Newborn Screening for Severe Combined Immunodeficiency and T-Cell Lymphopenia in California, 2010−2017 George S

Newborn Screening for Severe Combined Immunodeﬁciency and T-cell Lymphopenia in California, 2010–2017 George S. Amatuni, BS,a,b Robert J. Currier, PhD,a Joseph A. Church, MD,c Tracey Bishop,d Elena Grimbacher,e Alan Anh-Chuong Nguyen, MD,f Rajni Agarwal-Hashmi, MD,g Constantino P. Aznar, PhD,d Manish J. Butte, MD, PhD,h Morton J. Cowan, MD,a Morna J. Dorsey, MD, MMSc,a Christopher C. Dvorak, MD,a Neena Kapoor, MD,c Donald B. Kohn, MD,h M. Louise Markert, MD, PhD,i Theodore B. Moore, MD,h Stanley J. Naides, MD,j Stanley Sciortino, PhD, MPH,d Lisa Feuchtbaum, DrPH, MPH,d Rasoul A. Koupaei, PhD,d Jennifer M. Puck, MDa

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in abstract California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000–1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

aDepartment of Pediatrics, University of California, San Francisco and Benioff Children’s Hospital, San Francisco, WHAT’S KNOWN ON THIS SUBJECT: Earlier results California; bDepartment of Cell Biology, Stem Cell Institute, Albert Einstein College of Medicine, Bronx, New York; showed that newborn screening can be highly effective cDepartment of Pediatrics, Keck School of Medicine, University of Southern California and Children’s Hospital Los for the early detection of severe combined d Angeles, Los Angeles, California; Genetic Disease Screening Program, California Department of Public Health, immunodeﬁciency (SCID). Richmond, California; eSchool of Architecture and Urban Planning, University of Stuttgart, Stuttgart, Germany; fBroward Health Medical Center, Fort Lauderdale, Florida; gDepartment of Pediatrics, School of Medicine, Stanford WHAT THIS STUDY ADDS: Screening 3.25 million h University, Palo Alto, California; Department of Pediatrics, University of California, Los Angeles and University of California infants of diverse ethnicity with the T-cell California, Los Angeles Mattel Children’s Hospital, Los Angeles, California; iDepartment of Pediatrics, School of Medicine, Duke University, Durham, North Carolina; and jImmunology Department, Quest Diagnostics Nichols receptor excision circle test substantiates the value of Institute, San Juan Capistrano, California newborn screening for the diagnosis of SCID and non- Dr Puck conceptualized and designed the study, collected and analyzed data, and revised the SCID T-cell lymphopenia. Both are more common and manuscript; Mr Amatuni collected and analyzed data and wrote the initial manuscript; Dr Currier genetically heterogeneous than previously thought. collaborated on the study design, conducted data analysis and interpretation, and critically reviewed and revised the manuscript; Drs Church, Cowan, Dorsey, Dvorak, Agarwal-Hashmi, Butte, To cite: Amatuni GS, Currier RJ, Church JA, et al. Newborn ﬁ Kapoor, Kohn, Markert, and Moore contributed essential clinical data and reviewed and revised the Screening for Severe Combined Immunode ciency and T-cell Lymphopenia in California, 2010–2017. Pediatrics. manuscript; Ms Bishop and Drs Aznar, Feuchtbaum, Sciortino, and Koupaei organized (Continued) 2019;143(2):e20182300

