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Characteristics and Outcomes of Heart Transplantation in DiGeorge Syndrome

Authors:
Peter Woolman at University Hospitals
Peter Woolman
David W. Bearl at Vanderbilt University
David W. Bearl
Jonathan H Soslow at Vanderbilt University
Jonathan H Soslow
Debra A Dodd at Vanderbilt University
Debra A Dodd
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Background: DiGeorge syndrome (DGS) is commonly associated with both congenital heart disease (CHD) and immunologic abnormalities. While CHD may prompt consideration for heart transplantation (HTx), little is known about HTx management or outcomes in this group. The aim of this study was to describe the spectrum of patients with DGS who undergo HTx and report post-HTx outcomes. Methods: All pediatric HTx recipients (2002-2016) with DGS were identified using ICD codes from a linked billing and clinical registry database. Patient characteristics and outcomes were described and compared to non-DGS HTx recipients with CHD. Kaplan-Meier methods were used to assess overall survival, freedom from infection, and freedom from rejection. Results: A total of 17 patients with DGS who underwent HTx at 12 different centers were included. Median age at HTx was 5yrs (IQR 0–13yrs). Steroids were used for induction in all patients in addition to thymoglobulin in 13/17 (76%) and IL2R antagonists in 3/17 (18%). Maintenance immunosuppression was a combination of tacrolimus or cyclosporine and mycophenolate or azathioprine in 16/17 (94%). Half received steroids at the time of discharge. There were 6 deaths (35%). The median post-HTx survival was 5.4yrs with no difference in freedom from rejection, infection, or overall survival between patients with and without DGS. Conclusions: Patients with DGS syndrome undergoing HTx receive standard immunosuppression. We found no difference in freedom from infection, rejection, or overall post-HTx survival compared to non-DGS patients, although the small size of our study resulted in limited statistical power. Given the potential for favorable outcomes, patients with DGS may be considered for HTx in the appropriate clinical setting.
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Vol:.(1234567890)
Pediatric Cardiology (2019) 40:768–775
https://doi.org/10.1007/s00246-019-02063-w
1 3
ORIGINAL ARTICLE
Characteristics andOutcomes ofHeart Transplantation inDiGeorge
Syndrome
PeterWoolman1· DavidW.Bearl2· JonathanH.Soslow2· DebraA.Dodd2· CaryThurm3· MattHall3·
BrianFeingold4· JustinGodown2
Received: 15 September 2018 / Accepted: 29 January 2019 / Published online: 7 February 2019
© Springer Science+Business Media, LLC, part of Springer Nature 2019
Abstract
DiGeorge syndrome (DGS) is commonly associated with both congenital heart disease (CHD) and immunologic abnormali-
ties. While CHD may prompt consideration for heart transplantation (HTx), little is known about HTx management or out-
comes in this group. The aim of this study was to describe the spectrum of patients with DGS who undergo HTx and report
post-HTx outcomes. All pediatric HTx recipients (2002–2016) with DGS were identified using ICD codes from a linked
billing and clinical registry database. Patient characteristics and outcomes were described and compared to non-DGS HTx
recipients with CHD. Kaplan–Meier methods were used to assess overall survival, freedom from infection, and freedom from
rejection. A total of 17 patients with DGS who underwent HTx at 12 different centers were included. Median age at HTx
was 5years (IQR 0–13years). Steroids were used for induction in all patients in addition to thymoglobulin in 13/17 (76%)
and IL2R antagonists in 3/17 (18%). Maintenance immunosuppression was a combination of tacrolimus or cyclosporine
and mycophenolate or azathioprine in 16/17 (94%). Half received steroids at the time of discharge. There were six deaths
(35%). The median post-HTx survival was 5.4years with no difference in freedom from rejection, infection, or overall sur-
vival between patients with and without DGS. Patients with DGS undergoing HTx received standard immunosuppression.
We found no difference in freedom from infection, rejection, or overall post-HTx survival compared to non-DGS patients,
although the small size of our study resulted in limited statistical power. Given the potential for favorable outcomes, patients
with DGS may be considered for HTx in the appropriate clinical setting.
