Bradycardia, asystole, and sudden cardiac death in ZC4H2 R198Q–associated Wieacker-Wolff syndrome

Key Teaching Points.

• ▪Advanced genetic testing, beyond chromosomal microarray, such as whole-exome sequencing, can be important when clinical symptoms are not explained by identifying single gene disorders. Identifying specific genes and knowledge about specific variants can affect therapeutic management strategies for patients.
• ▪Specific variants within disease-causing genes may confer arrhythmia risk, not seen among other affected individuals.
• ▪In this report, the specific ZC4H2 variant (c.593G>A, p.R198Q) in affected males with Wieacker-Wolff syndrome (WRWF) seems to confer an increased risk of profound sinus pauses and asystole, which can lead to cardiac arrest and early, unexplained sudden death. Prophylactic pacemaker placement may be warranted among male patients with the R198Q variant of WRWF.
• ▪Electrophysiologists need to be aware of the rare genes that can be associated with lethal arrhythmia syndromes.

Introduction

Wieacker-Wolff syndrome (WRWF) (Online Mendelian Inheritance in Man [OMIM] #31450) is an X-linked recessive disorder caused by loss-of-function variants in the zinc-finger gene ZC4H2.¹ This rare condition leads to multisystem disease including skeletal and neurodevelopmental abnormalities. Single case reports of cardiac sequelae have been reported but not well described and are currently not included in online resources such as OMIM.^2,3 However, caregivers need to be aware that cardiac arrhythmias in WRWF can lead to cardiac arrest and contribute to sudden death. We present a case of a 22-month-old male with WRWF, hemizygous ZC4H2: c.593G>A, p.R198Q. He had recurrent, prolonged sinus pauses with asystole requiring cardiopulmonary resuscitation (CPR) and ultimately required implantation of a single-chamber pacemaker.

Case report

The patient is a 2-year-old term male whose medical history includes developmental delays, hypoglycemia, seizures, and feeding difficulties since birth. Initial genetic testing (comprehensive skeletal dysplasia panel, chromosomal microarray, and fluorescence in situ hybridization) identified a 124 kb copy loss on chromosome 6 (6q21). At 3 months of age, he was hospitalized for seizures and hypoglycemia in the setting of a viral respiratory illness during which intermittent bradycardia and 3- to 4-second sinus pauses were noted. An electrophysiology (EP) consult was obtained. The pauses were initially suspected to be caused by vagal stimulation because they were brief and decreased in frequency with recovery from illness, although a cardiac workup was pursued because the 6q21 deletion did not explain his syndromic features, which included short stature (<1%), rocker bottom feet, arthrogryposis, and contractures (Figure 1). His echocardiogram showed no structural heart disease. His electrocardiogram was normal with normal intervals (Figure 2B). As he recovered from his illness, his rhythm improved and a repeat Holter monitor before discharge revealed sinus rhythm (average heart rate 142 beats per minute [bpm]; range 121–165 bpm) and episodes of sinus bradycardia with junctional escape without any further significant pauses (longest RR interval 2.2 seconds). Genetic sequencing was recommended to evaluate his syndromic features and rule out genes associated with sinus node dysfunction and pauses, and trio whole-exome sequencing was ordered. However, results were not available at the time of discharge. After discharge, trio whole-exome sequencing revealed a de novo hemizygous pathogenic variant in ZC4H2 (c.593G>A, p.R198Q). Although the diagnosis of WRWF was made at the age of 3 months, the association with cardiac arrhythmias was not well described and not included in OMIM.

Figure 1.

Common physical exam findings in Wieacker-Wolff syndrome including (A) characteristic facial features (high anterior hairline, ptosis, low-set ears, long philtrum, retrognathia), (B) musculoskeletal anomalies (arthrogryposis, contractures, long tapering fingers), and (C) rocker bottom feet.

Figure 2.

Telemetry recording showing an unprovoked 8.5-second asystolic pause during hospitalization and before pacemaker implant (A), baseline normal electrocardiogram (B), and outpatient routine Holter during health (C) demonstrating persistent episodes of sinus slowing and atrioventricular block with appropriate hysteresis pacing.

