International Journal of Neonatal Screening

15 pages, 2383 KiB

Open AccessArticle

Harmonizing Newborn Screening Laboratory Proficiency Test Results Using the CDC NSQAP Reference Materials

by Charles Austin Pickens, Maya Sternberg, Mary Seeterlin, Víctor R. De Jesús, Mark Morrissey, Adrienne Manning, Sonal Bhakta, Patrice K. Held, Joanne Mei, Carla Cuthbert and Konstantinos Petritis

Int. J. Neonatal Screen. 2020, 6(3), 75; https://doi.org/10.3390/ijns6030075 - 17 Sep 2020

Cited by 10 | Viewed by 3809

Abstract

Newborn screening (NBS) laboratories cannot accurately compare mass spectrometry-derived results and cutoff values due to differences in testing methodologies. The objective of this study was to assess harmonization of laboratory proficiency test (PT) results using quality control (QC) data. Newborn Screening Quality Assurance [...] Read more.

Newborn screening (NBS) laboratories cannot accurately compare mass spectrometry-derived results and cutoff values due to differences in testing methodologies. The objective of this study was to assess harmonization of laboratory proficiency test (PT) results using quality control (QC) data. Newborn Screening Quality Assurance Program (NSQAP) QC and PT data reported from 302 laboratories in 2019 were used to compare results among laboratories. QC materials were provided as dried blood spot cards which included a base pool and the base pool enriched with specific concentrations of metabolites in a linear range. QC data reported by laboratories were regressed on QC data reported by the Centers for Disease Control and Prevention (CDC), and laboratory’s regression parameters were used to harmonize their PT result. In general, harmonization tended to reduce overall variation in PT data across laboratories. The metabolites glutarylcarnitine (C5DC), tyrosine, and phenylalanine were displayed to highlight inter- and intra-method variability in NBS results. Several limitations were identified using retrospective data for harmonization, and future studies will address these limitations to further assess feasibility of using NSQAP QC data to harmonize PT data. Harmonizing NBS data using common QC materials appears promising to aid result comparison between laboratories. Full article

(This article belongs to the Special Issue Newborn Screening: Promoting Quality to Optimise Benefit and Reduce Harm)

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5 pages, 465 KiB

Open AccessEditorial

Newborn Critical Congenital Heart Disease Screening Using Pulse Oximetry: Value and Unique Challenges in Developing Regions

by Lisa A. Hom and Gerard R. Martin

Int. J. Neonatal Screen. 2020, 6(3), 74; https://doi.org/10.3390/ijns6030074 - 15 Sep 2020

Cited by 5 | Viewed by 3082

Abstract

Newborn screening for critical congenital heart disease (CCHD) is recommended for implementation in many developed countries as the standard of care. Efforts to implement this point of care screen in developing regions face unique barriers, and present important opportunities. The First Pan-African Newborn [...] Read more.

Newborn screening for critical congenital heart disease (CCHD) is recommended for implementation in many developed countries as the standard of care. Efforts to implement this point of care screen in developing regions face unique barriers, and present important opportunities. The First Pan-African Newborn Screening Conference, held in Rabat in June 2019, incorporated a workshop dedicated specifically to identifying and discussing CCHD screening issues in the Middle East Northern Africa (MENA) region. The issues explored may be beneficial as part of the greater discussion of CCHD screening’s growing importance in developing regions around the world. Screening experts presented education and lessons learned from previous CCHD implementations, including a hands-on technical demonstration of CCHD screening. Children’s HeartLink, The Newborn Foundation, and Children’s National Hospital each presented on their experiences working with teams and pilot projects from around the world. Experience in implementation from Children’s Hospital Marrakesh was presented and highlighted some of the unique findings, challenges, and experiences of screening in Morocco. As developing regions investigate the implementation of CCHD screening using pulse oximetry either as part of research studies, pilots, regional studies, or as part of a nationally supported program, data to inform policymakers on the benefits of screening and specific needs for infrastructure development and resources are essential. This special issue contains initial lessons learned on newborn CCHD screening from a select number of developing countries, including Saudi Arabia and Morocco and regions such as Latin America. Full article

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

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6 pages, 202 KiB

Open AccessArticle

Newborn Screening for Mucopolysaccharidosis Type II in Illinois: An Update

by Barbara K. Burton, Rachel Hickey and Lauren Hitchins

Int. J. Neonatal Screen. 2020, 6(3), 73; https://doi.org/10.3390/ijns6030073 - 3 Sep 2020

