistently and significantly decreased across 3 years of deferasirox therapy from a median of 1775.5 to 1250.5 µg/L (P < 0.001). Serum ferritin decreases were noted in TDT (1804.9 to 1241 µg/L), SCA (1655.5 to 1260 µg/L), and across age groups of 2-6 years (1971.5 to 1499 µg/L), 7-12 years (1688.5 to 1159.8 µg/L), and 13-18 years (1496.5 to 1107 µg/L). Serum ferritin decreases were also noted for all deferasirox dose groups but only significant in patients with doses ≥30 mg/kg/d (n = 120, -579.6 median reduction, P < 0.001). Only 9 (2%) patients had adverse events suspected to be related to deferasirox. Serum creatinine slightly increased but remained within the normal range. CONCLUSIONS: Deferasirox has long-term efficacy and safety in children with TDT and SCA, although higher doses (≥30 mg/kg/d) may be required to achieve iron balance.


Asunto(s)
Anemia de Células Falciformes/complicaciones , Deferasirox/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Talasemia/complicaciones , Adolescente , Anemia de Células Falciformes/terapia , Biomarcadores , Transfusión Sanguínea , Niño , Preescolar , Estudios de Cohortes , Deferasirox/administración & dosificación , Deferasirox/efectos adversos , Femenino , Ferritinas/sangre , Ferritinas/metabolismo , Humanos , Hierro/sangre , Hierro/metabolismo , Quelantes del Hierro/administración & dosificación , Quelantes del Hierro/efectos adversos , Sobrecarga de Hierro/metabolismo , Masculino , Talasemia/terapia , Resultado del Tratamiento , Turquía
10.
J Pediatr Hematol Oncol ; 41(3): 243-246, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30339652

RESUMEN

A unique consanguineous family with 2 genomic instability disorders, Fanconi anemia and ataxia telangiectasia, revealed exceptional combinations of null mutations in the FANCA and ATM genes. Two siblings with Fanconi anemia had novel homozygous consecutive microdeletions (c.1361-1370delCCTCCTTTGG, c.1374delC) adjoined to upstream 65 nucleotide direct tandem repeats and deletion hotspot motifs in the FANCA gene. The sibling with ataxia telangiectasia revealed a homozygous p.Arg2993Stop (c.8977C>T) null mutation in the ATM gene. All patients were also heterozygous for the opposite mutations without any additional clinical or laboratory manifestations. Double heterozygote parents did not present any clinical symptoms suggestive of the 2 disorders.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/genética , Ataxia Telangiectasia/genética , Proteína del Grupo de Complementación A de la Anemia de Fanconi/genética , Anemia de Fanconi/genética , Femenino , Heterocigoto , Homocigoto , Humanos , Masculino , Eliminación de Secuencia , Hermanos
11.
Minerva Pediatr ; 71(5): 449-454, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26200522

RESUMEN

BACKGROUND: The purpose of this study was to compare the effectiveness of different oral iron preparations in children with iron deficiency anemia (IDA). METHODS: Sixty children with IDA, aged between 6 months and 180 months, were randomly assigned into three treatment groups. Group I included children with IDA who received ferrous sulfate (Fe-S); Group II included children receiving iron polymaltose complexes (Fe-OH-PM), and Group III included children receiving a single preparation of combined iron and zinc (Fe-Zn). The effect of different iron preparations were evaluated and compared. The duration of treatment was 8 weeks. Hemoglobin (Hgb) levels, as well as other hematological parameters were determined at admission and the first, fourth, and eighth weeks of the treatment. RESULTS: The Hgb levels of patients in all three groups were statistically higher in the fourth (P=0.001) and eighth (P<0.001) weeks compared to baseline; although there was no difference between the groups at the end of the treatment period (P>0.05). CONCLUSIONS: Our results indicate that, Fe-OH-PM and Fe-Zn preparations may also be preferred as a choice like Fe-S for treatment of children with IDA.


Asunto(s)
Anemia Ferropénica/tratamiento farmacológico , Compuestos Férricos/administración & dosificación , Compuestos Ferrosos/administración & dosificación , Zinc/administración & dosificación , Administración Oral , Adolescente , Niño , Preescolar , Femenino , Hematínicos/administración & dosificación , Hemoglobinas/metabolismo , Humanos , Lactante , Masculino , Resultado del Tratamiento
12.
Haematologica ; 103(2): 231-236, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29146706

