International Journal of Neonatal Screening最新文献

X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal disorder, caused by mutations in the ABCD1 gene. Early diagnosis is critical to manage adrenal insufficiency and cerebral forms of the disease. Since 2021, a pilot newborn screening (NBS) program for X-ALD has been launched in Lombardy, Italy. From September 2021 to June 2025, 138,116 newborns (≥37 weeks' gestational age) were screened for elevated C26:0-lysophosphatidylcholine (C26:0-LPC) levels using a two-tier algorithm. Genetic testing was performed in non-negative cases. Males found to be ABCD1 variant carriers were enrolled in multidisciplinary follow-up, including neurological, endocrinological, and nutritional assessments. Eleven individuals (six males, five females) carried pathogenic or likely pathogenic ABCD1 variants. Three males were diagnosed with adrenal insufficiency and started hydrocortisone therapy between 1 and 2 years of age. Growth parameters were within normal range overall, but two children showed signs of stunting associated with poor dietary compliance. Additionally, three patients were diagnosed with Zellweger spectrum disorders (ZSDs). No patients affected with Aicardi-Goutières Syndrome were identified. Newborn screening for X-ALD in Italy is feasible and enables early detection and intervention. Biochemical markers and genetic analysis are reliable tools for identifying affected males and female carriers. Multidisciplinary management is essential to address medical and psychosocial challenges during follow-up.

Medium-Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) is a metabolic disorder caused by mutations in the ACADM gene, leading to impaired fatty acid oxidation. The present study aims to analyze the prevalence and genetic mutation characteristics of MCADD among newborns in Hefei, China, providing insights for the diagnosis, treatment, and prevention of MCADD. A retrospective analysis was conducted on data from newborns diagnosed with MCADD at the Hefei Newborn Disease Screening Center between January 2016 and December 2024. Screening was performed using tandem mass spectrometry (MS/MS), complemented by next-generation sequencing (NGS) for genetic testing. Out of 880,224 screened newborns, 16 cases of MCADD were diagnosed, resulting in a prevalence of 1 in 55,014. A total of 31 mutation sites in the ACADM gene were identified, with 18 different mutation types. The hotspot mutations were c.449-452del (p.T150Rfs*4) and c.1085G>A (p.G362E), each with a mutation frequency of 16.13% (5 out of 31). Additionally, three novel mutations were identified: c.468+5G>A, c.854C>G, and c.428_431delinsTCTTCTTTTGTT. Following diagnosis, patients received health education, dietary guidance, and symptomatic treatment, all resulting in favorable prognoses without any acute metabolic decompensation events. The prevalence of MCADD is lower in Asia compared to Europe and America. The hotspot mutations for MCADD in Hefei are c.449-452del and c.1085G>A. Diagnosis should integrate results from both octanoylcarnitine (C8) levels and genetic testing. Early screening, diagnosis, treatment, and scientific prevention strategies are essential for reducing adverse outcomes in children with MCADD.

Developmental dysplasia of the hip (DDH) is a common neonatal musculoskeletal disorder. In Germany, sonographic screening is recommended at 1-10 days of life for neonates with specific risk factors. This study aims to determine reference values for early sonographic screening and to evaluate associated risk factors. Between 2007 and 2022, 3383 neonates (6766 hips) underwent hip ultrasound according to Graf. Of these, 967 neonates were screened universally (2007-2015) and 1900 based on predefined risk factors (2015-2022). DDH was defined as ≥type IIc, according to Graf. A subgroup of 20 neonates with borderline alpha angles (51-52°) was followed up after 3-6 weeks. The mean alpha angle was 61.2° ± 5.3° (range 50.5-71.9°), and beta angle 70.8° ± 8.6° (range 53.6-88.0°). DDH prevalence was 2.5% in the universal and 3.2% in the risk-based cohort (p = 0.350). Logistic regression revealed associations with abnormal birth presentation (OR = 3.09, p < 0.001) and female sex (OR = 3.77, p < 0.001), not with Cesarean section or familial predisposition. In the follow-up subgroup, all hips showed a sufficient maturation to an alpha angle of 61.0° (range 57-66°). This study provides reference values for early DDH screening and confirms abnormal birth presentation and female sex as relevant risk factors.