Cited by 19 | Viewed by 3068

Abstract

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, progressive multisystemic lysosomal storage disorder with significant morbidity and premature mortality. Infants with MPS II develop signs and symptoms of the disorder in the early years of life, yet diagnostic delays are very [...] Read more.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, progressive multisystemic lysosomal storage disorder with significant morbidity and premature mortality. Infants with MPS II develop signs and symptoms of the disorder in the early years of life, yet diagnostic delays are very common. Enzyme replacement therapy is an effective treatment option. It has been shown to prolong survival and improve or stabilize many somatic manifestations of the disorder. Our initial experience with newborn screening in 162,000 infants was previously reported. Here, we update that experience with the findings in 339,269 infants. Measurement of iduronate-2-sulfatase (I2S) activity was performed on dried blood spot samples submitted for other newborn screening disorders. A positive screen was defined as I2S activity less than or equal to 10% of the daily median. In this series, 28 infants had a positive screening test result, and four other infants had a borderline result. Three positive diagnoses of MPS II were established, and 25 were diagnosed as having I2S pseudodeficiency. The natural history and the clinical features of MPS II make it an ideal target for newborn screening. Newborn screening was effective in identifying affected infants in our population with an acceptable rate of false positive results. Full article

(This article belongs to the Special Issue Neonatal Screening for Mucopolysaccharidoses)

9 pages, 1135 KiB

Open AccessArticle

Current Practices for U.S. Newborn Screening of Pompe Disease and MPSI

by Elizabeth G. Ames, Rachel Fisher, Mary Kleyn and Ayesha Ahmad

Int. J. Neonatal Screen. 2020, 6(3), 72; https://doi.org/10.3390/ijns6030072 - 2 Sep 2020

Cited by 14 | Viewed by 3472

Abstract

Two lysosomal storage disorders (LSDs), Pompe disease and Mucopolysaccharidosis type I (MPSI) were added to the Recommended Uniform Screening Panel (RUSP) for newborn screening (NBS) in 2015 and 2016, respectively. These conditions are being screened with variable practice in terms of primary and [...] Read more.

Two lysosomal storage disorders (LSDs), Pompe disease and Mucopolysaccharidosis type I (MPSI) were added to the Recommended Uniform Screening Panel (RUSP) for newborn screening (NBS) in 2015 and 2016, respectively. These conditions are being screened with variable practice in terms of primary and reflex analytes (either biochemical or molecular testing) as well as collection of short- and long-term follow-up elements. The goal of this study is to evaluate practices of state health departments in regards to screening methods and follow-up data collected. We conducted online surveys and phone questionnaires to determine each U.S. state’s practices for screening and follow-up of positive newborn screens. We report the first snapshot of practices for NBS for the LSDs included on the RUSP. All 50 U.S. states responded to our survey. The majority of U.S. states are not currently screening for Pompe disease and MPSI as of March 2020, but this number will increase to 38 states in the coming 1–3 years based on survey results. Our survey identifies data elements used by state health departments for short-and long-term follow-up that could serve as the basis of common elements for larger, public health-based analyses of the benefits and efficacy of screening for Pompe disease and MPSI. Full article

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7 pages, 675 KiB

Open AccessArticle

Update on the Swedish Newborn Screening for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

by Rolf H. Zetterström, Leif Karlsson, Henrik Falhammar, Svetlana Lajic and Anna Nordenström

Int. J. Neonatal Screen. 2020, 6(3), 71; https://doi.org/10.3390/ijns6030071 - 28 Aug 2020

Cited by 22 | Viewed by 4720

Abstract

Congenital adrenal hyperplasia (CAH) was the fourth disorder added to the national Swedish neonatal screening program in 1986, and approximately 115,000 newborns are screened annually. Dried blood spot (DBS) screening with measurement of 17-hydroxyprogesterone (17OHP) is also offered to older children moving to [...] Read more.

Congenital adrenal hyperplasia (CAH) was the fourth disorder added to the national Swedish neonatal screening program in 1986, and approximately 115,000 newborns are screened annually. Dried blood spot (DBS) screening with measurement of 17-hydroxyprogesterone (17OHP) is also offered to older children moving to Sweden from countries lacking a national DBS screening program. Here, we report an update on the CAH screening from January 2011 until December 2019. Results: During the study period, 1,030,409 newborns and 34,713 older children were screened. In total, 87 newborns were verified to have CAH, which gives an overall positive predictive value (PPV) of 11% and 21% for term infants. Including the five missed CAH cases identified during this period, this gives an incidence of 1:11,200 of CAH in Sweden. Among the older children, 12 of 14 recalled cases were found to be true positive for CAH. All patients were genotyped as part of the clinical follow-up and 70% of the newborns had salt wasting (SW) CAH and 92% had classic CAH (i.e., SW and simple virilizing (SV) CAH). In the group of 12 older children, none had SW CAH and two had SV CAH. Conclusion: The incidence of classic CAH is relatively high in Sweden. Early genetic confirmation with CYP21A2 genotyping has been a valuable complement to the analysis of 17OHP to predict disease severity, make treatment decisions and for the follow-up and evaluation of the screening program. Full article

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

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9 pages, 219 KiB

Open AccessReview

CAH Newborn Screening in India: Challenges and Opportunities

by Aashima Dabas, Meenakshi Bothra and Seema Kapoor

Int. J. Neonatal Screen. 2020, 6(3), 70; https://doi.org/10.3390/ijns6030070 - 27 Aug 2020

Cited by 10 | Viewed by 3511

Abstract

Congenital adrenal hyperplasia (CAH) is a common treatable disorder which is associated with life-threatening adrenal crisis, sexual ambiguity, and/or abnormal growth if undiagnosed. Newborn screening is a cost-effective tool to detect affected babies early after birth to optimize their treatment and follow-up. Newborn [...] Read more.