During his second hospitalization at the age of 22 months for a respiratory illness, he again had multiple bradycardic (heart rates as low as 11–27 bpm) and asystolic events. Factors associated with marked pauses and asystole (typically 6–15 seconds) initially seemed to be vagally mediated and predominantly associated with oropharyngeal suctioning. One event, lasting for 35 seconds, occurred during agitation with intrapulmonary percussive ventilation, triggering a code. He received 3 total chest compressions and was briefly manually ventilated. This event prompted a repeat EP consultation. A second event occurred when he awoke agitated during an echocardiogram. He had a second bradycardic arrest requring required CPR and 2 code doses of epinephrine before normal sinus rhythm resumed and he returned to his baseline. Even as he recovered from his illness, crying, agitation, and even slight turning of the head continued to elicit abrupt bradycardia and marked pauses. Glycopyrrolate was trialed but had no effect and was eventually discontinued. Events increasingly began occurring with minimal stimulation, and at times, no obvious trigger could be identified.

The question of how to manage this patient was directed toward the EP consult team who was unaware of the updated genetic diagnosis until his second hospitalization and after his bradycardic arrest. Owing to the prolonged pauses seemingly out of proportion to stimuli and illness, additional investigation into the cardiac sequelae of his syndrome was pursued. Although WRWF is included in OMIM (# 314580), arrhythmias are not reported. However, isolated case reports of patients with bradycardic events requiring CPR and sudden death at a young age from unclear etiologies were identified through an additional literature search. In each of these case reports, the same R198Q variant was reported, raising concerns by our team that this specific ZC4H2 variant conferred a risk of cardiac arrest and sudden death. Given the frequency and severity of his episodes and concerning case reports of the R198Q variant, he underwent uncomplicated single-chamber epicardial pacemaker implantation. The pacemaker was programmed with a hysteresis rate of 50 bpm and a lower rate limit of 80 bpm. Pacemaker interrogation prior to discharge showed pacing ∼1% of the time. The frequency of pacing in the patient was ∼0.2%–0.3% in the months after discharge, with slight increases up to 0.4% during hospitalization for respiratory illness. Outpatient Holter monitoring during baseline health demonstrates continued episodes of sinus bradycardia and atrioventricular block with pacemaker utilization (Figure 2C). After hospital discharge, his parents noted a difference. Before the pacemaker, he would “cry, gasp, start shaking, and turn blue in his lips, face and arms” up to 3 times per day. Although none of these events were seen after pacemaker placement, suggesting that these episodes may have been caused by prolonged pauses, there was no previous documentation of these symptoms to definitively correlate these specific symptoms to pauses.

Discussion

WRWF is a rare X-linked recessive multisystem condition caused by loss-of-function pathogenic variants in the zinc-finger ZC4H2 gene. Zinc-finger proteins are involved in multiple cellular processes across many tissue types.⁴ Less than 120 cases have been described in the literature with an estimated prevalence of <1:1,000,000.^2,3,5 Given that the disease is X-linked, surviving males tend to have more severe presentations.¹ Common characteristics include dysmorphic facial features, developmental delays, neonatal respiratory distress, apnea, seizures, feeding difficulties, and skeletal anomalies.^2,3 Cardiac sequela are reported less frequently. In a large case series of 105 patients with WRWF by Frints et al,² 13 had arrhythmia, 5 had bradycardia, and 5 had sick sinus syndrome.²

Patients with the ZC4H2 c.593G>A, p.R198Q variant represent a subset of WRFW. A total of 9 patients with this variant have been reported, 8 of whom are males. Of these, 2 males had bradycardic arrests requiring CPR and 6 had unexplained death at a young age.^1,2,5 The only known surviving case also had marked pauses but received a pacemaker.² Thus, based on current reported cases, of the 13 patients with reported arrhythmias by Frints et al,² 9 had the R198Q variant. Although it is possible that other ZC4H2 variants are associated with arrhythmias and have not yet been reported, our data suggest that the risk of life-threatening bradyarrhythmias may in particular be higher among those with the R198Q variant. The etiology for the differential cardiac findings among the ZC4H2 gene variants is unclear at this time but patients with this variant should be carefully monitored with consideration of a pacemaker.

In this case, the association of lethal bradyarrhythmias and this particular variant was only made after a literature review. This highlights the importance of case reports of new findings and the increasing need to incorporate genetics as part of clinical care.

Conclusion

Although rare, clinicians should recognize that the R198Q ZC4H2 variant in the hemizygous state increases risks of profound bradycardia and sinus pauses, placing patients at risk of cardiac arrest and early, unexplained deaths. Further studies are needed to determine whether all patients with this variant are at risk and whether male patients with the R198Q variant warrant prophylactic pacemaker placement.

Disclosures

The authors have no conflicts of interest to disclose with the exception that Dr Miyake is an advisor for Boston Scientific’s Fierce Program and an editor. Fierce is a program to help advocate for females in EP and is not expected to conflict with this submission.