International Journal of Neonatal Screening

12 pages, 366 KiB

Open AccessArticle

Exceptionally High Cystic Fibrosis-Related Morbidity and Mortality in Infants and Young Children in India: The Need for Newborn Screening and CF-Specific Capacity Building

by Priyanka Medhi, Grace R. Paul, Madhan Kumar, Grace Rebekah, Philip M. Farrell, Jolly Chandran, Rekha Aaron, Aaron Chapla and Sneha D. Varkki

Int. J. Neonatal Screen. 2025, 11(3), 67; https://doi.org/10.3390/ijns11030067 - 22 Aug 2025

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

8 pages, 279 KiB

Open AccessCase Report

MCT8 Deficiency in Infancy: Opportunities for Early Diagnosis and Screening

by Ilja Dubinski, Belana Debor, Sofia Petrova, Katharina A. Schiergens, Heike Weigand and Heinrich Schmidt

Int. J. Neonatal Screen. 2025, 11(3), 66; https://doi.org/10.3390/ijns11030066 - 21 Aug 2025

Abstract

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 [...] Read more.

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. Full article

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12 pages, 268 KiB

Open AccessReview

Is It Time to Expand Newborn Screening for Congenital Hypothyroidism to Other Rare Thyroid Diseases?

by Antonella Olivieri, Maria Cristina Vigone, Mariacarolina Salerno and Luca Persani

Int. J. Neonatal Screen. 2025, 11(3), 65; https://doi.org/10.3390/ijns11030065 - 20 Aug 2025

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Newborn Screening for Congenital Hypothyroidism)

15 pages, 4045 KiB

Open AccessArticle

Newborn Screening Program for Spinal Muscular Atrophy in the Campania Region (Italy): Current Limitations and Potential Perspectives

by Adelaide Ambrosio, Tiziana Fioretti, Barbara D’Andrea, Lucia Pezone, Ilaria Bitetti, Carmela Di Domenico, Sabrina Vallone, Valeria Maiolo, Angela Cioce, Mariano Giustino, Antonio Varone and Gabriella Esposito

Int. J. Neonatal Screen. 2025, 11(3), 64; https://doi.org/10.3390/ijns11030064 - 17 Aug 2025

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Abstract

Three targeted therapies are currently available for spinal muscular atrophy (SMA), which have dramatically changed the natural history of this severe and potentially fatal disease. More than 95% of SMA cases have a homozygous deletion of exon 7 of the SMN1 gene. Disease [...] Read more.

Three targeted therapies are currently available for spinal muscular atrophy (SMA), which have dramatically changed the natural history of this severe and potentially fatal disease. More than 95% of SMA cases have a homozygous deletion of exon 7 of the SMN1 gene. Disease expression mainly depends on the copy number of SMN2, a hypomorphic copy of SMN1. Many countries in the world have implemented newborn screening (NBS) programs for early identification and treatment of children with SMA. We herein present the first two-year results of the SMA NBS program in Campania, a region with one of the highest birth rates in Italy. Genomic DNA was extracted from dried blood spots (DBS) and peripheral blood. For DBS, the SMN1 gene copy number was evaluated by quantitative polymerase chain reaction (qPCR) targeting SMN1 exon 7 and a reference gene (RPP30). In positive newborns and their parents, SMN1/SMN2 copies were evaluated by multiplex ligation probe amplification (MLPA). We analyzed 77,945 newborns and identified 11 positive children. Six patients had 2 copies of SMN2, but only one showed severe SMA-related signs at birth. Eligible newborns were treated with gene therapy within 20 days of birth. Notably, qPCR failed to amplify the reference RPP30 gene in 10/77,945 DBS. Despite this limitation, we observed that about 1/40 DBS had ΔCt values consistent with the presence of one SMN1 copy. The semi-automated procedure used for SMA NBS showed excellent performance in detecting the presence of homozygous deletion of SMN1 exon 7, with the exception of a few cases with the absence of amplification of the reference gene. By solving this limitation, the screening procedure has the potential to detect heterozygous carriers of the SMN1 deletion and, consequently, identify families at procreative risk of SMA. Full article

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12 pages, 1071 KiB

Open AccessArticle

Seasonal Fluctuations and Stability of Adenosine in Dried Blood Spots for Neonatal Screening

by Xiangchun Yang, Jing Liu, Xia Li, Dongyang Hong, Shanshan Wu, Changshui Chen and Haibo Li

Int. J. Neonatal Screen. 2025, 11(3), 63; https://doi.org/10.3390/ijns11030063 - 13 Aug 2025

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Abstract

Seasonal and environmental factors, including temperature, humidity, and storage conditions, significantly impact the stability of biochemical markers in dried blood spot (DBS) samples. This study investigates these influences specifically for adenosine (ADO) levels, a critical biomarker for neonatal screening of adenosine deaminase (ADA) [...] Read more.

