Evaluation of the First Three Years of Treatment of Children with Congenital Hypothyroidism Identified through the Alberta Newborn Screening Program.

The effectiveness of newborn screening (NBS) for congenital hypothyroidism (CH) relies on timely screening, confirmation of diagnosis, and initiation and ongoing monitoring of treatment. The objective of this study was to ascertain the extent to which infants with CH have received timely and appropriate management within the first 3 years of life, following diagnosis through NBS in Alberta, Canada. Deidentified laboratory data were extracted between 1 April 2014 and 31 March 2019 from Alberta Health administrative databases for infants born in this time frame. Time to lab collection was anchored from date of birth. Timeliness was assessed as the frequency of monitoring of Thyroid Stimulating Hormone (TSH) and appropriateness as the frequency of children maintaining biochemical euthyroidism. Among 160 term infants, 95% had confirmation of diagnosis by 16 days of age. The cohort had a median of 2 (range 0-5) TSH measurements performed in the time interval from 0 to 1 month, 4 (0-12) from 1 to 6 months, 2 (0-10) from 6 to 12 months, and 7 (0-21) from 12 to 36 months. Approximately half were still biochemically hypothyroid (TSH > 7 mU/L) at 1 month of age. After becoming euthyroid, at least some period of hypo- (60%) or hyperthyroidism (TSH < 0.2 mU/L) (39%) was experienced. More work needs to be performed to discern factors contributing to prolonged periods of hypothyroidism or infrequent lab monitoring.

Genetic Screening-Emerging Issues.

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit-harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems.

Evaluation of the first 5 years of a glutaric aciduria type I neonatal screening programme in Asturias.

INTRODUCTION: . Neonatal screening of glutaric aciduria type 1 (GA-1) has brought radical changes in the course and outcomes of this disease. This study analyses the outcomes of the first 5 years (2015-2019) of the AGA1 neonatal screening programme in our autonomous community. MATERIAL: . We conducted an observational, descriptive and retrospective study. All neonates born between January 1, 2015 and December 31, 2019 that participated in the neonatal screening programme were included in the study. The glutarylcarnitine (C5DC) concentration in dry blood spot samples was measured by means of tandem mass spectrometry applying a cut-off point of 0.25 µmol/L. RESULTS: . A total of 30 120 newborns underwent screening. We found differences in the C5DC concentration based on gestational age, type of feeding and hours of life at sample collection. These differences were not relevant for screening purposes. There were no differences between neonates with weights smaller and greater than 1500 g. Screening identified 2 affected patients and there were 3 false positives. There were no false negatives. The diagnosis was confirmed by genetic testing. Patients have been in treatment since diagnosis and have not developed encephalopathic crises in the first 4 years of life. CONCLUSIONS: . Screening allowed early diagnosis of two cases of GA-1 in the first 5 years since its introduction in our autonomous community. Although there were differences in C5DC levels based on gestational age, type of feeding and hours of life at blood extraction, they were not relevant for screening.

Neonatal screening of ABO/RhD blood group and direct antiglobulin Coombs test. Experience of a single institution.

BACKGROUND: Evaluating the ABO/RhD blood group and the direct antiglobulin Coombs test (DAT) at birth is recommended good practice, but there is variability in its universal implementation. This study aims to show the comparative results in various variables of clinical impact during the hospital stay of neonates with positive DAT compared with those with negative DAT, based on the systematic detection of the ABO/RhD group and DAT at birth. METHODS: Newborns between 2017 and 2020 in a high-risk pregnancy care hospital were included. The ABO/RhD and DAT group was determined in umbilical cord samples or the first 24 hours of life. Demographic, maternal, and neonatal variables were recorded. The association between the variables was estimated using the odds ratio (OR). RESULTS: 8721 pairs were included. The DAT was positive in 239 newborns (2.7%), with the variables associated with positive PDC being maternal age > 40 years (OR: 1.5; 95% CI: 1.0 to 2.3), birth by cesarean section (1.4; 1.1-2.0), mother group O (6.4; 3.8-11.8), prematurity (3.6; 2.6-5.0), birth weight < 2500 g (2.1; 1.6-2.8), newborn group A (15.7; 10.7-23.1) and group B (17.6; 11.4-27.2), hemoglobin at birth < 13.5 g/dl (4.5; 2.8-7.1) and reticulocytosis > 9% (1.9; 1.2 to 3.1). DISCUSSION: The frequency of neonatal positive PDC was 2.7%, with a significant association with maternal/neonatal incompatibility to the ABO and RhD group, with a substantial impact on various neonatal variables. These results support the policy of universal implementation at the birth of the ABO/RhD and DAT determination.