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019:e20182300 ARTICLE Severe combined immunodeficiency and produce a leaky phenotype. 2018, all 50 states in the United (SCID) encompasses ∼20 known (and These infants usually have ,1500 States, plus the District of Columbia additional unknown), rare genetic autologous T cells per mL unless there and Puerto Rico, as well as an disorders of adaptive immunity. has been oligoclonal proliferation of increasing number of countries, Individuals who are affected lack T memory phenotype T cells, as occurs including Israel, New Zealand, and lymphocytes and have absent or in Omenn syndrome; infants with Norway, have adopted universal NBS nonfunctional B lymphocytes, leaky SCID generally have sufficient for SCID. Additional regional or pilot rendering them susceptible to life- T-cell function to prevent maternal programs are under way in many threatening bacterial, fungal, and viral engraftment, but immunity is other countries. Here we report the infections with both ordinary and insufficient to fight infections. experience and outcomes of 6.5 years opportunistic pathogens.1,2 Because of screening .3.25 million newborns The timely presymptomatic diagnosis ,20% of case patients with SCID for SCID in California, the state with of SCID is the primary goal of SCID have a recognized positive family the largest number of births and high NBS. California instituted population- history and because infants who are ethnic diversity. wide screening for SCID in August affected appear healthy at birth, 2010, following pilot programs in population-based newborn screening Wisconsin, Massachusetts, and the (NBS) is the only strategy to identify METHODS Navajo Reservation and on the all infants with SCID sufficiently early recommendation by the Advisory Details of methods, including the to provide treatment before the onset – Committee on Heritable Disorders in statistical analysis, are in the of infectious complications.3 7 Newborns and Children (endorsed by Supplemental Information. Briefly, Treatment of SCID most often the Secretary of the Department of DBS specimens collected from requires an allogeneic hematopoietic Health and Human Services) that essentially all infants born in cell transplant (HCT) from a suitably screening for SCID be added to the California since mid-2010 had TREC matched healthy donor; in addition, Recommended Uniform Screening testing for SCID, initially with – enzyme replacement therapy (ERT) is Panel.13 16 The SCID NBS test is a laboratory-developed assay at the available for adenosine deaminase based on detection of T-cell receptor Genetic Disease Laboratory (GDL) in 18 (ADA)–deficient SCID, and autologous excision circles (TRECs), DNA Richmond, California, as published. hematopoietic cell correction by gene biomarkers of normal T The EnLite neonatal TREC kit therapy (GT) has been successful lymphopoiesis that can be measured (PerkinElmer, Inc, Waltham, MA) was for ADA-deficient and X-linked by a polymerase chain reaction test adopted in June 2015, after which SCID.1,2,7–10 Best outcomes are by using dried blood spots (DBSs) testing moved to regional NBS achieved if infants are treated early to routinely obtained from newborns by laboratories. Reported TREC and avoid infectious complications, as heel stick.3 DBSs from newborns with b-actin copy numbers differed documented in single-center reports SCID have undetectable or low between these methods, requiring and by multicenter studies from the numbers of TRECs. Moreover, a low adjustment of thresholds. The Primary Immune Deficiency TREC copy number in a DBS is used categories of test results are Treatment Consortium (PIDTC).2,4,7,11 to detect not only the primary summarized in Table 1. After 1 screening target, SCID, but also positive or 2 incomplete TREC test The PIDTC has established several non-SCID conditions results, infants had liquid blood laboratory-based definitions for SCID characterized by T-cell lymphopenia analyzed for lymphocyte subsets and independent of complications, such as (TCL) that may also benefitfrom naïve and memory T-cell markers at opportunistic infections or failure to early diagnosis and intervention to a single laboratory (Quest thrive.12 Infants with typical SCID prevent infections. Diagnostics, San Juan Capistrano, CA). have ,300 autologous T cells per mL, absent naïve T cells, and proliferative In 2014, researchers of an analysis of Lymphocyte phenotypes were responses to the mitogen early pooled data from 11 screening interpreted by California Department phytohemagglutinin that are ,10% programs endorsed the effectiveness of Public Health (CDPH) immunology of control values. They often have of TREC screening.17 Although TREC- associates (M.J.B., J.A.C., S.A.M., and spontaneous engraftment of maternal based SCID screening was highly J.M.P.). Infants with ,300 CD3 T cells T cells, and the diagnosis is further effective for the diagnosis of SCID in per mL of blood or with ,2% of their confirmed by documenting all participating programs, the lack of helper T cells bearing the naïve T-cell pathogenic mutations in known SCID uniformity in assay methodology marker CD45RA were referred to genes. In addition, some infants have between the programs precluded pediatric hospitals with experience in hypomorphic mutations in SCID determination of rates of recall for treating SCID (Children’s Hospital Los genes that allow residual function further testing. As of December 10, Angeles; Stanford Lucille Packard

Downloaded from www.aappublications.org/news by guest on September 29, 2021 52 AMATUNI et al TABLE 1 TREC Test Results, Interpretation, and Actions Required TREC Copy No., per mL b-Actin Copy No., per mL TREC Test Interpretation Action Required .18a N/Ab Normal No further action Undetectable or ,4c .35d Urgent positive Immediate callback for liquid blood for lymphocyte subsets 4–18, infant not in NICU .35 Positive Callback for liquid blood for lymphocyte subsets 4–18, infant in NICU N/A Incomplete Second DBS test in 2 wk or at discharge from nursery; after 2 incomplete test results, liquid blood for lymphocyte subsets N/A, not applicable. a TREC copies per mL of peripheral blood equivalent for the EnLite kit; .25 copies per mL for the original laboratory-developed test; values for both methods after adjustments based on initial experience. b b-actin was not reported if the initial TREC value was normal. c Fewer than 6 copies per mL for the laboratory-developed test. d For the EnLite kit, the cutoff for the laboratory-developed test was .5000 copies per mL.

Children’s Hospital; University of to avoid exposing infants with primary immunodeficiencies; as TCL California, Los Angeles Mattel significant immune compromise to resulting from another condition and Children’s Hospital; or University of the otherwise-mandated live, resolving once that condition was California, San Francisco Benioff attenuated rotavirus vaccine, which corrected (25 cases); as preterm birth Children’s Hospital). Additionally, can cause serious diarrhea in alone, in which TCL was self-limited if infants with up to 1500 circulating immunodeficiency.20 TCL was the infant survived (33 cases); or as T cells per mL with naïve T cells documented in 38% (n = 213) of the idiopathic TCL (33 cases). present were referred to pediatric cohort of infants requiring follow-up immunology clinics for further flow-cytometry tests or in 1 per Cases of SCID management. Long-term follow-up 15 300 total newborns (95% Of the 50 infants with an was requested from transplant confidence interval [CI] 1 per immunophenotype of SCID, 49 were centers and immunologists according 13 500–1 per 17 700). An urgent immediately hospitalized at an to the standard, comprehensive CDPH positive TREC result (Table 1) was immunodeficiency center for program to monitor outcomes of all a specific predictor of both SCID and treatment with allogeneic HCT, California infants with positive NBS non-SCID TCL; of the 82 newborns autologous corrected cell GT, or ERT results.19 Children with SCID or TCL with urgent positive results, 38 (Table 4). One infant with SCID born detected by NBS were managed until (46%) had SCID and 21 (26%) had to a foreign visitor left the United resolution or for at least 1 year and non-SCID TCL. Positive or incomplete States before receiving any further up to 7.5 years. Diagnoses were TREC test results and documented immune evaluation or treatment. All established by standard clinical TCL in those infants who had infants with SCID were healthy at testing, including gene sequencing, abnormal TREC test results were diagnosis except for 2 who had except as noted below. more common in infants born very already been brought to medical prematurely, as assessed by attention with infection or rashes and gestational age (GA) at birth or by RESULTS 1 who was born prematurely and had birth weight (Tables 2 and 3; see feeding intolerance, bronchiolitis, and Between August 15, 2010, and March Supplemental Information for further leukopenia.21 Only 2 were known by 31, 2017, a total of 3 252 156 details). Ethnicity and sex were not providers at birth hospitals to be at newborns had SCID screening. Of significant risk factors for having risk for SCID because of a positive these, 562 (1 of 5800 total births) had a positive or incomplete TREC result family history, whereas 7 others who nonnormal TREC results followed by or TCL (data not shown). TREC were identified by SCID NBS had liquid blood lymphocyte phenotyping screening identified 50 cases of SCID older relatives who were affected and by flow cytometry (Fig 1A). Although (1 per 65 000 births [95% CI 1 per diagnosed with SCID, and 1 had only 9% of all infants were in NICUs, 51 000–1 per 90 000]), 44 cases from a sibling who had died of infantile this population had over half of the regular nurseries and 6 cases from pneumonia consistent with SCID. The TREC-positive screening results NICUs. The proportions of case median age at flow cytometry for (53%; n = 298; Fig 1B). Cases were patients with true SCID in NICUs was infants lacking a recognized family tracked to establish diagnoses of both the same as in regular nurseries (Fig 1 history of SCID was 21 days (range the primary target of screening, SCID, B and C). The 162 cases of non-SCID 6–40 days). and non-SCID TCL of ,1500 T cells TCL were categorized as congenital per mL, a clinically important syndromes (72 cases), including Of the 49 patients who were secondary target. This T-cell cutoff multisystem congenital abnormalities evaluable and treated (Table 4), 46 was chosen to be highly selective but with TCL and non-SCID single-gene survived (94%). Of the 3 deaths, 1