Seasonal and environmental factors, including temperature, humidity, and storage conditions, significantly impact the stability of biochemical markers in dried blood spot (DBS) samples. This study investigates these influences specifically for adenosine (ADO) levels, a critical biomarker for neonatal screening of adenosine deaminase (ADA) deficiency. This study analyzed seasonal fluctuations in ADO concentrations across three regions in China (Ningbo, Nanjing, and Changsha) over 11 months, and evaluated ADO stability under different storage conditions (4 °C, 20 °C, and 40 °C). ADO levels demonstrated significant seasonal variability, peaking in July–August. Median concentrations increased by 111–189% in warmer months compared to winter across all sites. Storage experiments showed that ADO was most stable at 4 °C (fluctuations < 5% over 7 days), while levels at 40 °C increased by 18%. Re-adjusting the ADO reference range based on seasonal data reduced false positive rates from 2.48% to 0.15%, a 94% reduction. This study underscores the necessity of implementing seasonally dynamic reference ranges and strict cold-chain storage (4 °C) to enhance screening accuracy for ADA deficiency. The findings provide a robust foundation for optimizing neonatal screening protocols globally, especially in regions with distinct seasonal climates. Full article

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12 pages, 234 KiB

Open AccessArticle

Communication of an Abnormal Metabolic Newborn Screening Result in the Netherlands: A Qualitative Exploratory Study of the General Practitioner’s Perspective

by Sietske Haitjema, Charlotte M. A. Lubout, Justine H. M. Zijlstra, Rendelien K. Verschoof-Puite and Francjan J. van Spronsen

Int. J. Neonatal Screen. 2025, 11(3), 62; https://doi.org/10.3390/ijns11030062 - 8 Aug 2025

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Abstract

Newborn screening (NBS) for inherited metabolic diseases (IMD) aims to find children in which immediate action can prevent severe symptoms. We previously studied parental satisfaction with the communication of the NBS result for phenylketonuria, which in the Netherlands is done by the general [...] Read more.

Newborn screening (NBS) for inherited metabolic diseases (IMD) aims to find children in which immediate action can prevent severe symptoms. We previously studied parental satisfaction with the communication of the NBS result for phenylketonuria, which in the Netherlands is done by the general practitioners (GPs). More than half of all parents were unsatisfied with the communication of the abnormal NBS result. The aim of this qualitative exploratory study was to portray a number of GPs’ opinions and experiences in communicating an abnormal metabolic NBS result. We performed semi-structured interviews with ten GPs to evaluate the process of communicating the abnormal NBS result. An additional two GPs provided their answers via email. The data revealed four key themes: (1) dealing with the urgency of the metabolic NBS result, (2) the role of the GP in the NBS process, (3) the current organization of NBS in the Netherlands and (4) evaluating roles and responsibilities in communicating abnormal metabolic NBS results. Despite the willingness of GPs to inform parents about NBS results, it is questionable whether they have the necessary tools to effectively conduct these conversations given their limited experience with IMDs. In light of the increasing number of diseases in the NBS program, it would be interesting to explore alternative tools for communicating the NBS result to parents. Full article

11 pages, 746 KiB

Open AccessArticle

Prediction of Congenital Portosystemic Shunt in Neonatal Hypergalactosemia Using Gal-1-P/Gal Ratio, Bile Acid, and Ammonia

by Sayaka Suzuki-Ajihara, Ikuma Musha, Masato Arao, Koki Mori, Shunsuke Fujibayashi, Ihiro Ryo, Tomotaka Kono, Asako Tajima, Hiroshi Mochizuki, Atsuko Imai-Okazaki, Ryuichiro Araki, Chikahiko Numakura and Akira Ohtake

Int. J. Neonatal Screen. 2025, 11(3), 61; https://doi.org/10.3390/ijns11030061 - 7 Aug 2025

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Abstract

Congenital portosystemic shunts (CPSSs) are often associated with life-threatening systemic complications, which may be detected by identifying hypergalactosemia in newborn screening (NBS). However, diagnosing CPSS at an early stage is not easy. The purpose of this study was to predict CPSS early using [...] Read more.

