International Journal of Neonatal Screening最新文献

Sweden has one neonatal screening laboratory and two centers conducting diagnostic workup for inborn errors of metabolism (IEM). Next-generation sequencing (NGS) has been gradually introduced as a confirmatory diagnostic test in the Swedish newborn screening program. Here, we describe the use of NGS in the diagnostic workup of IEM in screening-detected babies in Sweden between 2015 and 2023. During this period, 1,023,344 newborn children were screened, and 81 of 290 IEM cases were genetically confirmed using NGS. Planned improvements to the program are to perform genetic validation directly on the initial dried blood spot (DBS). As whole-genome sequencing (WGS) is superior in detecting causative genetic variants compared to Sanger sequencing, targeted NGS, and whole-exome sequencing (WES), it will likely become the method of choice more broadly in the future. A strong focus is to consolidate the nationally coordinated DBS newborn screening program, with all its individual components, including screening, targeted diagnostics, individualized treatment, and follow-up. This challenges the current regionalized organization of Swedish healthcare, which hinders close national collaboration between experts and sharing of data, as well as equal access to advanced treatments for identified patients, regardless of their place of birth.

Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase (GAA) deficiency. The use of umbilical cord blood (UCB) for newborn screening (NBS) of Pompe disease, compared to heel-prick sampling, has not been widely studied. This study compared GAA activity in UCB from term newborns with peripheral or heel-prick blood samples obtained on days 1, 2, and 3 after birth. Enzyme assays were performed using UPLC-MS/MS. Sanger sequencing was conducted in infants with low GAA activity to identify pathogenic variants. Among 4091 UCB samples analyzed over 18 months, the mean GAA activity was 10.04 ± 5.95 μM/h, higher in females than males [Median (IQR): 9.83 (5.45) vs. 9.08 (4.97) μM/h, respectively, p < 0.001], and similar across ethnicities. GAA levels in UCB and Day 3 heel-prick samples were comparable. A GAA cut-off value of 1.54 μM/h (0.1% of study population) identified one infant (0.024% prevalence) with a novel bi-allelic variant-c.2005_2010del (p.Pro669_Phe670del) and c.1123C>T (p.Arg375Cys), and 12 infants with non-pathogenic pseudodeficiency alleles. This study supports GAA measurement in UCB as a viable alternative for NBS, with enzyme activity remaining stable for up to 72 h post-collection. Larger-scale multicenter nationwide studies are warranted to confirm this prevalence in our population.

The authors wish to make the following correction to their paper published in the International Journal of Neonatal Screening [...].

The aim of this study was to improve screening efficiency by establishing reasonable interpretation criteria for the use of flow injection analysis tandem mass spectrometry (FIA-MS/MS) in newborn screening (NBS) for X-linked adrenoleukodystrophy (X-ALD). FIA-MS/MS was employed to analyze very-long-chain acylcarnitines (ACs) and lysophosphatidylcholines (LPCs) and their ratios in dried blood spot (DBS) obtained from five X-ALD patients in the neonatal period (0-7 days old) and 7123 healthy neonate controls. By comparing these results and analyzing receiver operating characteristic (ROC) curves, we identified sensitive indicators for X-ALD screening in newborns. To evaluate the performance of different FIA-MS/MS screening indicators, we simultaneously analyzed 7712 neonatal DBS samples obtained for X-ALD screening using FIA-MS/MS and the established liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantitative detection of C26:0-lysophosphatidylcholine (C26:0-LPC). Furthermore, 84,268 newborn X-ALD screening results were retrospectively analyzed to further evaluate the screening performance of FIA-MS/MS. After the three-step optimization evaluation, the optimized first-tier sensitive screening indicators of FIA-MS/MS were C24:0-AC, C26:0LPC, and C24:0/C22:0-AC. Among the 7712 newborns screened, one case was confirmed to be double-positive. Within separate statistical analyses, based on LC-MS/MS screening alone (positive cutoff > 0.17 µmol/L), only seven cases (0.09%) were initially positive, with a positive predictive value (PPV) of 42.8%, and two additional ABCD1 VUS hemizygous males were detected. Through the retrospective analysis of 84,268 newborns, eight ABCD1 variants (six hemizygous males and two heterozygous females) were ultimately identified. Our study showed that the optimization of first-tier screening performance is particularly important if second-tier screening is not performed. Using LC-MS/MS for second-tier screening for X-ALD can significantly reduce the number of false positives, but the method still misses some false negatives. If it is used as a first-tier assessment, more VUS variant neonates can be detected.

