http://informahealthcare.com/hem ISSN: 0363-0269 (print), 1532-432X (electronic) Hemoglobin, Early Online: 1–4 ! 2015 Informa Healthcare USA, Inc. DOI: 10.3109/03630269.2015.1030031
SHORT COMMUNICATION SEA Hb H Hydrops Fetalis Syndrome Caused by Association of the Deletion and Hb Constant Spring (HBA2: c.427T4C) Mutation in a Chinese Family Sheng He, Chenguang Zheng, Dahua Meng, Rongyu Chen, Qiang Zhang, Xiaoxian Tian, and Shaoke Chen
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Prenatal Diagnostic Centre, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, People’s Republic of China
Abstract
Keywords
Hb Constant Spring (Hb CS; HBA2: c.427T4C) is an unstable hemoglobin (Hb) variant that results from a nucleotide substitution at the termination codon of the a2-globin gene. SEA CS /a a) results in Hb H/ Compound heterozygosity for a0-thalassemia (a0-thal) and Hb CS ( Hb CS disease, which is generally characterized with mild hemolytic anemia, jaundice, and splenomegaly. Here, we describe one case with Hb H/Hb CS disease that presented with fetal anemia and fetal hydrops, known as Hb H (b4) hydrops fetalis. This is the first report of fetal SEA deletion and the aCSa mutation. Our study hydrops caused by association of the highlights the significance of watchful observation using a serial ultrasound method and care of pregnant women who have fetuses found to carry Hb H/Hb CS disease during pregnancy, to guard against the occurrence of fetal hydrops.
a-Globin gene, a-thalassemia (a-thal), Hb H hydrops fetalis, Hb H/Hb CS disease
The a-thalassemias are the most common inherited disorders of hemoglobin (Hb) synthesis in southern China, with an especially high prevalence rate of 17.5% in Guangxi Province (1). These disorders result from deletions or mutations (or both) on the a-globin genes, of which there are four in the normal genome, and are characterized by absent or decreased rate of a-globin synthesis. Hb Bart’s (g4) hydrops fetalis is the most severe form of a-thal, which typically arises from the deletion of all four functioning a-globin genes; individuals with this form always succumb in utero or soon after birth (2). Occasionally, hydrops fetalis can be caused by Hb H disease, in which there is only one functioning a-globin gene; these cases are recognized as having Hb H hydrops fetalis syndrome. Affected fetuses have severe anemia and findings consistent with the classic Hb Bart’s hydrops fetalis. There are sporadic reports of fetuses with Hb H hydrops fetalis syndrome (3–6). Here, we describe a new case of fetal SEA anemia and hydrops resulting from association of the deletion and a nondeletional a2-globin gene Hb Constant Spring (Hb CS; HBA2: c.427T4C) (aCSa) mutation.
Address correspondence to Professor Chenguang Zheng, Prenatal Diagnostic Centre, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, 59 Xiangzhu Road, Nanning, 530000, People’s Republic of China. Tel: +86-771-580-2285. Fax: +86-771-580-2075. E-mail: [email protected]
History Received 29 July 2014 Revised 11 October 2014 Accepted 15 October 2014 Published online 21 April 2015
A 28-year-old woman and her husband from Guangxi Zhuang Autonomous Region, China presented at our center for the first antenatal visit at 12 weeks’ gestation. This was the mother’s first pregnancy, and there was no history of miscarriage, fever, rash, headache or edema. Thalassemia testing showed the mother and father were both carriers of a-thal. The parents hematological data and genotypes are summarized in Table 1. Gap-polymerase chain reaction (PCR) and reverse dot blot were performed in order to detect the SEA three a-globin gene deletion mutations [ , a3.7 4.2 (rightward) and a (leftward)] and three nondeletional mutations [Hb Westmead (HBA2: c.369C4G), Hb CS and Hb Quong Sze (Hb QS; HBA2: c.377T4C or HBA1)] that are common in the Chinese population. The results showed that the woman was heterozygous for the Southeast Asian (SEA) SEA deletion ( /aa) and her husband was heterozygous for CS Hb CS (aa/a a). Anatomical scans of the fetus were normal at 12 weeks’ gestation, while an ultrasound at 24 weeks’ gestation identified fetal cardiomegaly and ascites. The cardiothoracic ratio was 0.60. Pericardial effusion was 2.5 mm and placental depth was 5.6 cm. The fetal middle cerebral artery peak systolic velocity (MCA-PSV) was 50 cm/s (41.55 MoM). The woman denied that she had taken any medicine during pregnancy. These signs indicated the onset of fetal hydrops. Maternal investigations, including Rh and ABO blood group, Kleihauer and screening for the TORCH (toxoplasma gondii, rubella virus, cytomegalovirus and herpes simplex virus),