Congenital adrenal hyperplasia (CAH) is a common treatable disorder which is associated with life-threatening adrenal crisis, sexual ambiguity, and/or abnormal growth if undiagnosed. Newborn screening is a cost-effective tool to detect affected babies early after birth to optimize their treatment and follow-up. Newborn screening however is in its nascent stage in India where it is not yet introduced universally for all babies. The following review briefly highlights the challenges (e.g., lack of universal screening, healthcare resources) and opportunities (e.g., reduction in morbidity and early correct gender assignment in females) associated with newborn screening for CAH in a large Indian birth cohort. Full article

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

13 pages, 3859 KiB

Open AccessArticle

Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

by Zackary M. Herbst, Leslie Urdaneta, Terri Klein, Maria Fuller and Michael H. Gelb

Int. J. Neonatal Screen. 2020, 6(3), 69; https://doi.org/10.3390/ijns6030069 - 26 Aug 2020

Cited by 29 | Viewed by 4676

Abstract

All newborn screening (NBS) for mucopolysaccharidosis-I (MPS-I) is carried out by the measurement of α-iduronidase (IDUA) enzymatic activity in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and studies from the Mayo Clinic have shown that the [...] Read more.

All newborn screening (NBS) for mucopolysaccharidosis-I (MPS-I) is carried out by the measurement of α-iduronidase (IDUA) enzymatic activity in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and studies from the Mayo Clinic have shown that the false positive rate can be greatly reduced by including a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, we obtained newborn DBS from 13 patients with severe MPS-I and 2 with attenuated phenotypes. These samples were submitted to four different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide; (2) endogenous disaccharide; (3) Sensi-Pro; (4) Sensi-Pro Lite (a variation of Sensi-Pro with a simplified workflow). Patients with attenuated MPS-I show less GAG elevation than those with severe disease, and all MPS-I patients were separated from the reference range using all four methods. The minimal differential factor (lowest GAG marker level in MPS-I samples divided by highest level in the reference range of 30 random newborns) was about two for internal disaccharide, Sensi-Pro, and Sensi-Pro Lite methods. The endogenous disaccharide was clearly the best method with a minimal differential of 16-fold. This study supports use of second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate. Full article

(This article belongs to the Special Issue Neonatal Screening for Mucopolysaccharidoses)

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10 pages, 365 KiB

Open AccessReview

The Success of a Screening Program Is Largely Dependent on Close Collaboration between the Laboratory and the Clinical Follow-Up of the Patients

by Svetlana Lajic, Leif Karlsson, Rolf H. Zetterström, Henrik Falhammar and Anna Nordenström

Int. J. Neonatal Screen. 2020, 6(3), 68; https://doi.org/10.3390/ijns6030068 - 26 Aug 2020

Cited by 15 | Viewed by 2905

Abstract

Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and [...] Read more.

Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and death. The screening laboratory can also play an important role in increasing the general awareness of the disease and act as the source of information and education for clinicians to facilitate improved initial care, ensure prompt and correct glucocorticoid dosing to optimize the long-term outcome for the patients. A National CAH Registry and CYP21A2 genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described. Full article

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

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17 pages, 1744 KiB

Open AccessReview

Newborn Screening for Congenital Adrenal Hyperplasia: Review of Factors Affecting Screening Accuracy

by Patrice K. Held, Ian M. Bird and Natasha L. Heather

Int. J. Neonatal Screen. 2020, 6(3), 67; https://doi.org/10.3390/ijns6030067 - 23 Aug 2020

Cited by 30 | Viewed by 10567

Abstract

Newborn screening for 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia, has been performed routinely in the United States and other countries for over 20 years. Screening provides the opportunity for early detection and treatment of patients with 21OHD, preventing [...] Read more.

Newborn screening for 21-hydroxylase deficiency (21OHD), the most common form of congenital adrenal hyperplasia, has been performed routinely in the United States and other countries for over 20 years. Screening provides the opportunity for early detection and treatment of patients with 21OHD, preventing salt-wasting crisis during the first weeks of life. However, current first-tier screening methodologies lack specificity, leading to a large number of false positive cases, and adequate sensitivity to detect all cases of classic 21OHD that would benefit from treatment. This review summarizes the pathology of 21OHD and also the key stages of fetal hypothalamic-pituitary-adrenal axis development and adrenal steroidogenesis that contribute to limitations in screening accuracy. Factors leading to both false positive and false negative results are highlighted, along with specimen collection best practices used by laboratories in the United States and worldwide. This comprehensive review provides context and insight into the limitations of newborn screening for 21OHD for laboratorians, primary care physicians, and endocrinologists. Full article

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

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7 pages, 640 KiB

Open AccessArticle

Family Attitudes regarding Newborn Screening for Krabbe Disease: Results from a Survey of Leukodystrophy Registries

by Karlita Blackwell, Michael H. Gelb, Anna Grantham, Natasha Spencer, Christin Webb and Tara West

Int. J. Neonatal Screen. 2020, 6(3), 66; https://doi.org/10.3390/ijns6030066 - 20 Aug 2020

Cited by 6 | Viewed by 3178

Abstract

Newborn screening (NBS) for Krabbe disease (KD) is currently underway in eight states in the USA, and there is continued discussion of whether to implement KD NBS in additional states. Workgroup members sought to survey a large number of families affected by KD. [...] Read more.

