厦门地区2960对育龄夫妇地中海贫血筛查及基因检测结果分析

目的 初步了解并分析厦门地区育龄青年地中海贫血(地贫)流行情况及其基因分布特征,为地贫基因诊断、遗传咨询及减少地贫漏诊和误诊提供理论依据.方法 对2013年4月至2016年4月来本院进行孕前优生健康检查的2 960对育龄夫妇进行血常规、血红蛋白电泳、血清铁、铁蛋白筛查,筛查阳性患者通过“PCR+膜杂交法”进行地贫基因检测.结果 2 960对育龄夫妇经血液学筛查结果中阳性共1 160例(占19.59％),检出地贫基因携带者408例,占6.89％;其中α地贫基因携带者286例,占4.83％,最常见的地贫基因型为--SEA/αα,占全部α地贫基因携带者的74.13％;β地贫基因携带者1 14例,占1.93％,最常见的地贫基因型为CD41-42(-TCTT)和IVS-2-654(C→T),分别占全部β地贫基因携带者的34.21％和32.46％;α地贫复合β地贫基因携带者8例,占0.14％.结论 厦门地区地贫基因突变类型复杂多样,α地贫基因携带者最常见的基因型为--SEA/α α,β地贫基因携带者最常见的基因型为CD41-42(-TCTT)和IVS-2-654(C→T);对于血液学筛查阳性的人群,进一步进行地贫基因诊断,可避免漏诊误诊,更好的为临床地贫诊断和遗传咨询提供依据.     

Parathyroid hormone,calcitonin and vitamin D metabolites in beta-thalassaemia major

Serum calcium (Ca), phosphorus (P), alkaline phosphatase (Al-P), parathyroid hormone (PTH), calcitonin (CT), 25-hydroxyvitamin D₃ (25OHD₃), 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) levels and urinary excretion of Ca, P, hydroxyproline (OH-P) and cyclic AMP (cAMP) were determined in summer and in winter in 13 thalassaemic children (7 aged 3–5 years-group 1-; and 6 aged 10–13 years-group 2-), who had never taken vitamin D supplements or therapy, and in two groups of 14 controls of the same age.In thalassacmics of group 1 only serum AL-P levels and OH-P urinary excretion were higher than in controls (P<0.01). In thalassaemics of group 2 Ca (P<0.05), P (P<0.05), PTH (P<0.001), CT (P<0.001), 25 OHD₃ (P<0.05), 1,25(OH)₂D₃ (P<0.001) levels and cAMP urinary excretion (P<0.001) were lower, whereas Al-P (P<0.001) and CT (P<0.001) levels and urinary excretion of P (P<0.05) and of OH-P (P<0.001) were higher than in controls, both in summer and in winter.Advancing age induces in thalassaemic patients a decrease in PTH secretion and a consequent deficit in synthesis of 1,25(OH)₂D₃ that may explain some aspects of bone changes, which CT hypersecretion may tend to counteract.Abbreviations Ca calcium - P phosphorus - Al-P alkaline phosphatase - PTH parathyroid hormone - CT calcitonin - 250HD₃ 25-hydroxyvitamin D₃ - 1,25(OH)₂D₃ 1,25-dihydroxyvitamin D₃ - OH-P hydroxyproline - cAMP cyclic AMP Presented in part at the 23rd annual meeting of the European Society for Paediatric Endocrinology, Heidelberg, September 2–5, 1984     

Growth of children with β-thalassemia major

Hypertransfusion and regular chelation therapy have allowed improved survival in patients with thalassemia major (TM). Despite medical advances, growth failure and hypogonadism remain significant clinical problems in these patients in adolescence. Disproportionate truncal shortening which is common especially among adolescents with thalassemia, is due to platyspondyly resulting from a combination of factors like hemosiderosis, desferrioxamine toxicity or deficiency of trace elements. Although growth hormone (GH) deficiency and GH neurosecretory dysfunction have been described in TM patients, most short TM patients have normal GH reserve. The low serum IGF-1 and IGFBP-3 concentrations in TM patients despite having normal GH reserve and serum GH binding protein levels suggest that a state of secondary GH insensitivity exists. The pubertal growth spurt may be impaired in TM patients going through spontaneous or induced puberty and may have a negative effect on final adult height. GH therapy in dosages ranging from 0.5–1.0 IU/kg/wk has resulted in a significant improvement in growth velocity in short TM children without any adverse effects on skeletal maturation, blood pressure, glucose tolerance and serum lipids. There is limited evidence that GH treatment can result in an improved final adult height in short TM children. Careful and regular clinical and biochemical monitoring should be preformed on these patients while they are treated with GH.     