2
S. He et al.
Hemoglobin, Early Online: 1–4
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Table 1. Summary of hematological findings and a genotypes of both parents and the fetus. Parameters
Father
Mother
Fetus
Hb (g/dL) RBC (1012/L) nRBC (/100WBC) MCV (fL) MCH (pg) MCHC (g/dL) Heinz bodies Hb A2 (%) Hb A (%) Hb F (%) Hb Bart’s (%) Hb H (%) Hb Portland (%) G6PD screening a Genotype
13.7 5.18 0.0 69.5 22.3 35.4 none 2.1 ND ND ND ND ND ND SEA CS /a a
11.1 5.10 0.0 79.5 26.5 36.7 none 2.3 97.9 ND ND ND ND ND aCSa/aa
5.3 2.43 4200.0 103.0 29.0 30.0 NA ND 97.7; 17.3 50.0 31.1 0.7 0.9 normal SEA CS /a a
Hb: hemoglobin, RBC: red blood cell count; nRBC: nucleated RBC; MCV: mean corpuscular volume; MCH: mean corpuscular Hb; MCHC: mean corpuscular Hb concentration; ND: not detected; G6PD: glucose-6-phosphate dehydrogenase; SEA: Southeast Asian; CS: Hb Constant Spring.
syphilis and parvovirus infections, were all negative. A fetal blood sample indicated severe fetal anemia (5.3 g/dL). Blood smear analysis revealed the red blood cells (RBCs) were microcytic and hypochromic, with mild anisopoikilocytosis, basophilic stippling and markedly increased nucleated RBCs (nRBCs) (Table 1). The white blood cell (WBC) and platelet morphology were normal. Hemoglobin analysis was performed by an automated capillary electrophoresis system (CapillaryS2; Sebia, Paris, France; software version 6.2), with the following hematological findings: Hb Bart’s 31.1%, Hb A 17.3%, Hb F 50.0%, Hb H 0.7% and Hb Portland 0.9%. The metHb reduction test showed that the glucose-6-phosphate dehydrogenase (G6PD) of the fetus was normal. No structural abnormality was identified using karyotyping analysis and array-based comparative genimic hybridization (aCGH) (Illumina human CytoSNP-12 Bead Chip; Illumina Inc., San Diego, CA, USA) containing unique oligonucleotides representing 300,000 probes (300 K) with average probe spacing across the human genome of 10 Kb. The fetal karyotype was 46,XY. Molecular analysis including DNA sequencing of the SEA CS a-globin genes indicated the fetal genotype was /a a (Figure 1). The diagnosis of Hb H hydrops fetalis syndrome was confirmed based on the finding that Hb Bart’s levels were within the range that is typically observed for classic Hb H disease at birth. The presence of a-globin production in the form of Hb F and Hb A was a notable difference from the classic case of Hb Bart’s hydrops fetalis. However, the fetus was severely anemic in utero, resulting in hydropic changes. It was decided that the levels of a-globin synthesis observed in the fetus would probably be compatible with postnatal life; the couple was counseled accordingly. However, they declined an intrauterine transfusion. The pregnancy continued. Another ultrasound scan was performed at 30 weeks. The fetal cardiothoracic ration was increased to 0.72 and the placental depth was increased to 6.2 cm. Mild ascites and pleural effusions were also noted. These findings indicated the progress of the disease. The couple was counseled again
about the prognosis of the fetus if no therapeutic measure was taken. After serious consideration, they decided to terminate the pregnancy. As third-trimester termination is permissible in China, the pregnancy was terminated at 31 weeks at the parents’ request. After feticide, labor was induced by intravaginal misoprostol. The male fetus had the appearance of hydrops and weighed 1850 g with an enlarged placenta weighing 920 g. The couple declined an autopsy. Hb CS is an Hb variant that results from a nucleotide substitution (TAA4CAA) at the termination codon of the a2-globin gene. This point mutation causes a marked decrease in synthesis of an elongated and unstable a-globin chain (7,8). Heterozygosity for this mutation is usually associated with normal hematological data (2). Compound heterozygosity of an a0-thal determinant with Hb CS ( /aCSa) results in a form of Hb H/Hb CS disease that is more clinically severe than the triple a gene deletion Hb H disease ( / a). Patients with this disease have lower baseline Hb and some are even transfusion dependent. Homozygosity