An acute life-threatening episode of rhabdomyolysis, renal failure, altered mental status and hyperammonemia in an adult with 3-methylcrotonyl-CoA carboxylase deficiency.

3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency is an autosomal recessive disorder of leucine metabolism. Since 3-MCC deficiency is thought to be a benign condition, a few newborn screening programs discontinued to screen this condition. We report a case of a 24-year-old previously healthy male patient who developed generalized rhabdomyolysis, weakness, respiratory and renal failure, acute pancreatitis, hyperammonemia, and altered consciousness after strenuous exercise. Diagnosis of 3-MCC was made based on increased plasma C5OH carnitine, urine 3-methylcrotonylglycine, and 3-hydroxyisovalerate, and later whole genome sequencing study confirmed the diagnosis. Low plasma carnitine and high creatine kinase (CK) levels were again noted after two months of poor compliance with carnitine therapy. Since 3-MCC deficiency is often incidentally diagnosed in asymptomatic mothers through positive newborn screening in the newborns and most positive newborn screening cases have benign clinical outcomes, 3-MCC deficiency has been considered a benign condition. Observation of a life-threatening episode triggered by strenuous exercise and recurrent occurrence of low carnitine and high CK without carnitine supplementation may support 3-MCC deficiency to be the condition covered by the newborn screen since carnitine supplementation likely prevents an episode that can be life-threatening. Asymptomatic adults with 3-MCC deficiency may benefit from periodic evaluation of plasma carnitine levels.

Improved detection of cystic fibrosis by the California Newborn Screening Program for all races and ethnicities.

BACKGROUND: Newborn screening (NBS) for cystic fibrosis (CF) is universal in the United States. Protocols vary but include an immunoreactive trypsinogen (IRT) level and CFTR variant panel. California CF NBS has a 3-step screening: IRT level, variant panel, and CFTR sequencing if only one variant identified on panel. METHODS: This was a cohort study of infants with CF born in California (2007-2021) to examine racial and ethnic differences in having a false-negative NBS result for CF and at which step the false-negative occurred. We examined how different CFTR variant panels would improve detection of variants by race and ethnicity: original 39-variant panel, current 75-variant panel, and all 402 disease-causing CFTR variants in the CFTR2 database. RESULTS: Of the 912 infants born in California with CF, 84 had a false-negative result: 38 due to low IRT level and 46 with a high IRT value (but incomplete variant detection). Asian (OR 6.3) and Black infants (OR 2.5) were more likely to have a false-negative screening result than non-Hispanic white infants. The majority of false-negative screening (but CF diagnosis) cases among American Indian/Native Alaskan and non-Hispanic White infants were due to low IRT levels. The majority of Asian and Hispanic infants with false-negative screening had no variants detected. Detection of two CFTR variants was improved with the 75-variant panel in Black, Hispanic, and non-Hispanic White infants and with the 402-variant panel in Black, Hispanic, non-Hispanic White, and other race infants. CONCLUSIONS: Larger CFTR panels in NBS improved the detection of CF in all races and ethnicities.

Inborn errors of amino acid metabolism - from underlying pathophysiology to therapeutic advances.

Amino acids are organic molecules that serve as basic substrates for protein synthesis and have additional key roles in a diverse array of cellular functions, including cell signaling, gene expression, energy production and molecular biosynthesis. Genetic defects in the synthesis, catabolism or transport of amino acids underlie a diverse class of diseases known as inborn errors of amino acid metabolism. Individually, these disorders are rare, but collectively, they represent an important group of potentially treatable disorders. In this Clinical Puzzle, we discuss the pathophysiology, clinical features and management of three disorders that showcase the diverse clinical presentations of disorders of amino acid metabolism: phenylketonuria, lysinuric protein intolerance and homocystinuria due to cystathionine ß-synthase (CBS) deficiency. Understanding the biochemical perturbations caused by defects in amino acid metabolism will contribute to ongoing development of diagnostic and management strategies aimed at improving the morbidity and mortality associated with this diverse group of disorders.

Differences in Hyperandrogenism Related to Early Detection of Non-Classical Congenital Adrenal Hyperplasia on Second Newborn Screen.

