Heart Transplantation in Children with Turner Syndrome: Analysis of a Linked Dataset

Abstract

Turner syndrome (TS) patients with hypoplastic left heart syndrome (HLHS) have poor single ventricle palliation outcomes; therefore, consideration of other potential management strategies is important. Little is known about heart transplantation (HTx) in this group, as standard HTx databases do not allow for identification of TS. This study describes experiences and outcomes of HTx in TS using a unique linkage between the Scientific Registry of Transplant Recipients and the Pediatric Health Information System databases. All pediatric HTx recipients (2002–2016) with TS were identified in the database using ICD-9 code 758.6 (gonadal dysgenesis) in conjunction with female sex. Patient characteristics and outcomes were described. Fourteen patients with TS were identified who underwent 16 HTx procedures at eight centers. For initial HTx, HLHS was the most common indication (10/14) with a median age of 10 months (IQR 3–73 months). Median transplant-free survival following initial HTx was 4.1 years (IQR 16 days–10.5 years), with all deaths occurring in the first year post-HTx. For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years) with no deaths observed. Our cohort demonstrates that while there is a clear risk for early mortality, there is the potential for favorable outcomes following HTx in patients with TS. Therefore, TS should not be viewed as an absolute contraindication to HTx, but careful assessment of candidate risk is needed. Primary palliation with HTx for HLHS and TS may be a reasonable consideration given the poor outcomes of single ventricle palliation in this group. Further research is needed to fully delineate the outcomes and characteristics of this unique population.

Introduction

Turner syndrome (TS) is a genetic syndrome characterized by monosomy X (45,XO) in phenotypic females, affecting approximately 1 in 2100–2500 live female births [1, 2]. Common features include growth failure, pubertal delay, edema of the hands and feet, nuchal folds, low hairline, low-set ears, characteristic facies, high arched palate, nail hypoplasia, cubitus valgus, and a spectrum of congenital heart defects [3]. In fact, congenital heart disease is present in 23–50% of individuals with TS and most commonly involves left-sided heart lesions, including hypoplastic left heart syndrome (HLHS), which is estimated to occur in 10% of live born females with TS [4].

Hypoplastic left heart syndrome (HLHS) in patients with TS is associated with significant morbidity and mortality. Reiss et al. reported outcomes in 10 such patients, with only two surviving to second stage palliation [5]. A more recent single center study demonstrated significant mortality in the first year of life in patients with HLHS and TS (75%), while an analysis from the Pediatric Cardiac Care Consortium similarly reported an overall mortality of 90.4% in this group [6, 7]. Given the poor outcomes of this patient population, determining the optimal management strategy is challenging.

There is limited experience with solid organ transplantation in patients with TS reported in the literature. Four prior cases of liver transplantation in TS have been reported, all in adults [8,9,10,11]. Of the three patients with reported outcomes, two were alive at last follow-up while one patient died 3 months following transplantation from respiratory failure and fungal urosepsis [9,10,11]. To our knowledge, there are no published reports of heart transplantation (HTx) in patients with TS. Current HTx databases do not readily allow for identification of patients with TS. We sought to describe the experience and outcomes of HTx in children with TS, with a particular focus on infants with TS and HLHS, using a unique linkage between the Scientific Registry of Transplant Recipients (SRTR) and the Pediatric Health Information System (PHIS) databases.

Methods

We utilized a unique linked dataset of the SRTR and PHIS databases that contains data from nearly 3000 pediatric HTx recipients transplanted within the US between 2002 and 2016. The methods for linkage and description of these data have been previously reported [12]. The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the US, submitted by the members of the Organ Procurement and Transplantation Network (OPTN), and has been described elsewhere [13]. The Health Resources and Services Administration, US Department of Health and Human Services, provides oversight to the activities of the OPTN and SRTR contractors. The SRTR collects and maintains data regarding organ transplantation in the US and includes data from every organ transplant and waitlist addition since October 1987. The PHIS database is an administrative dataset that collects clinical and resource utilization data from hospital encounters at 49 large children’s hospitals. This includes encounter-level data from inpatient hospitalizations, observation, ambulatory surgery, and emergency department visits. PHIS provides a rich dataset for assessing patient diagnoses, procedures, and resource utilization through collection of ICD diagnosis and procedure codes, as well as hospital charge data [12].