A case of relapsing Salmonella osteomyelitis in a thalassaemia trait patient

We report a case of chronic relapsing osteomyelitis caused by Salmonella Stanley in a β-thalassaemia trait patient who is otherwise normal. The importance of obtaining definitive bacteriological diagnosis and timely intervention to treat bone infection effectively is emphasised here.     

Dark blood versus bright blood T2* acquisition in cardiovascular magnetic resonance (CMR) for thalassaemia major (TM) patients: Evaluation of feasibility,reproducibility and image quality

Objectives

To compare the effectiveness of dark blood (DB) versus bright blood (BB) sequences. To assess the intra and inter-observer variability and inter-study reproducibility between BB versus DB. To evaluate image quality level in the two sequences.

Methods

In a setting of 138 patients we performed CMR using cardiac gated Gradient-multiecho single breath-hold BB and DB sequences in the middle ventricular septum.Each acquisition was repeated during the same exam. Truncation method was used to account for background noise. Image quality (IQ) was assessed using a 5 point grading scale and image analysis was conducted by 2 experienced observers.

Results

Compared with the conventional BB acquisition, the coefficient of correlation and significance of the DB technique was superior for intra-observer reproducibility (p < 0.001), inter-observer reproducibility (p < 0.001) and inter-study reproducibility (p < 0.001). The variability is also lower for DB sequences for T2* values <14 ms. Assessment of artifacts showed a superior score for DB versus BB scans (4 versus 3, p < 0.001).

Conclusions

Improvement in terms of inter observer and inter study variability using DB sequences was obtained. The greatest disparity between them was seen in inter-study reproducibility and higher IQ in DB was seen.Study demonstrates better performance of DB imaging compared to BB in presence of comparable effectiveness.     

海南省孕前及孕期地中海贫血筛查方案评价及优化研究

目的对海南省免费孕前及孕期地中海贫血筛查方案进行评价,为地贫筛查流程的优化提供理论依据。方法2020年11月—2021年7月对海南省19个市县参与海南省居民地中海贫血流行病学调查的10396例海南户籍成人进行调查,所有人均进行血常规检测、血红蛋白电泳检测及地贫基因检测。通过受试者工作特征曲线和灵敏度等筛检试验指标,判断平均红细胞体积(mean corpuscular volume,MCV)、平均红细胞血红蛋白含量(mean corpuscular he⁃moglobin,MCH)和血红蛋白2型(haemoglobin adult type 2,HbA2)筛查地贫的最佳诊断界值,并评估不同地贫基因携带者初筛方案的诊断效能。结果使用海南省现有MCV单指标地贫初筛方案,即MCV<82 fL时进行地贫基因检查,诊断地贫基因携带者的漏诊率较高(34.06%),灵敏度较低(65.94%)。海南省MCV筛查α-地贫和β-地贫的最佳截断值分别为84.45 fL和79.05 fL;MCH筛查α-地贫和β-地贫的最佳截断值分别为27.95 pg和25.15 pg。HbA2筛查α-地贫的最佳截断值为小于2.55%,筛查β-地贫则为大于3.35%。地贫初筛时使用本研究推荐截断值的“HbA2或MCH或MCV联合筛查方案”具有较好的性能,灵敏度(92.96%)和阴性预测值(92.67%)最高,漏诊率(7.04%)最低,与现有方案比较差异有统计学意义(P<0.05)。结论目前海南省地贫筛查流程有漏诊可能,联合使用MCV、MCH和HbA2筛查地贫,采用本地适宜的地贫初筛指标截断值,可以改善地贫漏报的发生,提高诊断效能。     