RESUMEN

Familial hemophagocytic lymphohistiocytosis is an autosomal recessive, life-threatening condition characterized by defective immune response. A retrospective analysis was performed on 57 patients diagnosed with familial hemophagocytic lymphohistiocytosis at Hacettepe University Pediatric Hematology Department, Ankara, Turkey. Mutation analysis was performed on 37 patients, and of these: 11 had UNC13D, 10 had PRF1 and 3 had STX11 gene mutation. Of these patients, 44% were found to have central nervous system involvement on admission and spinal cord involvement was also seen in 5 patients. Remission was achieved in 24 patients with the treatment, in a median time of 76 days (min-max: 15-705 days). Time to remission was prolonged 3.1 times in patients with a ferritin level 1500 mg/dL or more. When patients were grouped according to age [Group 1 (≤ 2 years), Group 2 (>2 years)]; patients in Group 1 had higher ferritin and aspartate aminotransferase levels but lower fibrinogen levels. The 5-year survival rate was also lower in Group 1. When patients in Group 1 were divided into two sub-groups according to hepatic involvement, the 5-year survival rate of patients who had hepatic involvement was significantly lower than those patients without hepatic involvement (0.7%, 27%, respectively) (P=0.002). The 5-year survival rate of patients who underwent hematopoietic stem cell transplantation was significantly higher than the patients who didn't (44%, 16%, respectively) (P=0.02). In conclusion, age two years and under, ferritin level above 1500 mg/dL, spinal cord or hepatic involvement should be considered as poor prognostic factors in familial hemophagocytic lymphohistiocytosis.


Asunto(s)
Linfohistiocitosis Hemofagocítica/patología , Adolescente , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/terapia , Niño , Preescolar , Femenino , Ferritinas/sangre , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Hepatopatías/diagnóstico , Hepatopatías/terapia , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/mortalidad , Linfohistiocitosis Hemofagocítica/terapia , Masculino , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Enfermedades de la Médula Espinal/diagnóstico , Enfermedades de la Médula Espinal/terapia , Tasa de Supervivencia
13.
J Assist Reprod Genet ; 35(12): 2149-2154, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30362058

RESUMEN

PURPOSE: Vanished twin (VT) has been associated with poor perinatal outcomes. Our research aimed to investigate the outcomes of pregnancies with vanished twin and its possible association with methylenetetrahydrofolate reductase (MTHFR) polymorphisms. METHODS: This study consisted of 30 of 38 VT pregnancies (group 1, VT group), 109 singletons (group 2), 70 spontaneous twins (group 3), and 101 in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) twins (group 4). RESULTS: Most patients in group 1 (28/30) were tested for MTHFR genes (C677T or A1298C polymorphisms). Eight of the 38 pregnancies with VT (21.1%) resulted in miscarriage. The prevalence of "2 or more pregnancy losses" in the "obstetric history" in group 1 was higher (23.3%) than those in the other groups (p = 0.007, χ2 = 17.8). The allelic frequencies of MTHFR 677 and MTHFR 1298 in group 1 were 0.268 and 0.429, respectively (higher than those in healthy population). The median birthweights in groups 1, 2, 3, and 4 were 2940, 3200, 2300, and 2095 g, respectively. The prevalence of respiratory distress syndrome was significantly higher in the IVF/ICSI twin pregnancy group (p < 0.001, χ2 = 21.2). Early pregnancy loss and the presence of "2 or more miscarriages" in the obstetric history of pregnancies with VT were more frequent. CONCLUSION: The coincidence of VT and MTHFR polymorphisms might play an incidental or factual role in this connection.


Asunto(s)
Estudios de Asociación Genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Resultado del Embarazo/genética , Embarazo Gemelar/genética , Aborto Espontáneo/genética , Aborto Espontáneo/fisiopatología , Adulto , Femenino , Fertilización In Vitro , Frecuencia de los Genes/genética , Humanos , Polimorfismo de Nucleótido Simple/genética , Embarazo , Complicaciones del Embarazo/genética , Complicaciones del Embarazo/fisiopatología , Resultado del Embarazo/epidemiología , Embarazo Gemelar/fisiología , Inyecciones de Esperma Intracitoplasmáticas , Gemelos/genética
14.
Hemoglobin ; 42(2): 113-116, 2018 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30200834

RESUMEN

Peripheral neuropathy is one of the complications of ß-thalassemia (ß-thal) that has been investigated in limited reports. We aimed to detect the rate of peripheral neuropathy and risk factors for neuropathy development in patients with ß-thal. The study was performed in patients with ß-thal intermedia (ß-TI) or ß-thal major (ß-TM). Prospective electrophysiological studies were achieved via standard procedures. A total of 27 patients were enrolled in the study. Electrophysiological studies for both motor and sensory nerves were within normal range. In motor nerve studies, delayed peroneal nerve latency was found in patients with high ferritin levels, increased ulnar nerve amplitude was detected in patients ≥20 years old, and increased tibial nerve amplitude was seen in patients with low copper levels. We could not show peripheral neuropathy in our patients. Increased ferritin level, older age, and copper deficiency may cause mild changes in electrophysiological studies of motor nerves.