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019 53 TABLE 2 Preterm Birth and TCL in Patients With Abnormal TREC Test Results by GA GA Group, wk Not TCL, n TCL, n 22–31 114 47 32–41 225 171 x2 (degrees of freedom = 1; N = 557) = 9.40; P , .05.

Table 4 indicates genotype, nursery type, TREC result, and whether the SCID was typical or leaky. Whereas ∼90% of infants with typical SCID had urgent positive TREC results, half of the infants with leaky SCID had TREC numbers in the positive, but not urgent, range. See Supplemental Table 11 for patient mutations. As reported previously in the literature, the X-linked interleukin-2 receptor g chain (IL2RG) gene was mutated most frequently.1,2,7,17,18 The 9 infants with ADA-deficient SCID had, in addition to lymphopenia of T, B, and natural killer (NK) cells, fewer neutrophils (mean 986 cells per mL) and monocytes (mean 372 cells per mL) than the other infants with SCID, who had means of 4700 neutrophils per mL and 1600 monocytes per mL, or healthy infants. Interestingly, the birth weights of infants with ADA- deficient SCID (median 2608 g) also tended to be lower than those of other infants with SCID (median 3288 g), perhaps reflecting that ADA deficiency is a systemic disorder of FIGURE 1 purine salvage. Despite clinical Summary of NBS for SCID in California. A, Number of infants at each stage of screening. B, Numbers sequencing of known SCID genes, 5 and proportions of infants in regular versus intensive care nurseries at each stage of the screening infants (10%) remained without a process. C, Final diagnosis category for infants with TCL in each nursery type. Total infants a proven genotype. Whole-exome screened included 91% of infants who were cared for in a regular well-infant nursery or born at home, and 9% who were cared for in a NICU. b Infants (47% from regular nurseries and 53% from sequencing failed to solve 4 of these, NICUs) with a liquid blood sample tested after 1 positive or 2 incomplete TREC test results made up whereas confirmatory experiments 0.17% of all births, excluding 20 newborns with TREC-positive test results who either died or were revealed 1 infant to have a defect in lost to follow-up before a liquid blood sample could be obtained and 2 infants born in another state a novel SCID gene, B cell lymphoma c , who had positive TREC screen results and relocated to California for follow-up. Infants with 1500 BCL11B 22 T cells per mLor,2% naïve CD3 CD4 CD45RA T helper cells (46% in the regular nursery and 54% in 11B ( ). the NICU) made up 0.007% of the population (1 per 15 000 births). In the right columns of Table 4 outcomes after therapy for patients infant of unknown genotype died of conditioning with high-dose busulfan with SCID are summarized. GT, cytomegalovirus (CMV) infection with chemotherapy, developed fatal consisting of an autologous transplant encephalitis. One with recombinase- hepatic sinusoidal obstruction of bone marrow–derived activating gene 1 (RAG1)–deficient syndrome post-HCT; 1 of these also hematopoietic stem cells transduced SCID and 1 with X-linked SCID, each had a concomitant CMV infection that with a vector encoding the correct of whom had received pretransplant had been present before HCT. complementary DNA, was used to