Screening for congenital adrenal hyperplasia (CAH) remains heterogenous across geographies-we sought to determine the proportion of non-classical CAH (NCAH) detection by one vs. two newborn screens (NBS) in two U.S. regions. Data were collected at tertiary centers in Houston (HOU) and Los Angeles (LA) on 35 patients with NCAH, comparing patients identified via the NBS vs. during childhood, 17-hydroxyprogesterone (17-OHP) levels, genotype, and phenotype. The NBS filter-paper 17-OHP levels and daily cutoffs were recorded on initial and second screens. In all, 53% of patients with NCAH in the HOU cohort were identified as infants via the second NBS. Patients identified clinically later in childhood presented at a similar age (HOU: n = 9, 5.5 ± 3.1 years; LA: n = 18, 7.9 ± 4 years) with premature pubarche in almost all. Patients in LA had more virilized phenotypes involving clitoromegaly and precocious puberty and were older at treatment onset compared with those identified in HOU by the second NBS (HOU: 3.2 ± 3.9 years; LA: 7.9 ± 4.0 years, p = 0.02). We conclude that the early detection of NCAH could prevent hyperandrogenism and its adverse consequences, with half of the cases in HOU detected via a second NBS. Further studies of genotyping and costs are merited.

Diagnostic and Communication Challenges in Cystic Fibrosis Newborn Screening.

As of December 2009, cystic fibrosis (CF) newborn screening (NBS) is performed in all 50 US states and the District of Columbia. Widespread implementation of CF newborn screening (CFNBS) in the US and internationally has brought about new and varied challenges. Immunoreactive trypsinogen (IRT) remains the first, albeit imperfect, biomarker used universally in the screening process. Advances in genetic testing have provided an opportunity for newborn screening programs to add CFTR sequencing tiers to their algorithms. This in turn will enable earlier identification of babies with CF and improve longer-term outcomes through prompt treatment and intervention. CFTR sequencing has led to the ability to identify infants with CF from diverse ethnic and racial backgrounds more equitably while also identifying an increasing proportion of infants with inconclusive diagnoses. Using the evolution of the New York State CF newborn screening program as a guide, this review outlines the basic steps in a universal CF newborn screening program, considers how to reduce bias, highlights challenges, offers guidance to address these challenges and provides recommendations for future consideration.

Meconium ileus and pancreatic sufficiency with D1152H mutation: A case report and review of the literature.

Meconium ileus (MI) is one presenting manifestation of Cystic Fibrosis (CF), classically associated with class I-III CF transmembrane conductance regulator (CFTR) mutations and pancreatic insufficiency (PI). D1152H is a class IV mutation that corresponds with a milder CF phenotype and pancreatic sufficiency (PS). We present the case of an infant with G542X/D1152H mutations and MI who required surgical intervention with small bowel resection. The sweat testing was normal, and this child presently remains PS, however at age 5 continues to experience short gut syndrome and failure to thrive. Eight cases were identified in the CF Registry and seven cases in the literature describing patients with D1152H and echogenic bowel (EB) or MI. Our case highlights the importance of CFTR gene sequencing in infants with EB or MI and sweat testing not suggestive of CF. It is our practice to perform full CFTR gene sequencing for infants who present with MI, recognizing protocols for newborn screening across the United States vary. Increased awareness of D1152H association with PS may also well inform both prenatal and postnatal genetic counseling.

Prospective study of thyroid function in the first year of life in infants with Down syndrome.

