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INTRODUCTION — The goal of newborn screening (NBS) is to detect treatable disorders that are threatening to life or long-term health before they become symptomatic . Early treatment of these rare disorders may significantly reduce mortality and morbidity in affected patients, making screening programs using a high-throughput, low-cost screening test with high sensitivity and specificity an important and cost-effective public health measure. Severe combined immunodeficiency (SCID) meets these criteria for inclusion in NBS due to the availability of an effective assay for T cell receptor excision circles (TRECs), a biomarker for normal T cell development. Other primary immunodeficiencies (PIDs) in addition to SCID are potential targets for NBS if suitable biomarkers can be identified and put to use in screening assays [1,2].
The rationale and tests available for NBS for PIDs are reviewed here. The general principles of NBS, screening policies, testing, and follow-up are discussed in detail separately. (See "Newborn screening".)
WHY SCREEN FOR PRIMARY IMMUNODEFICIENCY DISORDERS? — PIDs are a group of disorders of the immune system that result in recurrent infections, or, in some instances, predominantly dysregulated immunity, that can significantly impact long-term health and life expectancy . They are estimated to occur in as many as 1 in 1200 live births . Close to 300 PIDs have been described, encompassing a wide range of clinical presentations and disease severity . PIDs are classified according to the immunologic mechanisms and clinical presentations that result from the underlying defects, as well as the functional consequences of mutations upon their gene products. Adaptive immune defects predominantly affect antigen-driven processes. These defects include humoral immune deficiencies (due to impaired production of antibody by B cells) and combined immunodeficiencies (with impairments in both T and B cells). Innate immune disorders arise from impaired antigen-independent pathways and include defects in natural killer (NK) cell cytotoxicity, toll-like receptor (TLR) activation, phagocytosis, macrophage activation, and complement defects. More and more PIDs are associated with single gene defects. (See "Severe combined immunodeficiency (SCID): An overview" and "Combined immunodeficiencies", section on 'Overview' and "Primary humoral immunodeficiencies: An overview" and "Primary disorders of phagocytic function: An overview" and "Inherited disorders of the complement system" and "Approach to the child with recurrent infections" and "Approach to the adult with recurrent infections".)
Treatment for PIDs depends upon the part(s) of the immune system affected and can include hematopoietic cell transplantation (HCT), immune globulin replacement therapy, and antimicrobial therapy to prevent or limit infections. Delay in diagnosis and treatment of PIDs leads to significant morbidity and sometimes early death from recurrent infections. Thus, early identification via newborn screening (NBS) should decrease the morbidity and mortality associated with these disorders. A retrospective study of 240 infants diagnosed with severe combined immunodeficiency (SCID) showed that overall survival (OS) at five years after transplant was similar amongst infants who received HCT at age <3.5 months (94 percent OS, 95% CI 85-98), at age >3.5 months while continuously infection free (90 percent OS, 95% CI 67-98), and even at age >3.5 months provided all infections had been treated and resolved prior to HCT (82 percent OS, 95% CI 70-90). In contrast, infants who were older than 3.5 months with active infection at time of transplant had greatly reduced OS (50 percent OS, 95% CI 39-61) . These data further support the importance of NBS for SCID to allow early detection prior to the onset of infections. (See "Hematopoietic cell transplantation for primary immunodeficiency" and "Medical management of immunodeficiency" and "Immune globulin therapy in primary immunodeficiency" and "Gene therapy for primary immunodeficiency".)
SCREENING FOR SCID AND OTHER T CELL DEFECTS — The first group of PIDs targeted for newborn screening (NBS) was severe combined immunodeficiency (SCID). The term "SCID" encompasses a genetically heterogenous group of disorders characterized by profound impairment in T cell development and function with either primary or secondary defects in B cells (table 1). Infants with SCID are generally healthy at birth, protected by transplacentally acquired maternal immunoglobulin G (IgG) antibodies in the first few months of life. As this protection wanes, these infants develop severe and recurrent infections (including infections caused by live-virus vaccines given early in life), chronic diarrhea, and poor weight gain. Hematopoietic cell transplantation (HCT) has been shown to be an effective treatment for SCID, particularly if performed early in infancy, before the development of recurrent and increasingly severe infections. Infants with SCID without reconstitution of a functioning immune system usually die of overwhelming infection by one year of age. Only approximately 20 percent of infants with SCID have a family history that prompts early testing . (See "Severe combined immunodeficiency (SCID): An overview", section on 'Clinical manifestations' and "Hematopoietic cell transplantation for primary immunodeficiency", section on 'Early identification'.)