Keywords Pediatric· Heart transplantation· DiGeorge syndrome· 22q11 deletion
Introduction
DiGeorge syndrome (DGS), also known as 22q11.2 deletion
syndrome, is a common genetic condition affecting approxi-
mately 1 in 4000 live births [1–3]. The chromosomal dele-
tion in DGS impacts the development of the third and fourth
pharyngeal pouches causing a variety of abnormalities, of
which congenital heart disease (CHD) is prevalent. It is esti-
mated that 77% of all patients with DGS have abnormalities
of cardiac development [2], and it is one of the most com-
mon chromosomal causes of CHD, second only to trisomy
21 [4]. Patients with DGS may also manifest with hypocal-
cemia, palate deformities, developmental delay, and immune
abnormalities [2, 5, 6]. The spectrum of immunologic defi-
ciency in DGS is highly variable. Patients may have mild
lymphopenia with minimal immunologic abnormality, but
can also present with thymic aplasia and profound immuno-
logic alterations [6].
Hemodynamically significant CHD may prompt con-
sideration of heart transplantation (HTx) in patients with
DGS. However, outcomes in this population are unknown.
Additionally, management of immunosuppression in the
post-HTx period may be complicated by the presence of
immunodeficiency. The aim of this study was to describe
the population of patients with DGS who have undergone
* Justin Godown
justin.godown@vumc.org
1 Pediatrics, Monroe Carell Jr. Children’s Hospital, Nashville,
TN, USA
2 Pediatric Cardiology, Monroe Carell Jr. Children’s Hospital,
Nashville, TN, USA
3 Children’s Hospital Association, Lenexa, KS, USA
4 Pediatrics andClinical andTranslational Science, University
ofPittsburgh School ofMedicine, Pittsburgh, PA, USA
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Consequently, little is known regarding the long-term outcomes of heart transplantation in these patients. While the literature currently suggests that select genetic conditions do not negatively affect transplant outcomes, many institutions continue to regard genetic diseases as relative contraindications to transplantation [17][18][19]. To address this, we sought to analyze short-and midterm outcomes of children with genetic conditions undergoing heart transplantation at a single large-volume institution, where we could analyze clinical details with greater granularity. ...
... Similarly, a study of heart transplantation in children with 22q11.2 deletion syndrome found no difference in postoperative survival compared to their counterparts [17]; both patients in our study remained alive 6.1 and 8.5 years post-transplant. An analysis of the Pediatric Heart Information System database found no differences regarding inhospital mortality between children with and without chromosomal anomalies after heart transplant, although patients with aneuploidies experienced the highest in-hospital mortality [16]. ...
Mid-Term Outcomes of Heart Transplantation in Children with Genetic Disorders
Article
  • Jan 2022
BACKGROUND Many congenital heart diseases (CHD) are associated with genetic defects. Children with complex CHD often develop heart failure, requiring heart transplant. Given the broad spectrum of genetic pathologies and dearth of transplants performed in these children, little is known regarding their outcomes. METHODS We conducted a retrospective review of heart transplants performed at a high-volume center from 2007-2021. Patients were separated into pathogenic molecular and copy number variants, aneuploidies, and variants of uncertain significance, and compared to those without known genetic diagnoses. Variables included genetic diagnoses, bridge-to-transplant approach, preoperative comorbidities, operative characteristics, and postoperative complications. Outcomes included ICU-free days to 28 days, hospital mortality, survival, rejection, re-transplantation, and educational status at latest follow-up. RESULTS 223 patients were transplanted over the study period: 9.9% (22/223) had pathogenic molecular variants, 4.5% (10/223) had copy number variants, 1.8% (4/223) had aneuploidies, and 9.0% (20/223) had variants of uncertain significance. The most common anomalies were Turner syndrome (n=3) and 22q11.2 deletion syndrome (n=2). Children with aneuploidies had higher rates of hepatic dysfunction and hypothyroidism, while those with pathogenic copy number variants had higher rates of preoperative gastrostomy and stroke. Children with aneuploidies were intubated longer post-transplant, with greater need for re-intubation, and had the fewest ICU-free days. Mortality and mean survival did not differ. At median follow-up of 4.4 (1.9-8.8) years, 89.7% (26/29) of survivors with pathogenic anomalies were attending or had graduated school. CONCLUSIONS Despite more preoperative comorbidities, mid-term outcomes following heart transplant in children with genetic syndromes and disorders are promising.
