Newborn Screening For Congenital Hypothyroidism Research Articles

Newborn screening for congenital hypothyroidism and the time influence on the sampling

Newborn screening for congenital hypothyroidism and the time influence on the sampling

Experiences and Challenges with Congenital Hypothyroidism Newborn Screening in Indonesia: A National Cross-Sectional Survey.

The expansion of newborn screening (NBS) for congenital hypothyroidism (CH) is essential to reducing the number of preventable intellectual disabilities in children. Because of logistical issues, including geographic extremes, distinct cultures, and 4.8 million births annually, Indonesia has struggled to achieve universal NBS coverage. A national cross-sectional electronic survey was conducted to explore challenges in CH NBS. Responses from 423 healthcare professionals and program administrators across 30 provinces in Indonesia were collected. The major challenges reported were refusal from families (39.2%), newborns being discharged <24 h (38.3%), and limited availability of filter paper (35.9%). The respondents considered refusal from families to be due to fear, while others did not understand the necessity of CH NBS. The vast majority of respondents believed that parents do not have sufficient understanding regarding CH NBS (96.5%). Our study found that only 38.5% of respondents had received formal CH NBS training, with pediatric endocrinologists being the only profession in which all respondents had been trained. Concerted efforts are needed to improve the access to and availability of resources, increase the capacity for sample collection and analysis, empower healthcare professionals, and develop educational resources to promote understanding and acceptance of NBS amongst families.

Concurrent &lt;i&gt;THRB&lt;/i&gt; and &lt;i&gt;DUOX2&lt;/i&gt; variants in a patient detected via newborn screening for congenital hypothyroidism: a case of resistance to thyroid hormone

Concurrent &lt;i&gt;THRB&lt;/i&gt; and &lt;i&gt;DUOX2&lt;/i&gt; variants in a patient detected via newborn screening for congenital hypothyroidism: a case of resistance to thyroid hormone

Newborn screening for congenital hypothyroidism, congenital adrenal hyperplasia and glucose-6-phosphate dehydrogenase deficiency in Bihar: A pressing priority in today's time.

Newborn screening (NBS) aims towards early detection of congenital disorders or prevention of intellectual and physical defects and life-threatening illness. Three disorders namely congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH) and glucose-6-phosphate dehydrogenase deficiency (G-6-PDD) were selected for a preliminary study for NBS. The study aimed to establish NBS in the Indian scenario that could lay a framework for future such initiatives. A screening programme was conducted at a tertiary care hospital for 1 year. All the neonates born at All India Institute of Medical Sciences (AIIMS), Patna, were screened for their blood levels of glucose-6-phosphate dehydrogenase (G-6-PD), 17-hydroxyprogesterone (17-OHP) and thyroid-stimulating hormone (TSH). Heel-prick blood samples were collected within 48-72 h of birth, and the level of these parameters was accessed by enzyme immunoassay (EIA). A total of 492 neonates were born from January 2020 to December 2020, of which 369 newborns were screened for CAH, CH and G-6-PDD. Of 369 neonates, one case (male) had an increased level of TSH, six cases (all males) had an increased level of 17-OHP and no case was found with G-6-PDD. Preliminary data on the prevalence of various genetic disorders revealed that CAH is the most prevalent disorder followed by CH in the population of Bihar. More efforts need to be undertaken to create awareness and to make screening a successful programme in India. A cost-effective nationwide screening programme is highly recommended for the detection of such cases at the earliest to avoid their future complication.

Optimizing the Dutch newborn screening for congenital hypothyroidism by incorporating amino acids and acylcarnitines in a machine learning-based model.