Initial attempts at screening for one type of SCID, adenosine deaminase (ADA) deficiency, using a colorimetric ADA enzyme assay were unsuccessful [7-9]. A quantitative real-time polymerase chain reaction (PCR) test was subsequently devised that used dried blood spots (DBS) already collected for NBS for other conditions to measure T cell receptor excision circles (TRECs) as a biomarker of naïve T cells. The TREC screening test proved a sensitive and specific, as well as cost effective, method for SCID NBS [10-13]. Any genetic defect that disrupts T cell development, induces T cell apoptosis, or blocks T cell maturation in the thymus will result in T cell lymphopenia (TCL) and low TRECs . Thus, infants with SCID caused by genetic defects that adversely affect T cell development prior to the formation of TRECs are expected to be identified by the TREC assay, as well as infants with other non-SCID immunodeficiencies in which there is a profound decrease in circulating naïve T cells. Next-generation sequencing technologies are also under investigation for NBS [15,16]. Long-term follow-up data on treatment outcomes and complications are needed in order to fully assess the impact of NBS for SCID patients. (See 'Diseases identified by TREC testing' below and "Newborn screening" and 'Formation of TRECs' below.)
Overview of TREC screening test — T cell receptor excision circle (TREC) screening identifies infants who have low T cells. All typical infants with typical SCID have absent or very low production of T cells from their thymus, affecting both T cell number and diversity. Other diseases that have TCL as a feature, such as other genetic syndromes (eg, DiGeorge) or conditions (eg, congenital heart disease), also lead to reduced circulating T cells. Thus, while the primary target of the TREC screening test is to identify infants with SCID, other diseases with TCL are secondary targets of this screening test. (See 'Diseases identified by TREC testing' below.)
Formation of TRECs — T cell development occurs in the thymus, where T cell antigen receptor (TCR) gene rearrangements involve cutting and splicing of the DNA encoding the alternate variable, diversity, and joining (VDJ) segments to generate a wide repertoire of unique T cells with diverse specificities. Formation of T cell receptor excision circles (TRECs) from excised DNA occurs during the programmed gene rearrangements in the thymus. One particular rearrangement, excision of the TCR delta gene locus in precursors of alpha/beta TCR expressing T cells, gives rise to the delta-Rec and psi-Joining segment-alpha TREC. This circular DNA molecule is produced late in maturation and is found in 70 percent of all thymocytes that express alpha/beta TCRs . TRECs are stable but not replicated during mitosis. They therefore become diluted as mature T cells proliferate. Thus, the number of TREC copies per T cell reflects primarily the production of naïve T cells by the thymus, and a normal TREC number is a biomarker for adequate autologous T cell production . Conversely, low or absent TREC numbers indicate either poor T cell production or increased T cell loss, provided that the DNA quality is adequate for PCR. (See "Normal B and T lymphocyte development", section on 'T cell development' and "Normal B and T lymphocyte development", section on 'The mature phase'.)
Normal newborns have approximately 1 TREC per 10 T cells, reflecting high numbers of naïve T cells that have not yet proliferated extensively, whereas older children and adults have approximately 1 per 100 and 1 per 1000 T cells, respectively, reflecting peripheral T cell expansion by mitosis . Infants with SCID have very low or undetectable TRECs . Even maternal T cells that can be present in an infant with SCID do not falsely raise the TREC count, because maternal cells have few TRECs.
Adaptation and implementation for newborn screening — TRECs presenting in peripheral blood can be measured using quantitative PCR (qPCR) specific for the delta-Rec and psi-Joining segment-alpha signal joint, and this measurement reflects the number of recently formed T cells in the circulation . Newborn DBS can be used for screening for TRECs to detect SCID because TREC DNA circles are stable in DBS collected by screening programs. TRECs are quantified by extracting genomic DNA from DBS specimens and performing the above qPCR reaction.