The State Hygienic Lab at the University of Iowa (SHL) performs newborn blood spot screening (NBS) for IA, AK, ND, and SD. In October 2022, we halted in-house CFTR DNA testing due to the unexpected nonperformance of our newly expanded variant panel. Samples were sent to a reference laboratory to ensure uninterrupted testing and by December 2022, SHL had selected an alternative test that enabled CFTR panel expansion as envisioned. However, due to circumstances beyond our control, test implementation was severely delayed, and in-house testing was paused. These events were consequential. Firstly, our prolonged utilization of reference labs and fees was a financial strain on the lab. Secondly, our timeliness decreased significantly, and lastly, these issues were burdensome for staff. The lab overcame these problems using three strategies: effective communication; technical expertise; and staff perseverance. Finally, in Aug 2023, SHL successfully resumed in-house testing. As state labs ponder major CFTR algorithm changes, such as the addition of next generation sequencing, the strategies we utilized can be useful during sudden setbacks. Our experience of replacing our CFTR assay underscores the importance of emergency preparedness and partnership within the NBS community.

For more than 60 years, newborn (or neonatal) screening has flourished through global collaboration, demonstrating that collective action is key to success. This unity proved to be especially vital during the COVID-19 pandemic, when, despite severe disruptions, NBS services were largely preserved, reflecting the high value placed on early detection and care for vulnerable newborns. Today, the International Society for Neonatal Screening (ISNS) recognises that NBS programmes face increasing challenges due to global instability. While direct assistance is not always possible, ISNS emphasises the strength of the international NBS community-scientists, clinicians, patient groups, and industry partners-who are committed to mutual support and knowledge-sharing. Building on the proud legacy inspired by pioneers like Bob Guthrie, this community is enriched by diverse voices and is unified by a shared vision: to ensure that all children with rare disorders have access to life-saving screening and care. Safeguarding and advancing this foundation is a responsibility owed to future generations.

Ukraine's healthcare system has shown remarkable resilience in continuing newborn screening (NBS), beyond the challenges of war. Amid the conflict, a Ukrainian newborn screened positive for an extremely rare severe combined immunodeficiency (SCID)-purine nucleoside phosphorylase (PNP) deficiency. Ukraine successfully carried out NBS on a neonatal dried blood spot (DBS) by real-time PCR, which showed remarkably reduced T-cell receptor and kappa-deleting recombination excision circles (TREC/KREC). Retesting was delayed due to communication difficulties with the family. Whole exome sequencing on a new DBS confirmed the diagnosis. The newborn was a candidate for allogeneic hematopoietic stem cell transplantation (HSCT), the only curative treatment. HSCT is a complex procedure still ongoing in Ukraine despite the conflict. However, due to the psychosocial strain, the family sought medical support in Germany, where HSCT was performed successfully at 6 months. As part of a collaborative initiative with Italy, PNP biomarkers were quantified on the same DBSs using tandem mass spectrometry, according to the protocols established for SCID NBS in Tuscany, serving as a proof of concept of its diagnostic performance. This case highlights the importance of sustaining preventive and life-saving healthcare services, and reflects the key role of international partnerships in upholding the right to healthcare in times of crisis.

The absence of biochemical newborn screening (NBS) delays the diagnosis and treatment of congenital hypothyroidism (CH), resulting in irreversible neurodevelopmental damage. To determine the age at diagnosis for CH among Algerian children and to describe its clinical and biological characteristics, etiology, and outcome, we conducted a multicenter retrospective cohort study involving 288 children with CH across 20 pediatric centers between 2005 and 2023. The median age at diagnosis was 1.6 months, and only 28% of patients started treatment before 30 days. Prolonged neonatal jaundice was the most frequently presented symptom (58%), severe CH (fT₄ < 5 pmol/L) was observed in 35% and 52% received an insufficient initial dose of L-T₄. The median IQ of the 47 patients tested was 86; 11% had an IQ < 70, and a negative correlation was found between age at diagnosis and IQ (r = -0.48, p = 0.001). In children reassessed at age 3, 51% had normal thyroid function, indicating transient CH. Delayed diagnosis and suboptimal treatment of CH remain major challenges in Algeria, leading to substantial neurodevelopmental deficits. Pediatricians must remain cognizant of early clinical signs of CH to allow for timely diagnosis and intervention. Biochemical NBS for CH in Algeria is needed.