INTRODUCCIÓN: La determinación del grupo sanguíneo ABO/RhD y la prueba directa de Coombs (PDC) al nacimiento son una práctica recomendada, pero existe variabilidad en su implementación universal. Se presentan los resultados de la determinación al nacimiento del grupo ABO/RhD y la PDC en una cohorte institucional. MÉTODOS: Se incluyeron los recién nacidos entre 2017 y 2020 en un hospital de atención a embarazos de alto riesgo. Se determinó el grupo ABO/RhD y se realizó la PDC en muestras de cordón umbilical o en las primeras 24 horas de vida. Se registraron las variables demográficas, maternas y neonatales. Se estimó la asociación entre las variables mediante la razón de probabilidad (OR). RESULTADOS: Se incluyeron 8721 binomios. La PDC fue positiva en 239 recién nacidos (2.7%), siendo las variables asociadas a la PDC positiva la edad materna > 40 años (OR: 1.5;IC95%: 1.0-2.3), el nacimiento por vía cesárea (1.4; 1.1-2.0), la madre del grupo O (6.4; 3.8-11.8), la prematuridad (3.6; 2.6-5.0); el peso al nacer < 2500 g (2.1; 1.6-2.8); el neonato del grupo A (15.7; 10.7-23.1) o del grupo B (17.6; 11.4-27.2), la hemoglobina al nacer < 13.5 g/dl (4.5; 2.8-7.1) y la reticulocitosis > 9% (1.9; 1.2 a 3.1). DISCUSIÓN: La frecuencia de PDC positiva neonatal es del 2.7%, con asociación significativa la incompatibilidad materna/neonatal al grupo ABO y RhD, con impacto significativo en diversas variables neonatales. Estos resultados apoyan la política de implementación universal al nacimiento de la determinación de ABO/RhD y PDC.

Social determinants of gastrointestinal malformation mortality in Brazil: a national study.

Introduction: In Brazil, approximately 5% are born with a congenital disorder, potentially fatal without surgery. This study aims to evaluate the relationship between gastrointestinal congenital malformation (GICM) mortality, health indicators, and socioeconomic factors in Brazil. Methods: GICM admissions (Q39-Q45) between 2012 and 2019 were collected using national databases. Patient demographics, socioeconomic factors, clinical management, outcomes, and the healthcare workforce density were also accounted for. Pediatric Surgical Workforce density and the number of neonatal intensive care units in a region were extracted from national datasets and combined to create a clinical index termed 'NeoSurg'. Socioeconomic variables were combined to create a socioeconomic index termed 'SocEcon'. Simple linear regression was used to investigate if the temporal changes of both indexes were significant. The correlation between mortality and the different indicators in Brazil was evaluated using Pearson's correlation coefficient. Results: Over 8 years, Brazil recorded 12804 GICM admissions. The Southeast led with 6147 cases, followed by the Northeast (2660), South (1727), North (1427), and Midwest (843). The North and Northeast reported the highest mortality, lowest NeoSurg, and SocEcon Index rates. Nevertheless, mortality rates declined across regions from 7.7% (2012) to 3.9% (2019), a 51.7% drop. The North and Midwest experienced the most substantial reductions, at 63% and 75%, respectively. Mortality significantly correlated with the indexes in nearly all regions (p<0.05). Conclusion: Our study highlights the correlation between social determinants of health and GICM mortality in Brazil, using two novel indexes in the pediatric population. These findings provide an opportunity to rethink and discuss new indicators that could enhance our understanding of our country and could lead to the development of necessary solutions to tackle existing challenges in Brazil and globally.

Impact of national health insurance and socioeconomic disparities on newborn hearing screening performance in South Korea: A nationwide population-based evaluation.

OBJECTIVES: This study aimed to assess the impact of national health insurance coverage on newborn hearing screening (NHS) outcomes by analyzing hearing questionnaires from the National Infant Health Check-up Program (NIHCP) in South Korea. METHODS: This study evaluated the performance and referral rates of NHS using nationwide data from 814,875 infants enrolled in the 4-month NIHCP from January 2017 to December 2019. This period encompasses the periods before and after the National Health Insurance in South Korea began covering NHS expenses in October 2018. The study also investigated household income levels to determine their relationship with participation in the NIHCP and NHS outcomes. RESULTS: The performance of NIHCP increased year-on-year, with NHS performance rates increasing from 88.5 % in 2017 to 91.5 % in 2019. Analysis by household income level revealed that the medical benefit recipients' group had the lowest NHS performance rate of 81.9 % in 2019, whereas that of the higher income level group exceeded 90 %. The NHS referral rate remained consistent at 0.9 % nationally during the study period. CONCLUSION: The inclusion of NHS in national insurance coverage positively influenced its performance rates across South Korea. Nevertheless, the data indicate the need for more focused and customized support for low-income families to enhance early hearing detection and interventions in newborns and infants.