SCID NBS has been fully implemented in 41 states in the United States as of September 2016, and it is under development in a number of additional states [19-23]. Israel is performing universal SCID NBS, and several pilot programs are ongoing in Europe [24,25], the Middle East , and Asia . There have been no reports of typical SCID cases in screened populations that were not detected by NBS, although not all functional T cell disorders are detected with this screen. (See 'Diseases not identified by TREC testing' below.)
A retrospective study analyzed SCID screening results in over three million infants from 11 programs that had implemented population-based NBS with the TREC assay. Fifty-two cases of SCID and leaky SCID/Omenn syndrome were detected, an incidence of 1 in 58,000 births (95% CI, 1 in 46,000 to 1 in 80,000) . This incidence is nearly double that of previous estimates of 1 in 100,000, indicating that SCID was previously underdiagnosed in the absence of unbiased population screening. Although individual programs had different normal cutoffs for TRECs and different criteria to define TCL, cases of SCID and TCL were appropriately detected by screening, and infants were referred for early evaluation and treatment in all programs. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Epidemiology'.)
Diseases identified by TREC testing — Disorders identified by T cell receptor excision circle (TREC) testing include the following :
●Typical SCID – These forms of SCID are characterized by <300 autologous T cells/microL of blood and <10 percent of normal proliferation to mitogens (eg, phytohemagglutinin [PHA]). Patients frequently also had maternally engrafted T cells. Deleterious mutations in known SCID genes were often identified (table 1). (See "Severe combined immunodeficiency (SCID): Specific defects".)
●Leaky SCID or Omenn syndrome – These types of SCID are caused by incomplete or hypomorphic defects in known SCID genes, with 300 to 1500 or even greater autologous T cells/microL and no evidence of maternal engraftment. Patients with Omenn syndrome may have normal or elevated CD3 T cell counts, but they have restricted TCR diversity (oligoclonality) of T cells. (See "Combined immunodeficiencies", section on 'Hypomorphic RAG1 and RAG2 mutations' and "T-B-NK+ SCID: Pathogenesis and genetics", section on 'Omenn syndrome'.)
●Idiopathic TCL (or variant SCID) – This category is comprised of infants identified on NBS as having low TRECs who have 300 to 1500 autologous T cells/microL but do not have a recognized PID or mutations detected in known SCID genes.
●Syndromes with TCL – Some syndromes have a variable spectrum of immune involvement that can include TCL (CD3 T cells ≤1500/microL) or T cell impairment. Examples include DiGeorge and CHARGE (coloboma, heart defects, atresia choanae [also known as choanal atresia], retarded growth and central nervous system development, genital abnormalities, and ear abnormalities) syndromes, trisomy 21 (Down syndrome), Rac2 and dedicator of cytokinesis 8 (DOCK8) deficiencies, and ataxia-telangiectasia [13,20,28,29]. Not all infants with these syndromes will be identified by TREC screening, but the TREC test will flag infants affected with these syndromes who have T cells sufficiently low to be of clinical concern. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Severe combined immunodeficiency presentation (complete DGS)' and "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'CHARGE syndrome' and "Leukocyte-adhesion deficiency", section on 'Rac2 deficiency' and "Combined immunodeficiencies", section on 'Dedicator of cytokinesis 8 deficiency' and "Ataxia-telangiectasia".)
As an example, typical patients with DiGeorge syndrome (DGS) have impaired T cell production in the first months of life, but some have normal or near-normal T cell production, and a minority have almost no detectable T cell production. In general, the T cell deficit improves during the first two years of life. The TREC NBS test identifies DGS patients with the lowest TRECs. Patients with clinically significant TCL of ≤1500 CD3 T cells/microL confirmed by immunophenotyping have increased susceptibility to infection. However, patients with DGS who have >1500 CD3 T cells/microL are presumed to have enough immunity to combat infections. There have been no reports of patients with DGS who have low TRECs identified through NBS and >1500 CD3 T cells/microL who have succumbed to opportunistic infections, but further experience with screening is needed to establish the predictive value of screening for these patients. (See "DiGeorge (22q11.2 deletion) syndrome: Clinical features and diagnosis", section on 'Severe combined immunodeficiency presentation (complete DGS)'.)
