Enfermedad por hemoglobina H: primer caso de dobles heterocigotos hemoglobina Constant Spring / Sudeste Asiático en Costa Rica / Hemoglobin H disease: first case of double heterozygous hemoglobin Constant Spring / Southeast Asian in Costa Rica

Resumen La enfermedad por hemoglobina H es un cuadro clínico que se presenta en las alfa talasemias, las cuales son enfermedades que cursan con anemia microcítica hipocrómica, debidas principalmente a deleciones en el gen de alfaglobina, lo que disminuye la producción de la cadena de alfa globina y promueve la formación de variantes de hemoglobina. Cuando se detectan variantes de hemoglobina en las alfa talasemias, por lo general, se debe a genotipos homocigotas o dobles heterocigotas para mutaciones y deleciones del gen de alfa globina coheredadas. En este artículo se describe el primer caso en Costa Rica, de dos hermanos con enfermedad por hemoglobina H, que fenotípicamente presentaron las variantes de hemoglobina H y hemoglobina Constant Spring en el análisis electroforético de la hemoglobina, y cuyo análisis molecular del gen de alfa globina detectó tanto la deleción sudeste asiático como la mutación para hemoglobina Constant Spring, siendo diagnosticados como dobles heterocigotos por alfa talasemia (genotipo --SEA/ααCS).

Abstract Hemoglobin H disease occurs in patients with alpha thalassemia, diseases associated with hypochromic microcytic anemia, mainly due to deletions in the alpha globin gene, which decreases the production of the alpha globin chain and promotes the formation of hemoglobin variants. When hemoglobin variants are detected in alpha thalassemias it is usually due to homozygoys or doublé heterozygous genotypes, for mutations and deletions of the alpha globin gene. This article describes the first case in Costa Rica of two siblings with hemoglobin H disease, who phenotypically presented the hemoglobin H and Constant Spring hemoglobin variants in the electrophoretic analysis of the hemoglobin, and whose molecular DNA analysis of the alpha globin gene detected both, the Southeast Asian deletion and the mutation for Constant Spring Hemoglobin, being diagnosed as compound heterozygous for alpha thalassemia (genotipe --SEA/ααCS).

Evaluation of Thalassaemia Screening Tests in the Antenatal and Non-Antenatal Populations in Singapore

INTRODUCTION@#Haemoglobinopathy testing is performed for carrier screening and evaluation of microcytic anaemia. We evaluated the effectiveness of thalassaemia screening tests at our institution and suggest ways of improving the testing algorithm.@*MATERIALS AND METHODS@#A total of 10,084 non-antenatal and 11,364 antenatal samples with alkaline gel electrophoresis (AGE), capillary electrophoresis (CE), haemoglobin H (HbH) inclusion test, mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV) were retrospectively reviewed. A subgroup of 187 samples with genetic testing was correlated with HbH inclusions and MCH/ MCV. The effect of iron deficiency on percentage hemoglobin A2 (HbA2) was studied.@*RESULTS@#HbH inclusion test showed low sensitivity of 21.43% for α-thalassaemia mutations but higher sensitivity of 78.95% for deletion. By receiver operating characteristic (ROC) analysis, MCH ≤28 pg or MCV ≤80 fl for non-antenatal samples and MCH ≤27 pg or MCV ≤81 fl for antenatal samples had >98% sensitivity for HbH inclusions. Above these thresholds, the probability that HbH inclusions would be absent was 99%). MCH ≥28 pg had 100% sensitivity (95% CI 95.63%-100%) for α-thalassaemia mutations and 97.68% calculated NPV in the antenatal population. Detection of haemoglobin variants by CE correlated highly with AGE (99.89% sensitivity, 100% specificity). Severe iron deficiency reduced HbA2 in hemoglobin ( <0.001) and α-thalassaemia ( = 0.0035), but not in β-thalassaemia.@*CONCLUSION@#MCH/MCV thresholds have adequate sensitivity for α-thalassaemia in the antenatal population, and genotyping plays an important role as HbH inclusion test shows low sensitivity. CE without AGE, may be used as initial screening for haemoglobin variants. Our study provides contemporary data to guide thalassaemia screening algorithms in Singapore.