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... Outcomes data from 22q11.2 DS suggest mildly increased perioperative morbidity and increased length of stay, but overall similar long-term outcomes compared to nonsyndromic repair of matched congenital heart disease (Alsoufi et al., 2017;McDonald et al., 2013;Mercer-Rosa, Elci, Pinto, Tanel, & Goldmuntz, 2018;Michielon et al., 2009;Woolman et al., 2019). Part of this mild increase in perioperative morbidity and mortality in 22q11.2 ...
Congenital heart defects in CHARGE: The molecular role of CHD7 and effects on cardiac phenotype and clinical outcomes
Article
  • Dec 2019
CHARGE syndrome is characterized by a pattern of congenital anomalies (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth, Genital abnormalities, and Ear abnormalities). De novo mutations of chromodomain helicase DNA binding protein 7 (CHD7) are the primary cause of CHARGE syndrome. The clinical phenotype is highly variable including a wide spectrum of congenital heart defects. Here, we review the range of congenital heart defects and the molecular effects of CHD7 on cardiovascular development that lead to an over‐representation of atrioventricular septal, conotruncal, and aortic arch defects in CHARGE syndrome. Further, we review the overlap of cardiovascular and noncardiovascular comorbidities present in CHARGE and their impact on the peri‐operative morbidity and mortality in individuals with CHARGE syndrome.
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Solid Organ Transplantation for Children With Neurodevelopmental Disabilities—Ethical Considerations and a Call for Clarity
Article
  • Feb 2023
  • Semin Pediatr Neurol
Pediatric transplant centers are faced with the difficult task of maximizing the benefit of organs donated for transplantation while also ensuring that all patients undergoing transplant evaluation are fairly considered for this life-saving therapy. Children with neurodevelopmental disabilities are a complex patient population that on occasion may face the need for a solid organ transplant. Several concerns exist regarding transplantation in this population, yet standard transplant inclusion and exclusion criteria do not exist. Here we explore important factors regarding organ transplantation for children with neurodevelopmental disorders, including patient outcomes, quality of life considerations, and the fundamental ethical principles underlying this complex medical decision-making.
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Prevalence and Long-Term Outcomes of Solid Organ Transplant in Children with Intellectual Disability
Article
  • Mar 2021
  • J Pediatr
Objectives To describe the prevalence and long-term outcomes of kidney, liver, and heart transplant for children with intellectual disability. Study design We performed a retrospective cohort analysis of children receiving a first kidney, liver, or heart-alone transplant in the United Network for Organ Sharing dataset from 2008-2017. Recipients with definite intellectual disability were compared with those Possible/no ID. Kaplan-Meier survival estimates were calculated for graft and patient survival. Cox proportional hazard models were used to estimate the association between ID and graft and patient survival. Results Over the study period, children with definite ID accounted for 594 of 6747 (9%) first pediatric kidney-alone, 318 of 4566 (7%) first pediatric liver-alone, and 324 of 3722 (9%) first pediatric heart-alone transplant recipients. ID was not significantly associated with patient or graft survival among liver and heart transplant recipients. Among kidney transplant recipients, definite ID was significantly associated with higher graft survival and lower patient survival, but absolute differences were small. Conclusions Children with ID account for 7-9% pediatric transplant recipients with comparable long-term outcomes to other pediatric recipients. These findings provide important empirical support for policies that include children with ID as transplant candidates.