Congenital portosystemic shunts (CPSSs) are often associated with life-threatening systemic complications, which may be detected by identifying hypergalactosemia in newborn screening (NBS). However, diagnosing CPSS at an early stage is not easy. The purpose of this study was to predict CPSS early using screening values and general blood tests. The medical records of 153 patients with hypergalactosemia who underwent NBS in Saitama Prefecture between 1 December 1997 and 31 October 2023 were retrospectively analyzed. We provided the final diagnosis of the analyzed patients. Of the 153 patients, 44 (29%) were in the CPSS group and 83 (54%) were in the transient galactosemia group. Using the initial screening items and the six blood test items, we attempted to extract a CPSS group from the transient galactosemia group. Finally, a model for CPSS prediction was established. From multiple logistic regression analysis, filtered blood galactose-1 phosphate/galactose, serum total bile acid, and ammonia were adopted as explanatory variables for the prediction model. If the cut-off value for predicted disease probability value (P) was >0.357, CPSS was identified with 86.4% sensitivity (95%CI 72.6–94.8%) and 81.9% specificity (95%CI 72.0–89.5%). This predictive model might allow prediction of CPSS and early intervention. Full article

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

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15 pages, 1371 KiB

Open AccessSystematic Review

Refining CFTR-Related Metabolic Syndrome (CRMS)/Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) Diagnosis: Impact of CFTR2 Variant Classifications

by MacKenzie Wyatt, Alexandra Quinn, Lincoln Shade and Meghan McGarry

Int. J. Neonatal Screen. 2025, 11(3), 60; https://doi.org/10.3390/ijns11030060 - 30 Jul 2025

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Abstract

An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS who do not meet the diagnostic criteria for CF (two CF-causing variants and/or sweat chloride > 60 mmol/L). This indeterminate diagnosis is called cystic [...] Read more.

An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS who do not meet the diagnostic criteria for CF (two CF-causing variants and/or sweat chloride > 60 mmol/L). This indeterminate diagnosis is called cystic fibrosis transmembrane conductance regulator (CFTR)-related metabolic syndrome (CRMS) or CF screen positive, inconclusive diagnosis (CFSPID). CRMS/CFSPID occurs when it is not clearly known whether CFTR variants are disease-causing. In 2024, the CFTR2 classification of many CFTR variants was changed from unknown significance to either CF-causing variants or variants of varying clinical consequences (VVCCs). We conducted a meta-analysis of CRMS/CFSPID cases from manuscripts to describe how the diagnoses would change using two different variant panels: (1) only CF-causing CFTR variants (Panel_CF-causing) and (2) CF-causing variants and VVCCs (Panel_{CF-causing+VVCCs}). Using the Panel_CF-causing, 8.7% had two CF-causing variants (reclassified as CF), while 91.3% had less than two CF-causing variants (reclassified as Undetected). Using the Panel_{CF-causing+VVCCs}, 51.4% had either two VVCCs or one VVCC with one CF-causing variant detected (reclassified as CRMS/CFSPD), 39.9% had less than two CF-causing variants detected (reclassified as Undetected), and 8.7% had two CF-causing variants (reclassified as CF). In conclusion, using the updated CFTR2 classification of CFTR variants significantly decreases the number of children with CRMS/CFSPID and gives a definitive diagnosis of CF to some children while not detecting as many children who are unlikely to develop CF. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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14 pages, 882 KiB

Open AccessArticle

Advancing Neonatal Screening for Pyridoxine-Dependent Epilepsy-ALDH7A1 Through Combined Analysis of 2-OPP, 6-Oxo-Pipecolate and Pipecolate in a Butylated FIA-MS/MS Workflow

by Mylène Donge, Sandrine Marie, Amandine Pochet, Lionel Marcelis, Geraldine Luis, François Boemer, Clément Prouteau, Samir Mesli, Matthias Cuykx, Thao Nguyen-Khoa, David Guénet, Aurélie Empain, Magalie Barth, Benjamin Dauriat, Cécile Laroche-Raynaud, Corinne De Laet, Patrick Verloo, An I. Jonckheere, Manuel Schiff, Marie-Cécile Nassogne and Joseph P. Dewulf Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(3), 59; https://doi.org/10.3390/ijns11030059 - 30 Jul 2025

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Abstract

Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with [...] Read more.