Current American Academy of Pediatrics (AAP) Guidelines recommend monitoring thyroid function in infants with Down syndrome (DS) at birth, 6 and 12 months, and annually thereafter. This study aimed to determine whether these guidelines are optimal for early diagnosis and treatment of (subclinical) hypothyroidism. Enrolled infants with DS less than age 7 months, born at ≥ 30 weeks gestation to monitor thyroid function test (TFT). A filter paper (FP) blood sample was analyzed for TSH and total T4 at ages 2 and 4 weeks and monthly thereafter until 12 months. Subjects with abnormal FP sample and confirmatory serum TFT for hypothyroidism promptly started treatment. Subjects with thyroid dysfunction identified had thyroid antibodies measured at diagnosis and 12 months. Descriptive statistics determined average time to diagnosis of abnormal TFT. Sixteen (30%) of 54 subjects were diagnosed with a thyroid disorder, the majority with subclinical hypothyroidism (SH) and 1 with hyperthyroidism. Diagnosis occurred in 6 (11%), 9 (17%), and 12 (22.2%) infants in the first 30, 60, and 90 days of life (DOL), respectively. Eight infants had an abnormal NBS and half were diagnosed with a thyroid disorder by DOL 8 and the remainder prior to 4 months. Among subjects with a normal NBS, four were diagnosed at a mean of 104 days and three at a mean of 101 days prior to the 6-month and 12-month routine screens, respectively.  Conclusion: Based on current AAP guidelines, thyroid disorder diagnosis would have been delayed in nearly 20% of the subjects. An additional TFT screen at 1 and 3 months can lead to earlier diagnosis and treatment. What is Known: • Current American Academy of Pediatrics (AAP) Guidelines recommend thyroid function tests (TFT) in infants with Down syndrome (DS) at birth and 6 and 12 months. • Peer- reviewed retrospective studies report an increased incidence of hypothyroidism in infants with DS undetected by the newborn screen (NBS) and prior to 6 months. What is New: • This prospective study monitored TFT in infants with DS at age 2 weeks and monthly throughout the first year of life. • The findings in this study support additional TFT screens at 1 and 3 months in infants with DS.

Duchenne Muscular Dystrophy Presenting as Incidental Hyper-Transaminasasemia in a Two-Month-Old Male.

Duchenne's muscular dystrophy (DMD) is a debilitating X-linked recessive disorder of dystrophin gene expression that culminates in the downregulation of dystrophin in cardiac and skeletal muscle. As a result, there is progressive muscle weakness, fibrosis, and atrophy. The skeletal and cardiac muscle degeneration rapidly progresses to the respective loss of ambulation and death from cardiac muscle failure by the second and fourth decades of life. Although muscle degeneration has been demonstrated in utero patients are initially asymptomatic. Therefore, diagnosis is typically delayed until about five years of age when proximal muscle weakness initiates a diagnostic workup that uncovers the disease. We present the rare case of an early diagnosis of DMD. A two-month-old, the only male offspring of a family with three children, was discovered to have hyper-transaminisemia during hospitalization for pneumonia. His preceding medical history was only significant for fever, cough, and rhinorrhea. The pregnancy and birth were uneventful. No abnormalities were detected on the newborn screen. Physical examination was reassuring with no peripheral stigmata of liver disease. Ultrasonographic assessments, metabolic assays, and infectious disease markers were within normal limits. Creatine kinase (CK) was markedly elevated and our patient was subsequently confirmed to be positive for a pathogenic hemizygous variant of the DMD gene.  Reliance on an abnormal clinical presentation to trigger diagnostic workup for DMD has led to delays in the diagnosis of this genetic disorder. Incorporating CK analysis into newborn screening panels may enable more children to commence workup in infancy rather than at the current average age of 4.9 years. Early diagnosis is of value in the early initiation of monitoring, anticipatory guidance, and availing families' opportunities to harness current trends of care.

Cystic fibrosis year in review 2019: Section 3 multisystem-based care and research.

During the year 2019, numerous research studies and other reports were published that are interesting and instructive to professionals who care for people with cystic fibrosis (CF) and their families.  This report is the third of 3 CF year in review articles and focuses on the multisystem manifestations of CF care. Previous articles have addressed cystic fibrosis transmembrane regulator modulators and reports on CF pulmonary disease and airway infections. It is an exciting time to be involved in care and research that aims to improve care for people with CF and their families.

Natural history of propionic acidemia in the Amish population.