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Genetic disease and intellectual disability as contraindications to transplant listing in the United States: A survey of heart, kidney, liver, and lung transplant programs
Article
  • Nov 2020
Discrimination based on disability is prohibited in organ transplantation, yet studies suggest it continues in listing practices for intellectual disability and genetic diseases. It is not known if this differs between adult and pediatric programs, or by organ type. We performed an online, forced‐choice survey of psychosocial listing criteria for adult and pediatric heart, kidney, liver, and lung transplant programs in the United States. Of 650 programs contacted, 343 (52.8%) submitted complete. A minority of programs had formal listing guidelines for any condition considered (Down Syndrome, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, DiGeorge Syndrome, and Wolf Hirschhorn Syndrome; and mild [IQ < 70] and severe [IQ < 35] intellectual disability), although a majority had encountered most. Pediatric programs were significantly (P < .02) more lenient in the level of contraindication to listing for all genetic conditions considered except Duchenne Muscular Dystrophy, and for mild and severe intellectual disability. Level of contraindication differed significantly by organ type (heart, lung, liver, and kidney) for Duchenne Muscular dystrophy (P = <.001), Becker Muscular Dystrophy (P < .001), DiGeorge Syndrome (P < .001), Wolf‐Hirschhorn syndrome (P = .0012), and severe intellectual disability (P < .001). There is significant variation among transplant programs in availability of guidelines for as well as listing practices regarding genetic diseases and intellectual disability, differing by both adult vs pediatric program, and organ type. Programs with absolute contraindications to listing for specific genetic diseases or intellectual disability should reframe their approach, ensuring individualized assessments and avoiding elimination of patients based on membership in a particular group.
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Risk of malignancy in 22q11.2 deletion syndrome
Article
Full-text available
  • Feb 2017
Key Clinical Message 22q11.2DS is a significant health problem because of its fairly high incidence. It is relevant to be vigilant regarding the diagnosis of cancer amongst 22q11.2 patients as there might be an increased risk, especially amongst patients with the 22q11.2 distal deletion syndrome.
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The impact of cognitive delay on pediatric heart transplant outcomes
Article
Full-text available
  • Mar 2017
  • PEDIATR TRANSPLANT
The presence of CD may be viewed as a relative contraindication to transplantation; however, its impact on pediatric HTx outcomes is poorly characterized. The aim of this study was to assess the impact of CD on pediatric HTx outcomes using academic progress as a surrogate measure of cognitive performance. The OPTN database was queried for all pediatric HTx recipients (2004-2014) with reported academic progress. Multivariable analysis assessed the impact of DGL and the need for SE on post-HTx graft survival. A total of 2245 children were included: 1707 (76%) within grade level, 269 (12%) with DGL, and 269 (12%) who required SE. The need for SE was not a risk factor for post-HTx mortality; however, DGL was an independent risk factor for worse post-HTx outcomes (AHR 1.4, 95% CI 1.02, 1.79, P=.03). Patients who require SE have similar outcomes compared to those without CD, likely secondary to significant parental involvement. Children with DGL demonstrate inferior post-HTx survival, which could result from less parental oversight in children perceived to maintain compliance. Ensuring adequate social support for patients with evidence of CD may help to improve outcomes.
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Cardiac Transplantation in Children with Down Syndrome, Turner Syndrome and Other Chromosomal Anomalies: A Multi-Institutional Outcomes Analysis
Article
  • Jan 2018
  • J HEART LUNG TRANSPL
Background: The purpose of this study was to describe the prevalence, characteristics, and outcomes in pediatric patients with chromosomal anomalies (CA) undergoing orthotopic heart transplantation (OHT). Methods: A query of the database of the Pediatric Health Information System, a large administrative and billing database of 43 tertiary children's hospitals, was performed for the Years 2004 to 2016. Pediatric patients who received OHT were analyzed based on presence and type of CA. CA analyzed included: Down syndrome (DS); Turner syndrome (TS)/gonadal dysgenesis; conditions due to anomaly of unspecified chromosome; autosomal deletion; microdeletion; and autosomal anomaly. Healthcare-associated charge analysis during hospitalization for OHT and survival after OHT were assessed. Results: A total of 3,080 hospitalizations were identified in which OHTs were performed. Of these OHTs, 64 (2.1%) were performed in patients with a concomitant diagnosis of CA. The presence of CA did not confer a higher risk of in-hospital mortality after OHT (odds ratio 1.2 [0.5 to 3.2], p = 0.651). Differences in in-hospital mortality between different types of CA, including DS and TS, did not reach statistical significance. Survival at 1-year post-OHT was similar in patients with CA compared to those without CA (p = 0.248). Length of stay after OHT was longer in patients with CA: 76 (interquartile range [IQR] 76 to 142 days vs 49 [IQR 21 to 98] days) (p < 0.001), respectively. Overall adjusted hospital charges were significantly higher in the CA group: $1.2 million (IQR $740,000 to $2.2 million) vs $792,000 (IQR $425,000 to $1.5 million] (p < 0.001), respectively. Conclusions: CA is present in ~2% of pediatric patients undergoing OHT. The presence of CA was not associated with increased mortality in pediatric patients undergoing OHT. Limitations of this study include the small number of patients available for analysis and a likely highly selective cohort of patients with CA.
