Introduction
Kabuki syndrome is a rare genetic disorder that affects 1 in 32,000 live births. Reference Niikawa, Kuroki and Kajii1 It is characterised by hypotonia, developmental delay, intellectual disability, and distinct dysmorphic features. Through molecular genetic testing, 70% of Kabuki syndrome patients also carry a pathogenic variant in the KMT2D or KDM6A gene. Reference Adam, Banka and Bjornsson2 Kabuki syndrome may affect multiple organ systems, including musculoskeletal abnormalities, renal malformations (renal dysplasia, hypoplasia), gastrointestinal abnormalities (malrotation, anal atresia), immunologic deficiencies, and congenital heart disease(CHD).
The prevalence of CHD in Kabuki syndrome patients varies, though reported rates have been as high as 55–80%. Reference Digilio, Marino, Toscano, Giannotti and Dallapiccola3 Reference Van Laarhoven, Neitzel and Quintana4,–Reference Adam and Hudgins5 Left-sided lesions, including coarctation of the aorta, account for almost half of the cardiac defects in this population. Reference Conrey, Tume, Bonilla-Ramirez, Lalani, McKenzie and Anders6 Reference Kawame, Hannibal, Hudgins and Pagon7,Reference Ewart-Toland, Enns, Cox, Mohan, Rosenthal and Golabi8,–Reference Digilio, Gnazzo and Lepri9 Additional common cardiac defects include atrial and ventricular septal anomalies. Reference Conrey, Tume, Bonilla-Ramirez, Lalani, McKenzie and Anders6,Reference Digilio, Gnazzo and Lepri9,Reference Yuan10 These lesions commonly require surgical correction, ranging from surgeries for simple lesions to staged palliation for complex defects. Reference Yuan10 Kabuki syndrome patients with complex CHD are often considered at high risk for poor surgical outcomes, which impacts decisions for surgical candidacy.
While there have been studies examining the post-cardiac surgery outcomes of patients with other genetic conditions, Reference Zakaria, Tang, Bhakta, ElHassan and Prodhan11,Reference Michielon, Marino and Formigari12,Reference Cramer, Bartz, Simpson and Zangwill13,–Reference Hemmati, Dearani and Daly14 few studies have examined the post-cardiac surgery outcomes in Kabuki syndrome patients. One retrospective study examined the post-operative course of 15 Kabuki syndrome patients who underwent cardiac surgery with varying degrees of complexity. Reference Conrey, Tume, Bonilla-Ramirez, Lalani, McKenzie and Anders6 These patients experienced a prolonged hospital course and increased complications, but no increase in post-op mortality (94% survival rate at 6 years) compared to patients without genetic anomalies. The main complications examined were infection, glycemic disturbance, pleural effusion, and pericardial effusion. Other reports of post-cardiac surgery outcomes in Kabuki syndrome patients are primarily individual case studies that detail the course of surgical intervention but do not provide an aggregate understanding of surgical risk. Reference Onan, Aydın, Kahraman and Bakır15,Reference Ishidou, Ito, Murata, Hirose, Ikai and Sakamoto16,–Reference Dyamenahalli, Abraham, Fontenot, Prasad and Imamura17
We seek to contribute to the few studies that have examined outcomes in Kabuki syndrome patients after cardiac surgery and to broaden the outcomes that are considered. Improved understanding of surgical outcomes will aid in better identifying appropriate candidates for surgical intervention.
Materials and methods
Overview
This was a single-centre retrospective study of Kabuki syndrome patients undergoing neonatal surgery for CHD from January 2018 to September 2023 at a tertiary referral centre. Patients were identified through our local Pediatric Cardiac Critical Care Consortium (PC4) database and electronic medical record. No patient was denied surgery for Kabuki syndrome alone. Inclusion criteria were any patients with diagnosis of Kabuki syndrome who had undergone neonatal cardiac surgery. Diagnosis of Kabuki syndrome in all patients was confirmed by postnatal genetic testing. The outcomes of Kabuki syndrome patients were compared to the neonates with chromosomal abnormalities other than Kabuki syndrome who underwent cardiac surgery within the same time period in our centre. All chromosomal abnormalities were identified via genetic testing. The University of California San Francisco Institutional Review Board approved this study.