Serum level of soluble transferrin receptor in children with hemoglobin H disease / 中国当代儿科杂志

OBJECTIVE@#To investigate the serum level of soluble transferrin receptor (sTfR) and its association with the degree of anemia in children with hemoglobin H (HbH) disease.@*METHODS@#A total of 55 children with HbH disease were enrolled as the HbH group, and 30 healthy children were enrolled as the control group. The HbH group was further divided into a deletional HbH disease group and a non-deletional HbH disease group. A retrospective analysis was performed for hematological parameters and serum sTfR level in all groups.@*RESULTS@#Of the 55 children with HbH disease, 39 had deletional HbH disease and 16 had non-deletional HbH disease. Compared with the control group, the deletional and non-deletional HbH disease groups had significantly lower hemoglobin (Hb), mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) and a significantly higher serum level of sTfR. Compared with the deletional HbH disease group, the non-deletional HbH disease group had significantly lower red blood cell count (RBC) and Hb level and significantly higher MCV, MCH, and serum sTfR level. In children with HbH disease, serum sTfR level was negatively correlated with RBC and Hb level (r=-0.739 and -0.667 respectively, P<0.05) and positively correlated with MCV and MCH (r=0.750 and 0.434 respectively, P<0.05).@*CONCLUSIONS@#Serum sTfR level is associated the degree of anemia in children with HbH disease, and sTfR may be a target for the treatment of HbH disease.

Genotypes and clinical features of 595 children with HbH disease in Guangxi, China / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the genotypes and clinical features of children with HbH disease in Guangxi Zhuang Autonomous Region, China.</p><p><b>METHODS</b>A total of 595 children from Guangxi were recruited. Single-tube multiplex polymerase chain reaction combined with agarose gel electrophoresis, as well as reverse dot blotting, were performed to detect the three α-globin gene deletion mutations (--(SEA), -α(3.7), and -α(4.2)) and three non-deletion mutations (Hb Westmead, Hb Constant Spring, and Hb Quong Sze) which are common in the Chinese population.</p><p><b>RESULTS</b>Among the 595 cases, five common genotypes were identified, which were --(SEA)/-α(3.7) (232 cases), --(SEA)/α(CS)α (174 cases), --(SEA)/-α(4.2) (122 cases), --(SEA)/α(WS)α (35 cases), and --(SEA)/α(QS)α (24 cases). The genotype of THAI deletion associated with α-thalassemia-2 was detected in eight cases. Six β-mutations including CD41-42, CD17-28, CD26, IVS-II-654, IVS-I-1, and CD27-28 were identified in 23 cases. All children with HbH disease had microcytic hypochromic anemia; children with HbH-CS disease had the most severe anemia, and those with HbH-WS disease had the mildest anemia.</p><p><b>CONCLUSIONS</b>Deletional HbH disease is the main type in children with HbH disease in Guangxi, and some patients also have mild beta-thalassemia. Non-deletional HbH disease shows more severe phenotype than deletional HbH disease.</p>

Glomerular filtration rate is altered in children with sickle cell disease: a comparison between Hb SS and Hb SC

BACKGROUND Renal failure is common among older patients with sickle cell disease; this is preceded by subclinical glomerular hyperfiltration. Data about renal function of adults with sickle cell disease have been reported, but data on children is scarce, especially when comparing heterozygotic and homozygotic patients. OBJECTIVE The goal of this study was to investigate the glomerular filtration rate of heterozygotic and homozygotic children with sickle cell disease. METHODS The glomerular filtration rate of 11 children with sickle cell disease [7 homozygotic (SS) and 4 heterozygotic (SC)] with a mean age of 11 years (standard deviation: ± 5 years) was evaluated using standard laboratory techniques. Results are presented as descriptive analysis. RESULTS Our results suggest that glomerular hyperfiltration is present in children with sickle cell disease; this is more evident in homozygotic than heterozygotic children. CONCLUSION There is evidence of a need to monitor the renal function of children with sickle cell disease when special attention should be paid to homozygotic patients.

