International Journal of Neonatal Screening

16 pages, 1551 KiB

Open AccessReview

The Role of Extended CFTR Gene Sequencing in Newborn Screening for Cystic Fibrosis

by Anne Bergougnoux, Maureen Lopez and Emmanuelle Girodon

Int. J. Neonatal Screen. 2020, 6(1), 23; https://doi.org/10.3390/ijns6010023 - 21 Mar 2020

Cited by 17 | Viewed by 3920

There has been considerable progress in the implementation of newborn screening (NBS) programs for cystic fibrosis (CF), with DNA analysis being part of an increasing number of strategies. Thanks to advances in genomic sequencing technologies, CFTR-extended genetic analysis (EGA) by sequencing its [...] Read more.

There has been considerable progress in the implementation of newborn screening (NBS) programs for cystic fibrosis (CF), with DNA analysis being part of an increasing number of strategies. Thanks to advances in genomic sequencing technologies, CFTR-extended genetic analysis (EGA) by sequencing its coding regions has become affordable and has already been included as part of a limited number of core NBS programs, to the benefit of admixed populations. Based on results analysis of existing programs, the values and challenges of EGA are reviewed in the perspective of its implementation on a larger scale. Sensitivity would be increased at best by using EGA as a second tier, but this could be at the expense of positive predictive value, which improves, however, if EGA is applied after testing a variant panel. The increased detection of babies with an inconclusive diagnosis has proved to be a major drawback in programs using EGA. The lack of knowledge on pathogenicity and penetrance associated with numerous variants hinders the introduction of EGA as a second tier, but EGA with filtering for all known CF variants with full penetrance could be a solution. The issue of incomplete knowledge is a real challenge in terms of the implemention of NBS extended to many genetic diseases. Full article

(This article belongs to the Special Issue Newborn Screening for Cystic Fibrosis)

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8 pages, 216 KiB

Open AccessCase Report

A Newborn Screening, Presymptomatically Identified Infant With Late-Onset Pompe Disease: Case Report, Parental Experience, and Recommendations

by Raymond Y. Wang

Int. J. Neonatal Screen. 2020, 6(1), 22; https://doi.org/10.3390/ijns6010022 - 14 Mar 2020

Cited by 6 | Viewed by 3147

Abstract

Pompe disease is an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) enzyme deficiency, resulting in muscle and neuron intralysosomal glycogen storage. Clinical symptoms vary from the severe, infantile-onset form with hypertrophic cardiomyopathy, gross motor delay, and early death from respiratory insufficiency; [...] Read more.

Pompe disease is an inherited lysosomal storage disorder caused by acid alpha-glucosidase (GAA) enzyme deficiency, resulting in muscle and neuron intralysosomal glycogen storage. Clinical symptoms vary from the severe, infantile-onset form with hypertrophic cardiomyopathy, gross motor delay, and early death from respiratory insufficiency; to a late-onset form with variable onset of proximal muscle weakness and progressive respiratory insufficiency. Newborn screening programs have been instituted to presymptomatically identify neonates with infantile-onset Pompe disease for early initiation of treatment. However, infants with late-onset Pompe disease are also identified, leaving families and physicians in a state of uncertainty regarding prognosis, necessity, and timing of treatment initiation. This report presents a 31 5/7 weeks’ gestational age premature infant flagged positive for Pompe disease with low dried blood spot GAA activity; sequencing identified biparental c.-32-13T>G/c.29delA GAA variants predicting late-onset Pompe disease. The infant’s parents’ initial reactions to the positive newborn screen, subsequent experience during confirmatory testing, and post-confirmation reflections are also reported. While uncertainties regarding natural history and prognosis of presymptomatically-identified late-onset Pompe disease infants will be elucidated with additional experience, suggestions for education of first-line providers are provided to accurately communicate results and compassionately counsel families regarding anxiety-provoking positive newborn screen results. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

