Neurodevelopmental outcomes in children with congenital heart disease:  What do we know and what can we do?

Kathy Mussatto, RN, research manager, Herma Heart Center, Children's Hospital of Wisconsin.

The impact of congenital heart disease (CHD) on neuro-development has been a long-standing concern. Neuro-developmental outcomes in CHD were explored as early as the 1950s. The recent decade has witnessed a flourish of research in this area that has helped characterize the developmental "signature" of children from a variety of CHD diagnostic backgrounds and age groups. More importantly, this research has helped unravel the variety of factors that contribute to this complex, multifactorial process.

As survival increases, the impact of the long-term morbidity associated with CHD becomes increasingly important. Today it is estimated that more than 1 million people are living with CHD and by 2010 it is expected there will be more adults living with CHD than children. The personal and societal consequences of development impairment in these people cannot be underestimated. It is important we understand not only what outcomes are typical and what variables contribute to these outcomes; we also must explore what interventions can help children and adults with CHD achieve their full potential.

What do we know?

Multiple studies have identified that children with CHD, particularly those who require cardiac surgery in infancy, are at risk for a significantly higher incidence of academic difficulties, behavioral abnormalities, fine and gross motor delays, problems with visual-motor integration and executive planning, speech delays, inattention and hyperactivity. Many studies have found that samples of children with CHD have IQs that fall within the normal range, however, significant delays in very specific areas of cognitive function, such as visual-motor integration, are common. As an example, in a study of children ages 3 1⁄2 to 6 years who underwent treatment at Children's Hospital of Wisconsin for either transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS), found IQ scores for these children fell within the normal range – 110 for TGA vs. 97 for HLHS (p = NS). However, patients with HLHS scored lower than normal on motor function, visual motor integration, expressive language and behavioral problems (all p < 0.05). These delays will contribute to long-term outcomes in academic achievement, behavior, social integration, self-esteem and overall quality of life. In a cohort of 182 survivors of infant surgery for CHD, parents reported that problems with social and school function had the greatest negative impact on quality of life. 

Figure 1: Schematic representation of developmental abnormalities in children with CHD.

Early research focused on the impact of singular factors such as hypoxia or cardiopulmonary bypass management strategies on neurodevelopment, however, subsequent studies have consistently identified that children with CHD face multiple levels of risk that interact in complex ways. These risks include prenatal, preoperative, intra-operative, postoperative, socioeconomic and other long-term factors. CHD represents a heterogenous group of abnormalities and corresponding outcomes also vary widely. The interaction of multiple levels of risk results in some groups of children that demonstrate few or no developmental impairments while other high-risk groups, such as children with single ventricle heart disease, have a relatively high incidence of significant disabilities. In 2000, researchers found that more than 30 percent of school-aged subjects with hypoplastic left heart syndrome were receiving some form of special education and 18 percent had an IQ less than 70. This spectrum of impact is schematically represented in Figure 1.

Prenatal factors

The cardiovascular and central nervous systems form nearly simultaneously in early gestation. Therefore it is not surprising that structural abnormalities of the brain may occur in combination with structural cardiac abnormalities. Several prenatal factors may predispose a child to neurodevelopmental delays including:

• Genetic syndromes and/or polymorphisms.
• Additional extracardiac abnormalities.
• Altered cerebral blood flow in utero.
• Congenital brain malformations.

Preoperative factors

Abnormal preoperative neurological findings have been reported in up to 50 percent of newborns with CHD. Additional factors may include:

• Presentation – prenatal vs. postnatal diagnosis.
• Oxygen economy management including arterial, venous and regional tissue saturations.
• End-organ status prior to surgery.
• Interventions required for stabilization, such as intubation and ventilation, inotropic support, sedation, provision of nutrition.
• Failure to thrive prior to intervention.

Intraoperative factors

Intraoperative factors have long been implicated as having an impact on long-term neurodevelopmental outcomes, however, they likely are the most controllable variables and the area where we have had the greatest impact to date. They include:

• Age at operation.
• Surgical technique.
• Cardiopulmonary bypass management strategies.

Postoperative factors

Many factors contribute to neurologic vulnerability in the early postoperative period following infant cardiac surgery:

• Decreased cardiac output.
• Altered cerebral autoregulation following cardio-pulmonary bypass.
• Hyperthermia.
• Seizures – may occur in as many as 20 percent of postoperative neonates.
• Thrombotic or hemorrhagic events.
• Invasive monitoring, mechanical ventilation and significant medical support.
• Need for postoperative mechanical support.