Pyridoxine-dependent epilepsy (PDE) represents a group of rare developmental and epileptic encephalopathies. The most common PDE is caused by biallelic pathogenic variants in ALDH7A1 (PDE-ALDH7A1; OMIM #266100), which encodes α-aminoadipate semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine catabolism. Affected individuals present with seizures unresponsive to conventional anticonvulsant medications but responsive to high-dose of pyridoxine (vitamin B6). Adjunctive lysine restriction and arginine supplementation have also shown potential in improving neurodevelopmental outcomes. Given the significant benefit of early intervention, PDE-ALDH7A1 is a strong candidate for newborn screening (NBS). However, traditional biomarkers are biochemically unstable at room temperature (α-AASA and piperideine-6-carboxylate) or lack sufficient specificity (pipecolate), limiting their utility for biomarker-based NBS. The recent identification of two novel and stable biomarkers, 2S,6S-/2S,6R-oxopropylpiperidine-2-carboxylate (2-OPP) and 6-oxo-pipecolate (oxo-PIP), offers renewed potential for biochemical NBS. We evaluated the feasibility of incorporating 2-OPP, oxo-PIP, and pipecolate into routine butylated FIA-MS/MS workflows used for biochemical NBS. A total of 9402 dried blood spots (DBS), including nine confirmed PDE-ALDH7A1 patients and 9393 anonymized controls were analyzed using a single multiplex assay. 2-OPP emerged as the most sensitive biomarker, identifying all PDE-ALDH7A1 patients with 100% sensitivity and a positive predictive value (PPV) of 18.4% using a threshold above the 99.5th percentile. Combining elevated 2-OPP (above the 99.5th percentile) with either pipecolate or oxo-PIP (above the 85.0th percentile) as secondary marker detected within the same multiplex FIA-MS/MS assay further improved the PPVs to 60% and 45%, respectively, while maintaining compatibility with butanol-derivatized method. Notably, increasing the 2-OPP threshold above the 99.89th percentile, in combination with either pipecolate or oxo-PIP above the 85.0th percentile resulted in both 100% sensitivity and 100% PPV. This study supports the strong potential of 2-OPP-based neonatal screening for PDE-ALDH7A1 within existing NBS infrastructures. The ability to multiplex 2-OPP, pipecolate and oxo-PIP within a single assay offers a robust, practical, high-throughput and cost-effective approach. These results support the inclusion of PDE-ALDH7A1 in existing biochemical NBS panels. Further prospective studies in larger cohorts are needed to refine cutoffs and confirm clinical performance. Full article

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10 pages, 1202 KiB

Open AccessArticle

Incidence of Congenital Hypothyroidism Is Increasing in Chile

by Francisca Grob, Gabriel Cavada, Gabriel Lobo, Susana Valdebenito, Maria Virginia Perez and Gilda Donoso

Int. J. Neonatal Screen. 2025, 11(3), 58; https://doi.org/10.3390/ijns11030058 - 26 Jul 2025

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Abstract

Congenital hypothyroidism (CH) is a leading preventable cause of neurocognitive impairment. Its incidence appears to be rising in several countries. We analysed 27 years of newborn-screening data (1997–2023) from the largest Chilean screening centre, covering 3,225,216 newborns (51.1% of national births), to characterise [...] Read more.