26 pages, 338 KiB

Open AccessReview

CCHD Screening Implementation Efforts in Latin American Countries by the Ibero American Society of Neonatology (SIBEN)

by Augusto Sola, Susana Rodríguez, Alejandro Young, Lourdes Lemus Varela, Ramón Mir Villamayor, Marcelo Cardetti, Jorge Pleitez Navarrete, María Verónica Favareto, Victoria Lima, Hernando Baquero, Lorena Velandia Forero, María Elena Venegas, Carmen Davila, Fernando Dominguez Dieppa, Taína Malena Germosén, Ada Nidia Oviedo Barrantes, Ana Lorena Alvarez Castañeda, Mónica Morgues, Aldana Avila, Diana Fariña, Jose Luis Oliva, Erika Sosa and Sergio Golombek Show full author list Hide full author list

Int. J. Neonatal Screen. 2020, 6(1), 21; https://doi.org/10.3390/ijns6010021 - 14 Mar 2020

Cited by 10 | Viewed by 4058

Abstract

Congenital heart disease (CHD) is among the four most common causes of infant mortality in Latin America. Pulse oximetry screening (POS) is useful for early diagnosis and improved outcomes of critical CHD. Here, we describe POS implementation efforts in Latin American countries guided [...] Read more.

Congenital heart disease (CHD) is among the four most common causes of infant mortality in Latin America. Pulse oximetry screening (POS) is useful for early diagnosis and improved outcomes of critical CHD. Here, we describe POS implementation efforts in Latin American countries guided and/or coordinated by the Ibero American Society of Neonatology (SIBEN), as well as the unique challenges that are faced for universal implementation. SIBEN collaborates to improve the neonatal quality of care and outcomes. A few years ago, a Clinical Consensus on POS was finalized. Since then, we have participated in 12 Latin American countries to educate neonatal nurses and neonatologists on POS and to help with its implementation. The findings reveal that despite wide disparities in care that exist between and within countries, and the difficulties and challenges in implementing POS, significant progress has been made. We conclude that universal POS is not easy to implement in Latin America but, when executed, has not only been of significant value for babies with CHD, but also for many with other hypoxemic conditions. The successful and universal implementation of POS in the future is essential for reducing the mortality associated with CHD and other hypoxemic conditions and will ultimately lead to the survival of many more Latin American babies. POS saves newborns’ lives in Latin America. Full article

(This article belongs to the Special Issue Screening for Critical Congenital Heart Disease in Developing Countries)

8 pages, 1008 KiB

Open AccessArticle

Post-Analytical Tools for the Triage of Newborn Screening Results in Follow-up Can Reduce Confirmatory Testing and Guide Performance Improvement

by Patricia L. Hall, Angela Wittenauer and Arthur Hagar

Int. J. Neonatal Screen. 2020, 6(1), 20; https://doi.org/10.3390/ijns6010020 - 14 Mar 2020

Cited by 8 | Viewed by 2846

Abstract

Georgia uses post-analytical tools through Collaborative Laboratory Integrated Reports (CLIR) to triage abnormal newborn screening (NBS) results for follow-up. Condition specific tools are used to assign each case a risk level, which is used to guide follow-up recommendations. Follow-up recommendations include assessment by [...] Read more.

Georgia uses post-analytical tools through Collaborative Laboratory Integrated Reports (CLIR) to triage abnormal newborn screening (NBS) results for follow-up. Condition specific tools are used to assign each case a risk level, which is used to guide follow-up recommendations. Follow-up recommendations include assessment by the child’s primary care provider as well as testing, either a repeat NBS or confirmatory testing. Triaging abnormal cases using these tools has been advantageous in managing the workflow for the follow-up team, as well as prioritizing cases that appropriately require more attention and resources. The initial goal in utilizing these tools was to reduce the amount of confirmatory testing, particularly for disorders where there are many false positives. We assessed the performance of these tools retrospectively for three of the most commonly detected conditions by tandem mass spectrometry in Georgia: phenylketonuria, medium chain acyl-CoA dehydrogenase deficiency and very long chain dehydrogenase deficiency. The post-analytical tools appropriately assigned all true positive cases to the higher levels of follow-up testing and reduced the level of intervention for a significant number of cases as well. Based on the experience gained from our utilization of the tools in the follow-up program, we are well situated to move forward with using the tools in a more prospective manner, and reduce the number of cases that will be reported, rather than just assigning resources appropriately at follow-up. Post-analytical tools are an improvement over trying to capture the variation in the newborn population using multiple cutoffs. It also easily identifies significant abnormalities that are unrelated to inherited disease, such as large amino acid elevations due to total parenteral nutrition. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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7 pages, 867 KiB