Long-term factors

Despite reaching a state of physiologic stability following recovery from surgery, many patients with complex CHD remain at risk for new or ongoing neurologic injury due to:

• Chronic hypoxia.
• Congestive heart failure.
• Failure to thrive.
• Thrombotic events.
• Need for further operations or interventions.

Conversely, other variables the child is exposed to have the potential to impart a protective or reparative effect, such as:

• Socioeconomic status and parental IQ. (This may be the most powerful predictor of long-term neurodevelopmental outcome).
• Early intervention and therapy.

In summary, children born with CHD face multiple risks for impact on neurodevelopment at a variety of time points during their lives and treatments. Developmental disabilities in this population have a relatively high prevalence but tend to be of low severity in most cases.  Severe impairment is relatively rare. The children most at risk for significant delays are those with complex CHD who encounter multiple prenatal, preoperative, intra-operative, postoperative and long-term risks. The areas most affected are visual-motor integration, motor skills, behavior and language.

What can we do?

Prenatal factors

There is, of course, very limited ability to alter prenatal factors. However, the science and practice of fetal intervention for cardiac disease is rapidly advancing. Diagnosis and treatment of fetal arrhythmias is improving and may protect the developing brain from injury. Anatomic fetal intervention is theorized to have the potential to improve cerebral blood flow in the developing fetus.

The most important thing we can do may be to document significant prenatal factors at the time of presentation via preoperative brain imaging and careful genetic evaluation.  These findings can then be accounted for in interpreting a child's overall risk for long-term neurodevelopmental abnormalities. 

Preoperative factors

On presentation of a neonate with complex CHD, rapid stabilization with preservation of end-organ function should be accomplished. Invasive interventions should be minimized whenever possible and hypoxic or acidotic conditions should be rapidly remedied. Growth and nutrition must be actively monitored in any infant where surgery will be delayed. In addition, parental stress, bonding and caregiving should be assessed to ensure the infant is receiving healthy psychosocial stimulation.
Prior to surgery all newborns with CHD should undergo a thorough preoperative neurologic exam to look for baseline abnormalities. At Children's Hospital this is done during the preoperative neonatal admission.

Intraoperative factors

Intraoperative variables have the greatest potential for standardization and control. Manipulation of variables including the effects of cooling and rewarming, ph management strategy and the use of regional low-flow cerebral perfusion (RLFP) vs. deep hypothermic circulatory arrest (DHCA) are a focus of research currently underway at Children's Hospital. Also, tissue saturation values obtained with near infrared spectroscopy (NIRS) have added greatly to the intraoperative management of perfusion. The association of cerebral saturation with later development also is being tested with ongoing studies.

Postoperative factors

Goal-directed therapy to ensure adequate cardiac output, oxygen delivery and neuroprotection is the standard of care in the Children's Hospital intensive care unit. Regional tissue perfusion is monitored with NIRS with a goal of avoiding anaerobic thresholds and/or changes from baseline of > 20 percent. SvO2 values of > 50 percent are targeted to ensure a balance between oxygen delivery and consumption. Hyperthermia and clinical evidence of seizures are treated aggressively.

Long-term factors

Systematic, longitudinal assessment of neurodevelopment and the application of appropriate therapies in children with complex CHD are essential to reduce the risk of long-term complications and to treat identified delays. All high-risk cardiac infants discharged from Children's Hospital are referred to local "Birth-to-3" programs, however, it has been recognized that there is a significant degree of variability in the follow-up available from these programs.

Developmental Follow-up Program

(414) 266-2742 Program director: Laurel Bear, MD Program coordinator: Ann Chin, RN, BSN

In January 2007, Herma Heart Center began the Developmental Follow-up Program. The program, led by Laurel Bear, MD, and Program Coordinator Ann Chin, RN, BSN, is modeled after the Children's Hospital follow-up program designed for premature infants that graduate from the Neonatal Intensive Care Unit. The program uses a multidisciplinary approach to assess each child and is staffed by a developmental specialist and nurses, as well as physical, occupational and speech therapists that specialize in high-risk follow-up. All neonates undergoing open heart surgery, those with cyanotic heart disease and any other infant with CHD considered to be at high risk for developmental delay will be referred. Children will be seen every six months from age 6 months to 3 years. Children older than 3 years will receive ongoing care from Cheryl Brosig, PhD, a developmental specialist for older children. Each assessment includes a review of developmental milestones and standardized scoring of the child's motor and mental skills, feeding concerns, family impact and quality of life. If delays or concerns are identified, recommendations for appropriate interventions are made. For children who are not followed at Children's Hospital, guidance for a local program is readily available. 