Congenital hypothyroidism (CH) is a leading preventable cause of neurocognitive impairment. Its incidence appears to be rising in several countries. We analysed 27 years of newborn-screening data (1997–2023) from the largest Chilean screening centre, covering 3,225,216 newborns (51.1% of national births), to characterise temporal trends and potential drivers of CH incidence. Annual CH incidence was modelled with Prais–Winsten regression to correct for first-order autocorrelation; additional models assessed trends in gestational age, sex, biochemical markers, and aetiological subtypes. We identified 1550 CH cases, giving a mean incidence of 4.9 per 10,000 live births and a significant yearly increase of 0.067 per 10,000 (95 % CI 0.037–0.098; p < 0.001). Mild cases (confirmation TSH < 20 mU/L) rose (+0.89 percentage points per year; p = 0.002). The program’s recall was low (0.05%). Over time, screening and diagnostic TSH values declined, total and free T4 concentrations rose, gestational age at diagnosis fell, and a shift from thyroid ectopy toward hypoplasia emerged; no regional differences were detected. The sustained increase in CH incidence, alongside falling TSH thresholds and growing detection of in situ glands, suggests enhanced recognition of milder disease. Ongoing surveillance should integrate environmental, iodine-nutrition, and genetic factors to clarify the causes of this trend. Full article

(This article belongs to the Special Issue Newborn Screening for Congenital Hypothyroidism)

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2 pages, 173 KiB

Open AccessCorrection

Correction: Berardo et al. Expanded Newborn Screening in Italy: The First Report of Lombardy Region. Int. J. Neonatal Screen. 2025, 11, 31

by Clarissa Berardo, Alessandra Vasco, Alessia Mauri, Simona Lucchi, Laura Cappelletti, Laura Saielli, Manuela Rizzetto, Davide Biganzoli, Cristina Montrasio, Diana Postorivo, Michela Perrone Donnorso, Elisa Pratiffi, Andrea Meta, Stephana Carelli, Alessandro Amorosi, Sabrina Paci, Graziella Cefalo, Francesca Furlan, Francesca Menni, Serena Gasperini, Viola Crescitelli, Giuseppe Banderali, Gianvincenzo Zuccotti, Luisella Alberti and Cristina Cereda Show full author list Hide full author list

Int. J. Neonatal Screen. 2025, 11(3), 57; https://doi.org/10.3390/ijns11030057 - 22 Jul 2025

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Abstract

Addition of an author [...] Full article

16 pages, 593 KiB

Open AccessEditor’s ChoiceArticle

Historical Appreciation of World Health Organization’s Public Health Paper-34: Principles and Practice of Screening for Disease, by Max Wilson and Gunnar Jungner

by Peter C. J. I. Schielen

Int. J. Neonatal Screen. 2025, 11(3), 56; https://doi.org/10.3390/ijns11030056 - 21 Jul 2025

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Abstract

Biographies of Max Wilson and Gunnar Jungner were published in 2017 and 2020. An in-depth appreciation of the Wilson and Jungner principles, and the publication they were presented in, ‘Principles and Practice of Screening for Disease’, published as nr. 34 in the Public [...] Read more.

Biographies of Max Wilson and Gunnar Jungner were published in 2017 and 2020. An in-depth appreciation of the Wilson and Jungner principles, and the publication they were presented in, ‘Principles and Practice of Screening for Disease’, published as nr. 34 in the Public Health Paper-series of the World Health Organisation (W.H.O), called PHP-34 hereafter, was not published as yet. Here an analysis is given of PHP-34 and the ten screening principles, focusing on three subjects. First, by careful analysis of PHP-34, the literature published in the peer reviewed scientific literature, and other sources, the historical background and origin of the ten principles is determined. Second, the precise composition of PHP-34 is described, as parts of the monograph were derived from other seminal works published between roughly 1950 and 1965. Third, it is determined what the contributions of both authors of the monograph were. Results together are discussed in relation to the time PHP-34 was conceptualized and the importance of PHP-34 and the ten principles in the current era. Results show that in the 15 years preceding the publication of PHP-34, many principles of screening were published by authors in the United States of America, a selection of which ended up in PHP-34. Secondly, about 33% of the 145 pages of PHP-34 are drawn from other publications and studies on screening. Thirdly, the case can be made that the actual writing of PHP-34 was done (almost) entirely by Wilson. Regardless, Wilson and Jungner to this day should be applauded for their work. It is a testimony to the value of PHP-34 that we are still reflecting upon, discussing and seeking to intelligently apply the screening principles almost 60 years after their original publication. Full article

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12 pages, 245 KiB

Open AccessArticle

Implementation of Neonatal Screening Program for Congenital Hypothyroidism in Eastern Morocco

by Fatima Wahoud, Samia Essadki, Khadija Zirar, Rajae Lamsyah, Wissam Hajjaji and Rim Amrani

Int. J. Neonatal Screen. 2025, 11(3), 55; https://doi.org/10.3390/ijns11030055 - 17 Jul 2025

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Abstract

Congenital hypothyroidism (CH) is one of the major preventable causes of intellectual disability. This study evaluates the incidence of CH through a newborn screening (NBS) program in eastern Morocco. A descriptive cross-sectional design was used and heel prick blood samples were collected on [...] Read more.