●Secondary TCL – Secondary TCL (CD3 T cells ≤1500/microL) is diagnosed in a subset of infants with recognized congenital conditions, such as intestinal lymphangiectasia, hydrops, gastroschisis, a congenital heart defect, chylothorax, or neonatal leukemia. It can also occur due to transfer to the fetus of an immunosuppressant medication prescribed for maternal autoimmune diseases (eg, prenatal administration of glucocorticoids). Severe infant stress or inflammatory conditions (eg, sepsis) may cause acquired TCL. A small proportion of preterm infants, often those of very low birth weight, also have TCL with no other congenital abnormalities or recognizable disorder. While TCL of prematurity was not appreciated before the advent of NBS, these infants may be at increased risk for infections. The T cell numbers in these infants generally recover to normal as they mature.
Diseases not identified by TREC testing — A low T cell number is a common feature of many PID disorders. However, there are a number of circumstances in which the T cell receptor excision circle (TREC) test is not able to identify disorders characterized by impairment of T cell function. As an example, some incomplete and hypomorphic defects in SCID genes are sufficiently leaky to result in TRECs within the normal range. In some infants with SCID caused by a defect in ADA, maternal detoxification of purine intermediates in utero may rescue fetal T cells, resulting in normal TREC levels at birth. This protection wanes with time, TRECs and T cell numbers drop, and these children manifest delayed- or late-onset ADA-SCID. In addition, TRECs and T cells are present, but T cells are functionally compromised, in genetic defects that affect T cell development after VDJ recombination in the thymus (eg, ZAP-70 deficiency , major histocompatibility complex [MHC] class II deficiency , and CD40 ligand deficiency). Furthermore, PIDs limited to humoral immunity or to neutrophils will not be detected by TREC screening. Thus, a negative TREC test does not rule out the possibility of a PID. It is important for clinicians to maintain awareness of the clinical presentations of immunodeficient infants and to be vigilant for risk factors including family history of early childhood deaths, poor growth, recurrent or severe infections, and physical features and to investigate accordingly. (See "ZAP-70 deficiency" and "CD3/T cell receptor complex disorders causing immunodeficiency", section on 'MHC (HLA) class II deficiency' and "Hyperimmunoglobulin M syndromes" and "Approach to the child with recurrent infections" and "Recognition of immunodeficiency in the newborn period".)
Interpreting TREC results — The SCID NBS is considered abnormal if the T cell receptor excision circle (TREC) assay has a value below the designated cutoff determined by the laboratory (the cutoff values vary from laboratory to laboratory). The variability in newborn DBS specimen collection adds to the challenge of distinguishing abnormal samples.
Results can be artifactually low due to :
●An inadequate blood sample
●Failure to elute sufficient DNA from the DBS
●The presence of PCR inhibitors, such as heparin, which may be present in samples from infants in neonatal intensive care with percutaneous catheters
To determine whether a low TREC result is due to an artifact, SCID NBS employs amplification of a reference DNA segment, such as a sequence within the ribonuclease P (RNase P) or beta-actin genes. The following approach is typical :
●DBS samples with an abnormal TREC result are retested for TREC number plus copy number of the control DNA sequence.
●If the initial low TREC result is due to insufficient DNA or an inhibitor, both the repeat TREC and control qPCR will be low. These cases of DNA amplification failure are considered incomplete or indeterminate. The infant is recalled to give a further DBS sample obtained via heelstick to avoid contamination with heparin or other PCR inhibitors. If the second DBS specimen also results in low TRECs, the infant is recalled for venous blood sampling to measure T cells by flow cytometry and other confirmatory testing as indicated. (See 'Follow-up testing' below.)
●In a true-positive screen, TREC copy number is low, but the reference DNA copy number is normal. A true-positive screen will trigger the infant being recalled for immediate venous blood sampling for flow cytometric determination of lymphocyte subset numbers (algorithm 1). (See 'Follow-up testing' below.)
A normal TREC assay has a copy number value of above the designated cutoff determined by the laboratory. No further testing is recommended if the SCID NBS is normal, unless the infant begins to show signs of a PID. (See 'Diseases not identified by TREC testing' above and "Approach to the child with recurrent infections".)