Open AccessReview

Inconclusive Diagnosis after Newborn Screening for Cystic Fibrosis

by Anne Munck

Int. J. Neonatal Screen. 2020, 6(1), 19; https://doi.org/10.3390/ijns6010019 - 12 Mar 2020

Cited by 23 | Viewed by 3409

Abstract

An unintended consequence of newborn screening for cystic fibrosis (CF) is the identification of infants with a positive screening test but an inconclusive diagnostic testing. These infants are designated as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen-positive, [...] Read more.

An unintended consequence of newborn screening for cystic fibrosis (CF) is the identification of infants with a positive screening test but an inconclusive diagnostic testing. These infants are designated as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen-positive, inconclusive diagnosis (CFSPID) in Europe. Recently, experts agreed on a unified international definition of CRMS/CFSPID which will improve our knowledge on the epidemiology and outcomes of these infants and optimize comparisons between cohorts. Many of these children will remain free of symptoms, but a number may develop clinical features suggestive of CFTR-related disorder (CFTR-RD) or CF later in life. Clinicians should to be prepared to identify these infants and communicate with parents about this challenging and stressful situation for both healthcare professionals and families. In this review, we present the recent publications on infants designated as CRMS/CFSPID, including the definition, the incidence across Europe, the assessment of the CFTR protein function, the outcomes with the rates of conversion to a final diagnosis of CF and their management. Full article

(This article belongs to the Special Issue Newborn Screening for Cystic Fibrosis)

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18 pages, 1944 KiB

Open AccessReview

Newborn Screening for CF across the Globe—Where Is It Worthwhile?

by Virginie Scotet, Hector Gutierrez and Philip M. Farrell

Int. J. Neonatal Screen. 2020, 6(1), 18; https://doi.org/10.3390/ijns6010018 - 04 Mar 2020

Cited by 68 | Viewed by 7577

Abstract

Newborn screening (NBS) for cystic fibrosis (CF) has been performed in many countries for as long as four decades and has transformed the routine method for diagnosing this genetic disease and improved the quality and quantity of life for people with this potentially [...] Read more.

Newborn screening (NBS) for cystic fibrosis (CF) has been performed in many countries for as long as four decades and has transformed the routine method for diagnosing this genetic disease and improved the quality and quantity of life for people with this potentially fatal disorder. Each region has typically undertaken CF NBS after analysis of the advantages, costs, and challenges, particularly regarding the relationship of benefits to risks. The very fact that all regions that began screening for CF have continued their programs implies that public health and clinical leaders consider early diagnosis through screening to be worthwhile. Currently, many regions where CF NBS has not yet been introduced are considering options and in some situations negotiating with healthcare authorities as policy and economic factors are being debated. To consider the assigned question (where is it worthwhile?), we have completed a worldwide analysis of data and factors that should be considered when CF NBS is being contemplated. This article describes the lessons learned from the journey toward universal screening wherever CF is prevalent and an analytical framework for application in those undecided regions. In fact, the lessons learned provide insights about what is necessary to make CF NBS worthwhile. Full article

(This article belongs to the Special Issue Newborn Screening for Cystic Fibrosis)

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14 pages, 1166 KiB

Open AccessArticle

Determining Reference Ranges for Total T₄ in Dried Blood Samples for Newborn Screening

by Anna-Isabella Hijman, Daniel Konrad and Ralph Fingerhut

Int. J. Neonatal Screen. 2020, 6(1), 17; https://doi.org/10.3390/ijns6010017 - 04 Mar 2020

Cited by 5 | Viewed by 2923

Abstract

The purpose of this study was to define reference intervals for total thyroxine (tT₄) in dried blood samples (DBSs) obtained for newborn screening. The aim of our study was to assess the possible benefit of measuring tT₄ concentrations directly in [...] Read more.