Propionic acidemia (PA) in the Amish is caused by a homozygous pathogenic variant (c.1606A>G; p.Asn536Asp) in the PCCB gene. Amish patients can have borderline or normal newborn screening (NBS) results and symptoms can present at any time from early childhood to mid-adulthood. Early diagnosis and initiation of treatment for PA in the non-Amish population improves patient outcomes. Here, we present data from a retrospective chart review of Amish patients diagnosed with PA from three different medical centers in order to document its natural history in the Amish and determine the influence of treatment on outcomes in this population. A total of 38 patients with average current age 19.9 years (range 4y-45y), 57.9% males, were enrolled in the study. Fourteen patients (36.8%) were diagnosed with a positive newborn screening (NBS) while 24 patients (63.2%) had negative or inconclusive NBS or had no record of NBS in their charts. These 24 patients were diagnosed by screening after a family member was diagnosed with PA (14; 58.3%), following a hospitalization for metabolic acidosis (5; 20.8%), hospitalization for seizures (3; 12.5%) or via cord blood (2; 8.3%). The majority of patients were prescribed a protein restricted diet (32; 84.2%), including metabolic formula (29; 76.3%). Most were treated with carnitine (35; 92.1%), biotin (2; 76.3%) and/or Coenzyme Q10 (16; 42.1%). However, treatment adherence varied widely among patients, with 7 (24.1%) of the patients prescribed metabolic formula reportedly nonadherent. Cardiomyopathy was the most prevalent finding (22; 63.2%), followed by developmental delay/intellectual disability (15; 39.5%), long QT (14; 36.8%), seizures (12; 31.6%), failure to thrive (4; 10.5%), and basal ganglia strokes (3; 7.9%). No difference in outcome was obvious for those diagnosed by NBS and treated early with dietary and supplement management, especially for cardiomyopathy. However, this is a limited retrospective observational study. A prospective study with strict documentation of treatment adherence and universal screening for cardiomyopathy and long QT should be conducted to better study the impact of early detection and treatment. Additional treatment options such as liver transplantation and future therapies such as mRNA or gene therapy should be explored in this population.

Dynamic changes of metabolic characteristics in neonatal intrahepatic cholestasis caused by citrin deficiency.

Introduction: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a pan-ethnic complicated inborn error of metabolism but the specific mechanism is not fully understood. Methods: A total of 169 patients with NICCD who have biallelic pathogenic SLC25A13 variants detected by targeted next-generation sequencing were collected. They were divided into the "Newborn-screen Group" and "Clinical diagnosed Group" depending on the newborn screening results. Amino acid and acylcarnitine profiles were measured by MS/MS. The total bile acids, blood amino acids and acylcarnitines, general biochemistry, blood count, and coagulation parameters were monitored every 2-3 months. We compared the differences in metabolic indices and their dynamic changes between these two groups. The Mann-Whitney test and orthogonal partial least squares discrimination analysis (OPLS-DA) were used for statistical analysis. Results: At the onset of NICCD, we found that the "Clinical diagnosed Group" had higher levels of intermediate products of the urea cycle, free carnitine, and short-chain and long-chain acylcarnitines than those in the "Newborn-screen Group," but the levels of ketogenic/glucogenic amino acids and several medium-chain acylcarnitines were lower. Furthermore, concentrations of direct bilirubin, total bile acid, lactate, prothrombin time, and several liver enzymes were significantly higher while total protein, amylase, and hemoglobin were lower in the "Clinical diagnosed Group" than in the "Newborn-screen Group." Dynamic change analysis showed that direct bilirubin, albumin, arginine, and citrulline were the earliest metabolic derangements to reach peak levels in NICCD groups, followed by acylcarnitine profiles, and finally with the elevation of liver enzymes. All abnormal characteristic metabolic indicators in the "Newborn-screen Group" came back to normal levels at earlier ages than the "Clinical diagnosed Group." c.852_855del (41.2%), IVS16ins3kb (17.6%), c.615 + 5G>A (9.6%), 1638_1660dup (4.4%), and c.1177 + 1G>A (3.7%) accounted for 76.5% of all the mutated SLC25A13 alleles in our population. Conclusion: Argininosuccinate synthesis, gluconeogenesis, ketogenesis, fatty acid oxidation, liver function, and cholestasis were more severely affected in the "Clinical diagnosed Group." The "Newborn-screen Group" had a better prognosis which highlighted the importance of newborn screening of NICCD.