Congenital hypothyroidism (CH) is an inborn thyroid hormone (TH) deficiency mostly caused by thyroidal (primary CH) or hypothalamic/pituitary (central CH) disturbances. Most CH newborn screening (NBS) programs are thyroid-stimulating-hormone (TSH) based, thereby only detecting primary CH. The Dutch NBS is based on measuring total thyroxine (T4) from dried blood spots, aiming to detect primary and central CH at the cost of more false-positive referrals (FPRs) (positive predictive value (PPV) of 21% in 2007-2017). An artificial PPV of 26% was yielded when using a machine learning-based model on the adjusted dataset described based on the Dutch CH NBS. Recently, amino acids (AAs) and acylcarnitines (ACs) have been shown to be associated with TH concentration. We therefore aimed to investigate whether AAs and ACs measured during NBS can contribute to better performance of the CH screening in the Netherlands by using a revised machine learning-based model. Dutch NBS data between 2007 and 2017 (CH screening results, AAs and ACs) from 1079 FPRs, 515 newborns with primary (431) and central CH (84) and data from 1842 healthy controls were used. A random forest model including these data was developed. The random forest model with an artificial sensitivity of 100% yielded a PPV of 48% and AUROC of 0.99. Besides T4 and TSH, tyrosine, and succinylacetone were the main parameters contributing to the model's performance. The PPV improved significantly (26-48%) by adding several AAs and ACs to our machine learning-based model, suggesting that adding these parameters benefits the current algorithm.

A Positive Newborn Screen for Congenital Hypothyroidism in a Clinically Euthyroid Neonate—Avoiding Unnecessary Treatment

Newborn screening for congenital hypothyroidism (CH) has dramatically improved the neurocognitive outcomes for newborns with a confirmed positive screening test result. However, screening yields a small number of false positive and false negative results. This report describes the first known case of familial dysalbuminaemic hyperthyroxinaemia presenting with a positive newborn thyroid stimulating hormone screen. This condition is characterized by artefactually elevated free tetraiodothyronine (T4) and triiodothyronine (T3) levels due to increased albumin binding and subsequent dissociation during laboratory assays but normal true free thyroid hormone and thyroid stimulating hormone (TSH) levels in a clinically euthyroid subject. This highlights the need to take care when attributing clinical significance to discordant results.

A Preliminary Analysis of Thyrotropin Measurement from Finger Stick Dried Blood Spot with an Automated High-Throughput Immunoassay Analyzer.

Background: Hyper- and hypothyroidism are prevalent in Western countries and often go unnoticed for long periods. Thyrotropin (TSH) as a biomarker of thyroid dysfunction is regularly measured in venous plasma/serum. In newborn screening for congenital hypothyroidism, TSH is measured from dried blood spots (DBSs). DBS enables minimally invasive (at-home) sampling of a small blood volume that can be sent to diagnostic laboratories by regular mail. Methods: In this study, we included 109 patients who presented to the outpatient clinic of the University Medical Center Utrecht. Capillary finger stick was used to spot blood on a filter paper card and was dried. After extraction of TSH from DBS, method comparison with venous TSH was performed on an automated high-throughput immunoassay analyzer. Additional validation steps regarding stability, effect of hematocrit (Hct), precision, and limits of blank and quantitation were conducted according to corresponding Clinical and Laboratory Standards Institute evaluation protocol. Results: Method comparison of TSH from venous plasma versus finger stick DBSs showed an R2 [95% confidence interval] = 0.988 [0.986-0.990]. This enabled correct diagnosis of hypothyrotropinemia and hypothyroidism in 12 of 14 and 6 of 7 cases, respectively, with no false positives. Furthermore, TSH from DBS was stable for at least 4 days at temperatures between -20°C and +30°C, and the maximum decrease of eluate TSH was 1.13% for 1% increase in Hct. Conclusions: TSH from DBS may be accurately measured on an automated high-throughput immunoassay analyzer and could be used to diagnose hypothyroidism and, for the first time, hypothyrotropinemia. This method, when confirmed in larger field studies, may enable individuals to engage in (at-home) sampling of blood on DBSs for telediagnostics, screening programs, patient follow-up, and medication management.