Asunto(s)
Electrofisiología/métodos , Quelantes del Hierro/farmacología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Talasemia beta/complicaciones , Adulto , Factores de Edad , Cobre/metabolismo , Ferritinas/metabolismo , Humanos , Persona de Mediana Edad , Nervio Peroneo , Estudios Prospectivos , Nervio Tibial , Nervio Cubital , Adulto Joven
15.
Pediatr Transplant ; 21(3)2017 May.
Artículo en Inglés | MEDLINE | ID: mdl-28211259

RESUMEN

The use of extended criteria donors who might have previously been deemed unsuitable is an option to increase the organ supply for transplantation. This report presents a pediatric case of a successful liver transplantation from a donor with ß-thalassemia intermedia. A patient, 6-year-old female, with a diagnosis of cryptogenic liver cirrhosis underwent deceased donor liver transplantation from a thalassemic donor. Extreme hyperferritinemia was detected shortly after transplantation. The most probable cause of hyperferritinemia was iron overload secondary to transplantation of a hemosiderotic liver. Hepatocellular injury due to acute graft rejection might have contributed to elevated ferritin levels by causing release of stored iron from the hemosiderotic liver graft. Iron chelation and phlebotomy therapies were started simultaneously in the early postoperative period to avoid iron-related organ toxicity and transplant failure. Follow-up with monthly phlebotomies after discharge yielded a favorable outcome with normal transplant functions. Thalassemia intermedia patients can be candidates of liver donors to decrease pretransplant waitlist mortality. After transplantation of a hemosiderotic liver, it is important to monitor the recipient in terms of iron overload and toxicity. Early attempts to lower iron burden including chelation therapy and/or phlebotomy should be considered to avoid organ toxicity and transplant failure.


Asunto(s)
Sobrecarga de Hierro/diagnóstico , Cirrosis Hepática/congénito , Cirrosis Hepática/cirugía , Trasplante de Hígado , Talasemia beta , Quelantes/química , Terapia por Quelación/métodos , Niño , Contraindicaciones , Deferoxamina/uso terapéutico , Femenino , Ferritinas/sangre , Humanos , Hierro/sangre , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/terapia , Selección de Paciente , Flebotomía , Donantes de Tejidos
16.
J Pediatr Hematol Oncol ; 39(8): e504-e507, 2017 11.
Artículo en Inglés | MEDLINE | ID: mdl-28731923

RESUMEN

With improvements in molecular diagnostic methods, report of Human bocavirus (HBoV) as an etiologic agent in many studies on viral respiratory and gastrointestinal infections has been increasing. Two pediatric patients who presented with secondary hemophagocytic lymphohistiocytosis were examined for etiologic causes, including viruses. Whole bacterial and fungal cultures and viral serological studies were negative. Viral polymerase chain reaction of nasopharyngeal secretions showed HBoV. One was successfully treated with intravenous immunoglobulins, whereas the other died with multiorgan failure. Here we report 2 pediatric patients with secondary hemophagocytic lymphohistiocytosis and detection of HBoV as the sole agent, predicting an association.


Asunto(s)
Bocavirus Humano , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/etiología , Infecciones por Parvoviridae/complicaciones , Biomarcadores , Médula Ósea/patología , Preescolar , Exantema/patología , Resultado Fatal , Femenino , Bocavirus Humano/genética , Humanos , Inmunoglobulinas Intravenosas/uso terapéutico , Lactante , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Masculino , Infecciones por Parvoviridae/diagnóstico , Infecciones por Parvoviridae/virología , Reacción en Cadena de la Polimerasa , Resultado del Tratamiento
17.
Transfus Apher Sci ; 56(4): 539-543, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28818403

RESUMEN

OBJECTIVES: Iron is taken into enterocytes at the duodenum via apical divalent metal-ion transporter 1 protein. Besides iron, divalent metal-ion transporter 1 also transports other divalent metals. We aimed to investigate blood heavy metal levels in patients with ineffective erythropoiesis. METHODS: Blood levels of heavy metals including Pb, Al, Cd, Cr, Co, Cu, and Zn were measured in patients with thalassemia major (TM), thalassemia intermedia (TI), congenital dyserythropoietic anemia (CDA), and age- and sex-matched healthy controls. RESULTS: Blood samples were obtained from 68 patients (51 patients with TM, 8 with TI, 9 with CDA), and a control group that included 65 volunteers. Patients with TM were found to have lower Al, Pb, and Zn, and higher Cd levels compared with the control group. The patients treated with deferasirox were further analyzed and Pb and Zn levels were found lower compared with the control group. DISCUSSION: Patients with TM had tendency to have elevated levels of plasma cadmium; however, the median level was not at a toxic level. Increased metal-ion transporter 1 activity may cause heavy metal accumulation, but deferasirox chelation may be protective against heavy metals besides iron.


Asunto(s)
Anemia Diseritropoyética Congénita/sangre , Eritropoyesis , Metales Pesados/sangre , Talasemia beta/sangre , Adolescente , Adulto , Anemia Diseritropoyética Congénita/tratamiento farmacológico , Benzoatos/administración & dosificación , Niño , Preescolar , Deferasirox , Femenino , Humanos , Masculino , Triazoles/administración & dosificación , Talasemia beta/tratamiento farmacológico
18.
Br J Haematol ; 172(6): 958-65, 2016 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-26771086

RESUMEN

Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift ß(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins.


Asunto(s)
Enfermedades en Gemelos/genética , Mutación del Sistema de Lectura , Talasemia beta/genética , Proteínas Portadoras/genética , Femenino , Hemoglobina Fetal/análisis , Hemoglobina Fetal/genética , Genes myb , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Proteínas Represoras , Gemelos Dicigóticos/genética , Adulto Joven
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