for Hb CS (aCSa/aCSa) has been observed to cause hydrops fetalis (8), whereas, Hb H hydrops syndrome has never been mentioned as the result of a deletion and the aCSa mutation. Weatherall and Higgs (2) and Lorey et al. (9) found that fetuses with the SEA CS THAI CS genotypes of either /a a or /a a resulted in severe anemia in utero, but did not develop severe hydrops fetalis syndrome. Another case reported by Law et al. (10) presented prenatally with anemia and cardiomegaly but with no other signs of hydropic features. In this report, the fetus with Hb H/Hb CS increased fetal cardiothoracic ration from 0.52 at 21 weeks to 0.59 at 23 weeks (10). The Hb level at 23 weeks’ gestation was 6.7 g/dL with 40.0% Hb Barts and 60.0% Hb F. The MCA-PSV improved from 1.29 to 1.50 MoM with advancing gestation. No intrauterine transfusion was given. A healthy baby was delivered vaginally at 40 weeks’ gestation, with a Hb level of 13.0 g/dL, while in our case, the fetus with anemia and cardiomegaly could be seen. Other hydropic features such as ascites, pleural effusion and pericardial effusion were also noted at 24 weeks’ and 30 weeks’ gestation, respectively. Many of the known causes for hydrops fetalis, such as homozygous a0-thal, fetal-maternal blood group incompatibility, congenital TORCH infections (toxoplasma, rubella virus, cytomegalovirus, and herpes virus), congenital cardiac disease, G6PD deficiency and aneuploidy, were all excluded. The severe anemia in this fetus is thought to have been a result of hemolysis. As indicated in the results section, the hydropic changes became apparent along with markedly increased nRBC levels. Furthermore, the Hb Bart’s fraction (31.1%) in this fetus was similar to those previously reported in fetuses with the Hb H hydrops fetalis syndrome (31.0 to 66.0%) (5). Compound heterozygosity for /aCSa in this case appeared to produce a phenotype of fetal hydrops, similar to Hb H/Hb QS ( /aQSa), which was reported as hydrops fetalis in a Chinese family (6). However, the reasons for extreme severity of clinical presentation in these infants are not well understood. These findings may suggest that the genetic defects on a-globin genes are not the sole determinant of clinical outcome of Hb H disease and other non globin gene-related elements or external environmental factors can modify
Hydrops Fetalis Caused by Hb H/Hb CS Disease
3
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
DOI: 10.3109/03630269.2015.1030031
Figure 1. Results of chromosome karyotype analysis and array CGH. (A) Karyotype of the fetus showing a normal 46,XY karyotype. (B) Result of array CGH at chromosome 16. (C) DNA sequencing of a2-globin genes from the fetus showing a heterozygous TAA4CAA mutation at codon 142.
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
4
S. He et al.
the phenotype when a-globin chain production is critically low (4). In conclusion, our report serves to emphasize the phenotypic diversity and highlights the clinical significance of Hb H/Hb CS disease, which varies from a mild hypochromic, microcytic anemia to a lethal intrauterine anemia associated with hydrops fetalis that developed early SEA in life. As the and aCSa mutations are particularly prevalent in Southeast Asia, Hb H/Hb CS disease might not be as benign a condition as previously thought, and caution must be taken to ensure that at-risk couples are not overlooked by thalassemia prevention programs or prenatal diagnosis settings. Rather, families at-risk from the interacSEA tion of the and aCSa alleles should be identified and appropriately counseled. The sonographic findings were extremely helpful in detecting hydrops fetalis in this case. Therefore, we would recommend that fetus with Hb H/Hb CS disease should be followed by serial ultrasound after a gestational age of 20 weeks and if fetal hydrops is identified, intrauterine transfusion should be considered. Successful outcomes have been reported following intrauterine transfusion for Hb H hydrops fetalis disease (9).
Acknowledgements We are grateful to our current laboratory members for their helpful comments on the manuscript.