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A Unique Linkage of Administrative and Clinical Registry Databases to Expand Analytic Possibilities in Pediatric Heart Transplantation Research
Article
  • Dec 2017
  • AM HEART J
Background: Large clinical, research, and administrative databases are increasingly utilized to facilitate pediatric heart transplant (HTx) research. Linking databases has proven to be a robust strategy across multiple disciplines to expand the possible analyses that can be performed while leveraging the strengths of each dataset. We describe a unique linkage of the Scientific Registry of Transplant Recipients (SRTR) database and the Pediatric Health Information System (PHIS) administrative database to provide a platform to assess resource utilization in pediatric HTx. Methods: All pediatric patients (1999-2016) who underwent HTx at a hospital enrolled in the PHIS database were identified. A linkage was performed between the SRTR and PHIS databases in a stepwise approach using indirect identifiers. To determine the feasibility of using these linked data to assess resource utilization, total and post-HTx hospital costs were assessed. Results: A total of 3188 unique transplants were identified as being present in both databases and amenable to linkage. Linkage of SRTR and PHIS data was successful in 3057 (95.9%) patients, of whom 2896 (90.8%) had complete cost data. Median total and postHTx hospital costs were $518,906 (IQR $324,199 – $889,738) and $334,490 (IQR $235,506 - $498,803) respectively with significant differences based on patient demographics and clinical characteristics at HTx. Conclusions: Linkage of the SRTR and PHIS databases is feasible and provides an invaluable tool to assess resource utilization. Our analysis provides contemporary cost data for pediatric HTx from the largest U.S. sample reported to date. It also provides a platform for expanded analyses in the pediatric HTx population.
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The Impact of 22q11.2 Deletion Syndrome on Surgical Repair Outcomes of Conotruncal Cardiac Anomalies
Article
  • Jun 2017
Background We aim to describe the impact of 22q11.2 deletion syndrome (22q11DS) on clinical characteristics, postoperative course, and early and late outcomes of neonates undergoing surgery for conotruncal anomalies. Methods A retrospective review was performed (2002 to 2012) of 224 neonates who underwent surgery for interrupted aortic arch (n = 67), truncus arteriosus (n = 85), or ductal-dependent pulmonary atresia and ventricular septal defect (n = 72). Patients were divided into three groups: group 1, n = 119, no genetic syndrome; group 2, n = 64, 22q11DS; and group 3, n = 41, other genetic syndrome. Adjusted analysis to compare outcomes was performed. Results In comparison with group 1, group 2 had longer mechanical ventilation duration (148 versus 102 hours, p = 0.008), intensive care unit stay (268 versus 159 hours, p < 0.001), and hospital stay (19.3 versus 11.5 days, p < 0.001). On adjusted analysis, there was an insignificant increase in unplanned reoperation (odds ratio [OR] 2.4, 95% confidence interval [CI]: 0.7 to 8.4, p = 0.167) but no increased extracorporeal membrane oxygenation use (OR 1.5, 95% CI: 0.3 to 6.1, p = 0.612), hospital mortality (OR 0.6, 95% CI: 0.1 to 3.3, p = 0.570), or decreased late survival (hazard ratio 0.9, 95% CI: 0.4 to 2.1, p = 0.822). In comparison with group 1, group 3 had longer mechanical ventilation duration (190 versus 102 hours, p < 0.001), intensive care unit stay (236 versus 159 hours, p = 0.007), and hospital stay (21.5 versus 11.5 days, p < 0.001); and increased unplanned reoperation (OR 3.7, 95% CI: 1.1 to 12.5, p = 0.032), extracorporeal membrane oxygenation use (OR 4.4, 95% CI: 1.1 to 17.6, p = 0.038), hospital mortality (OR 4.2, 95% CI: 1.2 to 14.5, p = 0.021), and diminished late survival (hazard ratio 4.0, 95% CI: 2.1 to 8.1, p < 0.001). Conclusions In neonates with conotruncal anomalies, 22q11DS is associated with prolonged recovery and increased resource utilization. However, despite a small increase in unplanned reoperation, there is no significant impact on early or late survival. In comparison, other genetic syndromes are associated with increased unplanned reoperation, extracorporeal membrane oxygenation use, hospital mortality, and diminished late survival. These findings are important for family counseling and risk stratification.