Hematologic parameters and genotype analysis in 166 children with HbH disease in the North Guangxi region / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the characteristics of genotype spectrum and hematologic parameters in children with HbH disease in the North Guangxi region.</p><p><b>METHODS</b>HbH disease was identified by clinical manifestations, routine blood tests and hemoglobin electrophoresis in 166 children who came form the North Guangxi region. Genotypes were determined by Multi-PCR combined with PCR reverse dot blot. DNA sequencing was used when the genotype could not be identified by regular methods.</p><p><b>RESULTS</b>Of the 166 children with HbH disease, 8 genotypes were identified: --SEA/-α3.7 (82 cases), --SEA/-α4.2 (40 cases), --SEA/αCSα (38 cases), --SEA/αQSα (1 case), --SEA/αWSα (1 case), --SEA/αCD43/44 (-C) α (1 case), --SEA/-α3.7 plus CD17 (A→T) (1 case) and --SEA/-α4.2 plus CD41-42(-TTCT) (1 case). One case was confirmed as the heterozygote of --SEA and an unknown mutation. In the 134 cases with complete medical data, 2 had normal hemoglobin levels, 36 manifested mild anemia, 90 manifested moderate anemia, and 6 (genotype: --SEA/αCSα) showed severe anemia because of the coexistence of infection. Children with the genotype of --SEA/-α3.7 (69 cases), --SEA/-α4.2 (31 cases) and --SEA/αCSα (34 cases) had hemoglobin levels of 62-120, 69-127 and 34-110 g/L respectively. The hemoglobin level in the --SEA/αCSα group was significantly lower than in the deletional HbH disease group (genotypes: --SEA/-α3.7 and --SEA/-α4.2 ) (P<0.05). In contrast, MCV levels in the --SEA/αCSα group were significantly higher than in the deletional HbH disease group (P<0.05).</p><p><b>CONCLUSIONS</b>The genotype spectrum of HbH disease is diverse in the North Guangxi region. Deletional genotype is prevalent. The disease is heterogeneous. The children with --SEA/αCSα HbH disease have severer anemia and higher MCV levels than those with deletional HbH disease.</p>

The First Case of X-linked Alpha-thalassemia/Mental Retardation (ATR-X) Syndrome in Korea

Mutation of the ATRX gene leads to X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome and several other X-linked mental retardation syndromes. We report the first case of ATR-X syndrome documented here in Korea. A 32-month-old boy came in with irritability and fever. He showed dysmorphic features, mental retardation and epilepsy, so ATR-X syndrome was considered. Hemoglobin H inclusions in red blood cells supported the diagnosis and genetic studies confirmed it. Mutation analysis for our patient showed a point mutation of thymine to cytosine on the 9th exon in the ATRX gene, indicating that Trp(C), the 220th amino acid, was replaced by Ser(R). Furthermore, we investigated the same mutation in family members, and his mother and two sisters were found to be carriers.

Enfermedad por hemoglobina H: primer caso de la variante de hemoglobina H tipo, menos alfa elevado a potencia 3.7 / SEA, en Costa Rica / Hemoglobin H disease: first case of hemoglobin H variant type (-a 3.7 / SEA) in Costa Rica

La enfermedad por Hemoglobina H es la forma más común de talasemia intermedia y posee muchas características que requieren cuidadosa consideración en su manejo clínico. En lamayoría de los casos, la enfermedad por Hemoglobina H resulta de un estado doble heterocigoto producido por unadeleción tipo α0 que remueve ambos genes de α-globina en uno de los cromosoma 16 y de una deleción tipo α+ en uno de los genes de α-globina en el otro cromosoma 16, resultando enuna condición tipo (--/-α). El exceso de cadenas β de globina precipita y forma una hemoglobina anormal característica; la hemoglobina H (Hb H), un tetrámero de β globina (β4). Lospacientes con hemoglobina H que se encuentran en estado compensado pueden tener niveles de hemoglobina entre 9 y 10 g/dL, sin embargo durante las crisis hemolíticas, que se desarrollan durante o después de infecciones agudas con fiebres altas, la hemoglobina puede llegar a disminuirsignificativamente y los pacientes pueden desarrollar shock y fallo renal. Aún cuando la esplenectomía eleva la hemoglobina significativamente, no se recomienda porque la mayoría delos pacientes tienen un nivel aceptable de hemoglobina mientras se encuentren compensados. Se presenta el primercaso descrito en Costa Rica de enfermedad por hemoglobina H variante del sudeste asiático (-α3.7/ --SEA).