Congenital hypothyroidism (CH) is one of the major preventable causes of intellectual disability. This study evaluates the incidence of CH through a newborn screening (NBS) program in eastern Morocco. A descriptive cross-sectional design was used and heel prick blood samples were collected on blotting paper to measure Thyroid-Stimulating Hormone (TSH) using an immunofluorimetric assay. 4062 newborns were screened (51.3% male, 48.7% female). TSH levels significantly varied by age: newborns sampled before 24 h had a higher median TSH (3.7 µU/mL [0.10–28.90]) compared to those sampled at 24 h or more (2.1 µU/mL [0.10–32.30]; p < 0.001). Using age-specific cut-off values, 18 suspected CH cases were recalled (recall rate: 0.44%). Among the 16 cases who completed confirmatory testing, 4 had transient hyperthyrotropinemia (HTT), characterized by mildly abnormal serum TSH and T4 levels that normalized spontaneously after few months without treatment. Three cases were diagnosed with CH confirmed at birth with markedly elevated serum TSH concentrations and significantly reduced T4 levels. Consequently, the birth prevalence of CH confirmed at birth was 1:1354 live births. The median preanalytical delay was 6 days (IQR: 3–12) and the TSH result turnaround was 8 days (IQR: 5–15), potentially affecting timely intervention. This first report from eastern Morocco confirms the relevance of neonatal screening but highlights delays that must be addressed to enhance early diagnosis and management. Full article

(This article belongs to the Special Issue Newborn Screening for Congenital Hypothyroidism)

6 pages, 645 KiB

Open AccessBrief Report

Neonatology Providers Need Education About Cystic Fibrosis Newborn Screening Algorithms

by Nilesh Seshadri, Lori Christ, David Munson, Andrew Borowiec, Clement L. Ren and Ambika Shenoy

Int. J. Neonatal Screen. 2025, 11(3), 54; https://doi.org/10.3390/ijns11030054 - 17 Jul 2025

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Abstract

An essential link in the cystic fibrosis (CF) newborn screening (NBS) process is communication of results. While this is described between NBS programs and primary care providers, data of this occurrence is limited with neonatologists. Neonatology providers represent a group caring for critically [...] Read more.

An essential link in the cystic fibrosis (CF) newborn screening (NBS) process is communication of results. While this is described between NBS programs and primary care providers, data of this occurrence is limited with neonatologists. Neonatology providers represent a group caring for critically ill infants with conditions that can impact their ability to complete diagnostic testing after an abnormal NBS. Delays in testing can prolong time to diagnosis. We fielded a survey to assess neonatology provider knowledge and awareness of the Pennsylvania state CF NBS algorithm after an update occurred. Provider demographics, awareness of CF NBS update, and knowledge of the diagnostic testing process were measured. 86% of respondents were unaware of Pennsylvania CF NBS updates. Provider comfort with interpreting CF NBS results varied. 40% of providers identified the next diagnostic testing steps for a critically ill infant following an abnormal CF NBS. Our survey emphasizes the need for educating neonatology providers about CF NBS to improve knowledge and awareness of CF NBS algorithms to facilitate the early diagnosis of affected infants. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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16 pages, 860 KiB

Open AccessArticle

Cost–Effectiveness of Newborn Screening for X-Linked Adrenoleukodystrophy in the Netherlands: A Health-Economic Modelling Study

by Rosalie C. Martens, Hana M. Broulikova, Marc Engelen, Stephan Kemp, Anita Boelen, Robert de Jonge, Judith E. Bosmans and Annemieke C. Heijboer

Int. J. Neonatal Screen. 2025, 11(3), 53; https://doi.org/10.3390/ijns11030053 - 16 Jul 2025

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Abstract

X-linked adrenoleukodystrophy (ALD) is an inherited metabolic disorder that can cause adrenal insufficiency and cerebral ALD (cALD) in childhood. Early detection prevents adverse health outcomes and can be achieved by newborn screening (NBS) followed by monitoring disease progression. However, monitoring is associated with [...] Read more.