The purpose of this study was to define reference intervals for total thyroxine (tT₄) in dried blood samples (DBSs) obtained for newborn screening. The aim of our study was to assess the possible benefit of measuring tT₄ concentrations directly in DBSs obtained for newborn screening in premature and term-born infants. In order to have a sufficient number of samples for the extremely premature infants (<30 weeks), we set up a retrospective study, measuring the concentrations in DBSs collected over the previous 21 weeks. This time frame was a result of the included miniature study of tT₄ stability in DBSs. We found that tT₄ strongly correlated with gestational age (GA) in premature infants, highlighting the need for age-specific reference ranges. For term-born infants, the tT₄ ranges did not vary significantly among different gestational ages, allowing for the use of one single reference range. Full article

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12 pages, 1534 KiB

Open AccessArticle

Reducing False-Positive Results in Newborn Screening Using Machine Learning

by Gang Peng, Yishuo Tang, Tina M. Cowan, Gregory M. Enns, Hongyu Zhao and Curt Scharfe

Int. J. Neonatal Screen. 2020, 6(1), 16; https://doi.org/10.3390/ijns6010016 - 03 Mar 2020

Cited by 41 | Viewed by 5233

Abstract

Newborn screening (NBS) for inborn metabolic disorders is a highly successful public health program that by design is accompanied by false-positive results. Here we trained a Random Forest machine learning classifier on screening data to improve prediction of true and false positives. Data [...] Read more.

Newborn screening (NBS) for inborn metabolic disorders is a highly successful public health program that by design is accompanied by false-positive results. Here we trained a Random Forest machine learning classifier on screening data to improve prediction of true and false positives. Data included 39 metabolic analytes detected by tandem mass spectrometry and clinical variables such as gestational age and birth weight. Analytical performance was evaluated for a cohort of 2777 screen positives reported by the California NBS program, which consisted of 235 confirmed cases and 2542 false positives for one of four disorders: glutaric acidemia type 1 (GA-1), methylmalonic acidemia (MMA), ornithine transcarbamylase deficiency (OTCD), and very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Without changing the sensitivity to detect these disorders in screening, Random Forest-based analysis of all metabolites reduced the number of false positives for GA-1 by 89%, for MMA by 45%, for OTCD by 98%, and for VLCADD by 2%. All primary disease markers and previously reported analytes such as methionine for MMA and OTCD were among the top-ranked analytes. Random Forest’s ability to classify GA-1 false positives was found similar to results obtained using Clinical Laboratory Integrated Reports (CLIR). We developed an online Random Forest tool for interpretive analysis of increasingly complex data from newborn screening. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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11 pages, 5273 KiB

Open AccessConference Report

Max Wilson and the Principles and Practice of Screening for Disease

by Kate Hall

Int. J. Neonatal Screen. 2020, 6(1), 15; https://doi.org/10.3390/ijns6010015 - 29 Feb 2020

Cited by 4 | Viewed by 4344

Abstract

The name Wilson will be forever associated with co-author Jungner and ten principles of population screening published in 1968 by the World Health Organisation (WHO) as Public Health Papers No 34. These principles have since been used, modified or extended throughout much of [...] Read more.

The name Wilson will be forever associated with co-author Jungner and ten principles of population screening published in 1968 by the World Health Organisation (WHO) as Public Health Papers No 34. These principles have since been used, modified or extended throughout much of Europe and beyond. Very little was known about Dr. J.M.G. Wilson and his life and how he came to write this monograph until the Silver Jubilee meeting of the International Society for Neonatal Screening held in The Hague in 2016. The opening session was chosen to be ‘The Wilson and Jungner criteria for screening for disease’. Full article

(This article belongs to the Special Issue History, Present and Future of Neonatal Screening)

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12 pages, 1826 KiB

Open AccessArticle

Benzene Derivatives from Ink Lead to False Positive Results in Neonatal Hyperphenylalaninemia Screening with Ninhydrin Fluorometric Method

by Shuren Feng, Joanne Mei, Lu Yang, Ping Luo, Xiaonan Wang, Yuan Wang, Jingyi Yao, Lan Cui, Lei Pan, Zefang Wang and Li Xin

Int. J. Neonatal Screen. 2020, 6(1), 14; https://doi.org/10.3390/ijns6010014 - 29 Feb 2020

Cited by 2 | Viewed by 2321

Abstract

Ninhydrin-based fluorometric quantification of phenylalanine is one of the most widely used methods for hyperphenylalaninemia (HPA) screening in neonates due to its high sensitivity, high accuracy, and low cost. Here we report an increase of false positive cases in neonatal HPA screening with [...] Read more.

