A Rare Case of Prenatal G6PD Presenting with Hydrops and in Utero Demise
Prenatal Genetics
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Primary Categories:
- Prenatal Genetics
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Secondary Categories:
- Prenatal Genetics
Introduction
Glucose 6 Phosphate Dehydrogenase Deficiency (G6PD) is a common genetic enzymatic disorder affecting more than 400 million individuals worldwide. In cases of high stress or exposure to certain foods or medications, hemolytic anemia crises can occur. However, most individuals with G6PD will never have symptoms, as long as one abstains from those contraindicated exposures. G6PD-related symptoms, such as hemolytic anemia, typically do not present in utero. However, to date there have been 5 published cases of G6PD hemizygous mothers carrying fetuses with the same disorder where those fetuses have developed fetal anemia or nonimmune hydrops fetalis (NIHF). We add to this literature by describing the first known cases where a fetus presented with ascites and edema and ended in fetal demise.
Case Presentation
The patient was a 28-year-old G1P0, referred to the Children’s Hospital of Philadelphia Center for Fetal Diagnosis and Treatment (CFDT) for concern of abdominal ascites, abnormality of the intracranial structures, and head and neck edema in her fetus at 22 weeks in gestation. Unfortunately, during her ultrasound at the CFDT, a fetal heartbeat could not be appreciated and fetal demise was confirmed by 2 examiners. She was induced for delivery and a skin sample from the deceased fetus was obtained for genetic testing purposes.
Diagnostic Workup
Trio whole genome sequencing (GS) was performed on tissue from the deceased fetus. Whole genome short read sequencing was performed using the Illumina DNA PCR-free sequencing NovaSeq X plus system. Two pathogenic variants in G6PD at c.202G>A; c.376A>G (p.Val68Met; Asn126Asp) were identified in this male fetus, inherited from the fetus’ mother. This mutation has been reported in multiple individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and is known as the A- haplotype.
Treatment and Management
Since a fetal heartbeat could not be appreciated, the patient was induced for delivery and a skin sample from the deceased fetus was obtained for genetic testing purposes.
Outcome and Follow-Up
GS results were explained to the family and during this conversation, it was determined that the mother consumed fava beans regularly throughout her pregnancy. She was also completely unaware of her hemizygous carrier status. While she does report having siblings, including brothers, no family members have ever been diagnosed with this condition or have had health concerns that could be related to G6PD.
Discussion
While a very infrequent cause of NIHF, G6PD was the likely cause of the fluid accumulations in the fetus in this case and the ultimate cause of fetal demise. A review by Iyer et al., 2024 documented 5 cases of G6PD-related NIHF and one case of G6PD-caused severe anemia. Additionally, 4 of these cases documented the presence of abdominal ascites, which was reported in the presented case as well. Some of these previously reported cases were treated by in utero blood transfusion, while others (2 cases) resulted in either a stillbirth or early neonatal demise.
Conclusion
G6PD is the most common enzyme disorder in humans and rarely poses health risks to the individual as long as certain precautions are taken. However, as shown in this case and 5 other cases in the literature, special care should be taken to carrier mothers with advisements to stay away from contraindicated medications and foods to reduce the risk of hemolytic anemia, NIHF, or intrauterine fetal demise in their fetus. However, as shown by Iyer et al., 2024, even when abstaining from these agents, fetal anemia, NIHF, and as evidenced by this case, in utero demise, are still possible, supporting the careful surveillance of such pregnancies. Further, this case also highlights the utility of broad genetic testing, like GS, as G6PD is not a common genetic cause of NIHF and therefore is not included on hydrops panels.
Glucose 6 Phosphate Dehydrogenase Deficiency (G6PD) is a common genetic enzymatic disorder affecting more than 400 million individuals worldwide. In cases of high stress or exposure to certain foods or medications, hemolytic anemia crises can occur. However, most individuals with G6PD will never have symptoms, as long as one abstains from those contraindicated exposures. G6PD-related symptoms, such as hemolytic anemia, typically do not present in utero. However, to date there have been 5 published cases of G6PD hemizygous mothers carrying fetuses with the same disorder where those fetuses have developed fetal anemia or nonimmune hydrops fetalis (NIHF). We add to this literature by describing the first known cases where a fetus presented with ascites and edema and ended in fetal demise.
Case Presentation
The patient was a 28-year-old G1P0, referred to the Children’s Hospital of Philadelphia Center for Fetal Diagnosis and Treatment (CFDT) for concern of abdominal ascites, abnormality of the intracranial structures, and head and neck edema in her fetus at 22 weeks in gestation. Unfortunately, during her ultrasound at the CFDT, a fetal heartbeat could not be appreciated and fetal demise was confirmed by 2 examiners. She was induced for delivery and a skin sample from the deceased fetus was obtained for genetic testing purposes.
Diagnostic Workup
Trio whole genome sequencing (GS) was performed on tissue from the deceased fetus. Whole genome short read sequencing was performed using the Illumina DNA PCR-free sequencing NovaSeq X plus system. Two pathogenic variants in G6PD at c.202G>A; c.376A>G (p.Val68Met; Asn126Asp) were identified in this male fetus, inherited from the fetus’ mother. This mutation has been reported in multiple individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency and is known as the A- haplotype.
Treatment and Management
Since a fetal heartbeat could not be appreciated, the patient was induced for delivery and a skin sample from the deceased fetus was obtained for genetic testing purposes.
Outcome and Follow-Up
GS results were explained to the family and during this conversation, it was determined that the mother consumed fava beans regularly throughout her pregnancy. She was also completely unaware of her hemizygous carrier status. While she does report having siblings, including brothers, no family members have ever been diagnosed with this condition or have had health concerns that could be related to G6PD.
Discussion
While a very infrequent cause of NIHF, G6PD was the likely cause of the fluid accumulations in the fetus in this case and the ultimate cause of fetal demise. A review by Iyer et al., 2024 documented 5 cases of G6PD-related NIHF and one case of G6PD-caused severe anemia. Additionally, 4 of these cases documented the presence of abdominal ascites, which was reported in the presented case as well. Some of these previously reported cases were treated by in utero blood transfusion, while others (2 cases) resulted in either a stillbirth or early neonatal demise.
Conclusion
G6PD is the most common enzyme disorder in humans and rarely poses health risks to the individual as long as certain precautions are taken. However, as shown in this case and 5 other cases in the literature, special care should be taken to carrier mothers with advisements to stay away from contraindicated medications and foods to reduce the risk of hemolytic anemia, NIHF, or intrauterine fetal demise in their fetus. However, as shown by Iyer et al., 2024, even when abstaining from these agents, fetal anemia, NIHF, and as evidenced by this case, in utero demise, are still possible, supporting the careful surveillance of such pregnancies. Further, this case also highlights the utility of broad genetic testing, like GS, as G6PD is not a common genetic cause of NIHF and therefore is not included on hydrops panels.
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