Data collection
We collected basic demographics, including sex, race, ethnicity, gestational age, age at surgery, and birth weight. We then examined each patient’s baseline function across several organ systems (cardiac, respiratory, renal, gastrointestinal, neurologic, haematologic, and endocrine). Our post-operative primary outcomes were survival to discharge after index surgery and survival to date (as of September 2024). Secondary outcomes were hospital length of stay, post-operative complications, and comorbidities. This included cardiac complications (cardiac arrest, extracorporeal mechanical support (extracorporeal circulatory life support), unplanned re-interventions), respiratory support, renal failure requiring dialysis, infection, neurological complications, and gastrointestinal support (feeding tube at discharge). Where available, these variables were compared between Kabuki patients, patients with non-Kabuki genetic anomalies, and all neonates undergoing surgery for CHD during the same time period.
For the purposes of this study, neonates at time of operation were extended to 33 days to include all suitable candidates. Infection included necrotising enterocolitis (modified Bell’s staging criteria II or III), bacteremia (positive blood culture), urinary tract infection (positive urine culture), and pneumonia/tracheitis (positive respiratory, tracheal, bronchial lavage culture). Neurological complications included seizure (clinical or electroencephalogram evidence of epileptiform activity) and abnormal brain imaging (intraventricular haemorrhage or stroke as seen in head ultrasound or MRI).
Results
We identified seven patients with Kabuki syndrome who underwent cardiac surgery from January 2018 to September 2023. The majority of the patients were male (86%) and identified as Caucasian (43%), Asian (14%), or other/undisclosed (43%). Besides cardiac defects, preoperative structural renal (43%) and neurological anomalies (29%) were common (Table 1).
Table 1. Demographics and preoperative factors
Abbreviations: IVH (intraventicular haemorrhage).
All patients had left-sided lesions, including three with hypoplastic left heart syndrome (HLHS), three with aortic stenosis and/or aortic arch hypoplasia, and one with isolated coarctation of aorta. Accordingly, the three patients with HLHS underwent staged palliation. The index operation was Norwood with right ventricle to pulmonary artery conduit for two patients and hybrid for one patient. The three with aortic stenosis/arch hypoplasia underwent aortic arch repair, and the one patient with isolated coarctation underwent coarctation repair. The age at index operation was 17 to 33 days for HLHS and 3 to 30 days for arch repair.
Preoperatively, one patient had systolic dysfunction on echocardiogram. Comorbid organ dysfunction included non-invasive ventilation (n = 5), mechanical ventilation (n = 1), structural renal abnormalities (n = 3), neurologic abnormalities on imaging (n = 2), and coagulation disorder (n = 1). Notably, none had preoperative gastrointestinal dysfunction or renal dysfunction (i.e. acute kidney injury or chronic kidney disease) (see Table 1).
Postoperatively, 71% of patients with Kabuki syndrome survived to discharge, compared to 89% among neonates with other chromosomal abnormalities and 94% among neonates without known chromosomal abnormalities undergoing surgery for CHD. Four of five patients who survived to discharge remain alive, including one with HLHS. Three of the cohort survived until 3 years of age. Cardiac complications were present in a subset of Kabuki syndrome patients (one cardiac arrest, one extracorporeal circulatory life support, and three patients with unplanned re-interventions). Ventricular hypertrophy was found in all mortalities. For extracardiac morbidities, two patients developed pulmonary hypertension including one mortality. None required dialysis. All five surviving patients were discharged home with a gastrostomy or nasogastric tube.
Overall, a higher percentage of Kabuki syndrome patients experienced complications compared to patients with non-Kabuki chromosomal abnormalities. Most significantly, higher percentage of patients had unplanned re-interventions (43% versus 15% in non-Kabuki syndrome chromosomal abnormalities), abnormal brain imaging (29% versus 5%), and bacteremia (29% versus 9%) (Table 2). Median total ventilator days (16 days versus 6 days) and hospital length of stay (66 days versus 41 days) were both longer than in Kabuki syndrome patients than in non-Kabuki syndrome chromosomal abnormalities patients.
Table 2. Post-surgical outcomes following neonatal surgery
Abbreviations: 22q11 (22q11.2 deletion syndrome); T21 (Trisomy 21 syndrome).
There were 97 patients with non-Kabuki chromosomal abnormalities including 14 patients with 22q11.2 deletion and 10 patients with Trisomy 21. No Trisomy 13 or 18 patients underwent neonatal cardiac surgery during the study period. The most common neonatal operation in non-Kabuki genetic anomaly patients was coarctation of aorta repair (20%). Norwood palliation was the second most common operation (13%), followed by Truncus arteriosus repair (10%).