The linked dataset was queried for all female patients with ICD-9 code of 758.6 (gonadal dysgenesis) documented at any encounter to identify patients with TS who have undergone HTx. One patient was excluded who had ICD-9 code 279.11 (DiGeorge syndrome) documented on multiple encounters and a single occurrence of ICD-9 code 758.6 that was thought to represent a coding error. Demographics of TS patients were assessed and reported. Patient characteristics assessed at the time of HTx included age, ethnicity, diagnosis, listing status at the time of HTx, history of prior surgery, and the need for mechanical ventilation or mechanical circulatory support (ventricular assist device or extracorporeal membrane oxygenation) at the time of HTx. Post-HTx data analyzed included freedom from death or re-transplantation and freedom from various post-HTx complications prior to hospital discharge including rejection, infection, stroke, chest tube drainage for more than 2 weeks after HTx, and the need for dialysis, cardiac re-operation, and other surgical procedures. All analyses were performed using STATA (version 14; College Station, TX; StataCorp LP).

Results

A total of 14 unique female HTx recipients with TS were identified. Among the included patients, there were 16 total HTx procedures as two patients required re-transplantation (at 4.1 and 10.5 years post initial HTx). Patient demographics are shown in Table 1. Age at HTx ranged from 0 to 17 years; however, the majority (57%) of patients were < 1 year of age at the time of initial HTx. Most were Caucasian (11/14 patients, 79%), OPTN status 1A at HTx (14/16 HTx, 88%), and had an underlying cardiac diagnosis of HLHS (10/14 patients, 71%). All but three patients were known to have had cardiac surgery prior to their first HTx. Four patients were mechanically ventilated and two additional patients were supported with a ventricular assist device at the time of transplant. No patients were supported with extracorporeal membrane oxygenation (ECMO) at the time of HTx. Reporting of further pre-operative characteristics including measures of sensitization were limited by missing data in this small cohort.

Table 1 Patient demographics, pre-operative characteristics, and follow-up status in pediatric Turner syndrome patients undergoing heart transplantation

Post-transplant outcomes are shown in Fig. 1. Median length of follow-up after primary HTx was 2.6 years (IQR 18 days–8.0 years), and median transplant-free survival was 4.1 years (IQR 16 days–10.5 years). For patients that survived past 1 year (8/14), follow-up ranged from 4.1 to 10.9 years (median 8.0 years), during which no deaths were observed; however two patients underwent re-transplant at 4.1 and 10.5 years. Following initial HTx, 6 patients died, all in the first year following HTx, with five occurring within the first month. Three of these patients had HLHS and TS. Two deaths were from primary graft failure at 11 and 14 days post-HTx, 2 occurred following cardiac arrest (one with ventricular failure at 12 days post-HTx and one with anoxic brain injury 16 days post-HTx), and two were from multi-organ failure (one in the setting of bacterial infection) at 27 and 110 days post-HTx. Regarding the two patients that underwent re-transplantation at 4.1 and 10.5 years after primary HTx, one died 20 days post-HTx from multi-organ failure in the setting of sepsis and one was alive at last follow-up of 3.9 years.

Fig. 1

Heart transplant outcomes in pediatric Turner syndrome patients; Turner syndrome (TS), Heart transplantation (HTx), Hypoplastic left heart syndrome (HLHS), Idiopathic dilated cardiomyopathy (DCM), other congenital heart disease (CHD)

Five of the six deaths following initial HTx occurred in patients that were > 1 year of age. Only one death occurred amongst the eight patients < 1 year of age. All of the patients < 1 year of age carried a diagnosis of HLHS. Figure 2 is a visual representation of the freedom from death or re-transplantation in HLHS patients < 1 year of age with and without TS. Given the small number of patients in the TS cohort, the study was underpowered to detect a clinically significant difference between groups, and therefore, a statistical comparison was not performed. Amongst the six patients with TS > 1 year of age at HTx, HLHS was the indication for two patients. Both patients > 1 year of age transplanted for HLHS died within the first month post-HTx due to primary graft failure and cardiac arrest with ventricular failure, respectively.

Fig. 2

Freedom from death or re-transplant following heart transplantation for patients less than 1-year old with hypoplastic left heart syndrome; Hypoplastic left heart syndrome (HLHS)

Post-HTx complications prior to hospital discharge are summarized in Table 2. Drug-treated infection was the most common complication, occurring in 50% of patients. Five patients required post-HTx ECMO. Median days of post-HTx mechanical ventilation were 13 (IQR 3–18 days). Median days of post-HTx intensive care were 14 (IQR 10–24 days).

Table 2 Post-operative complications and characteristics following heart transplantation in pediatric Turner syndrome patients

Discussion

To our knowledge, this represents the first report of HTx in patients with TS to date. Overall outcomes in our cohort were mixed, with a clear risk of early mortality. All deaths occurred within 110 days of HTx, and six of the seven deaths within the first the 27 days. This is similar to overall pediatric HTx outcomes with the greatest risk of mortality in the first year following HTx [14]. While overall median survival in the TS cohort appears suboptimal, it is better than that reported for TS undergoing single ventricle palliation. Given the small number of patients included in our analysis, it remains unclear if HTx outcomes are different compared to non-TS patients with congenital heart disease. However, our analysis demonstrates the potential for favorable outcomes, and therefore TS should not be considered an absolute contraindication to HTx.