CblC deficiency is the most common intracellular disorder of vitamin B12 metabolism. Expanded newborn screening (NBS) plays a key role in early diagnosis, allowing timely treatment and preventing serious complications. However, traditional first-tier markers-such as propionylcarnitine (C3) and its ratios with other metabolites (e.g., methionine, carnitine, and acetylcarnitine)-have limited sensitivity, particularly for mild forms, leading to missed or delayed diagnoses. In this study, we analyzed data from the NBS Center of the Lazio region (Italy) and identified nine newborns with confirmed CblC deficiency. All were recalled due to abnormalities in C3 or related ratios, along with elevated methylmalonic acid (MMA) levels. Notably, three infants had completely normal C3 levels and ratios during the second screening test, yet they showed MMA levels above the cut-off value (2 µmol/L), enabling a diagnosis of otherwise undetectable mild CblC cases. Our center regularly measures MMA in dried blood spots, even when first-tier markers return to normal on the second sample. This approach allows for early diagnosis and immediate treatment with hydroxocobalamin in patients with mild CblC deficiency, resulting in early intervention, effective metabolic control, and, based on current follow-up, normal neurodevelopmental outcomes. Our findings highlight the essential role of second-tier MMA testing in improving the detection of mild CblC deficiency during NBS.

Acetoacetyl-CoA thiolase deficiency, also known as Beta-ketothiolase deficiency (BKTD), is an autosomal recessive organic aciduria included in the Italian newborn screening (NBS) panel. It is caused by mutations in the ACAT1 gene, which encodes the mitochondrial acetyl-CoA acetyltransferase. Its deficiency impairs the degradation of isoleucine and acetoacetyl-CoA, leading to the accumulation of toxic metabolites. We describe three cases of BKTD. The first newborn showed increase in C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. Urinary organic acids (uOAs) revealed marked excretion of 2-methyl-3-hydroxybutyrate. Tiglylglycine was absent. Genetic testing identified the compound heterozygosity for two pathogenic ACAT1 variants. The second patient showed increased levels of C5:1, C4DC/C5OH, C3DC/C4OH in the NBS. uOAs revealed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous VUS in ACAT1 was identified. The third case showed elevation of C4DC/C5OH, C3DC/C4OH in the NBS, with a slight increase in C5:1. uOAs showed 2-methyl-3-hydroxybutyrate and tiglylglycine. A homozygous missense VUS was identified in the ACAT1 gene. BKTD exhibited variable NBS biochemical phenotypes across the three cases. While C5OH and C5:1, the primary markers, were not consistently elevated in all our cases, C4OH strongly increased in all three. Our findings support the use of C4OH in a combined marker strategy to improve BKTD NBS.

Due to rapid technical advancements and increasing cost-effectiveness, the potential application of next-generation sequencing (NGS) in newborn screening (NBS) has raised great interest worldwide. Genomic NBS offers the possibility to improve current NBS programs when applied as follow-up tier, and, as first-tier, allows for inclusion of conditions lacking a detectable biomarker for conventional NBS. Obtaining enough high-quality DNA from typically limited dried blood spot (DBS) material to meet NGS requirements can be challenging. Selecting a DNA isolation method for genomic NBS requires balancing technical performance and laboratory feasibility with optimal cost-effectiveness. Ten DNA isolation protocols, including two column-based, five lysis-based, and three semi-automated magnetic bead-based protocols, were evaluated on technical outcomes and performance in targeted amplicon sequencing. Additionally, estimated costs, hands-on time, turnaround time, scalability, and plastic footprint were assessed. Although technical outcomes, including yield, purity, and molecular weight, differed between methods, qualitative results in amplicon sequencing, as defined by read output, mapping, and coverage depth, were found sufficient and comparable for various protocols. In conclusion, both technical requirements and operational parameters are crucial when selecting a DNA isolation protocol and will depend on the NGS application as well as the NBS approach, as either first-tier or follow-up tier.