Among the fourteen 22q11.2 deletion syndrome patients, four underwent interrupted aortic arch repair, four Truncus arteriosus repair, and two Yasui operation (See Supplemental Table 1 for details). Overall survival to discharge was 86% in 22q11.2 deletion syndrome neonates after cardiac surgery.
Out of the ten Trisomy 21 patients, six patients underwent coarctation of aorta repair while two had atrioventricular (AV) canal repair (Supplemental Table 1). There was no inpatient mortality among Trisomy 21 patients.
Discussion
Kabuki syndrome patients with cardiac defects usually present with left-sided lesions. Their outcomes can be stratified based on the complexity of cardiac lesions as well as extracardiac anomalies and preoperative risk factors. These factors should be weighed in the discussion for their surgical candidacy. While Kabuki syndrome patients have lower survival-to-discharge than counterpart cardiac patients with non-Kabuki syndrome genetic abnormalities, we found a significant portion (71%) of Kabuki syndrome patients survive the index operation. Three-quarters of our two-ventricle Kabuki syndrome patients in our cohort survived to discharge and to date. Two-thirds of our single ventricle Kabuki syndrome patients survived to discharge. Two underwent the bidirectional Glenn procedure, including one demise three years after bidirectional Glenn with hypertrophic cardiomyopathy, worsening heart and renal failure. Surgical intervention is associated with long-term survival in two-ventricle physiology, but likely yields only short-term survival in single-ventricle population with Kabuki syndrome. This result aligns with other reports where single ventricle Kabuki syndrome patients have successfully undergone Stage 1 palliation or bidirectional Glenn procedure with subsequent demise prior to reaching Fontan palliation. Therefore, the surgical candidacy of single ventricle Kabuki syndrome patients should be discussed within the context of surgical palliation where the patients may live beyond neonatal period and be discharged home but likely with limited life expectancy.
The two patients who did not survive to discharge did not have significant preoperative differences compared to the population who survived. Their underlying cardiac lesions also varied in complexity. One patient had an aortic stenosis, while the other had HLHS with aortic stenosis, mitral stenosis, and a ventricular septal defect. The former underwent an aortic arch repair, while the latter underwent single ventricle stage 1 palliation. Interestingly, all mortalities from Kabuki syndrome patients had ventricular hypertrophy on echocardiogram. However, baseline comorbidities and underlying cardiac function did not necessarily correlate with likelihood of overall survival in this small cohort. Further study with large patient numbers would help determine the predictor variables for survival.
Complications after surgery are common in Kabuki syndrome patients, including the need for unplanned re-interventions and end-organ complications (e.g. acute kidney injury, abnormal brain imaging, bacteremia, urinary tract infection, and pneumonia). All of our surviving patients were discharged home with feeding tube, which is consistent with feeding difficulty in Kabuki syndrome patients with or without cardiac involvement. Interestingly, our patients did not develop long-term ventilator dependency or chronic kidney disease. Improved understanding of these long-term comorbid risks of surgical intervention in Kabuki syndrome patients will help in making a more informed decision.
The primary limitation of our study is the small sample size. Our cohort was limited to a single institution, yielding a small sample size that was not powered for statistical significance. We compared Kabuki syndrome neonates with other chromosomal anomalies patients for clinically meaningful comparison. However, this came with a caveat that the pattern of cardiac lesions differed from Kabuki population to other chromosomal anomalies, as exemplified by only 13% of non-Kabuki genetic anomaly patients undergoing Norwood palliation. Also, we had expected a higher percentage of Trisomy 21 patients to have AV canal; we speculate that the majority of AV canal patients might have been repaired past the neonatal period, hence not captured in our neonatal surgical population. Further multi-institutional studies will be helpful to determine patient characteristics in evaluating surgical candidacy.
Conclusion
Kabuki syndrome patients with two-ventricle physiology seem to benefit from improved survival after neonatal cardiac surgical intervention. Kabuki syndrome patients with single ventricle physiology remain at high risk of mortality and morbidity after cardiac surgical intervention, although they may be discharged home without ventilator dependency and survive to toddler years. The development of ventricular hypertrophy is a marker for poor outcomes.
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