Newborn screening (NBS) for Krabbe disease (KD) is currently underway in eight states in the USA, and there is continued discussion of whether to implement KD NBS in additional states. Workgroup members sought to survey a large number of families affected by KD. Families in KD and leukodystrophy family registries were contacted to seek their participation in The Krabbe Newborn Screening—Family Perspective Survey. The 170 respondents are comprised of the following: 138 family members with a KD individual diagnosed after development of symptoms, 20 notified about KD via NBS, and 12 with a KD individual diagnosed through family history of KD. The key results are that all NBS families with an early-infantile KD family member elected to pursue hematopoietic stem cell transplantation therapy. Of the 170 responders, 165 supported the implementation of KD NBS in all states in the USA. Full article

(This article belongs to the Special Issue Newborn Screening and Follow-Up Diagnostic Testing for Krabbe Disease)

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6 pages, 180 KiB

Open AccessArticle

The Impact of Post-Analytical Tools on New York Screening for Krabbe Disease and Pompe Disease

by Monica M. Martin, Ryan Wilson, Michele Caggana and Joseph J. Orsini

Int. J. Neonatal Screen. 2020, 6(3), 65; https://doi.org/10.3390/ijns6030065 - 14 Aug 2020

Cited by 10 | Viewed by 2914

Abstract

New York uses a two-tier assay to screen newborns for Krabbe disease and Pompe disease. Individual enzyme activities are measured in the first-tier, and specimens from newborns with low activity are reflexed to second tier Sanger sequencing of the associated gene. Using only [...] Read more.

New York uses a two-tier assay to screen newborns for Krabbe disease and Pompe disease. Individual enzyme activities are measured in the first-tier, and specimens from newborns with low activity are reflexed to second tier Sanger sequencing of the associated gene. Using only this two-tiered approach, the screen positive and false positive rates were high. In this study, we added an additional step that examines the activity of four additional lysosomal enzymes. Results for all enzymes are integrated using the multivariate pattern recognition software called Collaborative Laboratory Integrated Reports (CLIR) to assess the risk for disease. Results after one year of screening using the new algorithm are compared to the prior year of screening without consideration of the additional enzymes and use of CLIR. With CLIR the number of babies referred for Krabbe disease was reduced by almost 80% (from 48 to 10) and the number of babies referred for Pompe disease was reduced by almost 32% (22 to 15). Full article

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

18 pages, 2515 KiB

Open AccessArticle

Landscape of Congenital Adrenal Hyperplasia Newborn Screening in the United States

by Sari Edelman, Hiral Desai, Trey Pigg, Careema Yusuf and Jelili Ojodu

Int. J. Neonatal Screen. 2020, 6(3), 64; https://doi.org/10.3390/ijns6030064 - 14 Aug 2020

Cited by 12 | Viewed by 3998

Abstract

Newborn screening (NBS) is a state-based public health program that aims to identify newborns at risk of certain disorders in the first days after birth to prevent permanent disability or death. Disorders on the Health and Human Services Federal Advisory Committee’s Recommended Uniform [...] Read more.

Newborn screening (NBS) is a state-based public health program that aims to identify newborns at risk of certain disorders in the first days after birth to prevent permanent disability or death. Disorders on the Health and Human Services Federal Advisory Committee’s Recommended Uniform Screening Panel (RUSP) have been adopted by most state NBS programs; however, each state mandates specific disorders to be screened and implements their own system processes. Congenital adrenal hyperplasia (CAH) was added to the RUSP in 2005, and currently all 53 NBS programs universally screen for it. This paper provides a landscape of CAH screening in the United States, utilizing data voluntarily entered by state NBS programs in the Newborn Screening Technical assistance and Evaluation Program data repository. Data reported encompasses NBS state profile data (follow-up, disorder testing and the reporting of processes and methodologies for screening), quality indicator data (timeliness of CAH NBS) and confirmed cases. This comprehensive landscape analysis compares the CAH NBS systems across the US. This is vital in ultimately ensuring that newborns with CAH at risk of salt crisis receive appropriate intervention in a timely manner. Full article

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

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12 pages, 592 KiB

Open AccessArticle

Evaluation of a Two-Tier Screening Pathway for Congenital Adrenal Hyperplasia in the New South Wales Newborn Screening Programme

by Fei Lai, Shubha Srinivasan and Veronica Wiley

Int. J. Neonatal Screen. 2020, 6(3), 63; https://doi.org/10.3390/ijns6030063 - 12 Aug 2020

Cited by 22 | Viewed by 4760

Abstract

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy [...] Read more.