Declaration of interest The study was supported by grants from the Health Department of Guangxi Province (Zhong 2012020), Guangxi Science and Technology Department (Gui
Hemoglobin, Early Online: 1–4
14124004-1-5) and the National Science Foundation of China (81260093). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Xiong F, Sun M, Zhang X, et al. Molecular epidemiological survey of haemoglobinopathies in the Guangxi Zhuang Autonomous Region of Southern China. Clin Genet. 2010;78(2):139–148. 2. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes, 4th ed. Oxford, UK: Blackwell Science, 2001. 3. Chan V, Chan VW, Tang M, et al. Molecular defects in Hb H hydrops foetalis. Br J Haematol. 1997;96(2):224–228. 4. Lorey F, Cunningham G, Vichinsky EP, et al. Universal newborn screening for Hb H disease in California. Genetic Test. 2001; 5(2):93–100. 5. Viprakasit V, Green S, Height S, et al. Hb H hydrops fetalis syndrome associated with the interaction of two common MED determinants of a-thalassaemia Hb H hydrops fetalis ( / aTSaudia). Br J Haematol. 2002;117(3):759–762. 6. Li DZ, Lao C, Li J, et al. Hemoglobin H hydrops fetalis SEA syndrome resulting from the association of the deletion Quong Sze and the a a mutation in a Chinese woman. Eur J Haematol. 2005;75(3):259–261. 7. Li DZ. Diversity in clinical phenotype of nondeletional Hemoglobin H disease with the same genetic defect. J Pediatr Hematol Oncol. 2009;31(12):991. doi: 10.1097/MPH. 0b013e3181bd4181. 8. Charoenkwan P, Sirichotiyakul S, Chanpraph P, et al. Anemia and hydrops in a fetus with homozygous Hemoglobin Constant Spring. J Pediatr Hematol Oncol. 2006;28(12):827–830. 9. Lorey F, Charoenkwan P, Witkowska HE, et al. Hb H hydrops foetalis syndrome: A case report and review of literature. Br J Haematol. 2001;115(1):72–78. 10. Law LW, Lau TK, Fung TY, et al. De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency. BJOG. 2009;116(2):339–343.
SHORT COMMUNICATION SEA Hb H Hydrops Fetalis Syndrome Caused by Association of the Deletion and Hb Constant Spring (HBA2: c.427T4C) Mutation in a Chinese Family Sheng He, Chenguang Zheng, Dahua Meng, Rongyu Chen, Qiang Zhang, Xiaoxian Tian, and Shaoke Chen
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Prenatal Diagnostic Centre, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, Nanning, People’s Republic of China
Abstract
Keywords
Hb Constant Spring (Hb CS; HBA2: c.427T4C) is an unstable hemoglobin (Hb) variant that results from a nucleotide substitution at the termination codon of the a2-globin gene. SEA CS /a a) results in Hb H/ Compound heterozygosity for a0-thalassemia (a0-thal) and Hb CS ( Hb CS disease, which is generally characterized with mild hemolytic anemia, jaundice, and splenomegaly. Here, we describe one case with Hb H/Hb CS disease that presented with fetal anemia and fetal hydrops, known as Hb H (b4) hydrops fetalis. This is the first report of fetal SEA deletion and the aCSa mutation. Our study hydrops caused by association of the highlights the significance of watchful observation using a serial ultrasound method and care of pregnant women who have fetuses found to carry Hb H/Hb CS disease during pregnancy, to guard against the occurrence of fetal hydrops.
a-Globin gene, a-thalassemia (a-thal), Hb H hydrops fetalis, Hb H/Hb CS disease
The a-thalassemias are the most common inherited disorders of hemoglobin (Hb) synthesis in southern China, with an especially high prevalence rate of 17.5% in Guangxi Province (1). These disorders result from deletions or mutations (or both) on the a-globin genes, of which there are four in the normal genome, and are characterized by absent or decreased rate of a-globin synthesis. Hb Bart’s (g4) hydrops fetalis is the most severe form of a-thal, which typically arises from the deletion of all four functioning a-globin genes; individuals with this form always succumb in utero or soon after birth (2). Occasionally, hydrops fetalis can be caused by Hb H disease, in which there is only one functioning a-globin gene; these cases are recognized as having Hb H hydrops fetalis syndrome. Affected fetuses have severe anemia and findings consistent with the classic Hb Bart’s hydrops fetalis. There are sporadic reports of fetuses with Hb H hydrops fetalis syndrome (3–6). Here, we describe a new case of fetal SEA anemia and hydrops resulting from association of the deletion and a nondeletional a2-globin gene Hb Constant Spring (Hb CS; HBA2: c.427T4C) (aCSa) mutation.
