Ten years' experience in prenatal diagnosis of α-thalassemia in a municipal hospital and retrospective analysis of ultrasonic abnormalities.

OBJECTIVE: This study reviewed and analyzed the prenatal diagnosis experience of thalassemia in our center over the past decade and the abnormal ultrasonic characteristics of fetuses with hemoglobin (Hb) Bart's hydrops fetalis. METHODS: Pregnant women and their partners who tested positive for α0-thalassemia or were diagnosed with thalassemia intermedia (HbH diseases) underwent genetic counseling, and a prenatal diagnostic procedure for α-thalassemia was recommended. Ultrasonography was performed before prenatal diagnosis. RESULTS: Invasive prenatal α-thalassemia diagnosis and ultrasonography were performed in 1049 patients at risk for Hb Bart's hydrops fetalis syndrome at our hospital from 2012 to 2021. Chorionic villus sampling (CVS) was performed in 58 cases (5.5%), amniocentesis in 902 cases (86%), and cordocentesis in 89 cases (8.5%). Hb Bart's hydrops fetalis syndrome was diagnosed in 280 fetuses. The most common body cavity effusion was pericardial effusion, ascites, and fetal systemic edema. CONCLUSIONS: The extensive experience at our center shows that carrier screening, molecular diagnostics, genetic counseling, and prenatal diagnosis are effective measures to prevent Hb Bart's hydrops fetalis syndrome. The ultrasonographic abnormalities in fetuses with Hb Bart's hydrops are mainly caused by an increase in cardiac output, which leads to the body cavity effusion from various organs.

Invasive prenatal diagnosis of α-thalassemia to control Hb Bart's hydrops fetalis syndrome: 15 years of experience.

PURPOSE: The aim of the present study was to report experiences with invasive prenatal diagnosis of α-thalassemia for the prevention of Hb Bart's hydrops fetalis syndrome in the Guangxi Zhuang Autonomous Region, China. METHODS: Pregnant women and their partners who tested positive for α0-thalassemia or were diagnosed with HbH diseases were counseled and suggested to undergo a prenatal diagnostic procedure for α-thalassemia. Fetal material was obtained by chorionic villus sampling (CVS) between 9 and 13 weeks of gestation, by amniocentesis between 16 and 24 weeks of gestation and by cordocentesis after 24 weeks of gestation. The α0-thalassemia gene types were detected by gap polymerase chain reaction (Gap-PCR). All results were finally confirmed by DNA analysis after delivery or termination of pregnancy. RESULTS: An invasive prenatal α-thalassemia diagnosis was performed in 3155 cases at risk for Hb Bart's hydrops fetalis syndrome at our hospital from 2002 to 2016. CVS was performed in 1559 cases (49.4%), amniocentesis in 1240 cases (39.3%) and cordocentesis in 356 cases (11.3%). In total, 786 fetuses were diagnosed as Hb Bart's hydrops fetalis syndrome. Among these cases, the α-thalassemia genotype was --SEA/--SEA in 784 cases and --SEA/--THAI in 2 cases. All affected pregnancies were terminated in time. CONCLUSIONS: This extensive experience suggests that carrier screening, molecular diagnostics, genetic counselling, and prenatal diagnosis are effective measures to prevent Hb Bart's hydrops fetalis syndrome.

Prenatal control of Hb Bart's hydrops fetalis: a two-year experience at a mainland Chinese hospital.

α-Thalassemia is a common inherited disease in southern China. The severest form is Hb Bart's hydrops fetalis, in which the affected fetuses almost always die in utero or shortly after birth, and the mothers are at high risk for severe morbidity. Therefore, this condition should be controlled, especially prenatally. In this study, we reported on a two-year experience in prenatal control of Hb Bart's hydrops fetalis at a mainland Chinese hospital. Totally, 573 pregnancies at risk for Hb Bart's hydrops fetalis were referred and different prenatal procedures were offered depending on the gestational age at presentation. One hundred fifty-two affected fetuses were diagnosed prenatally; among these, only half presented in early gestation, and were terminated in time. Although our prenatal program has successfully prevented the birth of children with severe thalassemia, it does not show a satisfactory outcome, considering the gestational age when an affected pregnancy is terminated.

Peripheral villous stromal hyperplasia: a distinctive placental lesion in hemoglobin bart hydrops fetalis.

In hydrops fetalis (HF) the placenta can be markedly enlarged and the villi show stromal edema, increased Hofbauer cells, and reduced numbers of capillaries. Hemoglobin (Hb) Bart is the most severe form of thalassemia, causing HF due to profound anemia. We report a previously undescribed histologic finding based on a review of Hb Bart HF cases, termed "peripheral villous stromal hypercellularity." This change was noted in 15 of 18 (83%) placentas with Hb Bart HF but not in placentas of 21 cases of HF due to other causes, including 11 cases involving anemia. The hyperplastic stromal cells were determined to be myofibroblastic by immunohistochemistry and electron microscopy, associated with a more complex capillary network in villi than is seen with other causes of HF. The authors hypothesize that this angiogenesis in villi is a response to fetal anemia from Hb Bart. In turn, there is increased villous blood flow, resulting in edematous villous stroma, leading to narrowing of the intervillous space in the placenta. Hyperplasia of myofibroblasts might then be a compensatory change, in that contraction by these cells would reduce the vascular lumina and the size of placental villi, thereby widening the intervillous space to improve capacity for maternal blood circulation. Curiously, this histologic change was restricted to cases of HF caused by Hb Bart. We speculate that in Hb Bart disease, the hypoxia and hydrops develop earlier in gestation, compared to other causes of HF, allowing the time for these adaptive changes to occur in the placenta.

