International Journal of Neonatal Screening

18 pages, 985 KB

Open AccessArticle

Too Early to Tell? Balancing Diagnostic Accuracy of Newborn Screening for Propionic Acidemia Versus a Timely Referral

by Nils W. F. Meijer, Hidde H. Huidekoper, Klaas Koop, Sabine A. Fuchs, M. Rebecca Heiner Fokkema, Charlotte M. A. Lubout, Andrea B. Haijer-Schreuder, Wouter F. Visser, Rendelien K. Verschoof-Puite, Eugènie Dekkers, Annet M. Bosch, Rose E. Maase and Monique G. M. de Sain-van der Velden

Int. J. Neonatal Screen. 2026, 12(1), 1; https://doi.org/10.3390/ijns12010001 - 24 Dec 2025

Abstract

In the Netherlands, the newborn screening (NBS) program includes screening for propionic aciduria (PA) and methylmalonic aciduria (MMA). When initial screening reveals elevated C3 concentrations or abnormal ratios (C3/C2, C3/C16), a second-tier test measuring methylcitric acid (MCA) for PA and methylmalonic acid (MMA [...] Read more.

In the Netherlands, the newborn screening (NBS) program includes screening for propionic aciduria (PA) and methylmalonic aciduria (MMA). When initial screening reveals elevated C3 concentrations or abnormal ratios (C3/C2, C3/C16), a second-tier test measuring methylcitric acid (MCA) for PA and methylmalonic acid (MMA^mb) for MMA is performed. While this two-tier approach reduces false positives effectively, it can delay referral from the NBS program and diagnosis of propionic aciduria. We describe four early-onset PA cases in which the current Dutch screening algorithm negatively impacted clinical outcomes, highlighting the need for expedited referral. We investigated different alternative screening strategies to identify the most effective approach for improving timeliness, while maintaining the high specificity of Dutch PA NBS. This revised approach prioritizes the evaluation of the C3/C2 ratio in first-tier screening. Specifically, samples with a C3/C2 ratio ≥ 0.75 should be referred directly for medical consultation and confirmatory testing. For all other samples with less pronounced biochemical abnormalities, the existing two-tier screening algorithm remains an appropriate NBS protocol. To position our approach internationally, a survey of European NBS programs was conducted to compare screening and referral protocols for PA across the region. Full article

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11 pages, 318 KB

Open AccessArticle

Neonatal Screening for Congenital Adrenal Hyperplasia in Guangzhou: 7 Years of Experience

by Xuefang Jia, Ting Xie, Xiang Jiang, Fang Tang, Minyi Tan, Qianyu Chen, Sichi Liu, Yonglan Huang and Li Tao

Int. J. Neonatal Screen. 2025, 11(4), 116; https://doi.org/10.3390/ijns11040116 - 17 Dec 2025

Abstract

This study was designed to assess the effectiveness of neonatal congenital adrenal hyperplasia (CAH) screening in Guangzhou, China. A total of 818,417 newborns were screened for CAH by measuring 17-hydroxyprogesterone (17-OHP) concentrations. Cut-off values were stratified based on gestational age (GA) and the [...] Read more.

This study was designed to assess the effectiveness of neonatal congenital adrenal hyperplasia (CAH) screening in Guangzhou, China. A total of 818,417 newborns were screened for CAH by measuring 17-hydroxyprogesterone (17-OHP) concentrations. Cut-off values were stratified based on gestational age (GA) and the timing of sample collection. Neonates with initial positive results (17-OHP ≥ cut-off value) were recalled for a second dried blood spot sample to reassess 17-OHP levels. Confirmatory testing involved biochemical analyses, Sanger sequencing, and multiplex ligation-dependent probe amplification of the CYP21A2 gene. From 2018 to 2024, a total of 40 patients with classical 21-hydroxylase deficiency were identified, including 28 cases (70%) of the salt-wasting form and 12 cases (30%) of the simple virilizing form. The overall incidence of CAH was 1 in 20,653 (95% confidence interval: 1:34,928, 1:14,661). No statistically significant differences in prevalence were observed between sexes or between preterm and full-term infants (p > 0.05). 17-OHP concentrations are influenced by GA and the timing of sample collection. The screening efficiency for CAH could be improved by adopting a multitiered cut-off value system adjusted for GA and collection time. Full article

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15 pages, 472 KB

Open AccessArticle

Psychological Impact of Newborn Screening for 3-Methylcrotonyl-CoA Carboxylase Deficiency: The Parental Experience

by Vincenza Gragnaniello, Giacomo Gaiga, Chiara Cazzorla, Elena Porcù, Daniela Gueraldi, Andrea Puma, Christian Loro, Mara Doimo, Leonardo Salviati and Alberto B. Burlina

Int. J. Neonatal Screen. 2025, 11(4), 115; https://doi.org/10.3390/ijns11040115 - 14 Dec 2025

Abstract

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a metabolic disorder with a wide clinical spectrum ranging from asymptomatic individuals to severe metabolic decompensation. Following the introduction of expanded newborn screening, a high number of asymptomatic individuals with 3-MCCD were identified, prompting debates about its inclusion [...] Read more.