As newborn screening (NBS) programs deal with growing complexities, including adding new disorders to their screening panels, adopting new technologies/screening methods, and workforce shortages, there is a greater need for continuous quality improvement (CQI) to ensure the NBS system is meeting its primary goal of identifying infants with NBS disorders in a timely fashion. In 2019, the Health Resources and Services Administration's (HRSA) Maternal and Child Health Bureau (MCHB) awarded funding to the Association of Public Health Laboratories' (APHL) Newborn Screening Technical assistance and Evaluation Program (NewSTEPs) to address CQI in the NBS system through a collaborative, data-driven process. From 2019-2024, NewSTEPs funded 36 quality improvement (QI) projects from a variety of state NBS programs and research centers across the U.S., to address timeliness, detection of out-of-range results, communication of results, and/or confirmation of diagnosis. Thirty-three QI teams completed their projects, and 85% achieved their specified goal outlined in their aim statement. Despite limitations, the QI Projects Collaborative provided NBS programs with funding and resources to begin and sustain quality improvement initiatives. This model of a technical assistance and central resource center for CQI was effective in achieving quality improvements within the national NBS system.

The implementation of newborn screening (NBS) has revolutionized the diagnostic landscape of cystic fibrosis (CF). In Portugal, NBS was initiated in October 2013 through a pilot study and was subsequently fully integrated into a nationwide program by December 2018. Infants with positive screening results are referred to a specialized CF reference center for diagnostic confirmation, employing Sweat Chloride Testing (SCT) and genetic testing for CFTR variants. We aimed to analyze infants with a positive CF screening and determine the false positive and false negative rates, as well as to calculate the positive predictive value and sensitivity of our NBS program. A retrospective nationwide analysis was conducted on infants with a positive NBS for CF between October 2013 and February 2023. Two hundred and forty infants were referred from the NBS program; 74 (30.8%) were confirmed to have CF through SCT and genetic testing. Sensitivity was 93.2%, and the positive predictive value (PPV) was 30.8%. In addition, 48.5% were homozygous for F508del variants, and 87.8% had at least one F508del variant. Guidelines set forth by the European Cystic Fibrosis Society advise NBS programs to achieve a minimum PPV of 30% and a minimum sensitivity of 95%. Our report demonstrated good compliance with these recommendations.

Mucopolysaccharidosis (MPS) type II, or Hunter syndrome, is an X-linked lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase. Glycosaminoglycan (GAG) accumulation leads to progressive multisystemic involvement, with coarse facial features, hepatosplenomegaly, short stature, recurrent upper respiratory infections, hearing loss, hernias, dysostosis multiplex, joint contractures, and cardiac valve disease. Individuals with the neuronopathic form of the disease also have central nervous system (CNS) involvement with developmental delay and progressive cognitive decline. Enzyme replacement therapy (ERT), idursulfase, is the only FDA-approved treatment for MPS II. MPS II was added to the Recommended Uniform Screening Panel (RUSP) in the United States in 2022, and screening is ongoing in several other countries, including Taiwan. Here, we report seven individuals from four families identified through newborn screening sharing the same IDS variant: c.817C>T, p.Arg273Trp. Confirmatory testing demonstrated low iduronate-2-sulfatase activity level and elevated GAGs in every individual, but they had no signs or symptoms of MPS II. They were aged 8 months to 60 years old according to the most recent assessment and all remained asymptomatic. ERT was not initiated for any of them. Our findings suggest that the IDS c.817C>T variant is associated with abnormal biochemical findings but no clinical phenotype of MPS II. Newborn screening will likely identify additional cases and provide a better understanding of the clinical significance of this variant.