缺铁性贫血和地中海贫血在血常规中的鉴别诊断

目的探讨IDA和THAL在血常规实验中简易的鉴别方法。方法用全自动血细胞分析仪检测血常规,全自动快速电泳分析系统作HB分析(部分标本做A.B-THAL基因分析)以及用化学发光免疫分析仪检测血清铁蛋白。结果共检测595例女性,正常组200例,IDA组50例THAL组共345例,分为3组:轻型-αTHAL组177例,轻型-βTHAL组124例,HB H组44例。在血常规的RBC.HB.RBC/HB.MCV.MCH.MCHC.RDW-CV等各项检测中,THAL组和IDA组都与正常组有非常显著差异(P<0.01),其中RBC.HB.及RDW-CV的比较中,IDA组与THAL组有非常显著差异(P<0.01)。结论以血常规分析鉴别IDA和THAL有几点:①IDA组RBC总数在4.50(×1012/L)以下,HB在5.0~9.5 g/L范围;THAL组RBC总数常在4.30(×1012/L)以上,HB值在8~11 g/L范围。②RBC/HB的比值中,IDA组多在0.054以上,THAL组则在0.048~0.054之间。③RDW-CV比较中,建议修订正常值在<0.150;轻型THAL组在0.151~0.185;IDA组在0.180~0.238;HB H组在0.220~0.310。THAL组的RDW-CV值并非在正常范围内。④当血常规显示明显小细胞低色素性贫血时,RDW-CV值>0.23以上,必须做HB电泳分析,以鉴别HB H病还是IDA。以血常规鉴别IDA与THAL,对于暂时无条件开展血清铁蛋白检测的情况下,对小细胞低色素性贫血鉴别诊断有积极的临床意义。     

The “lamellated” skull in β-thalassaemia

The skull in homozygous -thalassaemia may present several abnormalities, such as osteopenia, widening of the diploic space, and a hairon-end appearance. In some cases it presents also a particular stratified appearance caused by a variable number of osseous lamellae, parallel with the inner table. This lamellated skull was observed in 16 out of 150 patients affected by the disease (10.6%). Possible mechanisms are discussed. The lamellar osseous changes could be due to repeated periosteal osteoblastic reactions to the sinusoidal neovascularization associated with marrow hyperplasia in poorly transfused patients.     

Transition of Thalassaemia and Friedreich ataxia from fatal to chronic diseases

Thalassaemia major (TM) and Friedreich’s ataxia (FA) are autosomal recessive inherited diseases related to the proteins haemoglobin and frataxin respectively. In both diseases abnormalities in iron metabolism is the main cause of iron toxicity leading to increased morbidity and mortality. Major efforts are directed towards the prevention of these diseases and also in their treatment using iron chelation therapy. Both TM and FA are endemic in Cyprus, where the frequency per total population of asymptomatic heterozygote carriers and patients is the highest worldwide. Cyprus has been a pioneering nation in preventing and nearly eliminating the birth of TM and FA patients by introducing an organized health structure, including prenatal and antenatal diagnosis. Effective iron chelation therapy, improved diagnostic methods and transfusion techniques as well as supportive therapy from other clinical specializations have improved the survival and quality of life of TM patients. Despite the tiresome clinical management regimes many TM patients are successful in their professional lives, have families with children and some are now living well into their fifties. The introduction of deferiprone led to the elimination of cardiac failure induced by iron overload toxicity, which was the major cause of mortality in TM. Effective combinations of deferiprone with deferoxamine in TM patients caused the fall of body iron to normal physiological ranges. In FA different mechanisms of iron metabolism and toxicity apply to that of TM, which can be targeted with specific iron chelation protocols. Preliminary findings from the introduction of deferiprone in FA patients have increased the hopes for improved and effective therapy in this untreatable condition. New and personalised treatments are proposed in TM and FA. Overall, advances in treatments and in particular of chelation therapy using deferiprone are transforming TM and FA from fatal to chronic conditions. The paradigm of Cyprus in the prevention and treatment of TM can be used for application worldwide.     

The genetic basis of asymptomatic codon 8 frame‐shift (HBB:c25_26delAA) β0‐thalassaemia homozygotes

Two 21‐year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (–AA) frame‐shift β⁰‐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.