In conclusion, the evidence indicates that children with CHD, particularly those with complex disease, are indeed at risk of neurologic injury and subsequent developmental impairments. It is likely there is no single point of injury or risk but rather that these impairments result from a complex, multifactorial process. Concern for how and when these injuries occur and what can be done to prevent them is warranted. The good news is we have a much better understanding of these risk factors and recognize many of them may be modifiable. Today's children receiving care for complex CHD are benefiting from a variety of neuroprotective strategies at multiple stages in their care. The impact of these interventions is not yet known, but we are hopeful they will have a positive benefit on outcomes. Pediatric specialists recognize that outcomes cannot be measured in terms of months or even years for our youngest patients. Rather, outcome analyses must be conducted with a lifetime perspective. None of us would be eager to approach our work each day if we thought significant developmental impairment in the patients we care for was inevitable. Together, we can help our patients achieve lives full of potential and promise.

A list of references is available upon request.

The use of intraoperative transcranial doppler at Children's Hospital of Wisconsin

Michael E. Mitchell, MD, pediatric cardiothoracic surgeon, Herma Heart Center, Children's Hospital of Wisconsin; assistant professor, Surgery (Cardiothoracic), Medical College of Wisconsin.

As survival rates for congenital heart surgery have improved to well over 90 percent for even the most complex cases, improving neurologic outcomes has become a priority for Children's Hospital of Wisconsin and leading centers around the world. Neuroprotective strategies championed by Children's Hospital, particularly the use of regional low flow cerebral perfusion strategies and NIRS monitoring, are developing wider appeal. However, neurologic injury still occurs.

Often technically related, emergent and readily reversible causes of neurologic injury during congenital heart surgery include low flow states, gas and particle emboli, and venous and arterial obstruction. All of these may be reflected by impressive, but potentially delayed, decreases in NIRS cerebral oxygen saturation monitoring. The key limitation of NIRS is that a sharp drop in cerebral O2 saturation does not specifically identify the cause. The clinician is left to troubleshoot, time can be lost and injury can occur. 

These rare but often life-changing problems can be specifically and immediately detected by transcranial doppler (TCD). TCD monitoring of the middle cerebral artery (MCA) is a technology that allows real time detection of changes in cerebral blood flow velocity (CBFV). The nature of the change reflects the specific cause of the problem. The interpretation is straightforward after training and TCD has been employed successfully at a number of pediatric and adult heart centers with dramatic results. TCD monitoring has been proposed for use in cardiac cases at Children's Hospital. 

The technology

The available pediatric TCD instruments consist of a single probe that emits pulsed-wave ultrasounds at 2 to 4 MHz. These ultrasonic waves penetrate and scatter through the tissue and then are backscattered from moving red blood cells. The frequency shift is detected by the receiver, which is contained within the probe. The output from the instrument is audible with clicks representing micro emboli, graphical with waveforms representing flow, and numerical with calculated velocities and volumes.

Figure 1

The set up 

The most reproducible and comfortable technique for clinical use in pediatric patients is to insonate the MCA through the temporal window. This is found 1 cm in front of the external auditory meatus and 1-2 cm above the zygomatic arch. The ultrasonic beam is directed horizontally.  The depth of the sample volume and angle of insonation is adjusted until the bifurcation of the MCA and the anterior cerebral artery (ACA) is found. The typical set up is depicted below with the white arrow pointed toward the transmitter, which is held onto the head by an elastic or gauze bandage. In practice this takes a trained provider between 5 and 10 minutes to secure for an open cardiopulmonary bypass case. While there are no lower size limitations for TCD, positioning on neonates smaller then 2 kg can be challenging.

Figure 2

The data    

TCD provides continuous feedback on three critical parameters: CBFV, embolic events and the pulsatile wave form, all of which are continuously measured and graphically depicted. 