Hemoglobin H (Hb H) disease is the most common form of thalassemia intermedia and has many features that require careful consideration in its management. In the majority of cases, the disease results from double heterozygosity for α0- thalassemia due to deletions that remove both linked α-globin genes on one chromosome 16, and deletional α+ from single α-globin gene deletions on the other chromosome 16 resulting in a (--/-α) condition. The excess β globin chainprecipitates and forms a characteristic abnormal hemoglobin: hemoglobin H a β globin tetramer (β4). In a steady state,patients with Hb H disease have hemoglobin levels around 9 to 10 g/dL however, during a hemolytic crisis, which frequently occur in or after acute infections causing high fever, the hemoglobin may drop significantly and the patients can develop shock or renal shutdown. Even though splenectomy leads to significant elevation of hemoglobin levels, it is not recommended because the majority of patients do well with said steady-state hemoglobin levels. We present here the first case of hemoglobin H (-α3.7/ --SEA) southeast Asia variant described in Costa Rica.

Dificuldades na identificação laboratorial da talassemia alfa / Difficulty on laboratory identification of alpha thalassemia

Introdução: Talassemia alfa é uma síndrome associada à redução da síntese de cadeias de globina do tipo alfa. A gravidade das manifestações clínicas está relacionada com a quantidade de globinas produzida e a estabilidade das cadeias beta presentes em excesso. A talassemia alfa mínima resulta da deleção de apenas um dos quatro genes a (-α/αα). Clinicamente apresenta anemia leve com microcitose ou ausência de anemia, sendo o diagnóstico realizado por meio de visualização da hemoglobina (Hb) H por eletroforese alcalina em acetato de celulose ou por identificação de inclusões celulares de Hb H coradas pelo azul de crezil brilhante. Objetivo: Avaliar portadores de talassemia alfa e seus respectivos progenitores, correlacionando perfil hematológico e presença de Hb H, utilizando procedimentos laboratoriais clássicos em três diferentes amostragens. Discussão e conclusão: Os dados obtidos mostram que a presença de Hb H, indicativo de talassemia alfa, pode não ser confirmada em uma análise posterior. Entre os fatores que podem influenciar no não aparecimento de Hb H em pessoa comprovadamente com talassemia alfa está a deficiência de ferro. A talassemia alfa está associada a defeitos envolvendo os genes codificadores da cadeia alfa, mas também pode estar relacionada com desbalanciamento temporário na expressão dos genes globina, diminuição de alfa ou aumento de beta, o que poderia explicar o aparecimento de tetrâmeros de cadeia beta (Hb H), sugerindo diagnóstico de talassemia alfa mínima.

Introduction: Alpha thalassemia is a syndrome with associated with the reduction of alpha globin chain synthesis. The severity of clinical manifestations is related to the amount of globins produced and the stability of beta chains that are present in excess. Alpha thalassemia minor is caused by the deletion of one of the four genes a (-α/αα). Clinically, it presents mild anemia with microcytosis or absence of anemia. The diagnosis is made by the visualization of Hb H through alkaline electrophoresis on cellulose acetate or by the identification of inclusion bodies stained with brilliant cresyl blue. Objective: Evaluate alpha thalassemia carriers and their respective progenitors, correlating their hematology profile and the presence of Hb H by means of standard laboratory procedures in three different samplings. Discussion and conclusion: The results show that the presence of Hb H, which is indicative of alpha thalassemia, may not be confirmed in a subsequent analysis. Iron deficiency in Hb H carriers is among the factors that may influence on the absence of Hb H in alpha thalassemia proven patients. Alpha thalassemia is associated with genetic defects involving alpha chain encoding genes, but may be also associated with a temporary imbalance of globin gene expression, alpha chain reduction or beta increase, which could explain the presence of beta chain tetramer (Hb H) leading to the diagnosis of alpha thalassemia minor.

alpha-Thalassaemia in Tunisia: some epidemiological and molecular data.