Building research capacity for sickle cell disease in Africa: Lessons and challenges from establishing a birth cohort in Tanzania.

Sickle Cell Disease (SCD) is a known public health burden in sub-Saharan Africa (SSA). The manifestation of SCD starts in early childhood and if not well-managed may lead to early death (before the age of 5 years). Understanding the underlying mechanisms that influence early SCD manifestation is of great importance for early disease and intervention management which will in turn, reduce both morbidity and mortality rates in children. One approach of achieving this is by establishing SCD birth cohorts that can be followed for a period of time (3-5 years) whilst documenting necessary information related to early childhood illnesses. To date, there are few SCD birth cohorts in Africa. To address this gap, we have established a birth cohort of babies with and without SCD (with sickle cell trait and healthy babies). These babies are followed up for 3 years with their study visits synchronized to the immunization schedule. During enrollment and follow-up visits, information on demographic, clinical, and laboratory parameters are collected. To date, we have enrolled a total of 341 babies with and without SCD. Out of these, a total of 311, 186, 133, 81, 44, and 16 babies have returned for their 1st, 2nd, 3rd, 4th, 5th, and 6th visits, respectively. We have collected both demographic and clinical information for these babies at enrollment and during follow-up. We have also utilized this platform to learn on the best approaches of establishing and maintaining a research birth cohort in an African context. We have analyzed the practical issues pertaining to the integration of the birth cohort with the immunization platform which seems to be the most effective and sustainable strategy for maintaining a birth cohort in our context.

In-utero exposure to immunosuppressive medications resulting in abnormal newborn screening for severe combined immunodeficiency: a case series on natural history and management.

Exposure to immunosuppressive medication in utero is an important cause of secondary T cell lymphopenia in infancy, which can be detected via T cell receptor excision circle (TREC) quantification on severe combined immunodeficiency (SCID) newborn screening (NBS). At present, there is a paucity of literature surrounding management of these infants. A protocol including recommendations for vaccinations and follow-up is needed to augment care. Patients referred to immunology for abnormal TREC results on NBS were identified as having in utero exposure to immunosuppressive medications and were followed until lymphopenia improved. The natural history of these patients' lymphopenia was used to develop general management guidelines. Four infants with low TRECs secondary to in utero immunosuppressive exposure were evaluated. Medication exposures included azathioprine, infliximab, hydroxychloroquine, and fingolimod. All infants were born full term. TRECs ranged from 101-206 (normal value in IL ≥ 250 at time of testing, B-actin control). T cell lymphopenia (CD3 < 1500) was present in 50% of cases. Undetectably low effector CD4 naïve T cell population was present in 100% of cases. Mitogen proliferation was uniformly normal. Severity of TREC abnormality did not correlate with presence of T cell lymphopenia. Immune abnormalities normalized in 75% patients by age 4 months. All age-appropriate vaccinations, including live vaccines, were administered to all patients by age 4 months. It is critical to assess for in utero immunosuppressive exposure in infants with abnormal TREC results on NBS. In the infants evaluated, secondary T cell lymphopenia associated with maternal immunosuppressive use resolved or significantly improved by age 4 months. Once abnormal TREC count is deemed to be secondary to in utero immunosuppression and there are no other contraindications, infants may safely receive live vaccination, are able to drink breast milk, and do not require prophylactic anti-microbials.

Five cases of missed cystic fibrosis heterozygous mutations identified after a positive newborn screen on a sibling.

In Michigan (MI), NBS for CF was started in October 2007 using the IRT/DNA protocol. In 2016, a component of the Hologic molecular test kit used by the MI NBS lab was recalled (40 CF mutation 2nd tier test). This recall had a major impact on states using the Hologic test kits in their NBS programs. Michigan specimens were sent to another state's NBS Lab for 2nd tier testing using the Luminex 60 mutation test kit until the Luminex kit could be procured and validated in MI. In this report, we present five cases born during this time period. These cases were initially reported out as having normal NBS results for CF but had heterozygous F508 del (c.1521_1523delCTT) mutations later identified. Of the five cases, one was diagnosed with CF (Case1), one with CF related metabolic syndrome (CRMS), and the other three were carriers.