CBFV as directly measured in the MCA has an extremely high correlation with flow in the basal cerebral arteries. This can be essential to fine-tuning perfusion strategies (for example, avoiding both hyper- and hypo-perfusion) particularly during regional low flow or selective antegrade cerebral perfusion. Changes in cerebral saturation by NIRS can be immediately and definitively correlated to changes in MCA doppler flow velocities. At times where NIRS data can be difficult to interpret (for example, low flow, hypothermia, rewarming), TCD velocity measurements can be particularly useful. The prospective benefit to combined TCD and NIRS monitoring during Norwood procedures with methods of perfusion similar to those used at Children's Hospital has been reported.

Emboli, particularly air emboli, remain a uniquely important neurological risk factor to children undergoing congenital heart surgery. An incomplete list of sources of this air includes inadvertent air boluses through peripheral arterial or venous lines, minor injury to cardiac structures during reoperative dissections, air entrapment in the pump or cannulae, or residual intracardiac air following repair. Emboli are depicted as sharp discrete vertical lines on the pulse waveform graph and as clicks or "hits" providing immediate audible feedback to the entire operating room staff. Solid emboli may be distinguished from air by a different signal pattern. Austin et al reported a profound decrease in the number of hits incurred during pediatric cases since the introduction of TCD monitoring at their institution (JTCVS 1997).

Pulsatile wave form pattern changes can be used to rapidly diagnose venous versus arterial obstructive causes for changes in cerebral blood flow (often associated with minor problems of cannulae or clamp position). In the next two strips (Figure 3), inflow obstruction has a distinct morphology, which allows it to be differentiated from outflow obstruction. In each example cannulae were adjusted slightly, resulting in normalization of wave form and cerebral blood flow. Several case reports describe near disasters averted with simple adjustments of cannulae or clamp position because of this information.

Figure 3

TCD is a readily available non-invasive monitoring modality that provides critical real time and value added data to clinicians taking care of children undergoing congenital heart surgery. TCD provides information during cardiopulmonary bypass essential in fine-tuning perfusion rates in order to avoid both hypo- and hyper-perfusion. This is particularly relevant to institutions that, like Children's Hospital, rely on regional low flow perfusion strategies. In addition, TCD can provide specific and immediate data regarding readily reversible disturbances of flow velocities or emboli, which lead to immediate intervention and improved neurological outcomes on an anecdotal basis.

Identifying genetic risk factors of congenital heart disease

Aoy Tomita-Mitchell, PhD, assistant professor, Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin.

Congenital heart disease (CHD) is one of the most common major birth defects, occurring in 0.8-1 percent of all live births. As advances in pediatric cardiac surgery and medical care allow more neonates with complex disease to survive, CHD is becoming even more common in children and adults. Despite the prevalence and clinical significance of these malformations, the etiology remains largely unknown. While a few causal links, including environmental exposures, exposure to medications during gestation, maternal diabetes, chromosomal disorders and genetic factors have been established, these known causes contribute to only a small percentage of CHD. The majority of cases occur without any known genetic or environmental cause.
Elucidating the genetic etiology of CHD presents several challenges. While CHD appears to have an increased risk of recurrence within families, large families with CHD that would be amenable to genetic linkage studies are rare. There is evidence of variable expressivity, indicating that the etiology of these defects cannot be explained by simple Mendelian genetics but arise through complex mechanisms. As an example, while chromosomal abnormalities such as trisomy 21 (Down syndrome) and 22q11.2 deletions (DiGeorge syndrome) clearly associate with CHD, the genetics are complex. Indeed many children with trisomy 21 and 22q11.2 deletions have normal hearts. Theories of multifactorial inheritance have been suggested whereby multiple genetic factors, perhaps interacting with environmental factors, combine to increase the risk for abnormal cardiac development.  Molecular analyses of clinical syndromes have identified some disease-related loci and genes. Animal models also contribute to our knowledge of cardiac development and have identified genes that could contribute to human disease. However, much work remains to define the genetic basis of these defects.