Unlike the other haemoglobinopathies, few researches have been published concerning alpha-thalassaemia in Tunisia. The aim of the present work is to acquire further data concerning alpha-thalassaemia prevalence and molecular defects spectrum in Tunisia, by collecting and studying several kinds of samples carrying alpha-thalassaemia. The first survey conducted on 529 cord blood samples using cellulose acetate electrophoresis, have displayed the prevalence of 7.38% Hb Bart's carriers at birth. Molecular analyses were conducted by PCR and DNA sequencing on 20 families' cases from the above survey carrying the Hb Bart's at birth and on 10 Hb H diseased patients. The results showed six alpha-globin gene molecular defects and were responsible for alpha-thalassaemia: -alpha(3.7), - -(MedI), alpha(TSaudi), alpha(2)(cd23GAG->Stop), Hb Greone Hart: alpha(1)(119CCT->TCT) corresponding to 11 genotypes out of which two are responsible for Hb H disease (- -(Med)/-alpha(3.7)) and (alpha(TSaudi)alpha/alpha(TSaudi)alpha) and a newly described polymorphism: alpha+6C->G. The geographical repartition of alpha-thal carriers showed that the -alpha3.7 deletion is distributed all over the country, respectively the alpha(HphI) and alpha(TSaudi) seem to be more frequent in the central region of the northeast region. The haematological and clinical data showed a moderate phenotype with a late age of diagnosis for Hb H disease. This work had permitted, in addition to an overview on alpha-thalassaemia in the country, the optimization of protocols for alpha-thalassaemia detection in our lab, allowing further investigations concerning phenotype-genotype correlation in sickle cell disease or beta-thalassaemia.

Alternative method of smearing samples on slides facilitate visualization of hemoglobin H inclusion bodies in alpha thalassemia: [letter to the editor]

Nas talassemias alfa, a HbH pode ser detectada, nos eritrócitos do sangue periférico como inclusões celulares quando coradas com azul crezil brillante. Este teste simples é útil para o diagnóstico de talassemia alfa, no entanto, a identificação dos corpos de inclusão de HbH é um processo laborioso e os resultados são altamente dependentes do observador. No intuito de melhorar a identificação das inclusões, foi testado um método alternativo para espalhar as amostras nas lâminas. Amostras de sangue foram espalhadas nas lâminas usando-se o método clássico e o método alternativo. O método alternativo permitiu uma melhor identificação das inclusões de HbH do que o método clássico. Nossos resultados mostraram que o método alternativo é uma opção útil para a pesquisa dos corpúsculos de inclusão de HbH naquelas amostras onde o método clássico não o permite.

Hemoglobin H disease in Muscat, Oman - a 5 year study

Published data indicate that Alpha thalassemia trait is prevalent in 45% of population of Sultanate of Oman. Recent unpublished data suggest that this prevalence is higher than 45%. Yet clinical suspicion or investigations into alpha-thalassemias are lacking. Moreover, Hemoglobin H disease is considered rare in Oman. We decided, therefore to look for Hemoglobin H disease and characterize the clinico-hematopathological features of the disease. Patient demographics, clinical details and detailed hematology parametry of Hemoglobin H disease cases, diagnosed by Department of Laboratory over a period of 5 years between February 2002 and January 2007 in patients presenting at Al-Nahdha Hospital and Genetic counseling unit in Muscat were compiled from hospital and laboratory records and analyzed. Twenty cases of Hemoglobin H disease in Omanis were diagnosed mainly during the second decade. 60% belonged to Al-Balushi tribe. 40% of cases presented with body pains. 35% presented with nonspecific symptoms. 50% of cases were erroneously labeled as Iron deficiency anemia. Microcytic erythrocytosis, high Red Cell Distribution Width, numerous misshapen Red Blood Cells, pseudothrombocytosis, low A2 and normal Ferritin were important diagnostic clues. Hemoglobin H inclusions in special reticulocyte smears and Hemoglobin H on HPLC or Electrophoresis were diagnostic. Hemoglobin H disease is common in Oman. The need to do HPLC, G6PD activity and Ferritin studies in all cases of anemia in Oman to avoid missing diagnosis of Hemoglobin H disease is stressed. This study is intended to create awareness about Hemoglobin H disease in order to diagnose early, treat rightly, counsel correctly and pave the path for prevention of alpha-thalassemia disease in Oman