X-linked adrenoleukodystrophy (ALD) is an inherited metabolic disorder that can cause adrenal insufficiency and cerebral ALD (cALD) in childhood. Early detection prevents adverse health outcomes and can be achieved by newborn screening (NBS) followed by monitoring disease progression. However, monitoring is associated with high costs. This study evaluates the cost–effectiveness of NBS for ALD in The Netherlands compared to no screening using a health economic model. A decision tree combined with a Markov model was developed to estimate societal costs, including screening costs, healthcare costs, and productivity losses of parents, and health outcomes over an 18-year time horizon. Model parameters were derived from the literature and expert opinion. A probabilistic sensitivity analysis (PSA) was performed to assess uncertainty. The screening costs of detecting one ALD case by NBS was EUR 40,630. Until the age of 18 years, the total societal cost per ALD case was EUR 120,779 for screening and EUR 62,914 for no screening. Screening gained an average of 1.7 QALYs compared with no screening. This resulted in an incremental cost–effectiveness ratio (ICER) of EUR 34,084 per QALY gained for screening compared to no screening. Although the results are sensitive to uncertainty surrounding costs and effectiveness due to limited data, NBS for ALD is likely to be cost–effective using a willingness-to-pay (WTP) threshold of EUR 50,000– EUR 80,000 per QALY gained. Full article

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10 pages, 1024 KiB

Open AccessArticle

The Promising Role of Intestinal Organoids in the Diagnostic Work-Up of Cystic Fibrosis Screen Positive Inconclusive Diagnosis/CFTR-Related Metabolic Syndrome (CFSPID/CRMS)

by Noelia Rodriguez Mier, Marlies Destoop, Sacha Spelier, Anabela Santo Ramalho, Jeffrey M. Beekman, François Vermeulen, Karin M. de Winter-de Groot and Marijke Proesmans

Int. J. Neonatal Screen. 2025, 11(3), 52; https://doi.org/10.3390/ijns11030052 - 11 Jul 2025

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Abstract

Cystic Fibrosis Screen Positive Inconclusive Diagnosis/CFTR-related Metabolic Syndrome (CFSPID/CRMS) presents a significant clinical challenge due to its variable diagnostic outcomes and uncertain disease progression. Current diagnostic strategies, including sweat chloride testing and genetic analysis fall short in delivering clear guidance for clinical decision-making [...] Read more.

Cystic Fibrosis Screen Positive Inconclusive Diagnosis/CFTR-related Metabolic Syndrome (CFSPID/CRMS) presents a significant clinical challenge due to its variable diagnostic outcomes and uncertain disease progression. Current diagnostic strategies, including sweat chloride testing and genetic analysis fall short in delivering clear guidance for clinical decision-making and risk assessment. Here, we comment on the potential of CFTR functional tests in patient-derived intestinal organoids (PDIOs) to enhance early risk stratification in CFSPID/CRMS cases. Using four hypothetical cases based on real-world data, we illustrate diverse clinical trajectories: diagnosis of cystic fibrosis (CF), reclassification as a CFTR-related disorder (CFTR-RD), non-CF designation, and persistent diagnostic uncertainty. Organoid-based assays—such as forskolin-induced swelling (FIS), steady-state lumen area (SLA) analysis, and rectal organoid morphology analysis (ROMA)—offer functional insights into CFTR activity and drug responsiveness. Compared to existing CFTR functional tests, such as Intestinal Current Measurement (ICM) and Nasal Potential Difference (NPD), these assays are more accessible, highly reproducible, and when needed support personalized medicine approaches. PDIO-based assays could help identify infants at high risk of disease progression, facilitating earlier interventions while minimizing unnecessary follow-ups for those unlikely to develop CF-related symptoms. Although not yet widely implemented, these assays hold promise for refining CFSPID diagnostics and management. Future research should focus on establishing standardized protocols allowing validation of clinical utility. Full article

(This article belongs to the Special Issue Advances in Cystic Fibrosis Newborn Screening: From Laboratory Testing to Diagnosis)