Quantification of N-acetyl-l-aspartate in dried blood spots: A simple and fast LC-MS/MS neonatal screening method for the diagnosis of Canavan disease.

BACKGROUND: Canavan disease is a devastating neurometabolic disorder caused by accumulation of N acetylaspartate in brain and body fluids due to genetic defects in the aspartoacylase gene (ASPA). New gene therapies are on the horizon but will require early presymptomatic diagnosis to be fully effective. METHODS: We therefore developed a fast and highly sensitive liquid chromatography mass spectrometry (LC-MS/MS)-based method for quantification of N-acetylaspartate in dried blood spots and established reference ranges for neonates and older controls. With this test, we investigated 45 samples of 25 Canavan patients including 8 with a neonatal sample. RESULTS: Measuring N-acetylaspartate concentration in dried blood with this novel test, all Canavan patients (with variable severity) were well separated from the control group (median; range: 5.7; 1.6-13.6 µmol/L [n = 45] vs 0.44; 0.24-0.99 µmol/L [n = 59] (p < 0.05)). There was also no overlap when comparing neonatal samples of Canavan patients (7.3; 5.1-9.9 µmol/L [n = 8]) and neonatal controls (0.93; 0.4-1.8 µmol/L [n = 784]) (p < 0.05). CONCLUSIONS: We have developed a new LC-MS/MS-based screening test for early postnatal diagnosis of Canavan disease that should be further evaluated in a population-based study once a promising treatment becomes available. The method meets the general requirements of newborn screening and should be appropriate for multiplexing with other screening approaches that combine chromatographic and mass spectrometry techniques.

40 years neonatology : An academic life.

BACKGROUND: A complete review of the development of neonatology in the last 40 years would probably require a compendium with several volumes, to bring to view the remarkable improvements in survival rates and neurodevelopmental outcomes of ill babies in Austria, most industrial countries and to some extent worldwide. The challenge I had to solve here was to integrate my own contributions to the field of neonatology during this period and particularly the contributions of my team from the Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatrics and Adolescence Medicine, Medical University Vienna where I was working first as an intern and resident and later had the privilege to become head of department. AIM: This very personal review was conceived to showcase the milestones of neonatology where, in my opinion, our department made some meaningful contributions in research and clinical practice during the past 40 years. METHODS: A total of 10 areas of interest were selected which most likely influenced survival rates of preterm infants born at increasingly younger gestational ages and ameliorated long-term clinical and neurodevelopmental outcomes, including: 1) Construction and continuous modernization of neonatal intensive care units (NICUs). 2) Installation of the "Regionalization Program for NICUs in Vienna". 3) Treatment of respiratory distress syndrome (RDS) of premature babies. 4) Fine tuning of glucose metabolism for growth and outcome. 5) Neurodevelopmental care. 6) Neonatal hematology. 7) Infection control. 8) The toxoplasma screening program. 9) The newborn screening program. 10) Quality control: the Vermont Oxford Neonatal Network (VONN). RESULTS: Over the past four decades advancements in research and technology have allowed a transformative development of neonatal medicine. Survival rates without increased morbidity for very premature infants with gestational ages reaching to what we consider nowadays the border of viability have constantly increased. In my professional life as a neonatologist in Austria I have had the possibility to support and shape some of these developments together with my team. CONCLUSION: As we look ahead it is imperative to build upon the progress made, harnessing the power of science and technology to further improve the survival and quality of life for preterm infants in Austria and worldwide. At the same time, neonatology must continue to prioritize ethical reflection and education, fostering a culture of integrity, interdisciplinary collaboration, and the development of guidelines and protocols that uphold ethical standards while addressing the evolving needs and complexities of neonatal medicine.

The significance of machine learning in neonatal screening for inherited metabolic diseases.

Background: Neonatal screening for inherited metabolic diseases (IMDs) has been revolutionized by tandem mass spectrometry (MS/MS). This study aimed to enhance neonatal screening for IMDs using machine learning (ML) techniques. Methods: The study involved the analysis of a comprehensive dataset comprising 309,102 neonatal screening records collected in the Ningbo region, China. An advanced ML system model, encompassing nine distinct algorithms, was employed for the purpose of predicting the presence of 31 different IMDs. The model was compared with traditional cutoff schemes to assess its diagnostic efficacy. Additionally, 180 suspected positive cases underwent further evaluation. Results: The ML system exhibited a significantly reduced positive rate, from 1.17% to 0.33%, compared to cutoff schemes in the initial screening, minimizing unnecessary recalls and associated stress. In suspected positive cases, the ML system identified 142 true positives with high sensitivity (93.42%) and improved specificity (78.57%) compared to the cutoff scheme. While false negatives emerged, particularly in heterozygous carriers, our study revealed the potential of the ML system to detect asymptomatic cases. Conclusion: This research provides valuable insights into the potential of ML in pediatric medicine for IMD diagnosis through neonatal screening, emphasizing the need for accurate carrier detection and further research in this domain.