In Australia, all newborns born in New South Wales (NSW) and the Australia Capital Territory (ACT) have been offered screening for rare congenital conditions through the NSW Newborn Screening Programme since 1964. Following the development of the Australian Newborn Bloodspot Screening National Policy Framework, screening for congenital adrenal hyperplasia (CAH) was included in May 2018. As part of the assessment for addition of CAH, the national working group recommended a two-tier screening protocol determining 17α-hydroxyprogesterone (17OHP) concentration by immunoassay followed by steroid profile. A total of 202,960 newborns were screened from the 1 May 2018 to the 30 April 2020. A threshold level of 17OHP from first tier immunoassay over 22 nmol/L and/or top 2% of the daily assay was further tested using liquid chromatography tandem mass spectrometry (LC-MS/MS) steroid profiling for 17OHP (MS17OHP), androstenedione (A4) and cortisol. Samples with a ratio of (MS17OHP + A4)/cortisol > 2 and MS17OHP > 200 nmol/L were considered as presumptive positive. These newborns were referred for clinical review with a request for diagnostic testing and a confirmatory repeat dried blood spot (DBS). There were 10 newborns diagnosed with CAH, (9 newborns with salt wasting CAH). So far, no known false negatives have been notified, and the protocol has a sensitivity of 100%, specificity of 99.9% and a positive predictive value of 71.4%. All confirmed cases commenced treatment by day 11, with none reported as having an adrenal crisis by the start of treatment. Full article

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

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9 pages, 443 KiB

Open AccessArticle

The Clinical Impact of CLIR Tools toward Rapid Resolution of Post-Newborn Screening Confirmatory Testing for X-Linked Adrenoleukodystrophy in California

by Hao Tang, Jamie Matteson, Piero Rinaldo, Silvia Tortorelli, Robert Currier and Stanley Sciortino

Int. J. Neonatal Screen. 2020, 6(3), 62; https://doi.org/10.3390/ijns6030062 - 5 Aug 2020

Cited by 7 | Viewed by 2834

Abstract

Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the [...] Read more.

Since the start of X-linked adrenoleukodystrophy (ALD) newborn screening in California, more than half of the diagnosed cases were found to have an ATP binding cassette subfamily D member 1 (ABCD1) gene variant of uncertain significance (VUS). To determine retrospectively the likelihood that these were true positive cases, we used a web-based post-analytical tool in Collaborative Laboratory Integrated Reports (CLIR). Confirmatory plasma very long-chain fatty-acids (VLCFA) profiles for ALD screen positive infant boys were run through the CLIR ALD tool. We compared the distribution by ABCD1 variant classification (pathogenic, likely pathogenic, VUS, and no variant) with the CLIR tool score interpretation (non-informative, possibly ALD, likely ALD, and very likely ALD) and the current case diagnosis. The study showed that CLIR tool positive interpretations were consistent with 100% of the pathogenic and likely pathogenic variants on the ABCD1 gene if a more conservative guideline was used. The tool interpretations were also consistent with screened cases that were determined to not have disease (our no-disorder group). The CLIR tool identified 19 diagnosed ALD cases with VUS to be potential false positives, representing a 40% reduction among all diagnosed ALD cases with VUS. The reduction could be extended to 65% if a more aggressive threshold was used. Identifying such preventable false positives could alleviate the follow-up burden for patients, their families, and California Special Care Centers. Full article

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

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8 pages, 1292 KiB

Open AccessEditorial

Dr. Louis Isaac Woolf: At the Forefront of Newborn Screening and the Diet to Treat Phenylketonuria—Biography to Mark His 100th Birthday ^†

by José Ramón Alonso-Fernández

Int. J. Neonatal Screen. 2020, 6(3), 61; https://doi.org/10.3390/ijns6030061 - 3 Aug 2020

Cited by 7 | Viewed by 6947

Abstract

In mid 2019, the author reminded the (International Society for Neonatal Screening) ISNS of the happy occasion of the 100th birthday of one of the living pioneers of neonatal screening, Professor Louis Isaac Woolf [...] Full article

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

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8 pages, 208 KiB

Open AccessArticle

Long-Term Outcomes of Adult Patients with Homocystinuria before and after Newborn Screening

by Kenji Yamada, Kazunori Yokoyama, Kikumaro Aoki, Takeshi Taketani and Seiji Yamaguchi

Int. J. Neonatal Screen. 2020, 6(3), 60; https://doi.org/10.3390/ijns6030060 - 30 Jul 2020

Cited by 12 | Viewed by 3291

Abstract

Background: Homocystinuria (HCU) is a rare inherited metabolic disease. In Japan, newborn screening (NBS) for HCU (cystathionine β-synthase deficiency) was initiated in 1977. We compared the outcomes between patients detected by NBS (NBS group) and clinically detected patients (non-NBS group). Methods: We administered [...] Read more.