It is difficult to identify characteristics that may place a TS patient at increased risk for early death following HTx. Interestingly, early mortality was skewed toward older patients in our cohort, with all but one early death occurring in patients > 1 year of age. Certainly, this finding may not be clinically significant given the small sample size. However, one must wonder if there are inherent differences in the older sub-population, such as having more co-morbidities or worse functional status. Unfortunately, the size of our cohort and the data available limit our ability to identify risk factors for early mortality.

Given the association of TS with left-sided obstructive cardiac lesions, it is not surprising that HLHS was the most common indication for HTx in this cohort. HLHS with TS is associated with significant morbidity and mortality. Specifically, Reiss et al. reported that in a cohort of 10 infants with HLHS and TS who underwent first stage palliation, only two survived and underwent second stage palliation [5]. In a cohort of four patients with HLHS and TS, Cramer et al. described one death following initial palliation, two deaths following second stage palliation, and one surviving patient with significant medical issues who was in palliative care at the time of the report [6]. Two additional analyses, one utilizing the Texas Birth Defects Registry and the other using the Pediatric Cardiac Care Consortium, demonstrated 90% mortality in HLHS with TS (9/10 and 19/21 patients, respectively) [7, 15]. The fact that many pediatric cardiologists recommend hospice care for infants with HLHS and a chromosomal abnormality further demonstrates the lack of favorable management strategies in this population [16]. Clearly, the current management approach to HLHS with TS is suboptimal and suggests the need for alternate management strategies, such as HTx, that may result in improved long-term survival.

The significant early mortality in our cohort, with 6 deaths occurring following initial HTx, may cause some hesitation when considering HTx in TS patients. However, the outcomes demonstrated in our analysis compare favorably to the current outcomes of single ventricle palliation in this group [5,6,7, 15]. HTx may offer better long-term outcomes for patients with HLHS and TS, but further research is needed to define risk factors for early mortality to optimize patient outcomes. Additionally, careful consideration of candidate risk is needed prior to pursuing HTx given the limited availability of donor organs.

Although they remain unexplored at this time, the inherent co-morbidities related to TS coupled with standard post-HTx care raise the question for potential unique management considerations. TS portends an increased risk of diabetes mellitus that may be heightened by post-HTx immunosuppression including calcineurin inhibitors and corticosteroids [17,18,19,20]. Despite decreasing use of corticosteroids post-HTx in the recent era, corticosteroid use post-HTx may increase the risk of osteoporosis in TS [21, 22]. Approximately, 30–40% of TS patients have structural renal abnormalities [3]. Although TS patients do not typically have renal dysfunction, the resulting increased risk of renal infections with these structural abnormalities coupled with known nephrotoxicity of post-HTx immunosuppressive regimens may place these patients at increased risk of renal dysfunction relative to other pediatric HTx recipients [23]. Both TS and HTx are independently associated with increased risk of autoimmune diseases [17, 24,25,26,27,28,29]. Clearly, the overlapping risk profile of TS and HTx patients raises the question of unique challenges post-HTx.

Limitations

Our study has inherent limitations. While the linkage between SRTR and PHIS provides a platform to assess HTx outcomes in this population, it does not contain data from all pediatric HTx centers and therefore may miss some patients with TS who have undergone HTx. In addition to this, the SRTR–PHIS linkage does not include patients who were listed but not transplanted and therefore waitlist outcomes for this group cannot be assessed. Also, there may be a selection bias in patients with TS listed for HTx, with only the healthiest patients progressing to HTx. However, the dataset is multicenter and reporting for all patients cared for at these centers is mandatory, limiting the chance of a post-HTx selection bias as could be seen in single center case series. While ICD coding allowed identification of patients with TS, there may be inaccuracies in coding and limited options to verify these data. The limited patient numbers prohibited performance of a robust multivariable analysis, as well as further comparison of HTx outcomes to patients without TS.

Conclusions

There is limited experience with HTx in patients with TS. Although there is a risk of early mortality, our cohort demonstrates the potential for favorable outcomes. Given the poor outcomes associated with single ventricle palliation in this group, it is reasonable to consider HTx in the discussion of management options for TS patients, although careful consideration of candidate risk is needed to optimize outcomes with this limited resource. Further research is needed to determine the optimal management of this complex group of patients and to define risk factors for early mortality following HTx.