3-Methylcrotonyl-CoA carboxylase deficiency (3-MCCD) is a metabolic disorder with a wide clinical spectrum ranging from asymptomatic individuals to severe metabolic decompensation. Following the introduction of expanded newborn screening, a high number of asymptomatic individuals with 3-MCCD were identified, prompting debates about its inclusion in screening panels. In order to inform policy and healthcare decisions regarding the inclusion of 3-MCCD in newborn screening programs, we evaluated the long-term outcomes for newborns with positive results over a decade of screening experience in North-East Italy, as well as the psychological impact on their parents. Of the 336,668 newborns screened between 2014 and 2025, 9 were confirmed to be affected. These infants underwent annual clinical and biochemical assessments, including dried blood spot acylcarnitine profile, plasma free carnitine, and urinary organic acids assays. An emergency protocol was provided to all affected children to manage intercurrent illnesses. An ad hoc survey was developed to assess the psychological impact of the disease on parents. During follow-up (mean age at last visit: 4.2 years), one patient experienced metabolic decompensation during an intercurrent illness, which was promptly treated. One patient presented with growth retardation and another with transient psychomotor delay. Five patients developed carnitine deficiency, requiring supplementation. Psychological assessments revealed an initial high level of parental psychological impact, which decreased over time. All parents strongly supported the screening program. Newborn screening for 3-MCCD enabled the early identification and management of affected individuals, thereby avoiding severe metabolic decompensation. Although there is an initial psychological burden on parents, it significantly decreases over time. Therefore, the long-term benefits of newborn screening for 3-MCCD seem to outweigh the psychological drawbacks. Full article

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31 pages, 2037 KB

Open AccessArticle

A 25-Year Retrospective on Bavaria’s Newborn Screening Programme: Achievements, Challenges and Long-Term Follow-Up

by Uta Nennstiel, Inken Brockow, Birgit Odenwald, Carola Marzi, Marianne Hanauer, Esther Maier, Wulf Röschinger, Ralph Fingerhut and Bernhard Liebl

Int. J. Neonatal Screen. 2025, 11(4), 114; https://doi.org/10.3390/ijns11040114 - 13 Dec 2025

Abstract

The German federal state of Bavaria implemented newborn screening (NBS) using dried blood spots (DBS) as an integrated public health programme with centralised coordination. The Bavarian NBS Centre collaborates with NBS laboratories, obstetric and paediatric facilities, specialised centres of expertise, and parents. It [...] Read more.

The German federal state of Bavaria implemented newborn screening (NBS) using dried blood spots (DBS) as an integrated public health programme with centralised coordination. The Bavarian NBS Centre collaborates with NBS laboratories, obstetric and paediatric facilities, specialised centres of expertise, and parents. It is responsible for coordination, evaluation, quality assurance, and a long-term follow-up study. In this paper, an analysis of NBS in Bavaria from 1999 to 2023 and a long-term follow-up for the birth cohort until 2013 is presented. Of the 2,854,190 babies screened, 2500 were diagnosed and treated early thanks to NBS. An NBS coverage rate of 99.83% was achieved, with 99.09% of all requested repeat tests completed. Around 87% of infants with time-sensitive conditions underwent a clinical intervention within the first 14 days of life. Systematic tracking enabled all but 54 NBS-positive results to be clarified and 122 newborns to be diagnosed in due time. The results of the long-term follow-up study demonstrate that almost all the children identified through NBS receive ongoing medical care, and that NBS has contributed to the age-appropriate development of most affected children. This 25-year evaluation of NBS in Bavaria shows that near-universal participation in NBS and follow-up of almost all positive NBS results can be achieved through centralised coordination and ongoing cooperation of all those involved. Full article

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20 pages, 10141 KB

Open AccessSystematic Review

Incidence of Organic Acid Disorders in 13 Million Chinese Newborns: A Systematic Review and Meta-Analysis

by Shuting Huang, Qiongfang Yao, Fei Kong, Min Wu, Xiaolong Qiu, Peiran Zhao, Yinglin Zeng, Jinying Luo, Liangpu Xu and Jinfu Zhou

Int. J. Neonatal Screen. 2025, 11(4), 113; https://doi.org/10.3390/ijns11040113 - 13 Dec 2025

Abstract

Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, [...] Read more.

