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Case Report: A novel KNCH2 variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure.

ABSTRACT: Background: Fetal bradycardia is a common but severe condition. In addition to autoimmune-mediated fetal heart block, several types of channelopathies induce high-degree atrioventricular block (AVB). Long QT syndrome (LQTS) is a major cause of non-autoimmune-mediated fetal heart block. Due to the limitations of prenatal diagnostic technologies, LQTS is seldom identified unless fetal genetic screening is performed. Thus, long-term prenatal dexamethasone (DEX) exposure can become a challenge for these patients. We report on a rare case of a novel KCNH2 variant related to LQTS and associated with high-degree fetal AVB with long-term DEX exposure. This case led us to review our prenatal administration strategy for such patients. Case Presentation: A fetus was identified with high-degree AVB (2:1 transduction at 28 + 2 gestational weeks). Typical tests of immune function in the pregnant woman were conducted including tests for thyroid function, rheumatic screening, autoimmune antibodies (such as anti-Ro/SSA and anti-La/SSB), and anti-nuclear antibodies (anti-ANA). Following the recommended protocol, the pregnant patient received DEX (0.75 mg/day) during pregnancy. Subsequently, the fetal AVB changed from 2:1 to prolonged AV intervals with ventricular tachycardia, which suggested a therapeutic benefit of DEX in some respects. However, a high-degree AVB with a significantly prolonged QTc interval was identified in the neonate following birth. Genetic testing revealed that a KCNH2 c.1868C>A variant induced LQTS. The body length remained approximately -3.2 SD from the reference value after prenatal long-term DEX exposure, which indicated a developmental restriction. Additionally, the functional validation experiments were performed to demonstrate the prolonged duration of calcium transit both in depolarization and repolarization with the KCNH2 c.1868C>A variant. Conclusion: Genetic screening should be recommended in fetuses with autoimmune antibody negative high-degree AVB, especially for 2:1 transduction AVB and in fetuses with changes in fetal heart rhythm following initial DEX treatment. Genetic screening may help identify genetic variant-related channelopathies and avoid unexpected prenatal exposure of DEX and its possible long-term adverse postnatal complications.

SUBMITTER: Huang H

PROVIDER: S-EPMC9745090 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Case Report: A novel <i>KNCH2</i> variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure.

Huang Huiping H Jing Siyuan S Wu Shaoying S Wei Li L Zhang Qian Q Hua Yimin Y Li Yifei Y Yu Haiyan H Zhou Kaiyu K

Frontiers in genetics 20221129

<b>Background:</b> Fetal bradycardia is a common but severe condition. In addition to autoimmune-mediated fetal heart block, several types of channelopathies induce high-degree atrioventricular block (AVB). Long QT syndrome (LQTS) is a major cause of non-autoimmune-mediated fetal heart block. Due to the limitations of prenatal diagnostic technologies, LQTS is seldom identified unless fetal genetic screening is performed. Thus, long-term prenatal dexamethasone (DEX) exposure can become a challeng ...[more]

PMID: 36523767

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Project description:BackgroundAmong all fetal heart block patients, > 50% cases are associated with maternal autoimmune diseases, and such patients should receive treatment. However, nearly half of fetal heart block cases involve a mother with negative results following autoimmune antibody screening. A few studies have reported long QT syndrome (LQTS) can also present as a severe fetal bradycardia, which does not respond to fetal treatment. Herein, we reported a rare case of an infant who presented with high-degree autoimmune-mediated fetal atrioventricular block (AVB) with LQTS induced by a novel KCNH2 variant. This case led us to review our prenatal therapeutic strategy.Case presentationA 1-year-old boy presented to our heart center having experienced syncope 5 times in the past year. He had previously presented with fetal bradycardia during the fetal stage from 27 + 3 gestational weeks. The fetal echocardiography demonstrated AVB (2:1 transmission). As the maternal autoimmune antibody results were positive, his mother had received dexamethasone treatment during pregnancy; subsequently, the fetal AVB had changed from 2:1 to 4:3 transmission with elevated ventricular beating rates. However, this patient was identified to have complete AVB after birth. The initial electrocardiogram and Holter measurements at hospital administration showed complete AVB, pleomorphic ventricular tachycardia, a prolonged QT interval (QT = 602 ms, corrected QT = 538 ms), and wide and deep inverted T-waves. Meanwhile, torsades de pointes could be observed in several transit ventricular tachycardias based on Holter monitoring review. Genetic testing revealed KCNH2 c.2483G > A variant-induced LQTS. An implantable cardioverter defibrillator device and permanent pacemaker were both considered as therapeutic alternations; his parents ultimately accepted the implantation of a permanent pacemaker.ConclusionsFor fetuses with autoimmune-mediated AVB, intrauterine treatment should still be pursued immediately. However, once the treatment outcomes are deemed unacceptable or unexpected, other genetic variant-related channelopathies should be highly suspected. If the fetus lacks a positive family history, fetal genetic testing should be recommended to improve the prognosis of such patients by introducing integrative therapeutic strategies between the prenatal and postnatal phases.

Project description:Negative associations of prenatal tobacco and alcohol exposure (PTE and PAE) on birth outcomes and childhood development have been well documented, but less is known about underlying mechanisms. A possible pathway for the adverse fetal outcomes associated with PTE and PAE is the alteration of fetal autonomic nervous system development. This study assessed PTE and PAE effects on measures of fetal autonomic regulation, as quantified by heart rate (HR), heart rate variability (SD-HR), movement, and HR-movement coupling in a population of fetuses at ≥ 34 weeks gestational age. Participants are a subset of the Safe Passage Study, a prospective cohort study that enrolled pregnant women from clinical sites in Cape Town, South Africa, and the Northern Plains region, United States. PAE was defined by six levels: no alcohol, low quit early, high quit early, low continuous, moderate continuous, and high continuous; while PTE by 4 levels: no smoking, quit early, low continuous, and moderate/high continuous. Linear regression analyses of autonomic measures were employed controlling for fetal sex, gestational age at assessment, site, maternal education, household crowding, and depression. Analyses were also stratified by sleep state (1F and 2F) and site (South Africa, N = 4025, Northern Plains, N = 2466). The final sample included 6491 maternal-fetal-dyad assessed in the third trimester [35.21 ± 1.26 (mean ± SD) weeks gestation]. PTE was associated with a decrease in mean HR in state 2F, in a dose dependent fashion, only for fetuses of mothers who continued smoking after the first trimester. In state 1F, there was a significant increase in mean HR in fetuses whose mother quit during the first trimester. This effect was driven by the Norther Plains cohort. PTE was also associated with a significant reduction in fetal movement in the most highly exposed group. In South Africa a significant increase in mean HR both for the high quit early and the high continuous group was observed. In conclusion, this investigation addresses a critical knowledge gap regarding the relationship between PTE and PAE and fetal autonomic regulation. We believe these results can contribute to elucidating mechanisms underlying risk for adverse outcomes.

Dataset Information

Case Report: A novel KNCH2 variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure.

Publications

Case Report: A novel <i>KNCH2</i> variant-induced fetal heart block and the advantages of fetal genomic sequencing in prenatal long-term dexamethasone exposure.

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