Background: Homocystinuria (HCU) is a rare inherited metabolic disease. In Japan, newborn screening (NBS) for HCU (cystathionine β-synthase deficiency) was initiated in 1977. We compared the outcomes between patients detected by NBS (NBS group) and clinically detected patients (non-NBS group). Methods: We administered questionnaires about clinical symptoms and social conditions to 16 attending physicians of 19 adult HCU patients treated with methionine-free formula. Results: Eighteen patients (nine patients each in the NBS and non-NBS groups) participated. The frequency of patients with ocular, vascular, central nervous system, and skeletal symptoms in the NBS group was lower than that in the non-NBS group. Intellectual disability was observed in one and eight patients in the NBS and non-NBS groups, respectively. Concerning their social conditions, all patients in the NBS group were employed or still attending school, while only two patients in the non-NBS group were employed. Three of the four patients who discontinued treatment presented some symptoms, even in the NBS group. Conclusion: The social and intellectual outcomes of adult Japanese patients with HCU detected by NBS were favorable. However, even in the patients in the NBS group, some symptoms might not be preventable without continuous treatment. Full article

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

4 pages, 528 KiB

Open AccessReview

The Early History of PKU

by Louis I. Woolf and John Adams

Int. J. Neonatal Screen. 2020, 6(3), 59; https://doi.org/10.3390/ijns6030059 - 29 Jul 2020

Cited by 22 | Viewed by 7383

Abstract

The story of phenylketonuria (PKU) started in 1934 with Asbjørn Følling’s examination of two mentally retarded siblings from a Norwegian family. However, if their mother had not been so persistent in her search for somebody who could give her a reason why both [...] Read more.

The story of phenylketonuria (PKU) started in 1934 with Asbjørn Følling’s examination of two mentally retarded siblings from a Norwegian family. However, if their mother had not been so persistent in her search for somebody who could give her a reason why both her children were retarded, Asbjørn Følling’s name might never have been associated with PKU and surely the history of PKU would have started differently. In the short review below, the authors give a partly personal and therefore rare account of the early history of PKU, its treatment and the start of neonatal screening. Prof. Woolf is a pioneer of both the dietary treatment of PKU and neonatal screening; Mr. Adams is a long-time advocate for PKU patient interests. Full article

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

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9 pages, 236 KiB

Open AccessArticle

Neonatal Screening on Tandem Mass Spectrometry as a Powerful Tool for the Reassessment of the Prevalence of Underestimated Diseases in Newborns and Their Family Members: A Focus on Short Chain Acyl-CoA Dehydrogenase Deficiency

by MariaAnna Messina, Alessia Arena, Agata Fiumara, Riccardo Iacobacci, Concetta Meli and Federica Raudino

Int. J. Neonatal Screen. 2020, 6(3), 58; https://doi.org/10.3390/ijns6030058 - 28 Jul 2020

Cited by 6 | Viewed by 2704

Abstract

Early detection of disabling diseases, prior to clinical manifestations, is the primary goal of newborn screening (NS). Indeed, the required number of core and secondary conditions selected for screening panels is increasing in many countries. Furthermore, newborn screening can lead to diagnosis of [...] Read more.

Early detection of disabling diseases, prior to clinical manifestations, is the primary goal of newborn screening (NS). Indeed, the required number of core and secondary conditions selected for screening panels is increasing in many countries. Furthermore, newborn screening can lead to diagnosis of maternal diseases such as vitamin B12 deficiency or 3-MethylcrotonylCoA-carboxylase deficiency (3MCC). NS became mandatory in Sicily in December 2017. Here we report NS data collected between December 2017 and April 2020. Our results show that tandem mass spectrometry is a powerful tool for discovery of underestimated disease in newborns and their family members. Our panel included short chain acyl-CoA dehydrogenase deficiency (SCADD). Here, we report that results of our investigation led to reassessment of SCADD prevalence in our population. The infant and adult patients diagnosed in our study had previously not shown overt symptoms. Full article

(This article belongs to the Special Issue Selected Papers from 10th ISNS International Symposium/11th Asia Pacific Regional Meeting)

2 pages, 165 KiB

Open AccessEditorial

Newborn Screening for Cystic Fibrosis: Over the Hump, Still Need to Fine-Tune It

by Carlo Castellani

Int. J. Neonatal Screen. 2020, 6(3), 57; https://doi.org/10.3390/ijns6030057 - 9 Jul 2020

Cited by 2 | Viewed by 2294

Abstract

Today, newborn screening (NBS) is considered an essential component in the standards of care for cystic fibrosis (CF) [...] Full article

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

3 pages, 147 KiB

Open AccessEditorial

Why Do We Screen Newborn Infants for Cystic Fibrosis?

by Jürg Barben and Kevin W. Southern

Int. J. Neonatal Screen. 2020, 6(3), 56; https://doi.org/10.3390/ijns6030056 - 8 Jul 2020

Cited by 4 | Viewed by 2308

Abstract

The introduction and widespread implementation of newborn bloodspot screening (NBS) for cystic fibrosis (CF) has offered earlier diagnosis and better outcomes for children with CF in many countries of the world [...] Full article

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

7 pages, 201 KiB

Open AccessReview

Establishing Pompe Disease Newborn Screening: The Role of Industry

by Joan M. Keutzer

Int. J. Neonatal Screen. 2020, 6(3), 55; https://doi.org/10.3390/ijns6030055 - 5 Jul 2020

Cited by 7 | Viewed by 3112

Abstract

When clinical trials for enzyme replacement therapy for Pompe disease commenced, a need for newborn screening (NBS) for Pompe disease was recognized. Two methods for NBS for Pompe disease by measuring acid α-glucosidase in dried blood spots on filter paper were developed in [...] Read more.