Organic acid disorders (OADs) are inherited metabolic defects in the enzymes and cofactors involved in metabolic pathways. This systematic review and meta-analysis investigated the incidence and regional differences in OADs between the northern and southern regions of China. Searches of the PubMed, Embase, Web of Science, and Chinese databases (CNKI, Veipu, and Wanfang) revealed 1784 studies indexed between January 2002 and December 2024. After quality assessment and data extraction, the meta-analysis was conducted on OAD screening data from 57 studies involving 13,314,056 newborns and 1501 OAD cases in China. The seven most prevalent OADs were methylmalonic acidemia (MMA), 3-methylcrotonyl-CoA carboxylase deficiency, glutaric acidemia type I, isobutyryl-CoA dehydrogenase deficiency, isovaleric acidemia, 2-methylbutyryl-CoA dehydrogenase deficiency (2-MBD), and propionic acidemia. The meta-analysis revealed an OAD prevalence of 112.38 (95% confidence interval 106.70–118.07) per 1,000,000 newborns. The incidence of OADs and MMA was significantly higher in northern China than in southern China, whereas the incidence of 2-MBD was significantly lower in northern China than in southern China (p < 0.0001). Additionally, the ratio of MMA combined with homocystinuria to MMA was higher in northern China than in southern China (p < 0.05). These results provide valuable epidemiological insights and guidance for newborn screening for OADs in China. Full article

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11 pages, 209 KB

Open AccessArticle

Expanded Newborn Screening for Inborn Errors of Metabolism at a Single Center in Louisiana (2005–2024): Outcomes

by Jariya Upadia, Grace Noh, Kea Crivelly, Elise Aziz, Amy Cunningham and Hans C. Andersson

Int. J. Neonatal Screen. 2025, 11(4), 112; https://doi.org/10.3390/ijns11040112 - 9 Dec 2025

Abstract

This study evaluates the incidence of metabolic disorders detected from January 2005 to December 2024 and their clinical outcomes. Data were retrospectively collected from the Louisiana Newborn Screening database. Clinical outcomes were obtained through review of corresponding medical records. In addition, an electronic [...] Read more.

This study evaluates the incidence of metabolic disorders detected from January 2005 to December 2024 and their clinical outcomes. Data were retrospectively collected from the Louisiana Newborn Screening database. Clinical outcomes were obtained through review of corresponding medical records. In addition, an electronic questionnaire assessing educational attainment and neurodevelopmental disorders was sent to the patients’ families. Of 1,230,356 infants screened, 478 were diagnosed with metabolic disorders, corresponding to an incidence of 1 in 2574 live births. The three most commonly identified conditions were biotinidase deficiency, phenylketonuria (PKU), and medium-chain acyl-CoA dehydrogenase deficiency (MCADD). During the study period, at least 11 patients died. The program demonstrated a false-positive rate of 0.93%. Twelve patients (7%) were symptomatic before or at the time of NBS result notification. Recurrent metabolic decompensations occurred in 3 of 4 maple syrup urine disease (MSUD) cases, 7 of 7 methylmalonic acidemia (MMA) cases, 1 of 4 propionic acidemia (PA) cases and 1 of 7 urea cycle defect cases. Regarding long-term outcomes, 45.7% of survey respondents reported adverse neurodevelopmental outcomes of varying severity. Early detection and timely intervention have contributed to normal or near-normal outcomes in many cases. However, the morbidity and mortality observed in some patients despite early diagnosis highlights the severity and complexity of certain metabolic conditions. Additionally, the relatively high false positive rate underscores the need for ongoing efforts to improve the specificity of screening protocols to reduce unnecessary follow-ups and mitigate potential stress for families. Full article

2 pages, 120 KB

Open AccessEditorial

A Review of “My Life in Science: The Story of Biotinidase Deficiency” by Dr. Barry Wolf

by Harvey L. Levy

Int. J. Neonatal Screen. 2025, 11(4), 111; https://doi.org/10.3390/ijns11040111 - 4 Dec 2025

Abstract

This book by Dr [...] Full article

9 pages, 211 KB

Open AccessArticle

Genotype Characteristics and Hearing Phenotype Analysis of Newborns with Biallelic GJB2 Mutations: A 652-Case–Cohort Study

by Jianjun Li, Bo Wu and Wenlan Liu

Int. J. Neonatal Screen. 2025, 11(4), 110; https://doi.org/10.3390/ijns11040110 - 3 Dec 2025

Abstract

This study aims to investigate the genotype characteristics of newborns with biallelic GJB2 mutations and their correlation with hearing phenotypes, providing a basis for clinical genetic counseling and hearing management. A retrospective study was conducted on 652 newborns with biallelic GJB2 mutations detected [...] Read more.