Address correspondence to Professor Chenguang Zheng, Prenatal Diagnostic Centre, Guangxi Zhuang Autonomous Region Women and Children Care Hospital, 59 Xiangzhu Road, Nanning, 530000, People’s Republic of China. Tel: +86-771-580-2285. Fax: +86-771-580-2075. E-mail: [email protected]
History Received 29 July 2014 Revised 11 October 2014 Accepted 15 October 2014 Published online 21 April 2015
A 28-year-old woman and her husband from Guangxi Zhuang Autonomous Region, China presented at our center for the first antenatal visit at 12 weeks’ gestation. This was the mother’s first pregnancy, and there was no history of miscarriage, fever, rash, headache or edema. Thalassemia testing showed the mother and father were both carriers of a-thal. The parents hematological data and genotypes are summarized in Table 1. Gap-polymerase chain reaction (PCR) and reverse dot blot were performed in order to detect the SEA three a-globin gene deletion mutations [ , a3.7 4.2 (rightward) and a (leftward)] and three nondeletional mutations [Hb Westmead (HBA2: c.369C4G), Hb CS and Hb Quong Sze (Hb QS; HBA2: c.377T4C or HBA1)] that are common in the Chinese population. The results showed that the woman was heterozygous for the Southeast Asian (SEA) SEA deletion ( /aa) and her husband was heterozygous for CS Hb CS (aa/a a). Anatomical scans of the fetus were normal at 12 weeks’ gestation, while an ultrasound at 24 weeks’ gestation identified fetal cardiomegaly and ascites. The cardiothoracic ratio was 0.60. Pericardial effusion was 2.5 mm and placental depth was 5.6 cm. The fetal middle cerebral artery peak systolic velocity (MCA-PSV) was 50 cm/s (41.55 MoM). The woman denied that she had taken any medicine during pregnancy. These signs indicated the onset of fetal hydrops. Maternal investigations, including Rh and ABO blood group, Kleihauer and screening for the TORCH (toxoplasma gondii, rubella virus, cytomegalovirus and herpes simplex virus),
2
S. He et al.
Hemoglobin, Early Online: 1–4
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
Table 1. Summary of hematological findings and a genotypes of both parents and the fetus. Parameters
Father
Mother
Fetus
Hb (g/dL) RBC (1012/L) nRBC (/100WBC) MCV (fL) MCH (pg) MCHC (g/dL) Heinz bodies Hb A2 (%) Hb A (%) Hb F (%) Hb Bart’s (%) Hb H (%) Hb Portland (%) G6PD screening a Genotype
13.7 5.18 0.0 69.5 22.3 35.4 none 2.1 ND ND ND ND ND ND SEA CS /a a
11.1 5.10 0.0 79.5 26.5 36.7 none 2.3 97.9 ND ND ND ND ND aCSa/aa
5.3 2.43 4200.0 103.0 29.0 30.0 NA ND 97.7; 17.3 50.0 31.1 0.7 0.9 normal SEA CS /a a
Hb: hemoglobin, RBC: red blood cell count; nRBC: nucleated RBC; MCV: mean corpuscular volume; MCH: mean corpuscular Hb; MCHC: mean corpuscular Hb concentration; ND: not detected; G6PD: glucose-6-phosphate dehydrogenase; SEA: Southeast Asian; CS: Hb Constant Spring.