Downloaded from www.aappublications.org/news by guest on September 29, 2021 54 AMATUNI et al TABLE 3 Preterm Birth and TCL in Patients With Abnormal TREC Test Results by Birth Weight for 8 (11%) infants with syndromes; Birth wt Group, g Not TCL, n TCL resolved in 3 infants, 3 infants TCL, n died of nonimmune complications, 0–1500 108 42 and 2 were lost to follow-up. All 5 .1501 231 176 patients with ataxia telangiectasia x2 (degrees of freedom = 1; N = 557) = 10.69; P , .05. (AT) were healthy, term newborns from regular nurseries with 800 to 1323 T cells per mL. Rising treat 4 infants with X-linked SCID and X-linked IL2RG mutation, a-fetoprotein levels after age 8 infants with ADA-deficient SCID, Arg222Cys.23 His delayed-onset leaky 6 months led to the identification with uniform survival at 2.5 to SCID was successfully treated with of deleterious mutations in the AT 6.5 years and notable success. All a conditioned HCT from a matched, mutated gene.28 One infant with AT infants receiving GT for ADA-deficient unrelated donor. The other was developed infections requiring IgG SCID have had multilineage immune a delayed-onset case of incomplete infusions during his first year. Three reconstitution. Three recipients of ADA deficiency, diagnosed at infants with coloboma of the eye, GT for X-linked SCID have recovered 23 months of age after repeated otitis heart defect, atresia choanae, T-cell immunity; 1 recipient had and hospitalization for pneumonia.24 restricted growth and development, failed his initial haploidentical This child was successfully treated genital abnormality, and ear T-cell-depleted allogeneic HCT, and with GT. abnormality (CHARGE) syndrome 1 recipient no longer required required NICU care for congenital immunoglobulin G (IgG) infusions. Non-SCID TCL malformations unrelated to the However, 1 recipient of GT for After ruling out SCID, infants with immune system. One was considered X-linked SCID failed this initial non-SCID TCL identified by SCID NBS for a thymus transplant but died of treatment but recovered T- and B-cell were tracked by participating respiratory failure. The 3 case immunity after an allogeneic immunologists in the CDPH long-term patients with diabetic embryopathy transplant from a matched, follow-up program.19 Although many with TCL were from NICUs and had unrelated donor. infants received a diagnosis in the additional congenital abnormalities. Single patients with rare conditions Deficiency of the recombinase neonatal period, 22 required further constituted the remainder of case activating proteins RAG1 or RAG2, testing over the course of 3 to patients with syndromes (Table 5; both required for T- and 18 months to establish a diagnosis discussed in the Supplemental B-lymphocyte antigen receptor (Fig 2), and 33 others remained Information), including an infant with rearrangement, caused 4 cases of idiopathic (Fig 2). The most frequent a novel short-limbed immuno-skeletal typical SCID and 7 cases of leaky non-SCID TCL conditions were dysplasia in whom whole-exome SCID, of which 3 patients had Omenn congenital syndromes (Fig 2, sequencing revealed exostosinlike syndrome, in which a limited pool Table 5). Six infants with syndromes glycosyltransferase 3 (EXTL3) of poorly regulated T cells expands, died before flow cytometry could be deficiency.29 causing rashes, adenopathy, performed (Supplemental Table 12). splenomegaly, eosinophilia, and See the Supplemental Information for Secondary TCL in 25 case patients elevated immunoglobulin E. An details of patients with non-SCID TCL. (Table 6) resolved to normal once example was an infant with leaky The most common syndrome was excess T-cell losses or suppression of RAG1-deficient SCID who had .4500 DiGeorge syndrome, with 47 cases T-cell maturation had been reversed. T cells per mL. Although this was in (Fig 2, Table 5). More than 90% had T-cell losses were associated with the normal range, only 46 of his 3680 partial DiGeorge syndrome, in which vascular leakage, whereas 2 infants CD4 helper T cells (1.2%) had the T cells rose to age-adjusted reference had poor T-cell production because of naïve CD45RA phenotype. ranges12 over time or became in utero exposure to maternal During the 6.5 years of screening, 2 adequate as judged by the local immunosuppressive medications, cases of SCID were discovered to have immunologist. However, 4 infants fingolimod in 1 and azathioprine in been missed. Both had normal with complete DiGeorge syndrome the other. One infant had a thymic newborn DBS TREC numbers, each (having persistently ,300 T cells per teratoma, with T cells normalizing well above the designated cutoff for mL and/or absent naïve helper after it was resected. TCL was also follow-up testing. One infant, who T cells) received thymus transplants occasionally associated with preterm presented at age 7 months with at Duke University in Durham, North birth (Table 7, Supplemental Tables 9 Pneumocystis pneumonia, had the Carolina, with 3 surviving for at least and 10), affecting infants born at 32 known, recurrent, hypomorphic 2 years.25–27 Trisomy 21 accounted weeks’ gestation or earlier (median

