A Fetus with Diamond-Blackfan Anemia and HLHS: Expanding the Cardiac Phenotype
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Diamond-Blackfan Anemia (DBA) is a rare bone marrow failure syndrome caused primarily by variants in ribosomal protein genes. DBA is characterized by early-onset hypoplastic anemia, growth deficiency (30%), malignancy risks (2-5%), and congenital anomalies (50%).
Congenital heart defects (CHDs) previously reported in individuals with DBA include ventricular/atrial septal defect, coarctation of the aorta, pulmonic/aortic valve stenosis, tetralogy of Fallot, total anomalous pulmonary venous return, and others. We describe the first case of hypoplastic left heart syndrome (HLHS) in association with DBA.
Case Presentation
30-year-old primigravida referred at 24 weeks 5 days gestation for complex CHD. The pregnancy was conceived spontaneously, and exposures were denied. Significant family history included the father of the baby with DBA diagnosed at 1 year old and hypospadias. He was treated with blood transfusions and prednisone for 8 years with subsequent remission. His genetic testing confirmed a heterozygous, pathogenic RPS19 variant (c.384_385delAA, p.Asp130Serfs*23).
Ultrasound at our center identified fetal growth restriction (8th percentile estimated fetal weight [EFW]), HLHS, small pericardial effusion, trace ascites, and normal doppler studies, without evidence of anemia based on middle cerebral artery peak systolic velocity (MCA-PSV, 1.23 MoM). Fetal echocardiogram confirmed HLHS with mitral hypoplasia and aortic atresia with normal right ventricular (RV) systolic function. The pericardial effusion and trace ascites were concerning for potential hydrops fetalis, especially given the risk for hydrops associated with severe anemia if the fetus had DBA.
Diagnostic Workup
Diagnostic genetic testing via amniocentesis was pursued. Cytogenetic studies (FISH for common aneuploidies, chromosome analysis, and microarray) were normal. Targeted testing revealed the fetus was heterozygous for the paternal RPS19 variant, thus consistent with a fetal diagnosis of DBA.
Treatment and Management
Given concern for hydrops, serial monitoring of fetal MCA-PSV measurements and hydrops checks were recommended. Option of intrauterine transfusions (IUTs) in the setting of worsening hydrops or definitive evidence of anemia was reviewed. Cardiology discussed potential implications for survival/candidacy for single ventricle palliation due to risk for severe anemia at birth. The pregnancy was monitored locally without change until follow-up ultrasound at our center at 34 weeks 5 days. There was ongoing fetal growth restriction (4th percentile EFW). Doppler studies of the umbilical artery, umbilical vein, and MCA were normal, without suggestion of anemia. Severe cardiomegaly was present with a moderate pericardial effusion and trace ascites. Echocardiogram demonstrated HLHS with normal RV systolic function, but a highly restrictive atrial communication, prompting recommendation for cesarean delivery with immediate cardiac intervention anticipated at birth. Despite no specific evidence of fetal anemia, given the cardiomegaly out of proportion to the cardiac disease with the known DBA diagnosis, this raised concern for an underlying degree of fetal anemia. Cordocentesis with IUT was considered, however due to the risks of IUT without clear evidence of severe fetal anemia, expectant management was pursued.
Outcome and Follow-Up
Ultrasound at 35 weeks 5 days diagnosed intrauterine fetal demise and scalp edema. Delivery occurred via induction of labor. Fetal autopsy was declined.
Discussion
While CHDs are a known feature of DBA, HLHS is a previously unreported cardiac manifestation. Although most isolated CHDs are typically thought to be multifactorial in nature, this case emphasizes the value of considering testing for single gene etiologies, as the growth restriction and fluid accumulations were not initially identified. Confirming the DBA diagnosis had significant implications for prenatal management and planned postnatal care of this fetus. Recommendations for monitoring MCA-PSV measurements and hydrops checks, as well as consideration of IUT were facilitated by this genetic diagnosis.
Conclusion
This case thus expands the known cardiac phenotype of DBA, demonstrates a significant degree of intrafamilial variability, and highlights the value of a definitive molecular diagnosis in guiding prenatal/postnatal management and potential fetal therapy options.