When clinical trials for enzyme replacement therapy for Pompe disease commenced, a need for newborn screening (NBS) for Pompe disease was recognized. Two methods for NBS for Pompe disease by measuring acid α-glucosidase in dried blood spots on filter paper were developed in an international collaborative research effort led by Genzyme. Both methods were used successfully in NBS pilot programs to demonstrate the feasibility of NBS for Pompe disease. Since 2009, all babies born in Taiwan have been screened for Pompe disease. Pompe disease was added to the Recommended Uniform (Newborn) Screening Panel in the United States in 2015. NBS for Pompe disease is possible because of the unprecedented and selfless collaborations of countless international experts who shared their thoughts and data freely with the common goal of establishing NBS for Pompe disease expeditiously. Full article

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

8 pages, 187 KiB

Open AccessReview

The Changing Face of Cystic Fibrosis and Its Implications for Screening

by Lutz Naehrlich

Int. J. Neonatal Screen. 2020, 6(3), 54; https://doi.org/10.3390/ijns6030054 - 3 Jul 2020

Cited by 12 | Viewed by 3543

Abstract

Early diagnosis, multidisciplinary care, and optimized and preventive treatments have changed the face of cystic fibrosis. Life expectancy has been expanded in the last decades. Formerly a pediatric disease, cystic fibrosis has reached adulthood. Mutation-specific treatments will expand treatment options and give hope [...] Read more.

Early diagnosis, multidisciplinary care, and optimized and preventive treatments have changed the face of cystic fibrosis. Life expectancy has been expanded in the last decades. Formerly a pediatric disease, cystic fibrosis has reached adulthood. Mutation-specific treatments will expand treatment options and give hope for further improvement of quality of life and life expectancy. Newborn screening for CF fits perfectly into these care structures and offers the possibility of preventive treatment even before symptoms occur. Especially in countries without screening, newborn screening will fulfill that promise only with increased awareness and new care structures. Full article

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

7 pages, 339 KiB

Open AccessArticle

Pulse Oximetry and Congenital Heart Disease Screening: Results of the First Pilot Study in Morocco

by Nadia El Idrissi Slitine, Fatiha Bennaoui, Craig A. Sable, Gerard R. Martin, Lisa A. Hom, Amal Fadel, Soufiane Moussaoui, Nadir Inajjarne, Drissi Boumzebra, Youssef Mouaffak, Said Younous, Lahcen Boukhanni and Fadl Mrabih Rabou Maoulainine

Int. J. Neonatal Screen. 2020, 6(3), 53; https://doi.org/10.3390/ijns6030053 - 30 Jun 2020

Cited by 15 | Viewed by 5040

Abstract

Congenital heart disease (CHD) is the most common congenital malformation. Diagnosis of critical congenital heart disease (CCHD), the most severe type of congenital heart disease, in a newborn may be difficult. The addition of CCHD screening, using pulse oximetry, to clinical assessment significantly [...] Read more.

Congenital heart disease (CHD) is the most common congenital malformation. Diagnosis of critical congenital heart disease (CCHD), the most severe type of congenital heart disease, in a newborn may be difficult. The addition of CCHD screening, using pulse oximetry, to clinical assessment significantly improves the rate of detection. We conducted a pilot study in Morocco on screening neonates for critical congenital heart disease. This study was conducted in the maternity ward of Mohammed VI University Hospital of Marrakesh, Morocco, and included asymptomatic newborns delivered between March 2019 and January 2020. The screening of CCHD was performed by pulse oximetry measuring the pre- and post-ductal saturation. Screening was performed on 8013/10,451 (76.7%) asymptomatic newborns. According to the algorithm, 7998 cases passed the screening test (99.82%), including one inconclusive test that was repeated an hour later and was normal. Fifteen newborns failed the screening test (0.18%): five CCHD, five false positives, and five CHD but non-critical. One false negative case was diagnosed at 2 months of age. Our results encourage us to strengthen screening for CCHD by adding pulse oximetry to the routine newborn screening panel. Full article

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

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20 pages, 2431 KiB

Open AccessArticle

Follow-Up for an Abnormal Newborn Screen for Severe Combined Immunodeficiencies (NBS SCID): A Clinical Immunology Society (CIS) Survey of Current Practices

by Vijaya Knight, Jennifer R. Heimall, Nicola Wright, Cullen M. Dutmer, Thomas G. Boyce, Troy R. Torgerson and Roshini S. Abraham

Int. J. Neonatal Screen. 2020, 6(3), 52; https://doi.org/10.3390/ijns6030052 - 30 Jun 2020

Cited by 15 | Viewed by 3993

Abstract

Severe combined immunodeficiency (SCID) includes a group of monogenic disorders presenting with severe T cell lymphopenia (TCL) and high mortality, if untreated. The newborn screen (NBS) for SCID, included in the recommended universal screening panel (RUSP), has been widely adopted across the US [...] Read more.