Survival of homozygous alpha-thalassemia with aplasia/hypoplasia of phalanges and jejunal atresia.

We report a case of survival of homozygous alpha-thalassemia with aplasia/hypoplasia of phalanges and jejunal atresia. The occurrence of these malformations is consistent with the postulation that intra-uterine hypoxia due to the presence of hemoglobin Bart's (Hb Bart's) is the causative factor for the development of these malformations. There were two pitfalls in diagnosis: normal spun hematocrit level despite a low hemoglobin level and absence of hydropic features. Our case illustrated that nitric oxide and high frequency ventilation were ineffective in ameliorating persistent pulmonary hypertension of newborn until exchange transfusion was done replacing Hb Bart's with normal hemoglobin.

Hb Antalya [codons 3-5 (Leu-Thr-Pro-->Ser-Asp-Ser)]: a new unstable variant leading to chronic microcytic anemia and high Hb A2.

A novel beta-thalassemia mutation, not previously reported in the literature, was identified by direct DNA sequencing of the beta-globin gene. Hematological investigation of a 26-year-old woman due to her increased Hb A2 level (6.2%) led to the identification of a heterozygosity for a 9 bp (TCTGACTCT) deletion/insertion at codons 3-5. This was found to be the result of a deletion of cytosine (-C) at codon 5 (one of the nucleotides in the 13th or 14th position of exon 1). and an insertion of thymine (+T) in front of codon 3 at the 10th nucleotide in exon 1 of the beta-globin gene. As a result of these mutations, the amino acids at codons 3-5 were changed from Leu-Thr-Pro to Ser-Asp-Ser. The whole frameshift was prevented by this rearrangement in the beta-globin gene. In addition, this result may provide important clues to identify critical amino acids responsible for stabilization of the hemoglobin tetramer.

Hb Dartmouth [alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG)]: a novel alpha2-globin gene mutation associated with severe neonatal anemia when inherited in trans with Southeast Asian alpha-thalassemia-1.

We report a novel mutation at alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG), that we have named Hb Dartmouth for the medical center at which the patients were cared for, in monozygotic twins who also inherited the Southeast Asian alpha-thalassemia-1 deletion. The mother, of Khmer ancestry, is heterozygous for alpha-thalassemia-1. The father, who is of Scottish-Irish ancestry, is a silent carrier of the codon 66 mutation. The twins had severe neonatal anemia requiring transfusion.

Hb Bart's levels in cord blood and alpha-thalassemia mutations in Cyprus.

The purpose of this study was to examine the frequency of alpha-thalassemia in the population of Cyprus using cord blood samples. The levels of Hb Bart's were compared with the hematological indices and the results correlated with the presence of alpha-thalassemia mutations. The protocols for the polymerase chain reaction detection of the six most common alpha-globin mutations encountered in Cyprus were optimized, and the frequency of each mutation was determined through the screening of 495 random cord blood samples. The total allele frequency for the mutations examined was 10.6%, of which 1% is due to the triplication of the alpha-globin genes. The -alpha(3.7 kb) deletion accounts for 72.8% of all detectable mutations, while the--MED-I and -(alpha)-20.5 kb mutations account for 7.8%. The level of Hb Bart's and the MCV and MCH values in cord blood samples were found to correlate closely with the severity of alpha-thalassemia, although the -alpha(3.7 kb) deletion and perhaps other mild alpha-thalassemia mutations may not give detectable Hb Bart's levels. A reasonably accurate estimate of the alpha-thalassemia carrier frequency may be obtained from cord blood studies if Hb Bart's estimates are combined with hematological indices. When molecular methods are added, these give the best way to use cord bloods to survey populations for alpha-thalassemia.

The mutation associated with Hb Peterborough [beta111(G13)Val-->Phe] originated from Southern Italy.

Hb Peterborough [beta111(G13)Val-->Phe], an unstable hemoglobin variant with low oxygen affinity, was first described in two patients of Italian origin. This paper reports the first observation of this variant in Campania, Southern Italy, in two unrelated patients suffering from mild anemia. The variant was separated from Hb A by cation exchange chromatography on a high performance liquid chromatographic system with an automated procedure that might be useful for diagnostic purposes. The amino acid replacement, Val-Phe at [beta111, was assessed by tandem electrospray mass spectrometry analysis, and the corresponding DNA mutation was established as G-->T at the first position of codon 111 (GTC-TTC) by polymerase chain reaction amplification techniques. A family study showed that the two original carriers of Hb Peterborough were members of the same family as the proband examined in this study. This finding, and the presence of a second unrelated family carrying Hb Peterborough in Campania, strongly suggests that the DNA mutation associated with this variant originated in Southern Italy.