This study aims to investigate the genotype characteristics of newborns with biallelic GJB2 mutations and their correlation with hearing phenotypes, providing a basis for clinical genetic counseling and hearing management. A retrospective study was conducted on 652 newborns with biallelic GJB2 mutations detected at the Newborn Diseases Screening Center of Shenzhen Maternal and Child Health Care Hospital from January 2022 to December 2024. The differences in mutation types, hearing screening, and diagnostic results were analyzed and compared between the homozygous and compound heterozygous mutation groups to assess their correlation with hearing phenotypes. Genotype analysis identified 543 cases of homozygous mutations, mainly the c.109G>A/c.109G>A genotype (98.90%). Compound heterozygous mutations were identified in 109 cases, with the majority being c.109G>A/c.235delC (76.15%). Following two-stage hearing screening, 227 (34.82%) of the 652 cases were referred, with bilateral failure accounting for the majority (81.94%) of these cases. The referral rates showed no significant difference between the homozygous (35.54%) and compound heterozygous (31.19%) groups (p > 0.05). The overall hearing loss detection rate was 6.90% (45/652); among these, eight infants who had initially passed the newborn hearing screening were later found to have hearing loss between 2.5 and 6 months of age. Among the 45 confirmed deaf children, hearing loss was mainly mild to moderate (87.50%), and profound deafness was only seen in the homozygous mutation group (10.29%, 7/68 ears). Most newborns with biallelic GJB2 mutations passed the two-stage hearing screening, and associated hearing loss was typically mild to moderate. Long-term auditory monitoring remains essential for all genetically confirmed infants to monitor late-onset progression. Full article

11 pages, 645 KB

Open AccessArticle

A Nationwide Survey Investigating the Current Status of Genetic Counseling in Newborn Screening in Japan

by Eri Sakai, Takahiro Yamada, Takashi Hamazaki, Go Tajima and Toshiyuki Seto

Int. J. Neonatal Screen. 2025, 11(4), 109; https://doi.org/10.3390/ijns11040109 - 28 Nov 2025

Abstract

Following Newborn Screening (NBS), parents receiving positive results experience various psychosocial effects upon learning their child’s genetic information or unexpected findings. These factors warrant careful consideration. The Japanese Medical Association’s Guidelines for Genetic Testing and Diagnosis in Medical Care highlight the importance of [...] Read more.

Following Newborn Screening (NBS), parents receiving positive results experience various psychosocial effects upon learning their child’s genetic information or unexpected findings. These factors warrant careful consideration. The Japanese Medical Association’s Guidelines for Genetic Testing and Diagnosis in Medical Care highlight the importance of genetic counseling (GC) in NBS; however, its current implementation status remains unclear. This study aimed to determine current approaches to GC following positive NBS results in Japan. A questionnaire was conducted with pediatric metabolic specialists responsible for treating individuals who screen positive through NBS results to evaluate GC implementation and their views on its provision. GC was provided at most referral centers for NBS (although not routinely at approximately half of the facilities). In over 70% of cases, GC was performed by a metabolic specialist, regardless of clinical geneticist certification. Furthermore, some metabolic specialists may be reluctant to provide GC due to limited understanding or time constraints. Raising awareness that all parents are eligible for GC, regardless of their child’s diagnosis or health status, is essential. In addition, a GC system incorporating multidisciplinary and multidepartmental collaboration is important for the multifaceted support of patients and families. Full article

(This article belongs to the Collection Newborn Screening in Japan)

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14 pages, 1598 KB

Open AccessArticle

Progress of the Egyptian National Newborn Hearing Screening (ENHS) Program over a Four-Year Period

by Eman Abdelbadei, Ahmed Mustafa, Abir Omara, Wafaa Shehata-Dieler and Mohamed Hassany

Int. J. Neonatal Screen. 2025, 11(4), 108; https://doi.org/10.3390/ijns11040108 - 18 Nov 2025

Abstract

Universal newborn hearing screening (UNHS) has become widely adopted worldwide as a standard of care for the early detection of congenital hearing loss. The Egyptian UNHS program started as a presidential initiative by the Ministry of Health in November 2019. The program was [...] Read more.