Diagnosing Cystic Fibrosis in the 21st Century-A Complex and Challenging Task.

Cystic fibrosis (CF) is a chronic and potentially life-threatening condition, wherein timely diagnosis assumes paramount significance for the prompt initiation of therapeutic interventions, thereby ameliorating pulmonary function, addressing nutritional deficits, averting complications, mitigating morbidity, and ultimately enhancing the quality of life and extending longevity. This review aims to amalgamate existing knowledge to provide a comprehensive appraisal of contemporary diagnostic modalities pertinent to CF in the 21st century. Deliberations encompass discrete delineations of each diagnostic modality and the elucidation of potential diagnostic quandaries encountered in select instances, as well as the delineation of genotype-phenotype correlations germane to genetic counseling endeavors. The synthesis underscores that, notwithstanding the availability and strides in diagnostic methodologies, including genetic assays, the sweat test (ST) retains its position as the preeminent diagnostic standard for CF, serving as a robust surrogate for CFTR functionality. Prospective clinical investigations in the realm of CF should be orchestrated with the objective of discerning novel diagnostic modalities endowed with heightened specificity and sensitivity.

Carnitine palmitoyltransferase II (CPT II) deficiency responsible for refractory cardiac arrhythmias, acute multiorgan failure and early fatal outcome.

BACKGROUND: Carnitine palmitoyltransferase II (CPT II) deficiency is a rare inborn error of mitochondrial fatty acid metabolism with autosomal recessive pattern of inheritance. Its phenotype is highly variable (neonatal, infantile, and adult onset) on the base of mutations of the CPT II gene. In affected subjects, long-chain acylcarnitines cannot be subdivided into carnitine and acyl-CoA, leading to their toxic accumulation in different organs. Neonatal form is the most severe, and all the reported patients died within a few days to 6 months after birth. Hereby, we report on a male late-preterm newborn who presented refractory cardiac arrhythmias and acute multiorgan (hepatic, renal, muscular) injury, leading to cerebral hemorrhage, hydrocephalus, cardiovascular failure and early (day 5 of life) to death. Subsequently, extended metabolic screening and target next generation sequencing (NGS) analysis allowed the CPT II deficiency diagnosis. CASE PRESENTATION: The male proband was born at 36+ 4 weeks of gestation by spontaneous vaginal delivery. Parents were healthy and nonconsanguineous, although both coming from Nigeria. Family history was unremarkable. Apgar score was 9/9. At birth, anthropometric measures were as follows: weight 2850 g (47th centile, -0.07 standard deviations, SD), length 50 cm (81st centile, + 0.89 SD) and occipitofrontal circumference (OFC) 35 cm (87th centile, + 1.14 SD). On day 2 of life our newborn showed bradycardia (heart rate around 80 bpm) and hypotonia, and was then transferred to the Neonatal Intensive Care Unit (NICU). There, he subsequently manifested many episodes of ventricular tachycardia, which were treated with pharmacological (magnesium sulfate) and electrical cardioversion. Due to the critical conditions of the baby (hepatic, renal and cardiac dysfunctions) and to guarantee optimal management of the arrythmias, he was transferred to the Pediatric Cardiology Reference Center of our region (Sicily, Italy), where he died 2 days later. Thereafter, the carnitines profile evidenced by the extended metabolic screening resulted compatible with a fatty acid oxidation defect (increased levels of acylcarnitines C16 and C18, and low of C2); afterwards, the targeted next generation sequencing (NGS) analysis revealed the known c.680 C > T p. (Pro227Leu) homozygous missense mutation of the CPTII gene, for diagnosis of CPT II deficiency. Genetic investigations have been, then, extended to the baby's parents, who were identified as heterozygous carriers of the same variant. When we meet again the parents for genetic counseling, the mother was within the first trimester of her second pregnancy. Therefore, we offered to the couple and performed the prenatal target NGS analysis on chorionic villi sample, which did not detect any alterations, excluding thus the CPT II deficiency in their second child. CONCLUSIONS: CPTII deficiency may be suspected in newborns showing cardiac arrhythmias, associated or not with hypertrophic cardiomyopathy, polycystic kidneys, brain malformations, hepatomegaly. Its diagnosis should be even more suspected and investigated in cases of increased plasmatic levels of creatine phosphokinase and acylcarnitines in addition to kidney, heart and liver dysfunctions, as occurred in the present patient. Accurate family history, extended metabolic screening, and multidisciplinary approach are necessary for diagnosis and adequate management of affected subjects. Next generation sequencing (NGS) techniques allow the identification of the CPTII gene mutation, essential to confirm the diagnosis before or after birth, as well as to calculate the recurrence risk for family members. Our report broads the knowledge of the genetic and molecular bases of such rare disease, improving its clinical characterization, and provides useful indications for the treatment of patients.

