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Concept: Newborn screening


Congenital hypothyroidism, usually of the primary and permanent variety, is an eminently preventable cause of growth retardation and mental handicap whose outlook has been transformed by newborn screening, usually involving the measurement of capillary TSH. Severe primary congenital hypothyroidism, due for example to athyreosis, may result in subtle cognitive, behavioural and sensori-motor deficits, but the extent to which these can be offset by optimal postnatal diagnosis and management remains uncertain. This is because the available adult follow-up data reflect the outcome of previous management in the 1970’s and 1980’s, and also because the accurate neuro-psychological assessment of children is difficult, particularly in the preschool population. There is an urgent need to develop new consensus guidelines and to ensure that the children managed according to such guidelines are systematically and prospectively assessed so that good quality outcome data become available. In this review, key recommendations in the management of congenital hypothyroidism include: screening at day 3 so that severely affected infants can begin treatment within the first 10 days of life; setting the thyrotropin (TSH) referral cut-off at 8-10 mU/L; adopting a disciplined diagnostic algorithm to evaluate referred cases, with measurement of venous free thyroxine (T4), TSH and thyroglobulin combined with dual ultrasound and radioisotope imaging; initial treatment with a T4 dose of 50 μg daily in infants weighing ≥ 2.5 kg and 15 μg/kg/day in infants weighing < 2.5 kg followed by weekly review until thyroid function is normalised; and maintenance of free T4 levels between 15-26 pmol/L and TSH between 0.5-5 mU/L thereafter to avoid both under- and overtreatment.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Thyroxine, Newborn screening, Congenital hypothyroidism


Cerebrotendinous xanthomatosis (CTX) is a rare, difficult to diagnose genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be beneficial since an effective oral therapy for CTX is available to prevent disease progression. There is no suitable test to screen newborn dried bloodspots (DBS) for CTX. Blood screening for CTX is currently performed by GC-MS measurement of elevated 5α-cholestanol. We present here LC-ESI/MS/MS methodology utilizing keto derivatization with (O-(3-trimethylammonium-propyl) hydroxylamine) reagent to enable sensitive detection of ketosterol BA precursors that accumulate in CTX. The availability of isotopically enriched derivatization reagent allowed ready tagging of ketosterols to generate internal standards for isotope dilution quantification. Ketosterols were quantified and their utility as markers for CTX compared to 5α-cholestanol. 7α12α-Dihydroxy-4-cholesten-3-one provided the best discrimination between CTX and unaffected samples. In two CTX newborn DBS concentrations of this ketosterol (120-214 ng/ml) were around 10-fold higher than in unaffected newborn DBS (16.4±6.0 ng/ml), such that its quantification provides a test with potential to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefit those affected with CTX, preventing morbidity and mortality.

Concepts: Infant, Cancer, Disease, Death, Prevention, Quantification, Newborn screening, Cerebrotendineous xanthomatosis


Rectal atresia is a rare anorectal malformation, and its association with other anomalies is even more rare. This study presents a unique case of co-twin in which the surviving newborn male underwent surgery due to rectal atresia. Newborn screening tests identified congenital hypothyroidism. The surgical treatment consisted of three stages and thyroid hormones were replaced.

Concepts: Medicine, Thyroid disease, Hypothyroidism, Thyroid, Thyroid hormone, Congenital disorders, Newborn screening, Congenital hypothyroidism


Of the 2007 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) mutations, 202 have been assigned disease liability. California’s racially diverse population, along with CFTR sequencing as part of newborn screening model, provides the opportunity to examine the phenotypes of children with uncategorized mutations to help inform disease liability and penetrance.

Concepts: Cancer, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator, The Opportunity, Newborn screening, Sweat test, ΔF508, Congenital absence of the vas deferens


Newborn screening for cystic fibrosis enables early detection and management of this debilitating genetic disease. Implementing comprehensive CFTR analysis using Sanger sequencing as a component of confirmatory testing of all screen-positive newborns has remained impractical due to relatively lengthy turnaround times and high cost. Here, we describe CFseq, a highly sensitive, specific, rapid (<3 days), and cost-effective assay for comprehensive CFTR gene analysis from dried blood spots, the common newborn screening specimen. The unique design of CFseq integrates optimized dried blood spot sample processing, a novel multiplex amplification method from as little as 1 ng of genomic DNA, and multiplex next-generation sequencing of 96 samples in a single run to detect all relevant CFTR mutation types. Sequence data analysis utilizes publicly available software supplemented by an expert-curated compendium of >2000 CFTR variants. Validation studies across 190 dried blood spots demonstrated 100% sensitivity and a positive predictive value of 100% for single-nucleotide variants and insertions and deletions and complete concordance across the polymorphic poly-TG and consecutive poly-T tracts. Additionally, we accurately detected both a known exon 2,3 deletion and a previously undetected exon 22,23 deletion. CFseq is thus able to replace all existing CFTR molecular assays with a single robust, definitive assay at significant cost and time savings and could be adapted to high-throughput screening of other inherited conditions.