Severe combined immunodeficiency (SCID) includes a group of monogenic disorders presenting with severe T cell lymphopenia (TCL) and high mortality, if untreated. The newborn screen (NBS) for SCID, included in the recommended universal screening panel (RUSP), has been widely adopted across the US and in many other countries. However, there is a lack of consensus regarding follow-up testing to confirm an abnormal result. The Clinical Immunology Society (CIS) membership was surveyed for confirmatory testing practices for an abnormal NBS SCID result, which included consideration of gestational age and birth weight, as well as flow cytometry panels. Considerable variability was observed in follow-up practices for an abnormal NBS SCID with 49% confirming by flow cytometry, 39% repeating TREC analysis, and the remainder either taking prematurity into consideration for subsequent testing or proceeding directly to genetic analysis. More than 50% of respondents did not take prematurity into consideration when determining follow-up. Confirmation of abnormal NBS SCID in premature infants continues to be challenging and is handled variably across centers, with some choosing to repeat NBS SCID testing until normal or until the infant reaches an adjusted gestational age of 37 weeks. A substantial proportion of respondents included naïve and memory T cell analysis with T, B, and NK lymphocyte subset quantitation in the initial confirmatory panel. These results have the potential to influence the diagnosis and management of an infant with TCL as illustrated by the clinical cases presented herein. Our data indicate that there is clearly a strong need for harmonization of follow-up testing for an abnormal NBS SCID result. Full article

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25 pages, 1055 KiB

Open AccessArticle

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses

by Trine Tangeraas, Ingjerd Sæves, Claus Klingenberg, Jens Jørgensen, Erle Kristensen, Gunnþórunn Gunnarsdottir, Eirik Vangsøy Hansen, Janne Strand, Emma Lundman, Sacha Ferdinandusse, Cathrin Lytomt Salvador, Berit Woldseth, Yngve T. Bliksrud, Carlos Sagredo, Øyvind E. Olsen, Mona C. Berge, Anette Kjoshagen Trømborg, Anders Ziegler, Jin Hui Zhang, Linda Karlsen Sørgjerd, Mari Ytre-Arne, Silje Hogner, Siv M. Løvoll, Mette R. Kløvstad Olavsen, Dionne Navarrete, Hege J. Gaup, Rina Lilje, Rolf H. Zetterström, Asbjørg Stray-Pedersen, Terje Rootwelt, Piero Rinaldo, Alexander D. Rowe and Rolf D. Pettersen Show full author list Hide full author list

Int. J. Neonatal Screen. 2020, 6(3), 51; https://doi.org/10.3390/ijns6030051 - 27 Jun 2020

Cited by 34 | Viewed by 6904

Abstract

In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March [...] Read more.

In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies. Full article

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

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10 pages, 657 KiB

Open AccessArticle

Referral and Lost to System Rates of Two Newborn Hearing Screening Programs in Saudi Arabia

by Ahmad A. Alanazi

Int. J. Neonatal Screen. 2020, 6(3), 50; https://doi.org/10.3390/ijns6030050 - 27 Jun 2020

Cited by 8 | Viewed by 3843

Abstract

Congenital hearing loss has been commonly reported as a significant health problem. Lost to system (LTS) is a major challenge facing newborn hearing screening (NHS) programs. This retrospective cross-sectional descriptive study aimed to determine the referral and LTS rates after the two-stage NHS [...] Read more.

Congenital hearing loss has been commonly reported as a significant health problem. Lost to system (LTS) is a major challenge facing newborn hearing screening (NHS) programs. This retrospective cross-sectional descriptive study aimed to determine the referral and LTS rates after the two-stage NHS based on transient evoked otoacoustic emissions (TEOAEs) in two main hospitals in Riyadh, Saudi Arabia (SA). NHS was performed on newborns before hospital discharge. Newborns were only rescreened if NHS initially revealed a fail/refer outcome in one or both ears. Those who failed the first and second screenings or had risk factors were referred for auditory brainstem response (ABR) testing to confirm or exclude hearing loss. In total, 20,171 newborns (40,342 ears; 52% males; 48% females) were screened, of whom 19,498 (96.66%) passed the initial screening, while 673 (3.34%) failed. Of the 673 newborns, 235 (34.92%) were LTS, and 438 (65.08%) were rescreened, of whom 269 (61.42%) failed and were referred for a comprehensive audiological assessment to confirm the existence of hearing loss. The referral rate after the initial two-stage screening was equal to 1.33%. The lack of awareness of the importance of NHS among parents seems to be the major cause behind the LTS rate. The stakeholders have to work efficiently to reduce the LTS rate. Full article

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Int. J. Neonatal Screen., Volume 6, Issue 3 (September 2020) – 26 articles

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