Assessment of Blood Lead Levels in Mothers Addicted to Opium and Their Neonates in Kerman: A Cross-sectional Study.

Background: High blood lead levels (BLLs) in pregnant women are associated with poor outcome in neonates. One of the newest non-occupational sources of lead contamination is opium consumption. Accordingly, this study aimed to assess BLLs in mothers addicted to opium and their neonates in Kerman. Methods: This cross-sectional was conducted in Afzalipour hospital in Kerman, from February 2019 to February 2020. The BLLs were measured in 100 opium-addicted and non-addicted mothers and their newborns, and the lead levels higher than 5 µg/dL were considered contamination. Then, the demographic and anthropometric data were compared. Findings: Based on the results of the present study, the BLLs of opium-addicted mothers (33.40±9.22 µg/dL vs 3.2±1.5 µg/dL) and their neonates (13.46±4.86 vs 1.1±0.9) were significantly higher (P=0.001) than those of non-addicts. Moreover, the average birth weight of the newborns in the addicted group was significantly lower than in the non-addicted group (2572.8±77.49 vs 2946±46.87) (P=0.001). Besides, there was a significant relationship between the average birth weight and the BLL of the mother and baby, and the average weight of the babies was significantly lower at higher levels of lead. However, no correlation was observed regarding the average height and head circumference of the neonates (P>0.05). Conclusion: It seems that the serum level of lead in neonates of opium-addicted mothers contaminated with lead is significantly higher than that of non-addicts, but their anthropometric characteristics at birth were not different from those of the nonaddicted group.

Prevalence of high neonatal thyroid stimulating hormone levels as an indicator of iodine deficiency in the province of La Pampa: An epidemiological analysis. / Prevalencia de hipertirotropinemia neonatal como indicador de deficiencia de yodo en la provincia de La Pampa: un análisis epidemiológico.

Introduction. Iodine plays a key role in human metabolism, growth, and development. During pregnancy and childhood, the demand for this micronutrient increases notably. Increased neonatal thyroid stimulating hormone (nTSH) levels, defined as nTSH ≥ 5 mIU/L, are a marker of iodine deficiency in a population if its prevalence is higher than 3%. Objective. To establish the prevalence of nTSH ≥ 5 in La Pampa in the 2021-2022 period, analyze its correlation with different variables, and compare it with data from a historical cohort. Population and methods. Cross-sectional, descriptive-analytical study in a population of newborn infants born in the 5 health regions of the province of La Pampa in 2021 and 2022. Results. Of the 5778 assessed newborn infants, 9.6% had nTSH levels ≥ 5 mIU/L. It was reported that 70.4% of these measurements were done after the third day of life. No significant differences were observed in the frequency of high nTSH levels by year of birth, birth weight, or days until sample collection. A higher prevalence was observed among male infants (10.6% versus 8.5%; p = 0.007) and term infants (9.8% versus 6.6%; p = 0.02). The prevalence of high TSH levels was superior to that observed in the 2001-2002 cohort. Conclusions. The prevalence of high nTSH levels in La Pampa during 2021 and 2022 was 9.6%, suggesting the presence of mild iodine deficiency in the population of this province, higher that what had been reported 2 decades ago.