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019 55 56 TABLE 4 Characteristics, Treatments, and Outcomes of 49 Infants With SCID Diagnosed by Using NBS SCID Genotype (No. SCID Nursery TREC Result Outcome After Treatmentb a Cases) Phenotype Urgent Positivec Positive Died Full T and B Cell Recovery and Off IgG, T but Not B Cells Reconstituted, Still on (Posttransplant Treatmentd IgG, Treatment d, Cause) IL2RG (14) Typical Regular 12 0 1 (218 d, SOSe, CMV) 2 cond MUD, 1 GT, 1 cond MUD after GT 6 MMRD, 1 cond MUDf, 1 GT, 1 GT after MMRD NICU 2 0 ADA (9) Typical Regular 5 2 0 8 GT, 1 MSD 0 NICU 1 0 Downloaded from Leaky Regular 0 1 RAG1 (8) Typical Regular 2 0 1 (28 d, SOS) 1 cond MSD 0 Leaky Regular 2 leaky, 1 Omenn 1 leaky, 2 Omenn 0 4 cond MMRD 2 cond MMRD (1 of whom planning to syndrome syndrome stop IgG) IL7R (6) Typical Regular 5 0 0 4 MMRD, 1 MUD, 1 cond MSD after MSD 0 Typical NICU 0 1 www.aappublications.org/news JAK3 (3) Typical Regular 3 0 0 1 cond MSD, 1 cond MUD 1 MMRD RAG2 (3) Typical Regular 2 0 0 1 MSD, 2 cond MUD 0 Leaky Regular 0 1 BCL11B (1) Leaky Regular 1 0 0 1 cond MUD 0 RMRP (1) Leaky Regular 0 1 0 1 cond MUD 0 Unknown (4) Typical Regular 1 1 1 (69 d, CMV) 0 1 cond MUD planning to stop IgG NICU 1 0 0 0 1 Cond MUD Leaky Regular 1 0 0 0 1 cond MUD planning to stop IgG Cond, conditioning with busulfan chemotherapy and, in some instances, fludarabine or other agents; MMRD, mismatched related donor; MSD, matched sibling donor; MUD, matched adult or cord blood unrelated donor. a Criteria from the PIDTC for typical SCID and leaky SCID; Omenn syndrome, a subset of leaky SCID, includes erythroderma rash, adenopathy, oligoclonal T-cell expansion, eosinophilia, and elevated immunoglobin E levels. byguest on September29, 2021 b One infant not included in this table had urgent-positive TRECs and the T2B2NK+ SCID lymphocyte profile but left the United States before HCT; no genotype or follow-up is available. c Three or fewer TREC copies with a normal control polymerase chain reaction copy number by the EnLite kit assay or equivalent with a previous in-laboratory assay. d Treatments included GT with low-dose busulfan followed by autologous CD34+ bone marrow cells transduced with a correct copy of the mutated gene (IL2RG or ADA), MMRD (usually a parent who is haploidentical), MSD, MUD. Cond, conditioning with busulfan chemotherapy and (in some instances) fludarabine or other agents (other infants may have had serotherapy with rabbit antithymocyte globulin or anti-CD52). e Posttransplant hepatic sinusoidal obstruction syndrome after busulfan chemotherapy. f One patient left the United States after conditioned MUD HCT and reconstitution; it is not known if the patient is still on IgG. MTN tal et AMATUNI adaptable to additional conditions (including spinal muscular atrophy, as approved in July 2018) for addition to the Recommended Uniform Screening Panel on the basis of a review of evidence.30 TREC screening in California facilitated the diagnosis of SCID in 50 infants over a 6.5-year period, permitting timely referral to specialized treatment centers for immune-restoring therapy. Sensitivity appears complete in that no cases of typical or early-onset leaky SCID with low T cells are known to have been missed. Indeed, cases of SCID were readily identified by low TRECs, even when maternally engrafted T cells were present, or in Omenn syndrome, when up to several thousand T cells per micro liter had arisen from florid expansion of a small oligoclonal T-cell pool. TRECs are generated in newly differentiated T cells and are not replicated when T cells undergo mitosis. Thus, both maternally transferred cells and proliferating autologous cells have lost TRECs through dilution, and such cells also lack the naïve CD45RA FIGURE 2 marker and instead express the Conditions diagnosed in infants with TCL identified by NBS, including 50 infants with typical or leaky SCID (including Omenn syndrome), 72 infants with a final diagnosis of a syndrome associated with CD45RO memory maker, both part of T-cell impairment or of a non-SCID primary immunodeficiency disorder, 25 infants with congenital the standard California SCID flow- defects associated with secondary TCL, 33 infants with TCL and preterm birth alone, and 55 infants cytometry panel. A positive family with an initial diagnosis of idiopathic TCL (in whom a syndrome was later diagnosed in 22, leaving 33 history of SCID might be expected to idiopathic cases with no underlying defect identified). a Includes 3 cases of CHARGE syndrome, 3 cases of diabetic embryopathy, and 1 each of CLOVES syndrome, EXTL3 deficiency (immune-skeletal make NBS redundant in at least some 5 dysplasia with neurodevelopmental abnormalities), Fryns syndrome (multiple anomalies with di- case patients, but in our experience, aphragmatic defects), Nijmegen breakage syndrome (defect in the DNA repair protein nibrin, obtaining such a history proved causing immune defects, microcephaly, short stature, and malignancy), Noonan syndrome (con- problematic. Two of the 50 infants genital heart disease, characteristic facial and physical features, and short stature), and RAC2 deficiency (a non-SCID primary immunodeficiency affecting neutrophils and lymphocytes). b Includes with SCID were from known at-risk 2 cases of maternal immunosuppressive medication (azathioprine in 1, fingolimod in the other) and pregnancies and had a prenatal 1 case of neonatal teratoma of the thymus. c Infants with TCL associated with preterm birth alone diagnosis. However, neonatal were grouped by birth weight. medical providers were unaware that 6 other infants had a previous sibling GA at birth: 24 weeks), with a median idiopathic TCL (Table 8), 13 resolved who had been treated for SCID, birth weight of 610 g (range: or were improving, whereas 13 including 2 siblings who themselves 300–1720 g). TCL resolved or was patients had persistent TCL, and 6 had been identified by SCID NBS in improving in 26 of 33 preterm infants patients were lost to follow-up. California and received transplants. who were retested. Although the rate of false-positive TREC screen results was higher in DISCUSSION Idiopathic TCL included cases for NICUs than in regular nurseries which an underlying condition could TREC screening for SCID has been (Fig 1), 6 of the 50 case patients not be determined, even after used to establish the feasibility and with true SCID (12%) were in NICUs, immunologic evaluation and, in many utility of DNA-based, high-throughput proportional to the total number instances, sequencing of gene panels screening, which, like tandem mass of infants in NICUs (9% of all or whole exomes. Of the 33 cases of spectrometry, has already proven newborns).