Ninhydrin-based fluorometric quantification of phenylalanine is one of the most widely used methods for hyperphenylalaninemia (HPA) screening in neonates due to its high sensitivity, high accuracy, and low cost. Here we report an increase of false positive cases in neonatal HPA screening with this method, caused by contamination of blood specimen collection devices during the printing process. Through multiple steps of verification, the contaminants were identified from ink circles printed on the collection devices to indicate the positions and sizes of blood drops. Blood specimens from HPA-negative persons collected on these contaminated collection devices showed positive results in the fluorometric tests, but negative results in tandem mass spectroscopy (MS/MS) experiments. Contaminants on the collection devices could be extracted by 80% ethanol and showed an absorption peak around 245 nm, suggesting that these contaminants may contain benzene derivatives with similar structure to phenylalanine. High-performance liquid chromatography (HPLC) analysis of the ethanol extracts from contaminated collection devices identified two prominent peaks specifically from the devices. Methyl-2-benzoylbenzoate (MBB, CAS#606-28-0) was found as one of the major chemicals from contaminated collection devices. This report aims to remind colleagues in the field of this potential contamination and call for tighter regulation and quality control of specimen collection devices. Full article

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6 pages, 507 KiB

Open AccessReview

Universal Screening for CCHD in Saudi Arabia: The Road to a ‘State of the Art’ Program

by Fahad AlAql, Huda Khaleel and Vetha Peter

Int. J. Neonatal Screen. 2020, 6(1), 13; https://doi.org/10.3390/ijns6010013 - 24 Feb 2020

Cited by 2 | Viewed by 3597

Abstract

Critical congenital heart disease (CCHD) has been defined as structural heart defects that are usually associated with hypoxia in the newborn period and have potential for significant morbidity and mortality early in life. CCHD has been estimated to be present in ∼3 in [...] Read more.

Critical congenital heart disease (CCHD) has been defined as structural heart defects that are usually associated with hypoxia in the newborn period and have potential for significant morbidity and mortality early in life. CCHD has been estimated to be present in ∼3 in 1000 live births, including Saudi Arabia. Pulse Oximetry Screening (POS) is a highly specific and moderately sensitive test for detecting CCHD with very low false-positive rates. The Kingdom of Saudi Arabia is among high-income countries with a population of more than 33 million and more than 600,000 annual live births. In 2015, the Universal Screening Program for CCHD using Pulse Oximetry was approved in Saudi Arabia. It is expected that any new national program will undergo a learning curve and face many challenges. We believe that developing countries may face different challenges during implementation of such national projects, but the success achieved by Saudi Arabia in implementing the program was mainly due to good preparation before launching the project and advancements in the use of the technology involved in this project. Since starting the universal CCHD screening in 2016, more than 900,000 babies have been screened in Saudi Arabia and many lives have been saved using this safe, non-invasive, inexpensive, and reasonably sensitive test. Full article

(This article belongs to the Special Issue Screening for Critical Congenital Heart Disease in Developing Countries)

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27 pages, 298 KiB

Open AccessMeeting Report

Introducing and Expanding Newborn Screening in the MENA Region

by Victor Skrinska, Issam Khneisser, Peter Schielen and Gerard Loeber

Int. J. Neonatal Screen. 2020, 6(1), 12; https://doi.org/10.3390/ijns6010012 - 19 Feb 2020

Cited by 6 | Viewed by 3896

Abstract

This special edition of the International Journal of Neonatal Screening includes the presentations of the fourth Meeting of the Middle East North Africa (MENA) Region of the International Society for Neonatal Screening (ISNS) held in Limassol, Cyprus, March 8–11, 2020 [...] Full article

11 pages, 672 KiB

Open AccessArticle

Lessons Learned from Pompe Disease Newborn Screening and Follow-up

by Tracy L. Klug, Lori B. Swartz, Jon Washburn, Candice Brannen and Jami L. Kiesling

Int. J. Neonatal Screen. 2020, 6(1), 11; https://doi.org/10.3390/ijns6010011 - 14 Feb 2020

Cited by 19 | Viewed by 4790

Abstract

In 2015, Pompe disease became the first lysosomal storage disorder to be recommended for universal newborn screening by the Secretary of the U.S. Department of Health and Human Services. Newborn screening for Pompe has been implemented in 20 states and several countries across [...] Read more.