Follow-up testing — Immunophenotyping is performed in California (with varying rules in some other state screening programs) after a positive screening TREC test or two incomplete tests . This follow-up testing is integrated within the NBS program to facilitate speedy, consistent evaluation of the significance of the TREC screen result. The state-mandated flow panel consists of a complete blood count with differential white blood count and lymphocyte subsets: CD3, CD4, and CD8 T cells with CD45RA versus CD45RO CD4 and CD8 subsets to indicate naïve versus memory cells, CD19 B cells, and CD16/CD56 NK cells. Few or undetectable CD45RA naïve T cells with predominance of CD45RO memory cells suggest insufficient diverse T cell production, even if overall T cell number may appear normal due to expansion of oligoclonal T cells in the periphery or presence of maternally engrafted T cells. (See "Laboratory evaluation of the immune system".)
A CD3 T cell count of ≤1500 cells/microL is considered clinically significant, identifying infants at risk for life-threatening and/or opportunistic infections . The lymphocyte subsets permit determination of the T/B/NK cell phenotype, giving clues to probable gene defects as indicated in the table (table 1). The absence of naïve T cells is also significant, suggesting oligoclonal expansion rather than a properly diverse T cell repertoire. Establishing the diagnosis of SCID requires the further demonstration of abnormal T cell function, as measured by proliferation of lymphocytes after stimulation with the mitogen PHA. Another indicator of SCID is presence of maternal cells, transmitted through the placenta and not eliminated due to the infant's immune incompetence. Deleterious mutations in known SCID-associated genes also confirm the diagnosis of SCID. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Diagnosis'.)
Syndromes with insufficient T cells, or secondary depletion of circulating T cells, constitute a risk for infection in infancy. These infants require follow-up by pediatric immunology specialists to perform appropriate evaluations and institute protective measures that may include antibiotics, immune globulin replacement therapy, and avoidance of live vaccines until T cells have normalized. For an individual patient who might have SCID or a related disorder, any immunologic abnormalities are followed up by further testing, such as lymphocyte proliferation, determination of serum immunoglobulin concentrations, measurement of specific titers after administration of killed vaccines, and molecular diagnosis. (See "Severe combined immunodeficiency (SCID): An overview", section on 'Protective measures' and "Medical management of immunodeficiency" and "Laboratory evaluation of the immune system".)
SCREENING FOR B CELL DEFECTS — Generation of diverse B cell receptor (BCR) light chains results in kappa-deleting recombination excision circles (KRECs). Coding joint (cj) recombined sequences reside within the chromosome, whereas signal joint (sj) KRECs are excised and joined at their ends to form an extrachromosomal excision product similar to T cell receptor excision circles (TRECs). As with TRECs, the sjKRECs cannot replicate in the cell, are stable, and are found in peripheral blood. After hematopoietic cell transplantation (HCT), a rise in KRECs reflects newly derived bone marrow B cells [32,33]. (See "Normal B and T lymphocyte development", section on 'Immature B cells'.)
KREC levels in blood and in DNA isolated from dried blood spots (DBS) are undetectable in PIDs in which B cells are absent or dysfunctional, such as X-linked agammaglobulinemia (XLA) caused by mutations in Bruton tyrosine kinase (BTK) or B cell-negative severe combined immunodeficiency (SCID), whereas samples from unaffected infants have detectable KRECs. Thus, KREC testing of newborn blood spots is potentially useful in identifying neonates with defects of early B cell maturation [34,35]. KREC testing does not, however, predict which individuals may develop antibody deficiencies such as common variable immunodeficiency (CVID) later in life, the most common type of antibody deficiency.
TRECs and KRECs can be measured simultaneously using a multiplex polymerase chain reaction (PCR) reaction. When used in combination, TREC/KREC screening may identify certain PIDs including dedicator of cytokinesis 8 (DOCK8) deficiency, hyperimmunoglobulin E syndrome, ataxia-telangiectasia, and Comel-Netherton syndrome . It is not yet established whether the number of KRECs is sufficiently high in all unaffected infants (including preterm and ill infants) to achieve acceptably low rates of false-positive tests for a successful newborn screening (NBS) approach.