Machine learning to improve false-positive results in the Dutch newborn screening for congenital hypothyroidism

ObjectiveThe Dutch Congenital hypothyroidism (CH) Newborn Screening (NBS) algorithm for thyroidal and central congenital hypothyroidism (CH-T and CH-C, respectively) is primarily based on determination of thyroxine (T4) concentrations in dried blood spots, followed by thyroid-stimulating hormone (TSH) and thyroxine-binding globulin (TBG) measurements enabling detection of both CH-T and CH-C, with a positive predictive value (PPV) of 21%. A calculated T4/TBG ratio serves as an indirect measure for free T4. The aim of this study is to investigate whether machine learning techniques can help to improve the PPV of the algorithm without missing the positive cases that should have been detected with the current algorithm. Design & methodsNBS data and parameters of CH patients and false-positive referrals in the period 2007–2017 and of a healthy reference population were included in the study. A random forest model was trained and tested using a stratified split and improved using synthetic minority oversampling technique (SMOTE). NBS data of 4668 newborns were included, containing 458 CH-T and 82 CH-C patients, 2332 false-positive referrals and 1670 healthy newborns. ResultsVariables determining identification of CH were (in order of importance) TSH, T4/TBG ratio, gestational age, TBG, T4 and age at NBS sampling. In a Receiver-Operating Characteristic (ROC) analysis on the test set, current sensitivity could be maintained, while increasing the PPV to 26%. ConclusionsMachine learning techniques have the potential to improve the PPV of the Dutch CH NBS. However, improved detection of currently missed cases is only possible with new, better predictors of especially CH-C and a better registration and inclusion of these cases in future models.

Guidelines for Newborn Screening of Congenital Hypothyroidism (2021 Revision).

Purpose of developing the guidelines: Newborn screening (NBS) for congenital hypothyroidism (CH) was started in 1979 in Japan, and early diagnosis and treatment improved the intelligence prognosis of CH patients. The incidence of CH was once about one in 5,000-8,000 births, but has been increased with diagnosis of subclinical CH. The disease requires continuous treatment and specialized medical facilities should conduct differential diagnosis and treatment in patients who are positive by NBS to avoid unnecessary treatment. The Guidelines for Mass Screening of Congenital Hypothyroidism (1998 version) were developed by the Mass Screening Committee of the Japanese Society for Pediatric Endocrinology in 1998. Subsequently, the guidelines were revised in 2014. Here, we have added minor revisions to the 2014 version to include the most recent findings. Target disease/conditions: Primary congenital hypothyroidism. Users of the Guidelines: Physician specialists in pediatric endocrinology, pediatric specialists, physicians referring pediatric practitioners, general physicians, laboratory technicians in charge of mass screening, and patients.

A case of syndromic congenital hypothyroidism with a 15.2 Mb interstitial deletion on 2q12.3q14.2 involving &lt;i&gt;PAX8&lt;/i&gt;

Paired box 8 (PAX8) mutations are an established genetic cause of congenital hypothyroidism (CH). The majority of these mutations are found in the protein-coding exons of the gene. The proband, a 3-yr-old girl, had tetralogy of Fallot and polydactyly soon after birth. She was diagnosed with CH in the newborn screening for CH. She had a high serum TSH level (239 mU/L) and low free T4 level (0.7 ng/dL). Ultrasonography revealed thyroid hypoplasia. We performed array comparative genomic hybridization because the patient exhibited a variety of symptoms across multiple organ systems. The analysis revealed a novel heterozygous deletion that spanned a 15.2 Mb region in 2q12.3q14.3 (GRCh37; chr2:109,568,260-124,779,449). There were 71 protein-coding genes in this region, including two genes (PAX8 and GLI2) associated with congenital endocrine disorders. The common clinical features of the two previously reported patients with a total PAX8 deletion and our case were CH, short stature and intellectual disability, but the severity of hypothyroidism and other clinical features were variable. In conclusion, we describe a syndromic CH patient with a novel 2q12.3q14.3 deletion involving PAX8. Patients with CH, whose unifying diagnosis is not obvious, could have a genomic deletion involving PAX8.

Newborn Screening for Congenital Hypothyroidism and Congenital Adrenal Hyperplasia in Egypt

Newborn Screening for Congenital Hypothyroidism and Congenital Adrenal Hyperplasia in Egypt

Treatment of Congenital Hypothyroidism: Impact of Secular Changes in Levothyroxine Initial Dose on Early Growth