In 2015, Pompe disease became the first lysosomal storage disorder to be recommended for universal newborn screening by the Secretary of the U.S. Department of Health and Human Services. Newborn screening for Pompe has been implemented in 20 states and several countries across the world. The rates of later-onset disease phenotypes for Pompe and pseudodeficiency alleles are higher than initially anticipated, and these factors must be considered during Pompe disease newborn screening. This report presents an overview of six years of data from the Missouri State Public Health Laboratory for Pompe disease newborn screening and follow-up. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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12 pages, 585 KiB

Open AccessArticle

The First Year Experience of Newborn Screening for Pompe Disease in California

by Hao Tang, Lisa Feuchtbaum, Stanley Sciortino, Jamie Matteson, Deepika Mathur, Tracey Bishop and Richard S. Olney

Int. J. Neonatal Screen. 2020, 6(1), 9; https://doi.org/10.3390/ijns6010009 - 07 Feb 2020

Cited by 30 | Viewed by 4757

Abstract

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year [...] Read more.

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year of screening in a large and diverse screening population. With 453,152 screened newborns, the birth prevalence and GAA enzyme activity associated with various types of Pompe disease classifications are described. The frequency of GAA gene mutations and allele variants are reported. Of 88 screen positives, 18 newborns were resolved as Pompe disease, including 2 classic infantile-onset and 16 suspected late-onset form. The c.-32-13T>G variant was the most common pathogenic mutation reported. African American and Asian/Pacific Islander newborns had higher allele frequencies for both pathogenic and pseudodeficiency variants. After the first year of Pompe disease screening in California, the disease distribution in the population is now better understood. With the ongoing long-term follow-up system currently in place, our understanding of the complex genotype-phenotype relationships will become more evident in the future, and this should help us better understand the clinical significance of identified cases. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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10 pages, 1964 KiB

Open AccessArticle

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

by Dawn S. Peck, Jean M. Lacey, Amy L. White, Gisele Pino, April L. Studinski, Rachel Fisher, Ayesha Ahmad, Linda Spencer, Sarah Viall, Natalie Shallow, Amy Siemon, J. Austin Hamm, Brianna K. Murray, Kelly L. Jones, Dimitar Gavrilov, Devin Oglesbee, Kimiyo Raymond, Dietrich Matern, Piero Rinaldo and Silvia Tortorelli

Int. J. Neonatal Screen. 2020, 6(1), 10; https://doi.org/10.3390/ijns6010010 - 07 Feb 2020

Cited by 27 | Viewed by 5646

Abstract

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for [...] Read more.

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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7 pages, 220 KiB

Open AccessReview

History of Newborn Screening for Cystic Fibrosis—The Early Years

by Georges Travert, Mary Heeley and Anthony Heeley

Int. J. Neonatal Screen. 2020, 6(1), 8; https://doi.org/10.3390/ijns6010008 - 31 Jan 2020

Cited by 16 | Viewed by 3170

Abstract

This review summarises the trajectory of neonatal screening strategies for the detection of cystic fibrosis (CF) using the measurement of Immunoreactive Trypsin (IRT) in dried blood spots (DBS) from 1979 until the beginning of the 21st century when newborn screening (NBS) programmes started [...] Read more.

This review summarises the trajectory of neonatal screening strategies for the detection of cystic fibrosis (CF) using the measurement of Immunoreactive Trypsin (IRT) in dried blood spots (DBS) from 1979 until the beginning of the 21st century when newborn screening (NBS) programmes started to spread throughout many countries, using IRT measurement combined with a CF genotype analysis of DBS. Full article

(This article belongs to the Special Issue Newborn Screening for Cystic Fibrosis)

4 pages, 533 KiB

Open AccessCommunication

Clinical Utility of Confirmatory Genetic Testing to Differentiate Sickle Cell Trait from Sickle-β⁺-Thalassemia by Newborn Screening

by Lisa M. Shook, Deidra Haygood and Charles T. Quinn

Int. J. Neonatal Screen. 2020, 6(1), 7; https://doi.org/10.3390/ijns6010007 - 31 Jan 2020

Cited by 1 | Viewed by 3123

Abstract

Hemoglobin separation techniques are the most commonly used laboratory methods in newborn screening and confirmatory testing programs for hemoglobinopathies. However, such protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when β-thalassemia mutations are involved. Here, we describe a consecutive cohort of [...] Read more.