Universal newborn hearing screening (UNHS) has become widely adopted worldwide as a standard of care for the early detection of congenital hearing loss. The Egyptian UNHS program started as a presidential initiative by the Ministry of Health in November 2019. The program was initiated in 1346 primary health care units (PHCUs) located throughout the 26 governorates. A retrospective study was conducted to assess the performance of the Egyptian Program during the period from November 2019 to July 2023. Quality measures recommended by the Joint Committee on Infant Hearing including coverage rate, rate of referral to a second screening, follow up rate of attendance of second screening, referral for diagnosis rate, and follow up rate of attendance of diagnostic assessment, were analyzed. Over a period of 3 years and 9 months, more than five and half million infants underwent a first screening. The coverage rate was initially 39% and increased to reach 82% in 2023. The rate of referral to a second screen was 7.2% in 2019 and reached 5.2% in 2023. The follow-up rate of attendance of a second screening improved throughout the study period, from 75.5% to 92.1% but did not reach the benchmark of 95%. The rate of referrals for diagnosis was less than 1.7% and rate of attendance of a diagnostic assessment was initially 20% and improved to more than 65% in 2023. The very low rate of attendance of diagnostic assessment in 2020 and 2021 was attributed to the effects of the COVID pandemic. Full article

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13 pages, 1114 KB

Open AccessArticle

Cord Blood-Based Neonatal Screening for Hemoglobinopathies in Northern Tunisia

by Houyem Ouragini, Nizar Ben Halim, Sana Zitouni, Dorra Chaouachi, Imen Boudrigua, Naima Saidani, Imen Kraiem, Amira Ayachi, Salem Abbes, Mechaal Mourali and Samia Menif

Int. J. Neonatal Screen. 2025, 11(4), 107; https://doi.org/10.3390/ijns11040107 - 14 Nov 2025

Abstract

Hemoglobinopathies represent a major public health concern in Tunisia. Although early diagnosis is essential, systemic neonatal screening has not yet been implemented at the national level. We conducted a screening study in Northern Tunisia (Bizerte region) using cord blood samples. Complete blood counts [...] Read more.

Hemoglobinopathies represent a major public health concern in Tunisia. Although early diagnosis is essential, systemic neonatal screening has not yet been implemented at the national level. We conducted a screening study in Northern Tunisia (Bizerte region) using cord blood samples. Complete blood counts and hemoglobin analysis by capillary electrophoresis were performed. Samples showing abnormal profiles (HbBart’s, HbS, HbC, or HbA < 20%) underwent molecular testing. Correlations between hematological parameters, hemoglobin fractions, and β mutation types were assessed. Among 328 neonatal cord blood samples analyzed, we detected 3 silent α⁺-thalassemia, 6 β⁺-thalassemia traits, 3 β⁰-thalassemia traits, 7 HbS traits, 2 HbC traits, and 1 compound heterozygous for α⁺-thalassemia/HbC. No homozygous cases were identified. The heterozygous frequency was estimated at 1.2%, 2.7%, and 2.1% for α-thalassemia, β-thalassemia, and sickle cell disease, respectively. HbF levels were significantly associated with the β-thalassemia trait. This study represents the first hemoglobinopathy screening in Northern Tunisia using cord blood, highlighting the feasibility and reliability of this approach. While pilot programs have already been initiated in some regions, our findings reinforce the need for broader implementation to ensure early and accurate diagnosis across the country. Full article

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16 pages, 693 KB

Open AccessReview

Implementation Timeframes for the Addition of New Conditions to Newborn Bloodspot Screening Programmes: A Scoping Review

by Margaret M. Brennan, Aoife O’Connell, Loretta O’Grady, Mohamed Elsammak, Jennifer J. Brady, Paul Marsden, Heather Burns and Abigail Collins

Int. J. Neonatal Screen. 2025, 11(4), 106; https://doi.org/10.3390/ijns11040106 - 14 Nov 2025

Abstract

Severe combined immunodeficiency (SCID) and spinal muscular atrophy (SMA) are being added to the Newborn Bloodspot Screening (NBS) programme in the Republic of Ireland. To support this expansion, we conducted a scoping review to identify reported timeframes for implementing national, regional or state-wide [...] Read more.