Acquired haemoglobin H disease associated with myelodysplastic syndrome

A 60-year-old male patient presented with jaundice. Initial investigations showed anemia, indirect hyperbilirubinemia, raised Lactic Dehydrogenase [LDH] and increased reticulocyte count suggestive of hemolysis. Considering hemolysis low MCV and basophilic stippling on peripheral film, hemoglobin electrophoresis was done that showed Haemoglobin H [15.5%] that in the absence of family history was thought to be acquired. After bone marrow examination, the final diagnosis was Myelodysplastic Syndrome [MDS], Refractory anemia with excess of blast [RAEB] associated with acquired Haemoglobin H [Hb H] disease

Molecular spectrum of alpha-thalassemia in Jordan

The aim of this study was to define the spectrum of alpha-thalassemia determinants existing in Jordan. A total 286 suspected alpha-thalassemia subjects including 29 hemoglobin Hb [Hb H] patients were examined by polymerase chain reaction and restriction enzyme digestion. Polymerase chain reaction product was examined by agarose gel electrophoresis. Five different alpha-thalassemia determinants were characterized in 336 chromosomes. The most prevalent alpha -thalassemia determinant was the single gene deletion -alpha[3.7] [45%]. The non-gene deletion alpha [5nt] accounted for 27% of thalassemic chromosomes, followed by the non-gene deletional determinant alpha [T-Saudi][23%]. The two-gene deletional determinant -[MED] was characterized only in 4% of thalassemic chromosomes. Triplicated alpha -gene determinant was observed in two heterozygous individuals [alpha alpha alpha / alpha alpha]. Four different genotypes were found to be responsible for Hb H disease. Homozygosity for the non-deletional determinant alpha[T-Saudi] [alpha T-Saudi] alpha/alpha T-Saudi]alpha] was observed in the majority of those patients [76%] and was found to be associated with high Hb H levels. Less commonly, Hb H disease occurred as a result of compound hterozygosity between -[MED] determinant with other determinants; [-[MED] /alpha [T-Saudi] alpha] [--MED]/ alpha[5nt] alpha], [--[MED]/ -alpha[37] alpha]. The outcome of this pilot study provides valuable and basic information, about the spectrum of a-thalassemia mutations in Jordan that might be useful in setting a strategy for molecular diagnosis of alpha-thalassemia carrier status and Hb H disease in this country

Molecular characterization of the - -SEA alpha thalassemia allele in Mexican patients with HbH disease / Caracterización molecular del alelo - -SEA de talasemia alfa en pacientes mexicanos con enfermedad por HbH

α-Thalassemia is one of the most prevalent hemoglobin disorders in the world, in South-East Asians, the--SEA allele is widely found in the HbH disease patients. The purpose of this work is to describe the molecular characteristics of Hemoglobin H disease in three patients from two Mexican families, as well to analyze the DNA sequence of the --SEA allele to determine the precise site of the crossover. The -α3.7 and --SEA alleles were identified using an established long-PCR method modified in our laboratory. The crossover site of --SEA mutation was analyzed by DNA sequencing. The three HbH subjects showed the same genotype -α3.7/--SEA. The -α3.7 allele has been observed in almost every racial studied group, whereas the --SEA allele is predominant in South-East Asian countries. DNA analysis through the breakpoint sites of the --SEA allele in both families showed the 5' breakpoint at the third base of codon 28 in the ψα2 gene and the 3' breakpoint within an Alu-Jo sequence, 1,328 nucleotides upstream of the 3'HVR. Therefore the size of the deletion is 19,303 nucleotides. This is the first report in which the flanking deletion sites of the--SEA mutation have been analyzed in Mexican patients, the 5' and 3' ends of the deletion is well determined.