Introduction: Newborn screening of congenital hypothyroidism (CH) has enabled early treatment with levothyroxine (LT4), ensuring normal growth and development. The initial LT4 dose recommendation has increased over decades. We evaluated whether the increased LT4 dosing influenced thyroid-stimulating hormone (TSH) and thyroxine (fT4) concentrations, growth, or treatment-related symptoms. Methods: LT4 doses, TSH, fT4, anthropometrics, and treatment-related symptoms until age 2 years were evaluated in 172 Finnish CH patients born between 1980 and 2018. The patients were grouped according to birth decade: 1980s (n = 19, mean LT4 starting dose 6.8 μg/kg/day), 1990s (n = 50, 7.4 μg/kg/day), 2000s (n = 59, 9.7 μg/kg/day), and 2010s (n = 44, 10.8 μg/kg/day). Results: TSH concentrations were higher during the first 2 years of life in children born in the 1980s compared to children born later. TSH concentrations were often subnormal in children receiving higher LT4 doses (children born in the 2000s and 2010s). However, symptoms of overtreatment were uncommon. Linear or head growth showed no differences between the groups during the first 2 years of life. Although growth was within the normal spectrum, children in all groups were shorter than their target length at 2 years and their weight-for-length was above the mean through the first 2 years of life. Discussion: Current treatment practice with higher LT4 dose normalizes TSH rapidly without significant increase in side effects. However, irrespective of initial LT4 dose, children were shorter than expected at 2 years of age. Effects of different initial LT4 dose on cognitive development urges further investigation.

Effectiveness of Health Education toward Healthcare Knowledge Improvement about Congenital Hypothyroidism Newborn Screening

Effectiveness of Health Education toward Healthcare Knowledge Improvement about Congenital Hypothyroidism Newborn Screening

ESTABLISHING A NATIONWIDE NEWBORN SCREENING PROGRAM FOR CONGENITAL HYPOTHYROIDISM: A SYSTEMATIC REVIEW

Objective: The congenital hypothyroidism (CH) is a treatable hormonal disease that if left untreated in neonates, results in irreversible mental retardation. Newborn screening for CH and thyroid hormone replacement therapy started within two weeks of age can control cognitive development. This study aimed to estimate CH incidence in Pakistani population. Material and Methods: Electronic databases and the bibliography of articles were searched, and a systematic review of publications reporting the incidence of CH in Pakistan was carried out. The studies fulfilling the following criteria were analyzed: retrospective and prospective studies, adult population; pediatric population; Thyroid Stimulating Hormone (TSH); Dried Blood Spot (DBS); serum testing quantitative; English language. Results: We identified nine studies that narrated the incidence of CH in our country. According to this systematic review, the maximum estimated incidence of CH was 1:1600 reported for Pakistani population. Compared to the incidence of CH from other parts of the world (1:2000-1:4000), incidence from Pakistan is high. Conclusion: According to these findings, this high incidence highlights the need for a National Newborn Screening (NBS) program for CH. We have proposed a strategy for establishing a nationwide NBS program for CH. Key Words: Newborn screening, Congenital hypothyroidism, Pakistan, Thyroid-stimulating hormone, Mental retardation

Fifty years of newborn screening for congenital hypothyroidism: current status in Australasia and the case for harmonisation

Since its implementation 50 years ago in Quebec, Canada, newborn screening for congenital hypothyroidism has become one of the most successful public health measures worldwide. Screening programmes across Australia and New Zealand are characterised by significant commonalities in screening algorithms, and a high degree of regional cooperation in harmonisation efforts. We aimed to conduct a comprehensive survey of current performance and practices related to the total testing process for congenital hypothyroidism screening and provide recommendations for harmonisation priorities within our region. A survey was conducted involving the six newborn screening laboratories which provide complete geographic coverage across Australasia. Approximately 360,000 newborns are screened annually. Survey questions incorporated pre-analytical, analytical, and post-analytical aspects of the screening programmes and an extensive 5-year (2016-2020) retrospective analysis of individual programme performance data. Responses from individual screening programmes were collated. The uptake of newborn screening was over 98% for the six major jurisdictions. All programmes have adopted a single-tier thyroid stimulating hormone (TSH) strategy using the Perkin Elmer GSP instrument. Significant similarities exist between programmes for recommended age of collection and recollection protocols for low birthweight newborns. The process for the determination of TSH cutoffs varies between programmes. TSH lower cut-offs for borderline-positive and positive notifications between 12-15 and 12-25mIU/L blood, respectively. Recall rates vary between 0.08 and 0.20%. The case definition forcongenital hypothyroidism generally includes biochemical and radiological parameters in addition to the commencement of thyroxine. All programmes reported collecting biochemical and clinical data on infants with positive screening tests, and positive predictive values vary between 23.6 and 77.3%. Variation in reported incidence (1:1,300-2,000) cannot be entirely explained by cutoff or recall rate (although one programme reporting fewer cases includes only permanent disease). Despite similarities between newborn screening algorithms for congenital hypothyroidism across Australia and New Zealand, differences in reported programme performance provide the basis for further harmonisation. Surveillance of a large population offers the potential for the ongoing development of evidence-based screening guidelines.