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019 57 TABLE 5 Diagnoses and Mortality in 72 Infants With TCL Found by Using SCID NBS Who Had Syndromes and Non-SCID Primary Immunodeficiency, Including Cases That Were Initially Classified as Idiopathic TCL Syndrome (No. Typical Clinical Characteristics Nursery Type TREC Result Outcome Cases) Regular NICU Urgent Positive Immune Therapy Died During Positive (If Known) Follow-up, Cause DiGeorge Multiple congenital anomalies, including variable cardiac 19 28 3 44 4 received 1, post–thymus syndrome (47) outflow tract defects, parathyroid hypoplasia, thymic thymus transplant medical hypoplasia, and immunodeficiency, and other congenital transplants complication defects; most often due to interstitial deletion of chromosome 22q11.2 Trisomy 21 (8) Wide range of neurodevelopmental and physical defects, 170 8 — 3 including hypotonia, short stature, congenital heart disease, and defects in host defense against infection AT (5) Cerebellar ataxia with progressive neuromuscular 5 0 0 5 1 received IgG 0 deterioration, telangiectasias, immune defects, and infusions predisposition to malignancy; DNA repair defect CHARGE Ocular coloboma, heart defect, atresia choanae, restricted 0 3 3 0 1 received IgG 1, respiratory failure syndrome (3) growth and development, genital abnormality, and ear infusions abnormality Diabetic Multiple congenital malformations involving brain, 0 3 0 3 TCL resolved in 1 1 embryopathy cardiovascular, skeletal, and immune systems (3) CLOVES Congenital lipomas, overgrowth, vascular malformations, 0 1 1 0 IgG infusions 1, respiratory failure syndrome (1) epidermal nevi, and skeletal anomalies EXTL3 deficiency Immuno-skeletal dysplasia with neurodevelopmental 0 1 0 1 IgG infusions 0 (1) abnormalities Fryns syndrome Multiple congenital anomalies with diaphragmatic defects 010 1 — 1, respiratory failure (1) and lung maldevelopment Nijmegen Nibrin mutation causing DNA repair defect with 0 1 0 1 IgG infusions 0 syndrome (1) immunodeficiency, microcephaly, short stature, and frequent malignancy Noonan Several known genotypes causing congenital heart disease, 010 1 — 1 syndrome (1) characteristic facial and physical features, and short stature RAC2 deficiency Immunodeficiency affecting neutrophils and lymphocytes 1 0 0 1 — 0 (1) —, not applicable.

Survival of patients with SCID was immunity, no longer requiring IgG to 75%. The optimal treatment of 94% at 1 to 8 years of age. supplementation (Table 1); IgG SCID, HCT from a matched sibling, Furthermore, 31 of the 46 surviving production is expected to recover in was available to only 3 infants. As children (67%) have fully additional patients over time, raising previously published, the children reconstituted B- as well as T-cell the proportion of children fully cured with X-linked SCID who received HCT

TABLE 6 Causes of Secondary TCL Found by using SCID NBS With TRECs Primary Condition (No. Cases) Nursery Type TREC Result Comments (Deaths Occurred During the NICU Stay) Regular NICU Urgent Positive Positive Congenital heart disease (6) 0 6 1 5 All had urgent heart surgery; 1 died Hydrops (6) 0 6 1 5 1 died Gastroschisis (4) 0 4 0 4 All had urgent surgical intervention Chylothorax (2) 0 2 0 2 1 died Maternal immunosuppressive 2 0 1 1 Azathioprine or ﬁngolimod used by mothers during pregnancy; infants’ T-cell counts medication (2) normalized spontaneously Third-space ﬂuid leakage (2) 0 2 1 1 1 died Intestinal atresia (1) 0 1 1 0 Urgent surgical intervention Meconium ileus (1) 0 1 1 0 Surgical intervention (ileostomy) Teratoma of the thymus (1) 0 1 0 1 Surgery; patient also had hydrops, ascites, and chylothorax

Downloaded from www.aappublications.org/news by guest on September 29, 2021 58 AMATUNI et al TABLE 7 TCL Associated With Preterm Birth and Low Birth Weight evidence of previous CMV exposure.34 Birth wt, g No. Patients TREC Result One infant with SCID of unknown Urgent Positive Positive genotype may have acquired CMV from breast milk from his mother 300–450 5 1 4 451–550 7 0 7 who was CMV seropositive. On 551–650 11 1 10 admission to the hospital at 21 days 651–900 8 1 7 of age, this infant had CMV that was 901–1720 2 0 2 uncontrolled despite antiviral therapy and an accelerated haploidentical paternal HCT. California may have from a parent who was haploidentical inadequate T-cell recovery. reduced CMV exposure time among without chemotherapy achieved Importantly, and in contrast to infants with SCID by moving the T-cell reconstitution but continue previous unconditioned GT or TREC assay to regional laboratories to require IgG infusions.1,2,7,11 unconditioned HCT with donors other with a faster turnaround. After Chemotherapy conditioning, used in than matched siblings, current GT for regionalization, the median age at most cases of SCID in which B-cell both ADA-deficient and X-linked SCID, diagnosis of SCID by lymphocyte recovery occurred, nonetheless did when preceded by low-dose busulfan subsets for infants without not ensure the development of chemotherapy, restored both T- and a recognized family history was normal antibody production and was B-cell immunity, allowing 10 of the 12 8days(n = 5), compared with associated with 2 deaths (see below). recipients of GT to discontinue IgG 21 days (n = 40) before that time. Moreover, B-cell recovery was infusions. Further study will be required to achieved with unconditioned or establish the sources and best conditioned HCT for all 6 cases The 3 deaths among infants with SCID preventive measures to combat CMV of interleukin-7 receptor present a challenge to further infection. (IL7R)–deficient SCID, in which improve current therapy. One death SCID did not occur more frequently in B cells are intrinsically functional followed hepatic sinusoidal any ethnic group, nor did any once helper T cells are restored.31,32 obstruction from high-dose chemotherapy, 1 was due to CMV California population subgroups Autologous GT after low-dose infection, and 1 was due to combined demonstrate predominant founder fi busulfan conditioning is available in CMV infection and chemotherapy mutations, as previously identi ed for Navajo American Indians and the clinical trials for patients with toxicity. Individual targeting of 35,36 ADA-deficient and X-linked SCID who busulfan exposure to account for Amish. However, the frequent lack matched sibling donors.8–10 variable metabolism in young infants occurrence of SCID because of All 8 recipients of GT who were may prevent future chemotherapy- homozygous autosomal recessive ADA-deficient have had full immune associated deaths.33 CMV is highly mutations reveals a pattern of shared recovery, including independence pathogenic in the absence of T-cell parental ancestry. Of 30 cases of from IgG infusions, as did the sole immunity. Infants with SCID are autosomal recessive SCID with fi recipient of a matched-sibling HCT unlikely to have congenital CMV mutations identi ed, 9 (30%) were for ADA-SCID. ERT was used as because maternal primary infection homozygous (Supplemental a bridging therapy between diagnosis during pregnancy is uncommon; Table 11). and GT for most ADA cases. Four of however, they may acquire CMV at or A late diagnosis in 2 infants who had 14 case patients with X-linked SCID after birth from maternal virus shed normal TREC NBS but who proved to also received GT, although 1 required into secretions or breast milk because have missense defects in the ADA a subsequent allogeneic HCT for most mothers have serologic and IL2RG genes, respectively, reveals that SCID has a broad spectrum of mutations and phenotypic TABLE 8 Idiopathic TCL Detected by TREC Screening presentations. Mutations that are Status at Last Follow-up (No. Cases) Nursery Type TREC Result sufficiently leaky to produce some Regular NICU Urgent Positive T cells and TRECs may evade Positive neonatal detection. Importantly, TCL resolved (11) 9 2 0 11 raising the TREC cutoff would not TCL improving (2) 2 0 2 0 have helped to identify either of these TCL persistent (13) 12 1 3 10 case patients by NBS because both Infant died of respiratory failure, had a low CD4 T cell count (1) 0 1 0 1 had TREC counts well above the Status unknown; lost to follow-up (6) 5 1 1 5 designated level requiring follow-up.