Introducción. El yodo desempeña un rol fundamental en el metabolismo, el crecimiento y el desarrollo humano. Durante el embarazo y la infancia, la demanda de este micronutriente aumenta considerablemente. La tirotropinemia neonatal (TSHn) aumentada, definida como TSHn ≥5 mUI/l, es un marcador que señala la deficiencia de yodo en una población cuando su prevalencia supera el 3 %. Objetivo. Determinar la prevalencia de TSHn ≥ 5 en La Pampa durante el período 2021-2022, analizar su correlación con diferentes variables y compararla con datos de una cohorte histórica. Población y métodos. Estudio transversal, de diseño descriptivo-analítico, sobre una población de neonatos nacidos en las cinco zonas sanitarias de la provincia de La Pampa durante los años 2021 y 2022. Resultados. De los 5778 neonatos evaluados, el 9,6 % presentó niveles de TSHn ≥5 mUI/l. El 70,4 % de estas mediciones fueron realizadas después del tercer día de vida. No se observaron diferencias significativas en la frecuencia de niveles elevados de TSHn según el año de nacimiento, peso al nacer o días hasta la extracción. Se registró una mayor prevalencia en el sexo masculino (10,6 % versus 8,5 %; p = 0,007) y entre los neonatos nacidos a término (9,8 % versus 6,6 %; p = 0,02). La prevalencia de hipertirotropinemia fue superior a la observada en una cohorte de 2001-2002. Conclusiones. La prevalencia de hipertirotropinemia neonatal en La Pampa durante los años 2021 y 2022 fue del 9,6 %, lo que indica un estado de deficiencia leve de yodo en la provincia, superior al reportado hace dos décadas.

Outcomes after newborn screening for propionic and methylmalonic acidemia and homocystinurias.

The current German newborn screening (NBS) panel includes 13 inherited metabolic diseases (IMDs). In addition, a NBS pilot study in Southwest Germany identifies individuals with propionic acidemia (PA), methylmalonic acidemia (MMA), combined and isolated remethylation disorders (e.g., cobalamin [cbl] C and methylenetetrahydrofolate reductase [MTHFR] deficiency), cystathionine ß-synthase (CBS) deficiency, and neonatal cbl deficiency through one multiple-tier algorithm. The long-term health benefits of screened individuals are evaluated in a multicenter observational study. Twenty seven screened individuals with IMDs (PA [N = 13], MMA [N = 6], cblC deficiency [N = 5], MTHFR deficiency [N = 2] and CBS deficiency [N = 1]), and 42 with neonatal cbl deficiency were followed for a median of 3.6 years. Seventeen screened IMD patients (63%) experienced at least one metabolic decompensation, 14 of them neonatally and six even before the NBS report (PA, cbl-nonresponsive MMA). Three PA patients died despite NBS and immediate treatment. Fifteen individuals (79%) with PA or MMA and all with cblC deficiency developed permanent, mostly neurological symptoms, while individuals with MTHFR, CBS, and neonatal cbl deficiency had a favorable clinical outcome. Utilizing a combined multiple-tier algorithm, we demonstrate that NBS and specialized metabolic care result in substantial benefits for individuals with MTHFR deficiency, CBS deficiency, neonatal cbl deficiency, and to some extent, cbl-responsive MMA and cblC deficiency. However, its advantage is less evident for individuals with PA and cbl-nonresponsive MMA. SYNOPSIS: Early detection through newborn screening and subsequent specialized metabolic care improve clinical outcomes and survival in individuals with MTHFR deficiency and cystathionine-ß-synthase deficiency, and to some extent in cobalamin-responsive methylmalonic acidemia (MMA) and cblC deficiency while the benefit for individuals with propionic acidemia and cobalamin-nonresponsive MMA is less evident due to the high (neonatal) decompensation rate, mortality, and long-term complications.

Newborn screening in Colombia: The experience of a private program in Bogotá / Tamizaje neonatal en Colombia: la experiencia de un programa privado en Bogotá.

Introduction. The first neonatal screening program in Colombia ­ PREGEN ­ was set up in the medical private sector of Bogotá in 1988. We report the results from recent years that, given the scarcity of similar information in our country, may help estimate the frequency of the evaluated neonatal disorders and which ones should be included in the neonatal screening programs in our country. Objective. To describe the results of PREGEN´s newborn screening program between 2006 and 2019. Materials and methods. We analyzed databases and other informative documents preserved in PREGEN from the 2006-2019 period. Results. One in every 164 newborns screened in our program had an abnormal hemoglobin variant, and one in every 194 carried some hemoglobin S variant. Glucose-6- phosphate dehydrogenase deficiency and congenital hypothyroidism are next as the more common disorders. Conclusions. Abnormal hemoglobin causes the most frequent monogenic disorder in the world. Glucose-6-phosphate dehydrogenase deficiency is the most common enzymopathy affecting nearly 400 million individuals worldwide. Since both disorders are more common in people of African descent and confer some resistance to malaria, we believe that screening for both disorders may be more relevant in the areas with African ancestry in our country.