Hemoglobin separation techniques are the most commonly used laboratory methods in newborn screening and confirmatory testing programs for hemoglobinopathies. However, such protein-based testing cannot accurately detect several hemoglobinopathies in newborns, especially when β-thalassemia mutations are involved. Here, we describe a consecutive cohort of newborns who were identified by newborn screening to have a likely diagnosis of sickle-β⁺-thalassemia (having an “FSA” pattern) who were determined to have sickle cell traits by confirmatory and genetic testing. We illustrate the clinical utility of genetic testing to make a correct and timely diagnosis in the setting of newborn screening for hemoglobinopathies. Full article

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14 pages, 1478 KiB

Open AccessArticle

Measurement of 17-Hydroxyprogesterone by LCMSMS Improves Newborn Screening for CAH Due to 21-Hydroxylase Deficiency in New Zealand

by Mark R. de Hora, Natasha L. Heather, Tejal Patel, Lauren G. Bresnahan, Dianne Webster and Paul L. Hofman

Int. J. Neonatal Screen. 2020, 6(1), 6; https://doi.org/10.3390/ijns6010006 - 28 Jan 2020

Cited by 18 | Viewed by 4309

Abstract

The positive predictive value of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was <2% in New Zealand. This is despite a bloodspot second-tier immunoassay method for 17-hydroxyprogesterone measurement with an additional solvent extract step to reduce the number of false [...] Read more.

The positive predictive value of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was <2% in New Zealand. This is despite a bloodspot second-tier immunoassay method for 17-hydroxyprogesterone measurement with an additional solvent extract step to reduce the number of false positive screening tests. We developed a liquid chromatography tandem mass spectrometry (LCMSMS) method to measure 17-hydroxyprogesterone in bloodspots to replace our current second-tier immunoassay method. The method was assessed using reference material and residual samples with a positive newborn screening result. Correlation with the second-tier immunoassay was determined and the method was implemented. Newborn screening performance was assessed by comparing screening metrics 2 years before and 2 years after LCMSMS implementation. Screening data analysis demonstrated the number of false positive screening tests was reduced from 172 to 40 in the 2 years after LCMSMS implementation. The positive predictive value of screening significantly increased from 1.71% to 11.1% (X² test, p < 0.0001). LCMSMS analysis of 17OHP as a second-tier test significantly improves screening specificity for CAH due to 21-hydroxylase deficiency in New Zealand. Full article

(This article belongs to the Special Issue CAH Screening—Challenges and Opportunities)

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3 pages, 175 KiB

Open AccessEditorial

Development of Newborn Screening for Pompe Disease

by Wuh-Liang Hwu and Yin-Hsiu Chien

Int. J. Neonatal Screen. 2020, 6(1), 5; https://doi.org/10.3390/ijns6010005 - 24 Jan 2020

Cited by 2 | Viewed by 1949

Abstract

Pompe disease is an inborn error of lysosomal degradation of glycogen [...] Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

8 pages, 1512 KiB

Open AccessArticle

Newborn Screening for Pompe Disease in Illinois: Experience with 684,290 Infants

by Barbara K. Burton, Joel Charrow, George E. Hoganson, Julie Fleischer, Dorothy K. Grange, Stephen R. Braddock, Lauren Hitchins, Rachel Hickey, Katherine M. Christensen, Daniel Groepper, Heather Shryock, Pamela Smith, Rong Shao and Khaja Basheeruddin

Int. J. Neonatal Screen. 2020, 6(1), 4; https://doi.org/10.3390/ijns6010004 - 21 Jan 2020

Cited by 22 | Viewed by 4286

Abstract

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, [...] Read more.