SCREENING IN SUBPOPULATIONS WITH KNOWN GENETIC RISK — DNA screening, as employed in the T cell receptor excision circle (TREC) assay, opens the door to additional high-throughput screening for DNA variants. Certain populations derived from a restricted pool of ancestors may harbor recessive founder mutations for PIDs that raise the risk well above that of the general population and, as such, represent attractive targets for newborn screening (NBS) [15,16]. It is technically possible to screen newborns in such populations for the carrier state and homozygous mutation state for specific DNA mutations, as is now widely done as a second-tier test to screen for sickle cell disease in many programs. In addition, X-linked genetic mutations cause disease almost exclusively in males, suggesting that efficient NBS could be selective.
There are several known PID risk alleles in Amish, Native American, and many other populations worldwide, and several PIDs are caused by X-linked gene mutations. However, practical considerations regarding whom to test and how to implement subgroup testing in newborn nurseries, as well as ethical considerations, such as stigmatization of minority groups who may carry risk alleles, present major challenges, not the least of which would be failing to test and identify true cases.
DEEP SEQUENCING IN NEWBORNS FOR SCREENING OR DIAGNOSIS — The advent of massively parallel high-throughput sequencing has also presented the possibility of sequencing panels of genes or even whole exomes or whole genomes for "actionable" gene variants, recognizable mutations with a high probability of causing treatable diseases that would benefit from early recognition [15,16]. The DNA contained in dried blood spots (DBS) has proven adequate for whole-exome sequencing, though costs and turnaround time remain prohibitive for use of deep sequencing on a population-wide basis.
Further major problems exist. First, there is insufficient predictive value for many gene variants to be sure that the variants cause disease given the wide variety of observed DNA changes in PID genes combined with the rarity of the PID diseases. Second, a large number of novel variants and variants of uncertain significance are uninterpretable without a prior reason to suspect PID in otherwise healthy newborns. Sharing such results with primary clinicians and parents will cause anxiety and lead to expensive further testing that will not confirm disease in a great majority of cases. Finally, issues of parental consent and patient autonomy are raised. Rather than implement deep sequencing for all newborns as part of screening programs, optional sequencing with parental consent may be a more acceptable approach, even if this limits such testing to those with the means to pay for it.
●Primary immunodeficiencies (PIDs), such as severe combined immunodeficiency (SCID), are good candidates for newborn screening (NBS) because infants appear normal at birth, the natural history is understood, and treatment is more efficacious if initiated early. (See 'Why screen for primary immunodeficiency disorders?' above and 'Screening for SCID and other T cell defects' above.)
●T cell receptor excision circles (TRECs) are a biomarker of naïve T cells that can be detected in newborn dried blood spots (DBS). The TREC assay is expected to identify all infants with low T cells, including those with SCID and leaky SCID (primary target), as well as conditions that present with low T cells (secondary targets), such as congenital syndromes or other problems at birth that cause secondary loss of circulating naïve T cells. (See 'Overview of TREC screening test' above.)
●If the TREC level on NBS is abnormally low as determined by the performing laboratory, then the TREC test is repeated on another punch from the DBS, and a reference gene segment is also amplified. If the initial low TREC result is due to insufficient DNA, both the repeat TREC and reference gene will be low, and the test is considered incomplete or indeterminate. The infant is then recalled, and the TREC assay is repeated on a second DBS sample. If this assay is also abnormal, or if the initial repeat TREC on the DBS is low but the reference gene is normal (positive test), then immediate venous blood sampling is performed for flow cytometric determination of lymphocyte subset numbers (algorithm 1). (See 'Interpreting TREC results' above.)
●A CD3 T cell count of ≤1500 cells/microL on immunophenotyping is considered clinically significant, identifying infants at risk for life-threatening and/or opportunistic infections. The lymphocyte subsets permit determination of the T/B/natural killer (NK) cell phenotype, giving clues to likely gene defects as indicated in the table (table 1). Establishing the diagnosis of SCID requires the further demonstration of abnormal T cell function. (See 'Follow-up testing' above.)
●Kappa-deleting recombination excision circles (KRECs) are a biomarker of mature B cells. KREC testing of newborn blood spots is potentially useful in identifying neonates with defects of early B cell maturation. In addition, KRECs can be measured simultaneously with TRECs, giving a more comprehensive newborn screen for PID. (See 'Screening for B cell defects' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Antonia Kwan, PhD, MRCPCH who contributed to earlier versions of this topic review.
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