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Prevalence and outcomes of heart transplantation in children with intellectual disability
Article
  • Nov 2016
  • PEDIATR TRANSPLANT
Heart transplantation in children with intellectual disability is a controversial issue. We sought to describe the prevalence and outcomes of heart transplantation in children with intellectual disability and hypothesized that recipients with intellectual disability have comparable short-term outcomes compared to recipients without intellectual disability. We performed a retrospective cohort analysis of children receiving a first heart-alone transplant in the UNOS STAR database from 2008 to 2013. Recipients with intellectual disability were compared to those without using chi-square tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between intellectual disability and graft failure and patient survival. Over the study period, 107 children with intellectual disability underwent initial heart transplantation, accounting for 8.9% of first pediatric heart transplants (total=1204). There was no difference in the incidence of acute rejection between groups in the first year after transplant. Mean functional status scores at follow-up improved in both groups after transplantation, but tended to be lower among children with intellectual disability than children without. Log-rank tests did not suggest significant differences in graft survival between those with and without intellectual disability during the first 4 years following transplantation. Children with intellectual disability constitute a significant portion of total heart transplants with short-term outcomes comparable to children without intellectual disability.
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Prevalence and Outcomes of Liver Transplantation in Children With Intellectual Disability
Article
  • Dec 2015
Objective: We sought to describe the prevalence and outcomes of liver transplantation in children with intellectual disability (ID). We hypothesized that recipients with ID have comparable short-term outcomes compared to those without ID. Methods: We performed a retrospective cohort analysis of children receiving a first liver-alone transplant in the UNOS dataset from 2008-2013. Recipients with definite or probable ID were compared to children without ID using chi-square tests. Kaplan-Meier curves were constructed for patient and graft survival. Cox proportional hazard models were used to estimate the association between ID and graft failure and patient survival. Results: Over the study period, 254 children with definite (115) or probable (139) ID underwent first liver transplant, accounting for 15% of all first pediatric liver transplants (1721). Recipients with definite ID tended to be male, have a metabolic indication for transplant, a lower PELD score at listing than recipients with no ID, and were less likely to receive a living donor transplant. Recipients with ID were more likely to have public insurance and had more treatment-related hospitalizations in the first year than those without ID. Functional status tended to improve in all recipients at follow-up. ID was not significantly associated with patient or graft survival. Conclusions: Children with ID form a significant portion of total liver transplant recipients and their short-term graft and patient survival are comparable to children without ID. Further research is needed to examine long-term outcomes of transplant in this population.
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What Is the Role of Developmental Disability in Patient Selection for Pediatric Solid Organ Transplantation?
Article
  • Nov 2015
The National Organ Transplant Act stipulates that deceased donor organs should be justly and wisely allocated based on sound medical criteria. Allocation schemes are consistent across the country, and specific policies are publicly vetted. Patient selection criteria are largely in the hands of individual organ transplant programs, and consistent standards are less evident. This has been particularly apparent for patients with developmental disabilities (DDs). In response to concerns regarding the fairness of transplant evaluations for patients with DDs, we developed a transplant centerwide policy using a multidisciplinary, community-based approach. This publication details the particular policy of our center. All patients should receive individualized assessments using consistent standards; disability should be neither a relative nor an absolute contraindication to transplantation. External review can increase trust in the selection process. Patients in persistent vegetative states should not be listed for transplantation. © 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.
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