Severe combined immunodeficiency (SCID) and spinal muscular atrophy (SMA) are being added to the Newborn Bloodspot Screening (NBS) programme in the Republic of Ireland. To support this expansion, we conducted a scoping review to identify reported timeframes for implementing national, regional or state-wide expanded NBS programmes. We performed a scoping review of the literature published between 2015 and 2025. Eligible articles described the timeframes for implementation of expanded NBS programmes for SCID, SMA or additional metabolic conditions. Sources included PubMed, Embase, citation searching, the International Journal of Neonatal Screening and grey literature. A narrative synthesis was undertaken. Fourteen articles met the inclusion criteria, describing the addition of new conditions—SCID (N = 7), SMA (N = 4), or multiple conditions (N = 3) to expanded NBS programmes in the United States (US), Europe (Belgium, Catalonia, the Czech Republic, Estonia, Germany, Norway, Poland, Portugal, Slovakia, Slovenia, Sweden, and Tuscany), Hong Kong and New Zealand. In most jurisdictions, the implementation of NBS programmes for new conditions took two to six years. The implementation of NBS for new conditions requires considerable time and coordinated efforts. Further research providing greater detail on the specific implementation steps, along with associated timelines, would provide valuable guidance for jurisdictions aiming to expand NBS programmes globally. Full article

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9 pages, 420 KB

Open AccessCommentary

Universal Decentralized Cord Blood TSH Screening Should Be Offered as Routine Delivery Care in Limited-Resource Settings

by Nitash Zwaveling-Soonawala, Anju Virmani, Aman B. Pulungan, Joseph Haddad, Sirisha Kusuma Boddu, Feyza Darendeliler and A. S. Paul van Trotsenburg

Int. J. Neonatal Screen. 2025, 11(4), 105; https://doi.org/10.3390/ijns11040105 - 14 Nov 2025

Abstract

Newborn screening (NBS) for congenital hypothyroidism (CH) facilitates early diagnosis and treatment and prevents permanent intellectual disability. Sadly, 50 years after the first introduction of NBS for CH, only 29.6% of newborns worldwide are screened. Africa and Asia, the continents with the highest [...] Read more.

Newborn screening (NBS) for congenital hypothyroidism (CH) facilitates early diagnosis and treatment and prevents permanent intellectual disability. Sadly, 50 years after the first introduction of NBS for CH, only 29.6% of newborns worldwide are screened. Africa and Asia, the continents with the highest birth rates, have very limited screening coverage. Most NBS programs measure TSH in a dried-blood spot taken from a heel-prick on a filter paper after 24 to 72 h of life. Implementing national NBS programs is logistically complex and expensive, requiring parental consent, specialized laboratories, and excellent infrastructure. In limited-resource settings, introducing such a complex program is often impossible. We propose universal decentralized cord blood TSH screening, offered as routine delivery care for all newborns in limited-resource settings. TSH measurement may be performed by local laboratories using widely available, inexpensive radioimmunoassay kits, with the report available within a few hours. Since the TSH report would be available before discharge, suitable clinical decision making would be possible, with a minimal need for recall, thus minimizing the parental, medical, and financial burden and improving developmental outcomes. The most important requirement is to change to a grassroots approach, with the education of obstetricians and pediatricians worldwide to perform routine cord blood TSH and make sure the TSH result is available before the baby is discharged. Full article

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19 pages, 1678 KB

Open AccessReview

Multiplexable, High-Throughput DNA-Based Technologies in Screening and Confirmatory Testing of Newborn Conditions: A Scoping Review

by Terence Diane Fabella, Joery den Hoed, Lidewij Henneman, Wendy Rodenburg, Johannes C. F. Ket, Jan Schouten and Erik A. Sistermans

Int. J. Neonatal Screen. 2025, 11(4), 104; https://doi.org/10.3390/ijns11040104 - 13 Nov 2025

Abstract

Newborn screening (NBS) is evolving as novel technologies offer the opportunities to include a broader range of treatable disorders in its programs. Multiplexable, high-throughput DNA-based technologies such as next-generation sequencing (NGS) are being explored to improve and expand disease detection, although several issues [...] Read more.

Newborn screening (NBS) is evolving as novel technologies offer the opportunities to include a broader range of treatable disorders in its programs. Multiplexable, high-throughput DNA-based technologies such as next-generation sequencing (NGS) are being explored to improve and expand disease detection, although several issues have been raised with its use. This scoping review aimed to identify multiplexable, high-throughput, DNA-based technologies that were used for screening or confirmatory testing of newborn disorders in published studies. Available evidence on the appropriateness of technologies in the NBS context was extracted. A literature search (Medline, Embase, and Web of Science) was performed from inception up to April 2024 in collaboration with a medical information specialist. After selection, 26 journal articles were included that used these technologies for either screening (n = 12) or confirmatory testing (n = 14). Five technologies were identified: whole-genome sequencing, whole-exome sequencing, targeted gene sequencing (TGS), quantitative polymerase chain reaction, and MassARRAY. The majority used TGS (n = 19, 73.08%). The data extracted concern mainly technical aspects, and these suggest that a combined approach, i.e., testing via NGS plus a biochemical test, in parallel or reflex, emerges as the optimal option. Ethical and economic evidence is limited and rarely reported in the reviewed articles. Full article