Newborn Screening in Pediatric Endocrine Disorders

Two endocrine disorders, congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH), when untreated, can have devastating, irreversible and fatal outcomes. Permanent cognitive impairment, growth failure and dysmorphic appearance are seen in congenital hypothyroidism (CH) and early infant death in males with salt wasting CAH (as most females are discovered by presence of atypical genital appearance, while males appeared normal). Newborn screening (NBS) for CH was developed with broader engagement of centers, and was more rapidly adopted throughout the US and other large or developed countries, while NBS for CAH was pioneered by relatively few and was not fully adopted in the US until the initiation of Universal Expanded Newborn Screening Panel in 2005. Advances in genetic understanding of CH and CAH continue with NBS. Cost–benefit analysis, showing CH NBS as more successful than CAH NBS, may not fully recognize the cost of a life saved with CAH NBS. Early treatment of CH is much simpler with taking a pill a day unlike CAH requiring multiple medication doses, and possibly surgery apart from enteral and parenteral stress doses during adrenal crisis. CAH management outcomes with gender identity matters in persons with atypical genital appearance and androgen effects are still being studied.

EP001: Newborn screening experience for very long chain Acyl-CoA Dehydrogenase (VLCAD) deficiency in Kuwait

Among the various inborn errors of fatty acid oxidation disorders, very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is the most common disorder in Kuwaiti population, which has been noticed especially following the launch of the expanded newborn screening program in Kuwait in October 2014. VLCAD deficiency is a rare autosomal recessive disorder with a worldwide incidence of 1:30,000 to 1:100,000 births. It is caused by deficiency of VLCAD coenzyme, encoded by ACADVL gene which converts very-long-chain fatty acids into energy. In October 2014, the Kuwait Ministry of Health has started a publicly funded expanded newborn screening program meeting the highest international standards to screen for a wide range of metabolic and endocrine disorders including a total of 22 disorders via testing dried blood spots and thus replacing the old, limited newborn screening for congenital hypothyroidism and phenylketonuria that was introduced in 2005. A retrospective analysis of the data registry for the newborn screening over the 6-year period between January 2015 and December 2020 in Kuwait has been conducted after obtaining consent from the newborn screening program. This data included newborns delivered in hospitals all over Kuwait. Data on metabolite concentrations in dried blood spots at the time of screening obtained from all newborns were reviewed and only dried blood spots detecting elevated blood C14:1 (cutoff 0.29 mmol/L) and C14:1/C2 ratio (cutoff 0.03) via tandem mass spectrometry (MS/MS) were included in this study. The positive initial screening is followed by a confirmatory plasma or dried blood acylcarnitine analysis (cutoff ≥ 1 mmol/L) with or without a follow-up genetic analysis of ACADVL gene, either targeted variant testing using PCR amplification followed by Sanger sequencing, or through next generation sequencing technology. Total of 36 cases (19 male/17 female) out of 304,086 screened newborns have been identified and confirmed to have VLCAD deficiency with an incidence of ∼1:8300. The diagnosis was based on the detection of elevated blood C14:1 and C14:1/C2 ratio in the initial dried blood spots in the newborn screening, followed by a confirmatory plasma or dried blood acylcarnitines profile for VLCAD deficiency with or without a follow-up genetic analysis, except for three babies who had positive initial screen but have died before obtaining confirmatory acylcarnitine or genetic analyses. Out of the 36 individuals, there were 3 cases from Kingdom of Saudi Arabia, 2 cases from India and the rest were Kuwaiti. Molecular testing of 24 of them has revealed a founder truncating pathogenic variant in exon 2 of the ACADVL gene, * c.65C>A; p.(Ser22Ter); the reference transcript is NM_001178008.2(hg19/GRCh3). We have identified three genetically confirmed cases with VLCAD deficiency following a positive initial screen but negative confirmatory acylcarnitine analysis. Furthermore, we identified four heterozygous individuals for VLCAD deficiency via molecular testing, after a positive initial newborn screening and normal confirmatory acylcarnitine profile. This is the first study to review the Kuwaiti newborn screening experience of VLCAD deficiency since its launch in October 2014. We recommend including molecular genetic testing for ACADVL gene as part of the newborn screening for VLCAD deficiency particularly for the cases with negative confirmatory acylcarnitine profile. Our study provides evidence that the expanded newborn screening in Kuwait has led to the early detection of VLCAD deficiency cases and thus the initiation of the adequate management plan for these individuals aiming to prevent death and disability.