syphilis and parvovirus infections, were all negative. A fetal blood sample indicated severe fetal anemia (5.3 g/dL). Blood smear analysis revealed the red blood cells (RBCs) were microcytic and hypochromic, with mild anisopoikilocytosis, basophilic stippling and markedly increased nucleated RBCs (nRBCs) (Table 1). The white blood cell (WBC) and platelet morphology were normal. Hemoglobin analysis was performed by an automated capillary electrophoresis system (CapillaryS2; Sebia, Paris, France; software version 6.2), with the following hematological findings: Hb Bart’s 31.1%, Hb A 17.3%, Hb F 50.0%, Hb H 0.7% and Hb Portland 0.9%. The metHb reduction test showed that the glucose-6-phosphate dehydrogenase (G6PD) of the fetus was normal. No structural abnormality was identified using karyotyping analysis and array-based comparative genimic hybridization (aCGH) (Illumina human CytoSNP-12 Bead Chip; Illumina Inc., San Diego, CA, USA) containing unique oligonucleotides representing 300,000 probes (300 K) with average probe spacing across the human genome of 10 Kb. The fetal karyotype was 46,XY. Molecular analysis including DNA sequencing of the SEA CS a-globin genes indicated the fetal genotype was /a a (Figure 1). The diagnosis of Hb H hydrops fetalis syndrome was confirmed based on the finding that Hb Bart’s levels were within the range that is typically observed for classic Hb H disease at birth. The presence of a-globin production in the form of Hb F and Hb A was a notable difference from the classic case of Hb Bart’s hydrops fetalis. However, the fetus was severely anemic in utero, resulting in hydropic changes. It was decided that the levels of a-globin synthesis observed in the fetus would probably be compatible with postnatal life; the couple was counseled accordingly. However, they declined an intrauterine transfusion. The pregnancy continued. Another ultrasound scan was performed at 30 weeks. The fetal cardiothoracic ration was increased to 0.72 and the placental depth was increased to 6.2 cm. Mild ascites and pleural effusions were also noted. These findings indicated the progress of the disease. The couple was counseled again
about the prognosis of the fetus if no therapeutic measure was taken. After serious consideration, they decided to terminate the pregnancy. As third-trimester termination is permissible in China, the pregnancy was terminated at 31 weeks at the parents’ request. After feticide, labor was induced by intravaginal misoprostol. The male fetus had the appearance of hydrops and weighed 1850 g with an enlarged placenta weighing 920 g. The couple declined an autopsy. Hb CS is an Hb variant that results from a nucleotide substitution (TAA4CAA) at the termination codon of the a2-globin gene. This point mutation causes a marked decrease in synthesis of an elongated and unstable a-globin chain (7,8). Heterozygosity for this mutation is usually associated with normal hematological data (2). Compound heterozygosity of an a0-thal determinant with Hb CS ( /aCSa) results in a form of Hb H/Hb CS disease that is more clinically severe than the triple a gene deletion Hb H disease ( / a). Patients with this disease have lower baseline Hb and some are even transfusion dependent. Homozygosity for Hb CS (aCSa/aCSa) has been observed to cause hydrops fetalis (8), whereas, Hb H hydrops syndrome has never been mentioned as the result of a deletion and the aCSa mutation. Weatherall and Higgs (2) and Lorey et al. (9) found that fetuses with the SEA CS THAI CS genotypes of either /a a or /a a resulted in severe anemia in utero, but did not develop severe hydrops fetalis syndrome. Another case reported by Law et al. (10) presented prenatally with anemia and cardiomegaly but with no other signs of hydropic features. In this report, the fetus with Hb H/Hb CS increased fetal cardiothoracic ration from 0.52 at 21 weeks to 0.59 at 23 weeks (10). The Hb level at 23 weeks’ gestation was 6.7 g/dL with 40.0% Hb Barts and 60.0% Hb F. The MCA-PSV improved from 1.29 to 1.50 MoM with advancing gestation. No intrauterine transfusion was given. A healthy baby was delivered vaginally at 40 weeks’ gestation, with a Hb level of 13.0 g/dL, while in our case, the fetus with anemia and cardiomegaly could be seen. Other hydropic features such as ascites, pleural effusion and pericardial effusion were also noted at 24 weeks’ and 30 weeks’ gestation, respectively. Many of the known causes for hydrops fetalis, such as homozygous a0-thal, fetal-maternal blood group incompatibility, congenital TORCH infections (toxoplasma, rubella virus, cytomegalovirus, and herpes virus), congenital cardiac disease, G6PD deficiency and aneuploidy, were all excluded. The severe anemia in this fetus is thought to have been a result of hemolysis. As indicated in the results section, the hydropic changes became apparent along with markedly increased nRBC levels. Furthermore, the Hb Bart’s fraction (31.1%) in this fetus was similar to those previously reported in fetuses with the Hb H hydrops fetalis syndrome (31.0 to 66.0%) (5). Compound heterozygosity for /aCSa in this case appeared to produce a phenotype of fetal hydrops, similar to Hb H/Hb QS ( /aQSa), which was reported as hydrops fetalis in a Chinese family (6). However, the reasons for extreme severity of clinical presentation in these infants are not well understood. These findings may suggest that the genetic defects on a-globin genes are not the sole determinant of clinical outcome of Hb H disease and other non globin gene-related elements or external environmental factors can modify
Hydrops Fetalis Caused by Hb H/Hb CS Disease
3
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
DOI: 10.3109/03630269.2015.1030031
Figure 1. Results of chromosome karyotype analysis and array CGH. (A) Karyotype of the fetus showing a normal 46,XY karyotype. (B) Result of array CGH at chromosome 16. (C) DNA sequencing of a2-globin genes from the fetus showing a heterozygous TAA4CAA mutation at codon 142.