Concepts: DNA, Genetics, Bioinformatics, Molecular biology, Positive predictive value, Cystic fibrosis, Assay, Newborn screening


Purpose: We provide background information/education for national recommendations to include initial newborn screening dried bloodspot serial numbers in electronic birth registrations. Mutual data linking would provide quality checks for each data source, determinations of percentages of newborns screened, and identification of locations where screening is lacking.Methods: State newborn screening dried bloodspot programs were surveyed to determine the extent of newborn screening dried bloodspot and electronic birth registration linking and the states' level of interest in such linkages. These data were reviewed with federal and state policy makers and presented to the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children for national policy recommendations.Results: Only 40% of state newborn screening dried bloodspot programs reported comparing births with screens. All states use serially numbered newborn screening dried bloodspot collection cards, and electronic birth registrations exist in almost all states. Newborn screening dried bloodspot serial number data fields currently exist in only 24% of state electronic birth registrations.Conclusion: The Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children recommends the universal use of the newborn screening dried bloodspot serial number in a standardized format as part of state birth registration; consideration of including the initial newborn screening dried bloodspot serial number as a required data field; and, once established, using these data linkages to monitor completeness of newborn screening and to validate demographic information in both systems.Genet Med 2013:15(3):229-233.

Concepts: Childbirth, Number, Newborn screening, Genealogy, Serial number, Birth certificate, Birth registration in Ancient Rome, Serial numbers


Context:Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open.Objective:The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features.Methods:Data recorded in the Italian National Registry of infants with CH were analyzed.Results:Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of <15.0 μU/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 μU/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (≤15 μU/mL), 19.6% had thyroid dysgenesis with serum TSH levels at confirmation of the diagnosis ranging from 9.9 to 708 μU/mL. These babies would have been missed at screening if the cutoff had been higher.Conclusions:Lowering TSH cutoff in our country has enabled us to detect additional cases of permanent CH, a number of which had defects of thyroid development and severe hypothyroidism at confirmation of the diagnosis.

Concepts: Infant, Thyroid-stimulating hormone, Thyroid disease, Thyroid, Thyroid hormone, Pediatrics, Newborn screening, Congenital hypothyroidism


OBJECTIVE: To evaluate cardiac function in infants with congenital adrenal hyperplasia (CAH) before and after corticosteroid replacement therapy. STUDY DESIGN: This prospective, case-control study included 9 infants with CAH. Cardiac function was assessed by echocardiography at presentation and after corticosteroid replacement therapy. Six term infants underwent 2 echocardiograms each and served as the control group. Data on fractional shortening (FS), rate-corrected velocity of circumferential fiber shortening (V(cf)), wall stress, tissue Doppler indices, myocardial performance index, left ventricular mass, and V(cf)/wall stress were obtained. RESULTS: The infants with CAH exhibited myocardial dysfunction at baseline and lower systolic blood pressure (SBP) compared with the control group. FS, a measure of systolic contractility, differed significantly from before to after corticosteroid treatment (mean, 32.3% ± 4.7% pretreatment, 39.9% ± 5.0% posttreatment). V(cf), a preload-independent measure of cardiac contractility, also differed significantly before and after treatment (mean, 1.23 ± 0.16 circumferences/second pretreatment, 1.45 ± 0.22 circumferences/second posttreatment). SBP was also lower (mean, 84 ± 9.3 mmHg) and improved with treatment (mean, 95 ± 4.8 mmHg). The control group demonstrated no statistically significant changes in FS, V(cf), or SBP. There was a change in left ventricular mass in the control group between the 2 studies. CONCLUSION: Newborns with CAH have evidence for cardiac dysfunction at baseline that reverses with corticosteroid replacement therapy. These data suggest that corticosteroids play a direct role in modulating cardiac function in the newborn.

Concepts: Infant, Blood, Myocardial infarction, Cardiology, Heart, Congenital adrenal hyperplasia, Newborn screening, Adrenal insufficiency


Infants are screened for Cystic Fibrosis (CF) in New York State (NYS) using an IRT-DNA algorithm. The purpose of this study was to validate and assess clinical validity of the FDA-cleared Illumina MiSeqDx CF 139-Variant Assay (139-VA) in the diverse NYS CF population. The study included 439 infants with CF identified via newborn screening (NBS) from 2002-2012. All had been screened using the Abbott Molecular CF Genotyping Assay or the Hologic InPlex CF Molecular Test. All with CF and 0-1 mutations were tested using the 139-VA. DNA extracted from dried blood spots was reliably and accurately genotyped using the 139-VA. Sixty-three additional mutations were identified. Clinical sensitivity of three panels ranged from 76.2% (23 mutations recommended for screening by ACMG/ACOG), to 79.7% (current NYS 39-mutation InPlex panel), up to 86.0% for the 139-VA. For all, sensitivity was highest in Whites and lowest in the Black population. Although the sample size was small, there was a nearly 20% increase in sensitivity for the Black CF population using the 139-VA (68.2%) over the ACMG/ACOG and InPlex panels (both 50.0%). Overall, the 139-VA is more sensitive than other commercially-available panels, and could be considered for NBS, clinical or research laboratories conducting CF screening. This article is protected by copyright. All rights reserved.

Concepts: Sample, DNA, Cystic fibrosis, Pediatrics, All rights reserved, Copyright, Newborn screening, New York


Cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, continues to present diagnostic challenges. Newborn screening and an evolving understanding of CF genetics have prompted a reconsideration of the diagnosis criteria.

Concepts: DNA, Gene, Genetics, Bacteria, Evolution, Diagnosis, Cystic fibrosis, Newborn screening