La Talasemia-α es uno de los desórdenes de la hemoglobina más prevalences en el mundo. En el sureste de Asia, --SEA es el alelo más frecuente en pacientes con enfermedad por HbH (EHbH). En el presente trabajo se describen las características moleculares de tres pacientes con EHbH de dos familias mexicanas, y se analiza la secuencia de DNA del alelo --SEA, para determinar los sitios de ruptura. Los alelos -α3.7y --SEA se identificaron por un método de PCR modificado en nuestro laboratorio y los sitios de ruptura por secuenciación de DNA. Los tres pacientes con EHbH mostraron el genotipo -a3.7/--SEA. El alelo -α3.7 está ampliamente distribuido en el mundo, mientras que el alelo--SEA predomina en los países del sureste de Asia. El análisis de DNA del alelo--SEA mostró en 5' el sitio de ruptura en el codón 28 del pseudogén ψα2 y en 3', dentro de la secuencia Alu-Jo, localizada a 1,328 nucleótidos de la región HVR3', lo que da un segmento delecionado de 19,303 nucleótidos. Éste es el primer reporte en el que se analizan los sitios que flanquean la deleción del alelo --SEA en pacientes mexicanos y se definen con precisión los extremos 5' y 3' de la deleción.

Acquired hemoglobin H disease in a patient with aplastic anemia evolving into acute myeloid leukemia

CONTEXTO: O prognóstico da anemia aplástica grave melhorou com o advento do transplante de medula óssea e do tratamento imunossupressor com globulina antitimocitária. Em contraste com o sucesso destes protocolos, os estudos com seguimento a longo prazo mostraram a ocorrência de doenças clonais, tais como: hemoglobinúria paroxística noturna, síndrome mielodisplásica e leucemia aguda. RELATO DE CASO: Nós relatamos o primeiro caso descrito no Brasil de um paciente com anemia aplástica que evoluiu para síndrome mielodisplásica e leucemia mielóide aguda associada a presença de hemoglobina H e aumento da hemoglobina fetal.

Clinical phenotype genotype correlation in children with hemoglobin H disease in Zhuhai area of China / 中华儿科杂志

<p><b>OBJECTIVE</b>Alpha-thalassemia is one of the most common monogene disorders in the world. Most frequently, it is caused by deletions of alpha-globin gene (-alpha or --), and less commonly resulted from the non-deletional mutation (alpha(T)alpha). Hemoglobin H (HbH) disease is the most severe type among survivors of alpha-thalassemia. The clinical presentation of children with the disease was highly heterogeneous. The aim of this study was to investigate the effect of alpha-globin genotypes in the children with HbH disease on predicting the phenotypic severity and to define the factors involved in the disease progress.</p><p><b>METHODS</b>Forty-three children with the disease in Zhuhai area of Guangdong, China were examined by using established techniques to detect genotypes of alpha-globin and to determine all hematological parameters. All detailed clinical data of the cases were recorded. Then clinical and hematological findings, and the correlation with genotypes were evaluated.</p><p><b>RESULTS</b>Six alpha-thalassemia mutations were detected and interacted to produce 5 HbH disease genotypes. Of these genotypes, -alpha(3.7)/--(SEA)(60%), -alpha(4.2)/--(SEA) (19%) and alpha(CS)alpha/--(SEA) (12%) HbH diseases were prevalent in the area. Compared with -alpha(3.7)/--(SEA) HbH disease, significantly lower red blood cell (RBC) count, hemoglobin (Hb), mean corpuscular hemoglobin (MCHC) and HbA(2) (P < 0.05, 0.01, 0.01 and 0.01, respectively), and significantly higher mean corpuscular hemoglobin volume (MCV) and HbH levels (both P < 0.01), and more severe clinical phenotypes were found in the HbH disease with alpha(T)alpha/--(SEA) genotype. While the differences were much more significant when compared with -alpha(3.7)/--(SEA) then compared with -alpha(4.2)/--(SEA) not only in the hematological parameters, but also in the severity of clinical phenotypes. In addition, HbH levels showed anegatively correlation with the RBC count (r = -0.39, P < 0.01).</p><p><b>CONCLUSION</b>The phenotypes of HbH disease may be mainly related to the underlying genotypes. The children with alpha(T)alpha/--(SEA) genotype presented with more severe hematological and clinical phenotypes followed by the -alpha(4.2)/--(SEA) and then -alpha(3.7)/--(SEA) genotypes. But phenotypic severity was not simply related to the degree of alpha-globin deficiency. HbH levels were found to exacerbate anemia. These data might provide comprehensive and very valuable and basic information for the management of HbH disease, genetic counseling and prenatal diagnosis.</p>