Reference Intervals of Serum TSH from Mixed Distributions Using Truncation Points and the Kolmogorov-Smirnov Distance.

Serum TSH reference intervals (RIs) are methodology, population, and age specific. However, the ethical and practical challenges restrict the establishment of pediatric RIs using conventional approaches and advocates the use of indirect data mining-based algorithms. This study was carried out to estimate the reference interval of neonatal serum TSH in Pakistani population using an indirect approach. A data mining of serum TSH results of neonates (≤ 1 month of age) from 2013 - 2018 was done. Two subgroups on the basis of age from birth to 5 days and 6 - 30 days were assessed. The German study group's pre-validated indirect algorithm 'KOSMIC' was utilized for the statistical analysis. A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved over a period of 6 years, including 88% (n = 70,788) aged 0 - 5 days and 12% (n = 11,511) ranging from 6 days to 1 month. The estimated RIs for the first age partition was 0.7 (90% CI 0.6 - 0.8) to 15.5 (90% CI 12.9 - 16.2) and for the second group 0.7 (90% CI 0.5 - 0.9) to 7.8 (90% CI 6.1 - 9.9) µIU/mL. This study revealed age related trends in serum TSH. The study advocates the need for population specific RIs owing to the significant variations noted on comparison with previously published literature. Precise RIs become vital particularly when serum TSH is undertaken as a confirmatory test for presumptive positive results on newborn screening for congenital hypothyroidism.

50 Years of Newborn Screening for Congenital Hypothyroidism: Current Status in Australasia and the Case for Harmonisation

50 Years of Newborn Screening for Congenital Hypothyroidism: Current Status in Australasia and the Case for Harmonisation

Screening of hypothyroidism disorder in newborns by heel prick level of thyroid-stimulating hormones.

Background: Thyroid hormones are vital for fetal development and regulation of neuropsychological function. Therefore an adequate amount of thyroid hormone levels are necessary for brain development cognitive function. Newborn screening for congenital hypothyroidism is a great achievement in preventive medicine. Screening for hypothyroidism disorder using heel prick samples is considered essential for preventing intellectual dysfunction and delayed growth. The objective of the present study was to determine the frequency of hypothyroidism disorder in newborns.&#x0D; Methodology: A cross-sectional study was conducted at Abbasi Shaheed Hospital, Gynae &amp; Obstetrics Department, Karachi, Pakistan. Blood samples were obtained from 257 neonates between 3rd &amp; 5th day after birth by the heel prick method. Babies of Mothers having thyroid diseases were excluded from the study. Serum Thyroid-stimulating hormones (TSH) were tested using the enzyme-linked immunosorbent assay method. Newborn serum TSH &gt; 20 miu/L was considered abnormal.&#x0D; Results: The overall mean age of neonates was 3.47 ± 0.57 days. Out of the total 257 neonates screened, female babies had higher TSH levels and congenital hypothyroidism was found in 4(1.55%) cases. The observed mean TSH level was 4.09 ± 0.24 mIU/L. &#x0D; Conclusion: In conclusion, the observed frequency of neonatal hypothyroidism in this single-center study prompts the need for early screening and diagnosis. The screening should be included in the post-natal period to prevent sequels associated with hypothyroidism for timely diagnosis and treatment of newborns.