Hemoglobin Downloaded from informahealthcare.com by Nyu Medical Center on 06/20/15 For personal use only.
4
S. He et al.
the phenotype when a-globin chain production is critically low (4). In conclusion, our report serves to emphasize the phenotypic diversity and highlights the clinical significance of Hb H/Hb CS disease, which varies from a mild hypochromic, microcytic anemia to a lethal intrauterine anemia associated with hydrops fetalis that developed early SEA in life. As the and aCSa mutations are particularly prevalent in Southeast Asia, Hb H/Hb CS disease might not be as benign a condition as previously thought, and caution must be taken to ensure that at-risk couples are not overlooked by thalassemia prevention programs or prenatal diagnosis settings. Rather, families at-risk from the interacSEA tion of the and aCSa alleles should be identified and appropriately counseled. The sonographic findings were extremely helpful in detecting hydrops fetalis in this case. Therefore, we would recommend that fetus with Hb H/Hb CS disease should be followed by serial ultrasound after a gestational age of 20 weeks and if fetal hydrops is identified, intrauterine transfusion should be considered. Successful outcomes have been reported following intrauterine transfusion for Hb H hydrops fetalis disease (9).
Acknowledgements We are grateful to our current laboratory members for their helpful comments on the manuscript.
Declaration of interest The study was supported by grants from the Health Department of Guangxi Province (Zhong 2012020), Guangxi Science and Technology Department (Gui
Hemoglobin, Early Online: 1–4
14124004-1-5) and the National Science Foundation of China (81260093). The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
References 1. Xiong F, Sun M, Zhang X, et al. Molecular epidemiological survey of haemoglobinopathies in the Guangxi Zhuang Autonomous Region of Southern China. Clin Genet. 2010;78(2):139–148. 2. Weatherall DJ, Clegg JB. The Thalassaemia Syndromes, 4th ed. Oxford, UK: Blackwell Science, 2001. 3. Chan V, Chan VW, Tang M, et al. Molecular defects in Hb H hydrops foetalis. Br J Haematol. 1997;96(2):224–228. 4. Lorey F, Cunningham G, Vichinsky EP, et al. Universal newborn screening for Hb H disease in California. Genetic Test. 2001; 5(2):93–100. 5. Viprakasit V, Green S, Height S, et al. Hb H hydrops fetalis syndrome associated with the interaction of two common MED determinants of a-thalassaemia Hb H hydrops fetalis ( / aTSaudia). Br J Haematol. 2002;117(3):759–762. 6. Li DZ, Lao C, Li J, et al. Hemoglobin H hydrops fetalis SEA syndrome resulting from the association of the deletion Quong Sze and the a a mutation in a Chinese woman. Eur J Haematol. 2005;75(3):259–261. 7. Li DZ. Diversity in clinical phenotype of nondeletional Hemoglobin H disease with the same genetic defect. J Pediatr Hematol Oncol. 2009;31(12):991. doi: 10.1097/MPH. 0b013e3181bd4181. 8. Charoenkwan P, Sirichotiyakul S, Chanpraph P, et al. Anemia and hydrops in a fetus with homozygous Hemoglobin Constant Spring. J Pediatr Hematol Oncol. 2006;28(12):827–830. 9. Lorey F, Charoenkwan P, Witkowska HE, et al. Hb H hydrops foetalis syndrome: A case report and review of literature. Br J Haematol. 2001;115(1):72–78. 10. Law LW, Lau TK, Fung TY, et al. De novo 16p13.11 microdeletion identified by high-resolution array CGH in a fetus with increased nuchal translucency. BJOG. 2009;116(2):339–343.
