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CAH Screening—Challenges and Opportunities

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A special issue of International Journal of Neonatal Screening (ISSN 2409-515X).

Deadline for manuscript submissions: closed (30 June 2020) | Viewed by 51943

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Special Issue Editors

Dr. Natasha Heather

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Guest Editor

1. New Zealand Newborn Metabolic Screening Programme, LabPlus, Te Whatu Ora Te Toka Tumai Auckland, Auckland, New Zealand
2. Liggins Institute, University of Auckland, Auckland 1023, New Zealand
Interests: newborn screening; CAH; CH; quality improvements; screening outcomes
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Anna Nordenström

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Guest Editor

1. Department of Women’s and Children’s Health, Karolinska Institutet, S-171 76 Stockholm, Sweden
2. Department of Paediatric Endocrinology, Astrid Lindgren Children Hospital, Karolinska University Hospital, S-171 76 Stockholm, Sweden
Interests: CAH; newborn screening; disorders of sex development

Special Issue Information

Dear Colleagues,

21-Hydroxylase deficiency accounts for approximately 95% of cases of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis. Newborn screening for CAH is near-universal amongst developed countries, with some programs having over 30 years’ experience.
Babies with untreated severe CAH can develop a life-threatening salt-wasting crisis over the first weeks of life. Screening markedly reduces the time to diagnosis and morbidity of affected infants of both genders. Challenges include low screen specificity, especially amongst preterm babies. Programs have reported a variety of strategies, including birth weight- or gestational age-related cutoffs and the use of second tier LC–MS/MS.
The Special Issue on newborn screening for CAH in the International Journal of Neonatal Screening will focus on current and potential strategies in newborn screening for CAH. It will provide insight into the challenges and controversies of CAH screening, including screening premature babies and supporting adequate follow-up within resource-poor countries.

The following topics could be of interest for the reader. Further ideas can also be considered and should be discussed with the Guest Editors.

21-Hydroxylase deficiency: epidemiology, pathophysiology, and clinical course
Arguments for and against CAH newborn screening
False positive screens in preterm babies
Screening algorithms: collection time, GA/BW cutoffs, 2^nd tier methods
CAH screen evaluation and comparing data
Challenges in resource-poor countries
CAH genotyping and prediction of disease severity
Long-term follow-up and collaborative databases

Dr. Natasha Heather
Prof. Dr. Anna Nordenström
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Neonatal Screening is an international peer-reviewed open access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Congenital adrenal hyperplasia (CAH)
17-Hydroxyprogesterone (17-OHP)
CYP21A2
Newborn screening

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

5 pages, 177 KiB

Open AccessEditorial

Newborn Screening for CAH—Challenges and Opportunities

by Natasha L. Heather and Anna Nordenstrom

Int. J. Neonatal Screen. 2021, 7(1), 11; https://doi.org/10.3390/ijns7010011 - 13 Feb 2021

Cited by 7 | Viewed by 3061

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) using 17-hydroxyprogesterone (17-OHP) as an indicator of disease was first introduced in the 1970s [...] Full article

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

Research

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31 pages, 1282 KiB

Open AccessEditor’s ChoiceArticle

We All Have a Role to Play: Redressing Inequities for Children Living with CAH and Other Chronic Health Conditions of Childhood in Resource-Poor Settings

by Kate Armstrong, Alain Benedict Yap, Sioksoan Chan-Cua, Maria E. Craig, Catherine Cole, Vu Chi Dung, Joseph Hansen, Mohsina Ibrahim, Hassana Nadeem, Aman Pulungan, Jamal Raza, Agustini Utari and Paul Ward

Int. J. Neonatal Screen. 2020, 6(4), 76; https://doi.org/10.3390/ijns6040076 - 25 Sep 2020

Cited by 11 | Viewed by 6654

Abstract

CLAN (Caring and Living as Neighbours) is an Australian-based non-governmental organisation (NGO) committed to equity for children living with chronic health conditions in resource-poor settings. Since 2004, CLAN has collaborated with a broad range of partners across the Asia Pacific region to improve quality of life for children living with congenital adrenal hyperplasia (CAH). This exploratory case study uses the Knowledge to Action (KTA) framework to analyse CLAN’s activities for children living with CAH in the Asia Pacific. The seven stages of the KTA action cycle inform a systematic examination of comprehensive, collaborative, sustained actions to address a complex health challenge. The KTA framework demonstrates the “how” of CLAN’s approach to knowledge creation and exchange, and the centrality of community development to multisectoral collaborative action across a range of conditions, cultures and countries to redressing child health inequities. This includes a commitment to: affordable access to essential medicines and equipment; education, research and advocacy; optimisation of medical management; encouragement of family support groups; efforts to reduce financial burdens; and ethical, transparent program management as critical components of success. Improvements in quality of life and health outcomes are achievable for children living with CAH and other chronic health conditions in resource-poor settings. CLAN’s strategic framework for action offers a model for those committed to #LeaveNoChildBehind. Full article

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

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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 4700

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 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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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 3981

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 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 4746

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 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, 631 KiB

Open AccessArticle

Newborn Screening Protocols and Positive Predictive Value for Congenital Adrenal Hyperplasia Vary across the United States

by Phyllis W. Speiser, Reeti Chawla, Ming Chen, Alicia Diaz-Thomas, Courtney Finlayson, Meilan M. Rutter, David E. Sandberg, Kim Shimy, Rashida Talib, Jane Cerise, Eric Vilain, Emmanuèle C. Délot and

Int. J. Neonatal Screen. 2020, 6(2), 37; https://doi.org/10.3390/ijns6020037 - 8 May 2020

Cited by 25 | Viewed by 5198

Abstract

Newborn screening for congenital adrenal hyperplasia (CAH) caused by 21-hydroxylase deficiency is mandated throughout the US. Filter paper blood specimens are assayed for 17-hydroxyprogesterone (17OHP). Prematurity, low birth weight, or critical illness cause falsely elevated results. The purpose of this report is to highlight differences in protocols among US state laboratories. We circulated a survey to state laboratory directors requesting qualitative and quantitative information about individual screening programs. Qualitative and quantitative information provided by 17 state programs were available for analysis. Disease prevalence ranged from 1:9941 to 1:28,661 live births. Four state laboratories mandated a second screen regardless of the initial screening results; most others did so for infants in intensive care units. All but one program utilized birthweight cut-points, but cutoffs varied widely: 17OHP values of 25 to 75 ng/mL for birthweights >2250–2500 g. The positive predictive values for normal birthweight infants varied from 0.7% to 50%, with the highest predictive values based in two of the states with a mandatory second screen. Data were unavailable for negative predictive values. These data imply differences in sensitivity and specificity in CAH screening in the US. Standardization of newborn screening protocols could improve the positive predictive value. Full article

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

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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 21 | Viewed by 4994

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 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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Review

Jump to: Editorial, Research

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 3484

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 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)

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 2894

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 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 10531

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 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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