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019 59 In addition to diagnosing SCID, TREC transplant developed functional likely been diagnosed only after NBS has identified non-SCID TCL, T cells, although 1 subsequently died the appearance of neurologic permitting intervention to avoid live of an unrelated complication. Infants manifestations, ocular telangiectasias, rotavirus vaccination, which can with partial DiGeorge syndrome had or frequent infections.28 The cause severe diarrheal disease in stable or rising T cells over time, and remaining syndromes initially infants with insufficient T-cell those for whom data were available identified as idiopathic TCL by NBS immunity.20 Secondary and made protective responses to killed included 3 cases of diabetic premature TCL cases are expected to vaccines (data not shown). embryopathy and 1 each of CHARGE resolve, but until they do so, patients syndrome; congenital, lipomatous, are immunocompromised. Although Thirty-three infants with TCL from overgrowth, vascular malformations, the TCL definition of 1500 CD3 cells preterm birth alone (Table 7) had epidermal nevi, and spinal and/or . per mL as the upper limit provides 2% of their CD4 helper T cells with skeletal anomalies and/or scoliosis a medically prudent indication to the naïve CD45RA marker, and their (CLOVES) syndrome; Nijmegen intervene with immune supervision TCL resolved to normal over time. breakage syndrome38; EXTL3 and avoidance of live viral vaccines, However, longitudinal follow-up was deficiency29; and member 2 of Rac this cutoff does not ensure the essential to differentiate them from subfamily of r GTPases (RAC2) identification of all cases of non-SCID, infants with SCID who were born deficiency39 (A.P. Hsu, J.A. Church, persistent, mild TCL. prematurely. et al, unpublished observations). The Almost all infants with secondary TCL last 3 were diagnosed after whole- Most of the non-SCID syndromes were cared for in NICUs because of exome sequencing and analysis. were multisystem disorders recognized primary conditions, summarized in Table 5; of all important exceptions being those CONCLUSIONS individuals with these syndromes, whose mothers had taken those with low NBS TRECs and immunosuppressive medication during As an early adopter of TREC ,1500 T cells per mL were only the pregnancy. Although self-limiting, the screening, the California NBS program ones with the most profound effects of these medications on infant has demonstrated not only detection immunologic impairment. Thus, TREC T cells were profound. For example, of SCID and clinically important non- testing is not a screen for DiGeorge despite being contraindicated in SCID TCL with near-complete syndrome, trisomy 21, or any other fi pregnancy, fingolimod was taken sensitivity and outstanding speci city syndrome per se. Two-thirds of for multiple sclerosis by 1 woman but also implementation of high- patients with syndromic TCL had who was pregnant. This drug is throughput, DNA-based methodology DiGeorge syndrome, usually because a sphingosine-1-phosphate receptor applicable to other conditions, such of interstitial deletion of chromosome modulator that acts to sequester as spinal muscular atrophy. The 22q11.2, but also associated with lymphocytes in the thymus and lymph potential harm of live attenuated intragenic heterozygous mutations of nodes, preventing their release.37 The rotavirus vaccination in infants who fi T-box-containing transcription factor infant appeared healthy but at 8 days are immunode cient has been 1 (TBX1), a transcription factor of age, had only 126 T cells, with averted, strengthening this otherwise fi located within the common 22q undetectable naïve T cells, a profile bene cial public health measure. The deletion region. Additionally, some typical of SCID that would require HCT. incidence of SCID has proven higher patients with DiGeorge syndrome However, further workup revealed than originally thought, and new lacked a known genetic defect. In normal T-cell proliferation, and by the disease genes have been discovered fi complete DiGeorge syndrome, some age of 2 months, the immune profile in infants identi ed by SCID NBS. cases of CHARGE syndrome, and had completely resolved without Treatment of SCID detected by NBS some infants of mothers with treatment. has led to 94% survival while diabetes, profound TCL is due to the revealing areas for future further absence of a functional thymus. Out of an initial total of 55 idiopathic improvement in targeted Urgent intervention to protect such TCL cases, 22 defined syndromes chemotherapy and avoidance of infants from infections is required were eventually diagnosed, most CMV infection. as in typical SCID, but curative commonly DiGeorge syndrome in treatment requires a thymus 9 case patients who did not ACKNOWLEDGMENTS transplant, available only by demonstrate the commonly observed experimental clinical trial.26,27 All of neonatal cardiac disease, We thank Fred Lorey for his energy the 4 California infants found by NBS hypocalcemia, or dysmorphic and vision in bringing about SCID to have complete DiGeorge syndrome features. AT was also found in 5 cases screening in California. Important who were treated with a thymus that, without NBS, would have most support and encouragement for us