Introducción. En Colombia, el primer programa de tamizaje neonatal, PREGEN, inició labores en el sector privado de Bogotá en 1988. En este artículo se presentan los resultados obtenidos en los últimos años, que, dada la carencia de estos estudios en el país, pueden servir para evaluar la frecuencia de aparición de los trastornos congénitos evaluados y estimar cuáles de ellos deben ser objeto de tamizaje neonatal a nivel nacional. Objetivos. Reportar los resultados del programa de tamizaje PREGEN entre el 2006 y el 2019. Materiales y métodos. Para este análisis se examinaron las bases de datos y otros documentos informativos de PREGEN para el periodo 2006-2019. Resultados. Uno de cada 164 recién nacidos tamizados en el programa PREGEN en Bogotá presentó una variante anormal de la hemoglobina y uno de cada 194 es portador de hemoglobina S. Los siguientes dos trastornos más frecuentes encontrados fueron la deficiencia de la enzima glucosa-6-fosfato deshidrogenasa (frecuencia 1:2.231) y el hipotiroidismo congénito (frecuencia 1:3.915). Conclusiones. Las hemoglobinopatías mostraron ser uno de los desórdenes monogénicos más comunes, seguidos por la deficiencia de glucosa-6-fosfato deshidrogenasa y el hipotiroidismo congénito. Se calcula que cerca de 400 millones de personas en el mundo están afectadas por la deficiencia de glucosa-6-fosfato deshidrogenasa, por lo cual es la enzimopatía más común en el mundo. Como ambos desórdenes son más frecuentes en poblaciones de origen africano y confieren algún grado de resistencia a la malaria, es de prever que su tamizaje debe ser de mayor importancia en las zonas con ancestros africanos en Colombia.

Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS.

The Portuguese Neonatal Screening Program (PNSP) conducts nationwide screening for rare diseases, covering nearly 100% of neonates and screening for 28 disorders, including 24 inborn errors of metabolism (IEMs). The study's purpose is to assess the epidemiology of the screened metabolic diseases and to evaluate the impact of second-tier testing (2TT) within the PNSP. From 2004 to 2022, 1,764,830 neonates underwent screening using tandem mass spectrometry (MS/MS) to analyze amino acids and acylcarnitines in dried blood spot samples. 2TT was applied when necessary. Neonates with profiles indicating an IEM were reported to a reference treatment center, and subsequent biochemical and molecular studies were conducted for diagnostic confirmation. Among the screened neonates, 677 patients of IEM were identified, yielding an estimated birth prevalence of 1:2607 neonates. The introduction of 2TT significantly reduced false positives for various disorders, and 59 maternal cases were also detected. This study underscores the transformative role of MS/MS in neonatal screening, emphasizing the positive impact of 2TT in enhancing sensitivity, specificity, and positive predictive value. Our data highlight the efficiency and robustness of neonatal screening for IEM in Portugal, contributing to early and life-changing diagnoses.

High frequency of transient congenital hypothyroidism among infants referred for suspected congenital hypothyroidism from the Turkish National screening program: thyroxine dose may guide the prediction of transients.

PURPOSE: We aimed to determine the frequency of transient congenital hypothyroidism (TCH) in 17 participating centers in Türkiye, evaluate the etiological distribution in permanent congenital hypothyroidism (PCH) cases, and investigate the role of laboratory and clinical findings in predicting TCH. METHODS: This retrospective observational multicenter study included patients from 17 pediatric endocrinology centers identified by "National Newborn Screening Program" (NNSP) who were born in 2015 and followed for 6 years. Demographic, clinical, and laboratory information of the cases were compiled through the database http://cedd.saglik-network.org (CEDD-NET). RESULTS: Of the 239 cases initially treated for CH, 128 (53.6%) were determined as transient in whom a trial of levothyroxine (LT4) withdrawal was performed at a median age of 36 (34-38) months. Among the patients with PCH (n = 111), thyroid dysgenesis was diagnosed in 39.6% (n = 44). The predictive factors for TCH were: LT4 dose at the withdrawal of treatment, and initial newborn blood screening (NBS)-TSH level. Based on the receiver operating characteristic (ROC) curve analysis to predict optimal cut-offs for TCH predictors, LT4 dose < 2.0 µg/kg/day at treatment discontinuation was predictive for TCH and was associated with 94.5% specificity and 55.7% sensitivity, with an area under the curve (AUC) of 0.802. The initial NBS-TSH level value < 45 µIU/mL was predictive for TCH with 93.1% specificity and 45.5% sensitivity, with an AUC of 0.641. In patients with eutopic thyroid gland only LT4 dose < 1.1 µg/kg/day at withdrawal time was predictive for TCH with 84.7% sensitivity and 40.4% specificity, with an AUC of 0.750. CONCLUSION: According to our national follow-up data, the frequency of TCH was 53.6%. We determined the LT4 dose < 2.0 µg/kg/day at discontinuation of treatment and the initial NBS-TSH level < 45 µIU/mL as the best cut-off limits to predict TCH.

History of Neonatal Screening of Congenital Hypothyroidism in Portugal.