Since the publishing of the human genome, it has become clear to researchers that the identification of the genetic factors contributing to complex diseases, such as CHD, will require the resequencing of candidate genes many hundreds or even thousands of times. However, the cost of conventional sequencing has been prohibitive to this approach. Our laboratory is using a new approach called cycling temperature capillary electrophoresis (CTCE). CTCE is a capillary electrophoresis method, run on a 96 capillary platform, that can detect previously unknown DNA variants based on differential migration velocities of wild-type (normal)/mutant heteroduplex DNA sequences. These DNA sequences are drawn through a linear polyacrylamide matrix by an electric field. Excellent separations resulting in the comprehensive detection of mutations in a 100 to 150 base-pair target sequence can be obtained when the temperature is cycled by several degrees around the calculated melting temperature of DNA sequences. The approach is rapid and significantly more economical than sequencing.

Recent advances in resolution of comparative genomic hybridization and genomic sequence annotation may increase our ability to detect microsomal changes.  Although the majority of patients with CHD have normal karyotypes, a significant percentage have major chromosomal alterations (5-10 percent). We also will employ genome-wide approaches to establish the genetic background of our patient populations and to look for microsomal anomalies associating with CHD. These genome-wide approaches can be used to identify potential CHD candidate genes.  
By combining these technologies with the clinical resources at Children's Hospital of Wisconsin we are excited about the possibility of making significant inroads into understanding the genetic contributions to congenital heart malformations. It is our hope that the rapidly growing CHD tissue bank, the Wisconsin Pediatric Cardiac Registry and collaborations with centers across the country will provide us with the samples necessary to perform the large scale association studies, and that the use of these technologies position us well to answer some of these elusive questions. Although there is considerable work to be done, we are optimistic about the unique confluence of technology and clinical experience that exists at Children's Hospital.  

Interstage home monitoring benefits infants with hypoplastic left heart syndrome

Nancy Rudd, RN, PNP, Herma Heart Center, Children's Hospital of Wisconsin.

For the past six years, all infants discharged home following stage I palliation for hypoplastic left heart syndrome (HLHS) have had parents perform daily check of oxygen saturation, heart rate, weight and record total fluid intake. This concept has come to be called "home monitoring" and is an interstage surveillance program established by Children's Hospital of Wisconsin in an effort to allow early detection of potentially life-threatening events.

Prior to the initiation of the program, interstage death for HLHS infants at Children's Hospital was similar to other major pediatric cardiac centers. Unfortunately, despite improved early surgical survival, approximately 15 percent of infants with HLHS died at home prior to stage 2 surgical palliation. Since the home monitoring program started in October 2000, our incidence of interstage mortality has decreased dramatically.

The program has several key components. An infant scale and pulse oximeter are obtained for home use. Parents receive comprehensive education by a dedicated group of cardiac nurse practitioners in the areas of equipment use, nutrition and hydration goals, recording and interpretation of collected data, and criteria warranting notification of the cardiology team. In addition, set criteria for concern are maintained and include a decrease in oxygen saturation below 75 percent, weight loss of 30 grams or inability to gain 10-20 grams over a three-day span. Finally, the most important component is 24/7 availability of support staff to address parent concerns.

Since initiation of the program, more than 100 infants with HLHS have been monitored. There has been 100 percent participation by eligible families. Approximately 50 percent of these interstage infants experienced one or more breach of the established criteria for concern. These alterations in oxygen saturation or weight have resulted in the detection of intercurrent illness and even serious anatomic lesions. Necessary interventions range from over-the-phone adjustment of enteral feeds to hospitalization requiring cardiac catheterization or surgical intervention.

Results of the home monitoring program are many but none is more significant than a decrease in interstage death to less than 3 percent. Our results have been well recognized in the pediatric congenital heart disease community and include several publications and national presentations. To date, more than 30 national and international cardiac centers have inquired about replicating our program. The majority of these centers have adopted some form of home monitoring, and we have received reports of decreased interstage mortality at other institutions following our protocols. The concept of in-home daily assessment and trending of oxygen saturations and weight has allowed identification of infants at-risk for potentially life-threatening events and has positively impacted the outcomes of this high-risk group of infants both at our institution and nationally.  

A multidisciplinary approach to the diagnosis and management of infants with DiGeorge syndrome

Laurie Newton, RN, MSN, CPNP, Herma Heart Center, Children's Hospital of Wisconsin.