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28 pages, 1496 KB

Open AccessSystematic Review

Newborn Screening for Metachromatic Leukodystrophy: A Systematic Literature Review

by Lucia Laugwitz, Andrew Shenker, Erica F. Sluys, Stéphane Pintat, David Whiteman and Charlotte Chanson

Int. J. Neonatal Screen. 2025, 11(4), 103; https://doi.org/10.3390/ijns11040103 - 5 Nov 2025

Abstract

A systematic literature review was conducted to evaluate the emerging evidence on newborn screening (NBS) for metachromatic leukodystrophy (MLD; MIM #250100). The review focuses on (1) screening assay performance, (2) diagnostic confirmation methods and care pathways, (3) feasibility of population-based identification, and (4) [...] Read more.

A systematic literature review was conducted to evaluate the emerging evidence on newborn screening (NBS) for metachromatic leukodystrophy (MLD; MIM #250100). The review focuses on (1) screening assay performance, (2) diagnostic confirmation methods and care pathways, (3) feasibility of population-based identification, and (4) the impact of early diagnosis and treatment on health outcomes. Electronic databases were searched in February 2025, and supplementary searches were performed up to 17 June 2025, for articles referencing NBS for MLD and treatments for MLD; 52 publications were eligible for inclusion. Nationwide NBS for MLD is currently carried out in Norway and large prospective pilots are running in Germany, Austria, Italy and the US. MLD meets established Wilson and Jungner criteria, with a reliable screening algorithm, established confirmatory diagnostics, and actionable care pathways. There is ongoing work to develop tools to predict disease severity and subtype. Early intervention—via gene therapy for early-onset MLD and hematopoietic stem cell transplantation (HSCT) for late-onset forms—significantly improves outcomes when initiated before symptom onset. This review provides the first comprehensive synthesis of the evidence supporting MLD for inclusion in NBS programs, underscoring the public health value of early identification and intervention. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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4 pages, 183 KB

Open AccessComment

Treating Presymptomatic Spinal Muscular Atrophy Patients with Onasemnogene Abeparvovec in Italy: The Role of the National Health System and Drug Supply. Comment on Zaidman et al. Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States. Int. J. Neonatal Screen. 2024, 10, 58

by Riccardo Masson, Serena Gaballo, Raffaella Caravita and Stefano Parravicini

Int. J. Neonatal Screen. 2025, 11(4), 102; https://doi.org/10.3390/ijns11040102 - 31 Oct 2025

Abstract

We read with interest the recent study by Zaidman et al [...] Full article

22 pages, 539 KB

Open AccessArticle

A Qualitative Study on Parental Experiences with Genetic Counseling After a Positive Newborn Screen for Recently Added Conditions on the Recommended Uniform Screening Panel (RUSP)

by Macie Hricovec, Amy Gaviglio, Christina Mealwitz, Michelle Merrill and Aaron J. Goldenberg

Int. J. Neonatal Screen. 2025, 11(4), 101; https://doi.org/10.3390/ijns11040101 - 30 Oct 2025

Abstract

The goal of newborn screening (NBS) has remained the same despite its significant expansion from its inception as a public health initiative. This goal is to identify infants that are at risk for a set list of conditions and to implement a care [...] Read more.

The goal of newborn screening (NBS) has remained the same despite its significant expansion from its inception as a public health initiative. This goal is to identify infants that are at risk for a set list of conditions and to implement a care plan to prevent, delay, or mitigate adverse health outcomes for those affected. The role of genetic counselors (GCs) in the NBS space is currently evolving, and there is limited research on parental experiences with genetic counseling for more recently added conditions on a list approved by the U.S. Secretary of Health and Human Services called the Recommended Uniform Screening Panel (RUSP). This qualitative study interviewed parents who have spoken to a genetic counselor after their child was diagnosed with one of three following conditions in the past five years: Pompe disease, X-linked Adrenoleukodystrophy, and Spinal Muscular Atrophy. A total of 13 interviews were conducted and results were organized into five thematic areas: (1) NBS/Results Disclosure, (2) Diagnostic Process after NBS, (3) Treatment/Follow-Up, (4) Communication, and (5) Holistic Support. The findings of this study highlighted parental preferences for early involvement of genetic counselors, provider, and parent education on NBS, and the provision of family support beyond genetic resources. Full article