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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2 pages, 191 KiB

Open AccessEditorial

Acknowledgement to Reviewers of International Journal of Neonatal Screening in 2019

by International Journal of Neonatal Screening Editorial Office

Int. J. Neonatal Screen. 2020, 6(1), 3; https://doi.org/10.3390/ijns6010003 - 17 Jan 2020

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11 pages, 737 KiB

Open AccessArticle

Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction

by Patricia L. Hall, Rossana Sanchez, Arthur F. Hagar, S. Caleb Jerris, Angela Wittenauer and William R. Wilcox

Int. J. Neonatal Screen. 2020, 6(1), 2; https://doi.org/10.3390/ijns6010002 - 14 Jan 2020

Cited by 23 | Viewed by 3142

Abstract

We conducted a pilot newborn screening (NBS) study for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) in the multiethnic population of Georgia. We screened 59,332 infants using a two-tier strategy of flow injection tandem mass spectrometry (FIA-MSMS) enzyme assays. The first [...] Read more.

We conducted a pilot newborn screening (NBS) study for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) in the multiethnic population of Georgia. We screened 59,332 infants using a two-tier strategy of flow injection tandem mass spectrometry (FIA-MSMS) enzyme assays. The first tier of testing was a 2-plex assay measuring PD and MPS I enzyme activity, followed by a second-tier test with additional enzymes to improve specificity. Interpretation of results was performed using post-analytical tools created using Collaborative Laboratory Integrated Reports (CLIR). We identified a single case of infantile onset PD, two cases of late onset PD, and one pseudodeficiency. The positive predictive value (PPV) for PD screening during the study was 66.7%. No cases of MPS I were identified during the study period, but there were 2 confirmed cases of pseudodeficiency and 6 cases lost to follow up. The two-tier screening strategy was successful in reducing false positive results and allowed for the identification and early treatment of a case of infantile PD but the frequency of pseudodeficiency in MPS I is problematic. Molecular testing is required and should be covered by the screening program to avoid delays in case resolution. Full article

(This article belongs to the Special Issue CLIR Applications for Newborn Screening)

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14 pages, 442 KiB

Open AccessReview

Is Newborn Screening the Ultimate Strategy to Reduce Diagnostic Delays in Pompe Disease? The Parent and Patient Perspective

by Raymond Saich, Renee Brown, Maddy Collicoat, Catherine Jenner, Jenna Primmer, Beverley Clancy, Tarryn Holland and Steven Krinks

Int. J. Neonatal Screen. 2020, 6(1), 1; https://doi.org/10.3390/ijns6010001 - 09 Jan 2020

Cited by 8 | Viewed by 4653

Abstract

Pompe disease (PD) is a rare, autosomal-recessively inherited deficiency in the enzyme acid α-glucosidase. It is a spectrum disorder; age at symptom onset and rate of deterioration can vary considerably. In affected infants prognosis is poor, such that without treatment most infants die [...] Read more.

Pompe disease (PD) is a rare, autosomal-recessively inherited deficiency in the enzyme acid α-glucosidase. It is a spectrum disorder; age at symptom onset and rate of deterioration can vary considerably. In affected infants prognosis is poor, such that without treatment most infants die within the first year of life. To lose a baby in their first year of life to a rare disease causes much regret, guilt, and loneliness to parents, family, and friends. To lose a baby needlessly when there is an effective treatment amplifies this sadness. With so little experience of rare disease in the community, once a baby transfers to their home they are subject to a very uncertain and unyielding diagnostic journey while their symptomology progresses and their health deteriorates. With a rare disease like PD, the best opportunity to diagnose a baby is at birth. PD is not yet included in the current newborn screening (NBS) panel in Australia. Should it be? In late 2018 the Australian Pompe Association applied to the Australian Standing committee on Newborn Screening to have PD included. The application was not upheld. Here we provide an overview of the rationale for NBS, drawing on the scientific literature and perspectives from The Australian Pompe Association, its patients and their families. In doing so, we hope to bring a new voice to this very important debate. Full article

(This article belongs to the Special Issue Newborn Screening for Pompe Disease)

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Int. J. Neonatal Screen., Volume 6, Issue 1 (March 2020) – 23 articles

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