DiGeorge syndrome (DGS), velocardiofacial (VCFS) or Shprintzen syndrome – overlapping conditions also referred to collectively as 22q11 deletion syndrome – is the most common chromosomal deletion syndrome found in humans. A collective acronym "CATCH 22" – Cardiac, Abnormal facies, Thymic hypoplasia, Cleft palate, Hypocalcemia and 22 – signifying deletion of the long arm of chromosome 22 has been designated to describe all of these somewhat varying presentations. With an estimated incidence of 1 in 4,000 live births, DiGeorge syndrome is characterized by a triad of clinical features: congenital heart disease, particularly conotruncal defects, hypoparathyroidism and thymus defects. The associated parathyroid and thymic aplasia or hypoplasia may cause hypocalcemia and T-cell immune deficiencies. In addition to these main features of DGS, the phenotype is extremely broad and variable and may include a multitude of other key aspects (Table 1).

Laboratory testing/diagnosis

Because of the widely variable presentation of DGS, it is essential that both general practitioners and sub-specialists be aware of this diagnosis and how to appropriately test for it. On the basis of clinical findings, the diagnosis of DGS can be confirmed using fluorescent in situ hybridization (FISH) for the 22q11 region chromosomal deletion. Affected patients have only one copy of this region. However, it is estimated that up to 15 percent of patients will have a microdeletion not detected by FISH.  Furthermore, while cardiac defects often are associated with the diagnosis of DGS or VCFS, approximately 15-20 percent of patients with associated anomalies have no cardiac defect. Therefore health care providers must be aware of the variable presentation of DGS and proceed with further lab evaluation and genetic screening if suspicion of DGS remains high despite a negative FISH.  Other labs and studies to obtain if the diagnosis of DGS is suspected include CBC with differential, serum calcium, serum immunoglobulins, TSH, free T4, echocardiogram, renal ultrasound, X-rays of the spine and assessment of the palate. The Primary Immune Deficiency Lab at Children's Hospital will evaluate immune function in suspected cases of DGS by looking at T-cell, B-cell and natural killer cell populations, with T-cell analysis being the most important piece of information.

Many cases of DGS occur as a result of a sporadic mutation, however, DGS also is inherited in an autosomal dominant fashion. Approximately 10 percent of parents will have the deletion and be unknowingly affected, thus parents of a child with DGS need to be screened. For patients/parents with DGS there is a 50 percent risk that future offspring will be affected. Because of the variable penetration of the defect, siblings with DGS can have varying degrees of cardiac, endocrine or immune function abnormalities.

Treatment and long-term outlook       

For patients with heart defects, assessment and repair of the defect is indicated. While FISH analysis is not routinely ordered on every patient with congenital heart disease, it is obtained in patients with cardiac defects most commonly associated with DGS (for example, tetrology of Fallot with right aortic arch, truncus arteriosus), as well as based on clinical suspicion of associated characteristics (for example, cleft palate, hypocalcemia). Once the diagnosis of DGS is made, further evaluation – particularly looking for immune deficiencies, hypocalcemia, feeding and airway problems related to VCFS – is done. Calcium and vitamin D replacement are given to patients with hypocalcemia caused by hypoparathyroidism. Speech evaluation, feeding therapy, gastrostomy tube or tracheostomy placement may be necessary for infants and children with difficulty related to velopharyngeal insufficiency. Other consults, including renal, endocrine and genetics, are done based on the needs of each patient.

All patients with the diagnosis of DGS should have a thorough immunologic evaluation. Almost 90 percent of patients with the 22q11 deletion will have some level of immunodeficiency. Of these, 1 percent will be complete, meaning these patients have no T cells. Early diagnosis is essential, particularly for complete DiGeorge patients who have a 100 percent mortality rate without a thymus transplant, which ideally needs to be done by 6 months of age. In patients who have a thymic defect, antibiotic prophylaxis may be necessary if the CD4 count is less than 400 cells/mm3. Furthermore, no live vaccines should be given unless T-cell numbers are normal and all blood products given should be CMV negative, irradiated and leukocyte reduced. 

So what is the outlook for patients diagnosed with DiGeorge syndrome? Early and accurate diagnosis and referral to appropriate specialists is critical. With the proper treatment of heart defects, immune system disorders and other health problems, the majority of children with a 22q11 deletion will survive and grow well into adulthood. These children frequently require extra help throughout the school years and will need long-term care with multiple sub-specialists for their individual health needs.