Diamond-Blackfan Anemia (DBA) is a rare bone marrow failure syndrome caused primarily by variants in ribosomal protein genes. DBA is characterized by early-onset hypoplastic anemia, growth deficiency (30%), malignancy risks (2-5%), and congenital anomalies (50%).
Congenital heart defects (CHDs) previously reported in individuals with DBA include ventricular/atrial septal defect, coarctation of the aorta, pulmonic/aortic valve stenosis, tetralogy of Fallot, total anomalous pulmonary venous return, and others. We describe the first case of hypoplastic left heart syndrome (HLHS) in association with DBA.
Case Presentation
30-year-old primigravida referred at 24 weeks 5 days gestation for complex CHD. The pregnancy was conceived spontaneously, and exposures were denied. Significant family history included the father of the baby with DBA diagnosed at 1 year old and hypospadias. He was treated with blood transfusions and prednisone for 8 years with subsequent remission. His genetic testing confirmed a heterozygous, pathogenic RPS19 variant (c.384_385delAA, p.Asp130Serfs*23).
Ultrasound at our center identified fetal growth restriction (8th percentile estimated fetal weight [EFW]), HLHS, small pericardial effusion, trace ascites, and normal doppler studies, without evidence of anemia based on middle cerebral artery peak systolic velocity (MCA-PSV, 1.23 MoM). Fetal echocardiogram confirmed HLHS with mitral hypoplasia and aortic atresia with normal right ventricular (RV) systolic function. The pericardial effusion and trace ascites were concerning for potential hydrops fetalis, especially given the risk for hydrops associated with severe anemia if the fetus had DBA.
Diagnostic Workup
Diagnostic genetic testing via amniocentesis was pursued. Cytogenetic studies (FISH for common aneuploidies, chromosome analysis, and microarray) were normal. Targeted testing revealed the fetus was heterozygous for the paternal RPS19 variant, thus consistent with a fetal diagnosis of DBA.
Treatment and Management
Given concern for hydrops, serial monitoring of fetal MCA-PSV measurements and hydrops checks were recommended. Option of intrauterine transfusions (IUTs) in the setting of worsening hydrops or definitive evidence of anemia was reviewed. Cardiology discussed potential implications for survival/candidacy for single ventricle palliation due to risk for severe anemia at birth. The pregnancy was monitored locally without change until follow-up ultrasound at our center at 34 weeks 5 days. There was ongoing fetal growth restriction (4th percentile EFW). Doppler studies of the umbilical artery, umbilical vein, and MCA were normal, without suggestion of anemia. Severe cardiomegaly was present with a moderate pericardial effusion and trace ascites. Echocardiogram demonstrated HLHS with normal RV systolic function, but a highly restrictive atrial communication, prompting recommendation for cesarean delivery with immediate cardiac intervention anticipated at birth. Despite no specific evidence of fetal anemia, given the cardiomegaly out of proportion to the cardiac disease with the known DBA diagnosis, this raised concern for an underlying degree of fetal anemia. Cordocentesis with IUT was considered, however due to the risks of IUT without clear evidence of severe fetal anemia, expectant management was pursued.
Outcome and Follow-Up
Ultrasound at 35 weeks 5 days diagnosed intrauterine fetal demise and scalp edema. Delivery occurred via induction of labor. Fetal autopsy was declined.
Discussion
While CHDs are a known feature of DBA, HLHS is a previously unreported cardiac manifestation. Although most isolated CHDs are typically thought to be multifactorial in nature, this case emphasizes the value of considering testing for single gene etiologies, as the growth restriction and fluid accumulations were not initially identified. Confirming the DBA diagnosis had significant implications for prenatal management and planned postnatal care of this fetus. Recommendations for monitoring MCA-PSV measurements and hydrops checks, as well as consideration of IUT were facilitated by this genetic diagnosis.
Conclusion
This case thus expands the known cardiac phenotype of DBA, demonstrates a significant degree of intrafamilial variability, and highlights the value of a definitive molecular diagnosis in guiding prenatal/postnatal management and potential fetal therapy options.
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