Alpha 2 codon 30 deletion (deltaGAG) causing non-deletional hemoglobin H disease in Guangxi province / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To analyze genotypic profiles and understand the relationship between the genotype and phenotype of Hb H disease in Guangxi province.</p><p><b>METHODS</b>Hematologic and Hb analyses on the cases were performed to detect their alpha thalassemia genotypes using PCR method and DNA sequencing.</p><p><b>RESULTS</b>An unusual case was identified in one of the 298 patients with Hb H disease diagnosed in the First Affiliated Hospital of Guangxi Medical University from October 2002 to November 2003. The 25-year-old male patient, a native of Yulin in Guangxi province, had had jaundice and splenomegaly since childhood, and he had never received blood transfusion. Hematologic examinations revealed his hemoglobin 107 g/L, RBC 4.9+10(12) g/L, MCV 76.2 fl, MCH 21.8 pg, MCHC 287 g/L, HCT 0.373, reticulocyte 3%. Hb analysis showed the level of Hb H + Hb Bart's 34.41%. PCR and DNA sequencing confirmed the genotype of a deletion at codon 30 of alpha2 globin gene and SEA alpha-thalassemia-1.</p><p><b>CONCLUSION</b>This unusual case had no anemia, but had higher level of Hb H and Hb Bart's when compared to those non-deletional Hb H disease cases such as Hb CS-H, HbQS-H and alpha2 codon 31 mutation combined with SEA alpha-thalassemia-1 previously reported in mainland China. The discovery and recognition of this gene mutation and related genotype and phenotype is of importance to the genetic counseling and prenatal diagnosis in Guangxi province where the incidence of alphathalassemia is very high.</p>

Study on gene mutations of alpha-thalassemia in the South of China / 中国实验血液学杂志

There is a high prevalence of thalassemia in the South of China. To explore the genotype of alpha-thalassemia as well as the distribution of alpha globin gene mutation in the South of China, 356 patients with heterozygote alpha(+) thalassemia, heterozygote alpha(0) or homozygote alpha(+) thalassemia and 78 patients with HbH were analyzed. The gene diagnosis methods including Gap-PCR, nested-PCR, PCR-RE, PCR-SSCP, 4P-ASPCR and DNA sequence analysis were used. The results showed that among 356 patients, 295 patients with --SEA/alphaalpha (82.87%), 1 patient with alphaalpha/alpha-alpha(3.7) (0.28%), 3 patients with alphaalpha/alpha-alpha(4.2) (0.84%), 3 patients with alphaalpha/alpha(CS)alpha (0.84%), 1 patient with alphaalpha/alphaalpha(QS) (0.28%) and 2 patients with alphaalpha/alpha(Westmead) alpha (0.56%) were found. The homozygote with -alpha(4.2) or -alpha(3.7) was not found. In 78 patients with HbH, 29 patients with --SEA/alphaalpha(-3.7) (37.2%), 20 patients with --SEA/alphaalpha(-4.2) (25.6%), 19 patients with --SEA/alphaalpha(CS) (24.3%), 2 patients with --SEA/alphaalpha(QS) (2.6%) were detected, and other remaiming 8 patients were needed to be defined. Among the non-defined 8 patients, the synonymous mutation with C-->G transversion (GCC-GCG) at codon 65 in the exon 2 of alpha 2-globin gene was detected in 2 unrelated HbH patients came from Guangxi province. Whether it correlated with the phenotype of HbH disease or it is only a single nucleotide polymorphism site (SNPs), should be confirmed in the future. In addition, a set of gene diagnosis methods based on PCR to screen deletion and non-deletion genotypes of alpha-thalassemia in Chinese was improved. A new method, 4P-ASPCR, to detect Hb CS and Hb QS was also developed. The method was verified to be more accurate, time-saving and economic. In conclusion, the genotypes of alpha-thalassemia in Chinese are very complicated, the genotypes of alpha-thalassemia in Chinese need to be further studied, the results of this research probably have practical significance for the gene diagnosis or antenatal diagnosis of alpha-thalassemia in the South of China.