Early diagnosis of cystic fibrosis (CF) through newborn screening (NBS) improves clinical outcomes, but in countries like India, delayed diagnosis increases morbidity, mortality, and likely underestimates infant deaths from CF. We performed a retrospective study at a single center in south India from 2017 to 2025 reviewing children diagnosed with CF before one year of age. Patient demographic, clinical, and genetic data were analyzed to characterize early clinical features and identify factors linked to mortality. Of 56 infants diagnosed with CF, 59% survived (median current age 55 months) while 41% died (median age of death 5 months). Key clinical indicators included sibling death with CF-like symptoms, rapid weight loss, and persistent respiratory or nutritional complications. Mortality risk under one year was significantly linked to hypoalbuminemia (OR 9.7), severe malnutrition (OR 4.4), severe anemia (hemoglobin < 7 g/dL) requiring blood transfusions (OR 3.0), and peripheral edema (OR 4.2). A triad of anemia, hypoalbuminemia, and edema was found to strongly predict death (OR 4.2). Integrating clinical checklists of these manifestations into primary healthcare may improve prompt referrals for earlier diagnosis and treatment. Continued education and advocacy for NBS are essential to reduce potentially preventable CF-related deaths in young children.

Background: Monocarboxylate-transporter-8-(MCT8) deficiency, or Allan-Herndon-Dudley syndrome (AHDS), is a rare X-linked disorder caused by pathogenic variants in the SLC16A2 gene, leading to impaired transport of thyroid hormones, primarily T3 and T4, across cell membranes. The resulting central hypothyroidism and peripheral hyperthyroidism cause neurodevelopmental impairment and thyrotoxicosis. Despite the availability of therapy options, e.g., with triiodothyroacetic acid (TRIAC), diagnosis is often delayed, partly due to normal TSH levels or incomplete genetic panels. MCT8 deficiency is not yet included in newborn-screening programs worldwide.

Case description: We present a case of an infant genetically diagnosed with MCT8 deficiency at 5 months of age after presenting with muscular hypotonia, lack of head control, and developmental delay. Thyroid function testing revealed a normal TSH, low free T4, and significantly elevated free T3 and free T3/T4 ratio. Treatment with TRIAC (Emcitate^®) was initiated promptly, with close drug monitoring. Despite persistent motor deficits and dystonia, some developmental progress was observed, as well as reduction in hyperthyroidism.

Discussion/conclusions: This case underscores the importance of early free T3 and fT3/fT4 ratio testing in infants with unexplained developmental delay. Broader inclusion of SLC16A2 in genetic panels and consideration of newborn screening could improve early diagnosis and outcomes in this rare but treatable condition.

Congenital hypothyroidism (CH) is a heterogeneous condition present at birth, resulting in severe-to-mild thyroid hormone deficiency. This condition is difficult to recognize shortly after birth. Therefore, many countries worldwide have implemented newborn screening (NBS) programs for CH since the 1970s. The most recent European guidelines strongly recommend screening for primary CH, as well as for central CH when financial resources are available. However, no consensus has been reached yet to screen more rare forms of CH, such as Allan-Herndon-Dudley syndrome (AHDS), an X-linked condition linked to mutations in the gene encoding a transmembrane monocarboxylate transporter (MCT8), resistance to thyroid hormone beta (RTHβ), and resistance to thyroid hormone alfa (RTHα). The combined measurement of thyroid-stimulating hormone (TSH) and total thyroxine (TT4) on DBS currently allows the recognition of central CH (TSH low/normal and low TT4 without defects in transport proteins). With the introduction of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) for measurement of free triiodothyronine (FT3) and free thyroxine (FT4), it would be possible to screen for RTHβ (TSH normal/high and high FT4). More complicated would be the method to screen RTHα. It would require the combined measurement of FT4 and FT3 and the determination of FT3/FT4 ratio, while the combined measurement of FT3 and reverse T3 (rT3) to calculate FT3/rT3 ratio would be useful to screen AHDS. In this article, we provide some reflections on expanding NBS for primary CH also to other rare forms of CH.