Downloaded from www.aappublications.org/news by guest on September 29, 2021 60 AMATUNI et al and SCID families came from Fred CLOVES: congenital lipomatous JAK3: Janus kinase 3 and Vicki Modell, the SCID Angels for overgrowth, vascular NBS: newborn screening Life, and the Immune Deficiency malformations, NK: natural killer Foundation. epidermal nevi, and PIDTC: Primary Immune spinal and/or skeletal Deficiency Treatment ABBREVIATIONS anomalies and/or Consortium scoliosis RAC2: member 2 of Rac subfamily ADA: adenosine deaminase CMV: cytomegalovirus of r GTPases AT: ataxia telangiectasia DBS: dried blood spot RAG1: recombinase-activating BCL11B: B cell lymphoma 11B ERT: enzyme replacement therapy gene 1 CDPH: California Department of EXTL3: exostosinlike RAG2: recombinase-activating Public Health glycosyltransferase 3 gene 2 RMRP CHARGE: coloboma of the eye, GA: gestational age : RNA component of heart defect, atresia GDL: Genetic Disease Laboratory mitochondrial RNA choanae, restricted GT: gene therapy processing growth and HCT: hematopoietic cell transplant endoribonuclease development, genital IgG: immunoglobulin G SCID: severe combined IL2RG fi abnormality, and ear : interleukin-2 receptor immunode ciency abnormality g chain TCL: T-cell lymphopenia CI: confidence interval IL7R: interleukin-7 receptor TREC: T-cell receptor excision circle

and led the California severe combined immunodeficiency newborn screening program, for which Dr Koupaei was the Genetic Disease Laboratory Director in charge of T-cell receptor excision circle screening; Ms Grimbacher and Dr Nguyen collected and analyzed data and reviewed the manuscript; Dr Naides provided the analysis of flow-cytometric data and reviewed and revised the manuscript; and all authors approved of the final manuscript as submitted and agree to be accountable for all aspects of it. DOI: https://doi.org/10.1542/peds.2018-2300 Accepted for publication Nov 7, 2018 Address correspondence to Jennifer M. Puck, MD, Division of Allergy, Immunology, and Blood and Marrow Transplantation, Department of Pediatrics, University of California, San Francisco, Box 3118, 555 Mission Bay Blvd S., Room SC-252K, San Francisco, CA 94143. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2019 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: Dr Puck received support from grant R01 AI105776 and cooperative agreement U54 AI082973 for the Primary Immune Deficiency Treatment Consortium, a member of the Rare Diseases Clinical Research Network funded by the National Institute of Allergy and Infectious Diseases, the Office of Rare Diseases Research, the National Center for Advance Translational Sciences, and the National Institutes of Health; the Jeffrey Modell Foundation; the Lisa and Douglas Goldman Fund; and the Michelle Platt-Ross Foundation. Drs Butte and Church received support from the Jeffrey Modell Foundation. Dr Dvorak received support from grant U54 AI082973. Funded by the National Institutes of Health (NIH). POTENTIAL CONFLICT OF INTEREST: Dr Markert developed technology for RVT-802, which has been licensed to Enzyvant Therapeutics GmbH. Dr Markert has received royalties from Enzyvant. Portions of Dr Markert and her research team’s salaries are being paid by the funding from Enzyvant. If the technology is commercially successful in the future, Dr Markert and Duke University may benefit financially. Dr Naides is employed by Quest Diagnostics. Donald Kohn is an inventor of a lentiviral vector for gene therapy of adenosine deaminase severe combined immunodeficiency, which Orchard Therapeutics Ltd has licensed from the University of California Regents; Dr Kohn is a consultant to Orchard Therapeutics Ltd and a member of its Scientific Advisory Board. Dr Cowan serves on the Scientific Advisory Boards for Homology Medicine, Inc, and Exogen, Inc, and on the Data and Safety Monitoring Board for bluebird bio, Inc. Dr Puck discloses spousal employment at a clinical DNA sequencing company, Invitae; the other authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 143, number 2, February 2019 63 Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010−2017 George S. Amatuni, Robert J. Currier, Joseph A. Church, Tracey Bishop, Elena Grimbacher, Alan Anh-Chuong Nguyen, Rajni Agarwal-Hashmi, Constantino P. Aznar, Manish J. Butte, Morton J. Cowan, Morna J. Dorsey, Christopher C. Dvorak, Neena Kapoor, Donald B. Kohn, M. Louise Markert, Theodore B. Moore, Stanley J. Naides, Stanley Sciortino, Lisa Feuchtbaum, Rasoul A. Koupaei and Jennifer M. Puck Pediatrics 2019;143; DOI: 10.1542/peds.2018-2300 originally published online January 25, 2019;

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010−2017 George S. Amatuni, Robert J. Currier, Joseph A. Church, Tracey Bishop, Elena Grimbacher, Alan Anh-Chuong Nguyen, Rajni Agarwal-Hashmi, Constantino P. Aznar, Manish J. Butte, Morton J. Cowan, Morna J. Dorsey, Christopher C. Dvorak, Neena Kapoor, Donald B. Kohn, M. Louise Markert, Theodore B. Moore, Stanley J. Naides, Stanley Sciortino, Lisa Feuchtbaum, Rasoul A. Koupaei and Jennifer M. Puck Pediatrics 2019;143; DOI: 10.1542/peds.2018-2300 originally published online January 25, 2019;

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