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12 pages, 1564 KiB

Open AccessArticle

Training Primary Healthcare Professionals for Expanded Newborn Screening with Tandem Mass Spectrometry: Challenges for Community Genetics in Brazil

by Luzivan Costa Reis, Tassia Tonon, Marina Bernardes Acosta, Simone Martins de Castro, Vivian de Lima Spode Coutinho, Débora Gusmão Melo and Ida Vanessa Doederlein Schwartz

Int. J. Neonatal Screen. 2025, 11(3), 51; https://doi.org/10.3390/ijns11030051 - 30 Jun 2025

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Abstract

In Brazil, dried blood spots (DBSs) for newborn screening (NBS) should be collected between the 3rd and 5th days of life at local Basic Health Units (BHUs). This study reports the experience of face-to-face training at BHUs in southern Brazil during a pilot [...] Read more.

In Brazil, dried blood spots (DBSs) for newborn screening (NBS) should be collected between the 3rd and 5th days of life at local Basic Health Units (BHUs). This study reports the experience of face-to-face training at BHUs in southern Brazil during a pilot study for tandem mass spectrometry (MS/MS) inclusion in the NBS program. The pilot project involved screening for 22 inborn errors of metabolism (IEMs). The professionals at the BHUs were instructed to carry out the following: (a) explain the study to parents or guardians; (b) collect additional DBS samples on a different collection card (research card); and (c) deliver results to families. In-person visits were conducted at all 137 BHUs. These visits included an overview of the pilot project and distribution of educational materials, including a list of the 22 IEMs and informational leaflets on MS/MS-based NBS. Among the 486 healthcare professionals who participated, 91.2% were women. Overall, 97.1% of the BHUs reported being satisfied with the project. Questions regarding IEMs were raised in 40.1% of BHUs, and 13.1% reported complaints about the research card due to its lighter texture and drying difficulty. Training primary healthcare professionals in IEMs remains an urgent priority in Brazil, particularly in the context of expanded NBS using MS/MS, since they are the frontline professionals in the NBS program. Full article

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18 pages, 5349 KiB

Open AccessArticle

Qatar’s National Expanded Metabolic Newborn Screening Program: Incidence and Outcomes

by Tala Jamaleddin, Karen El-Akouri, Sumaya Abiib, Rola Mitri, Mamatha Ramaswamy, Sara Musa, Rehab Ali, Noora Shahbeck, Hilal Al Rifai, Ghassan Abdoh, Tawfeg Ben-Omran, Osama Y. Al-Dirbashi and Mashael Al-Shafai

Int. J. Neonatal Screen. 2025, 11(3), 50; https://doi.org/10.3390/ijns11030050 - 30 Jun 2025

Viewed by 859

Abstract

Background: Newborn screening is an essential public health strategy that aims to detect a range of conditions, including inborn errors of metabolism, in neonates shortly after birth. The timely identification is crucial due to the asymptomatic nature of many conditions at birth, but [...] Read more.

Background: Newborn screening is an essential public health strategy that aims to detect a range of conditions, including inborn errors of metabolism, in neonates shortly after birth. The timely identification is crucial due to the asymptomatic nature of many conditions at birth, but which can lead to significant health complications if left untreated. Through this study, we aimed to investigate the incidence of IEMs screened by the Qatar National Newborn Screening Program. Methods: We retrospectively analyzed a total of 351,223 newborns screened from 2010 to 2023. The incidence for the studied IEMs was calculated and correlated with demographics, consanguinity, and family history. In addition, the diagnostic yield of different tests utilized was assessed. Results: Our study revealed a total of 318 positive cases with IEMs, and a significantly high incidence of 1:1105 for IEMs in Qatar. Classical Homocystinuria was the most frequently detected condition, with a cumulative incidence of 1:6754 live births, linked to the founder variant p. Arg336Cys in the CBS gene. Aminoacidopathies were the most prevalent category, followed by fatty acid oxidation disorders, organic acidurias, biotinidase deficiency, and urea cycle disorders. Genetic testing showed a high diagnostic yield of 90%. Of the 60 cases that underwent targeted variant testing, 98% were confirmed, while 90% of the 59 cases tested by single gene testing were confirmed. Conclusions: Our study provides the incidence rates of IEMs in Qatar and novel insights that could facilitate setting up/developing IEM incidence-reducing strategies and improving outcomes for affected newborns and their families. Full article

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