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10 pages, 1480 KB

Open AccessBrief Report

Reclassifying IDUA c.250G>A (p.Gly84Ser): Evidence for a Possible Pseudodeficiency Allele

by Christopher Connolly, Rachel Fisher, Chen Yang, Susan Schelley, Bryce A. Mendelsohn, Chung Lee and Ayesha Ahmad

Int. J. Neonatal Screen. 2025, 11(4), 100; https://doi.org/10.3390/ijns11040100 - 27 Oct 2025

Abstract

Accurate variant classification is crucial for newborn screening (NBS) to prevent missed diagnoses or unnecessary interventions. The IDUA gene variant denoted as c.250G>A (p.Gly84Ser) has been identified in individuals with positive NBS for Mucopolysaccharidosis Type I (MPS I). This variant has conflicting pathogenicity [...] Read more.

Accurate variant classification is crucial for newborn screening (NBS) to prevent missed diagnoses or unnecessary interventions. The IDUA gene variant denoted as c.250G>A (p.Gly84Ser) has been identified in individuals with positive NBS for Mucopolysaccharidosis Type I (MPS I). This variant has conflicting pathogenicity reports including one publication classifying this variant as associated with a severe MPS I phenotype; therefore, we aim to clarify the clinical significance of this variant by presenting a case series describing three individuals, each homozygous for c.250G>A (p.Gly84Ser), identified in Michigan and California. All patients in this case series had low alpha-iduronidase (IDUA) enzyme activity with normal or mildly elevated glycosaminoglycans (GAGs) in blood or urine not falling into the range or pattern seen for affected individuals. None of these patients have developed clinical features of MPS I during follow-up ranging up to 3.5 years of age. Review of functional and population data supports a pseudodeficiency effect, resulting in no need for treatment. Based on our experience with three patients all homozygous for c.250G>A (p.Gly84Ser), despite causing low in vitro IDUA activity, homozygosity for the IDUA gene variant denoted as c.250G>A (p.Gly84Ser), does not cause symptoms of MPS I and may represent a pseudodeficiency allele. Caution should be exercised in newborns with this variant to help reduce unnecessary interventions and alleviate the psychosocial and economic consequences of false-positive NBS results, particularly for the South Asian population. Full article

(This article belongs to the Special Issue Advances in Newborn Screening for Lysosomal Disorders: From Laboratory Screening to Diagnosis)

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Open AccessReview

Celebrating 50 Years of Nationwide Newborn Screening in Hungary—Review, Current Situation, and Future Directions

by Péter Monostori, Ildikó Szatmári, Ákos Baráth, János Bókay, Marianna Csenki, Zsolt Galla, Balázs Gellén, Nóra Grecsó, Eszter Gyüre, Zita Halász, Krisztina Hegedűs, Judit Kincs, Erika Kiss, Magdolna Kósa, István Lénárt, Andrea Pálmay, Gábor Rácz, Hajnalka Szabó, Léna Szabó, Viktória Tőkési, Andrea Xue, Petra Zsidegh, Attila József Szabó and Csaba Bereczki Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(4), 99; https://doi.org/10.3390/ijns11040099 - 27 Oct 2025

Abstract

Newborn screening (NBS), one of the most important public health care prevention programs, aims at the early identification of asymptomatic newborns at increased risk for inherited disorders, facilitating timely intervention to reduce morbidity and mortality. NBS in Hungary is celebrating the 50th anniversary [...] Read more.

Newborn screening (NBS), one of the most important public health care prevention programs, aims at the early identification of asymptomatic newborns at increased risk for inherited disorders, facilitating timely intervention to reduce morbidity and mortality. NBS in Hungary is celebrating the 50th anniversary of the nationwide implementation of screening for phenylketonuria and galactosemia, as well as the 40th anniversary of congenital hypothyroidism screening. The present paper reviews the early years, the present situation, and future perspectives for the Hungarian NBS program. Today, screening for 27 disorders (opt-out) plus spinal muscular atrophy (opt-in) is supported by two centralized and well-equipped laboratories in Budapest and Szeged, in-depth laboratory knowledge, a robust follow-up system, and governmental financial support. Since 1975, 3,289 patients have been confirmed with a screened condition from over 5.6 million newborns screened. The 50-year anniversary of the Hungarian NBS program highlights the dedication of both past and current professionals, ongoing advancements in analytical methods and laboratory information management systems, and alignment with international standards. The equitable provision of screening services continues to be prioritized for all newborns nationwide and within the broader Euro-regional context. Full article

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International Journal of Neonatal Screening

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