Congenital hypothyroidism (CH) leads to growth and development delays and is preventable with early treatment. Neonatal screening for CH was initiated in Portugal in 1981. This study examines the history of CH screening in the country. Data were obtained from annual reports and from the national database of neonatal screening laboratory. The CH screening strategy primarily relies on the thyroid-stimulating hormone (TSH), followed by total thyroxine measurement as the second tier for confirmation. The TSH cutoff started at 90 mIU/L, decreasing to the actual 10 mIU/L. The coverage of the screening program has increased rapidly; although voluntary, it reached about 90% in 6 years and became universal in 10 years. Guideline and cutoff updates led to the identification of over 200 additional cases, resulting in specific retesting protocols for preterm and very-low-birth-weight babies. The actual decision tree considers CH when TSH levels are above 40 mIU/L. Data from the CH screening also provide an indication of the iodine status of the population, which is presently indicative of iodine insufficiency. The Portuguese neonatal screening for CH is a history of success. It has rapidly and continuously adapted to changes in knowledge and has become a universal voluntary practice within a few years.

Biochemical and genetic tools to predict the progression to Cystic Fibrosis in CRMS/CFSPID subjects: A systematic review.

OBJECTIVES: Aim of this study was to identify risk factors for a progression to cystic fibrosis (CF) in individuals detected as CF Screening Positive, Inconclusive Diagnosis (CFSPID). METHODS: This is a systematic review through literature databases (2015-2023). Blood immunoreactive trypsinogen (b-IRT) values, CFTR genotype, sweat chloride (SC) values, isolation of Pseudomonas aeruginosa (Pa) from respiratory samples, Lung Clearance Index (LCI) values in CFSPIDs who converted to CF (CFSPID > CF) and age at CF transition were assessed. RESULTS: Percentage of CFSPID > CF varies from 5.3 % to 44 %. Presence of one CF-causing CFTR variant in trans with a variant with variable clinical consequences (VVCC), an initial SC ≥ 40 mmol/L, an increase of SC > 2.5 mmol/L/year and recurrent isolation of pseudomonas aeruginosa (Pa) from airway samples could allow identification of subjects at risk of progression to CF. CONCLUSIONS: CFSPIDs with CF causing variant/VVCC genotype and first SC in the higher borderline range may require more frequent and prolonged clinical follow-up.

Newborn screening for aromatic l-amino acid decarboxylase deficiency - Strategies, results, and implication for prevalence calculations.

BACKGROUND: Aromatic l-amino acid decarboxylase deficiency (AADCD) is a rare, autosomal-recessive neurometabolic disorder caused by variants in dopa decarboxylase (DDC) gene, resulting in a severe combined deficiency of serotonin, dopamine, norepinephrine, and epinephrine. Birth prevalence of AADCD varies by population. In pilot studies, 3-O-methyldopa (3-OMD) was shown to be a reliable biomarker for AADCD in high-throughput newborn screening (NBS) allowing an early diagnosis and access to gene therapy. To evaluate the usefulness of this method for routine NBS, 3-OMD screening results from the largest three German NBS centers were analyzed. METHODS: A prospective, multicenter (n = 3) NBS pilot study evaluated screening for AADCD by quantifying 3-OMD in dried blood spots (DBS) using tandem mass spectrometry (MS/MS). RESULTS: In total, 766,660 neonates were screened from January 2021 until June 2023 with 766,647 with unremarkable AADCD NBS (766,443 by 1st-tier analysis and 204 by 2nd-tier analysis) and 13 with positive NBS result recalled for confirmatory diagnostics (recall-rate about 1:59,000). Molecular genetic analysis confirmed AADCD (c.79C > T p.[Arg27Cys] in Exon 2 und c.215 A > C p.[His72Pro] in Exon 3) in one infant. Another individual was highly suspected with AADCD but died before confirmation (overall positive predictive value 0.15). False-positive results were caused by maternal L-Dopa use (n = 2) and prematurity (30th and 36th week of gestation, n = 2). However, in 63% (n = 7) the underlying etiology for false positive results remained unexplained. Estimated birth prevalence (95% confidence interval) was 1:766,660 (95% CI 1:775,194; 1:769,231) to 1:383,330 (95% CI 1:384,615; 1:383,142). The identified child remained asymptomatic until last follow up at the age of 9 months. CONCLUSIONS: The proposed screening strategy with 3-OMD detection in DBS is feasible and effective to identify individuals with AADCD. The estimated birth prevalence supports earlier estimations and confirms AADCD as a very rare disorder. Pre-symptomatic identification by NBS allows a disease severity adapted drug support to diminish clinical complications until individuals are old enough for the application of the gene therapy.