Prenatal whole genome sequencing to diagnosis rare presentations of hydrops fetalis
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Hydrops fetalis is a prenatal condition characterized by a significant amount of abnormal fluid build-up in the fetus. There are two types of hydrops fetalis: immune and nonimmune. Immune is the result of a maternal reaction to the red blood cells of the fetus termed Rh incompatibility. Nonimmune hydrops is a heterogenous group of etiologies including cardiac, infectious, genetic, and hematologic causes. Prognosis for the neonate depends on the underlying diagnosis. Here we present two cases of fetal hydrops in which prenatal whole genome sequencing (WGS) provided diagnostic and prognostic information for pregnancy management.
Case Presentation
Case #1 is 33 year-old G2P1001 who was referred to Maternal Fetal Medicine at 29 weeks for fetal hydrops which was diagnosed at a routine prenatal visit. Pregnancy was otherwise complicated by intrahepatic cholestasis. Detailed fetal anatomy demonstrated intra-abdominal ascites, skin edema, and polyhydramnios without evidence of structural anomalies. Previously completed cell free DNA screening was low risk.
Case #2 is a 29 year-old G2P1001 presented to Maternal Fetal Medicine at 29 weeks for evaluation of hydrops. Detailed fetal anatomy demonstrated asymmetric pleural effusions, diffuse skin edema, and intra-abdominal ascites. No prior genetic screening was completed, and the pregnancy was otherwise uncomplicated.
Diagnostic Workup
Both patients underwent extensive work-ups including detailed fetal anatomy ultrasound, amniocentesis with prenatal WGS, fetal echocardiogram, and infectious etiologies.
Treatment and Management
Case 1: results of WGS returned prior to delivery and were significant for heterozygous de novo pathogenic variant in KMT2D (c.8056C>T, p. Arg2685Ter), consistent with Kabuki syndrome. The patient underwent an uncomplicated planned primary cesarean delivery at 36w2d weeks. The neonate was transferred to the Neonatal Intensive Care Unit after delivery and was admitted for approximately 4 weeks. Postnatal exam was significant for a cleft palate and development of seizures. G-tube feedings were required at time of discharge.
Case 2: the patient underwent thoracentesis and right thoracoamniotic shunt placement due to asymmetric pleural effusions. After placement, patient presented at 31w4d with contractions and underwent cesarean delivery for placental abruption. The neonate passed away at 38 hours of life from complications of hydrops. Results of prenatal WGS returned after neonatal demise and were significant for a maternally inherited pathogenic variant in the EPHB4 gene (c.2354G>A, p.Arg785Gln).
Outcome and Follow-Up
Kabuki syndrome has a wide spectrum of outcomes; common features include skeletal anomalies, intellectual disability, hearing loss, and kidney disease. There have been rare case reports of fetal hydrops with Kabuki syndrome, although it is not a common presentation.
Variants in the EPHB4 gene have been associated with autosomal dominant lymphatic malformation type 7. This is characterized by variable phenotypes including non-immune hydrops, edema, atrial septal defects, and varicose veins. Variable expression is observed within families.
Discussion
For both cases presented here, WGS provided additional diagnostic information. While the results in case #2 were not known prior to delivery, in case #1 antenatal results allowed for neonatology notification and appropriate postnatal planning. Results have also been important in counseling for recurrence risks.
Conclusion
Hydrops fetalis is a challenging prenatal diagnosis with multiple potential etiologies. Historically, approximately 25% of cases of fetal hydrops have an unknown etiology. Prenatal genome sequencing may provide further insight to potential etiology and additional information for antenatal and postnatal management and treatment, as well as counseling for recurrence risks.
Hydrops fetalis is a prenatal condition characterized by a significant amount of abnormal fluid build-up in the fetus. There are two types of hydrops fetalis: immune and nonimmune. Immune is the result of a maternal reaction to the red blood cells of the fetus termed Rh incompatibility. Nonimmune hydrops is a heterogenous group of etiologies including cardiac, infectious, genetic, and hematologic causes. Prognosis for the neonate depends on the underlying diagnosis. Here we present two cases of fetal hydrops in which prenatal whole genome sequencing (WGS) provided diagnostic and prognostic information for pregnancy management.
Case Presentation
Case #1 is 33 year-old G2P1001 who was referred to Maternal Fetal Medicine at 29 weeks for fetal hydrops which was diagnosed at a routine prenatal visit. Pregnancy was otherwise complicated by intrahepatic cholestasis. Detailed fetal anatomy demonstrated intra-abdominal ascites, skin edema, and polyhydramnios without evidence of structural anomalies. Previously completed cell free DNA screening was low risk.
Case #2 is a 29 year-old G2P1001 presented to Maternal Fetal Medicine at 29 weeks for evaluation of hydrops. Detailed fetal anatomy demonstrated asymmetric pleural effusions, diffuse skin edema, and intra-abdominal ascites. No prior genetic screening was completed, and the pregnancy was otherwise uncomplicated.
Diagnostic Workup
Both patients underwent extensive work-ups including detailed fetal anatomy ultrasound, amniocentesis with prenatal WGS, fetal echocardiogram, and infectious etiologies.
Treatment and Management
Case 1: results of WGS returned prior to delivery and were significant for heterozygous de novo pathogenic variant in KMT2D (c.8056C>T, p. Arg2685Ter), consistent with Kabuki syndrome. The patient underwent an uncomplicated planned primary cesarean delivery at 36w2d weeks. The neonate was transferred to the Neonatal Intensive Care Unit after delivery and was admitted for approximately 4 weeks. Postnatal exam was significant for a cleft palate and development of seizures. G-tube feedings were required at time of discharge.
Case 2: the patient underwent thoracentesis and right thoracoamniotic shunt placement due to asymmetric pleural effusions. After placement, patient presented at 31w4d with contractions and underwent cesarean delivery for placental abruption. The neonate passed away at 38 hours of life from complications of hydrops. Results of prenatal WGS returned after neonatal demise and were significant for a maternally inherited pathogenic variant in the EPHB4 gene (c.2354G>A, p.Arg785Gln).
Outcome and Follow-Up
Kabuki syndrome has a wide spectrum of outcomes; common features include skeletal anomalies, intellectual disability, hearing loss, and kidney disease. There have been rare case reports of fetal hydrops with Kabuki syndrome, although it is not a common presentation.
Variants in the EPHB4 gene have been associated with autosomal dominant lymphatic malformation type 7. This is characterized by variable phenotypes including non-immune hydrops, edema, atrial septal defects, and varicose veins. Variable expression is observed within families.
Discussion
For both cases presented here, WGS provided additional diagnostic information. While the results in case #2 were not known prior to delivery, in case #1 antenatal results allowed for neonatology notification and appropriate postnatal planning. Results have also been important in counseling for recurrence risks.
Conclusion
Hydrops fetalis is a challenging prenatal diagnosis with multiple potential etiologies. Historically, approximately 25% of cases of fetal hydrops have an unknown etiology. Prenatal genome sequencing may provide further insight to potential etiology and additional information for antenatal and postnatal management and treatment, as well as counseling for recurrence risks.
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