Variable disease manifestations and metabolic management within a single family affected by ornithine transcarbamylase deficiency.

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

Utility of Repeat Testing for Congenital Hypothyroidism in Infants with Very Low Birth Weight.

OBJECTIVE: To assess for possible missed hypothyroidism in infants of very low birth weight (VLBW) whose initial newborn screening (NBS) was within normal reference range. STUDY DESIGN: We analyzed serum thyroid-stimulating hormone (TSH) obtained at 36 weeks of corrected gestational age or at hospital discharge if earlier (retest TSH) in infants with VLBW in the neonatal intensive care unit to determine the prevalence and factors associated with retest TSH ≥5 mU/L, a concentration requiring close follow-up for hypothyroidism. Utility of alternative cut-offs for NBS TSH also was assessed. RESULTS: A total of 398 infants, median gestational age 29 (range 22-36) weeks, birth weight 1138 (470-1498) g, were included in this study. Retest TSH was obtained at 49.5 (12-137) days after birth. Median retest TSH was 3.1 (0.5-27.9) mU/L. Seventy-three (18.3%) of the cohort had retest TSH ≥5 mU/L. Adjusting NBS cut-off to ≥15 or ≥10 mU/L identified <50% of infants with TSH ≥5 mU/L, resulting in 6% false positives and >70% false negatives. Multiple regression modeling indicated that 35% of variance in retest TSH value was explained by NBS TSH concentration, birth weight, and gestational age, all P < .01. CONCLUSIONS: Retesting for hypothyroidism at 36 weeks of corrected gestational age in infants with VLBL and normal NBS could identify infants who require ongoing surveillance until thyroid function has been definitively ascertained. Adjusting NBS TSH cutoffs is not a valid option for identifying potential hypothyroidism in infants with VLBW because of lack of sensitivity and unacceptable false-positive and false-negative rates.

Congenital Hypothyroidism.

Congenital hypothyroidism (CH) is a disorder of thyroid hormone deficiency which develops secondary to incomplete thyroid development or inadequate thyroid hormone production. State-mandated newborn screening throughout the United States has increased the detection rate of CH, allowing for early intervention. Although the overall mortality rate of CH is low, delayed or omitted treatment can lead to devastating neurocognitive outcomes. As such, CH is regarded as the leading cause of preventable intellectual disability in children. Early identification, facilitated by astute neonatal nursing and medical care, is contingent upon an active working knowledge of the disease process and awareness of the limitations of the newborn screen.

Immunological Findings and Clinical Outcomes of Infants With Positive Newborn Screening for Severe Combined Immunodeficiency From a Tertiary Care Center in the U.S.

The implementation of severe combined immunodeficiency (SCID) newborn screening has played a pivotal role in identifying these patients early in life as well as detecting various milder forms of T cell lymphopenia (TCL). In this study we reviewed the diagnostic and clinical outcomes, and interesting immunology findings of term infants referred to a tertiary care center with abnormal newborn SCID screens over a 6-year period. Key findings included a 33% incidence of non-SCID TCL including infants with novel variants in FOXN1, TBX1, MYSM1, POLD1, and CD3E; 57% positivity rate of newborn SCID screening among infants with DiGeorge syndrome; and earlier diagnosis and improved transplant outcomes for SCID in infants diagnosed after compared to before implementation of routine screening. Our study is unique in terms of the extensive laboratory workup of abnormal SCID screens including lymphocyte subsets, measurement of thymic output (TREC and CD4TE), and lymphocyte proliferation to mitogens in nearly all infants. These data allowed us to observe a stronger positive correlation of the absolute CD3 count with CD4RTE than with TREC copies, and a weak positive correlation between CD4RTE and TREC copies. Finally, we did not observe a correlation between risk of TCL and history of prenatal or perinatal complications or low birth weight. Our study demonstrated SCID newborn screening improves disease outcomes, particularly in typical SCID, and allows early detection and discovery of novel variants of certain TCL-associated genetic conditions.