Background: An ENDO-European Reference Network (ERN) initiative was launched that was endorsed by the European Society for Pediatric Endocrinology and the European Society for Endocrinology with 22 participants from the ENDO-ERN and the two societies. The aim was to update the practice guidelines for the diagnosis and management of congenital hypothyroidism (CH). A systematic literature search was conducted to identify key articles on neonatal screening, diagnosis, and management of primary and central CH. The evidence-based guidelines were graded with the Grading of Recommendations, Assessment, Development and Evaluation system, describing both the strength of recommendations and the quality of evidence. In the absence of sufficient evidence, conclusions were based on expert opinion. Summary: The recommendations include the various neonatal screening approaches for CH as well as the etiology (also genetics), diagnostics, treatment, and prognosis of both primary and central CH. When CH is diagnosed, the expert panel recommends the immediate start of correctly dosed levothyroxine treatment and frequent follow-up including laboratory testing to keep thyroid hormone levels in their target ranges, timely assessment of the need to continue treatment, attention for neurodevelopment and neurosensory functions, and, if necessary, consulting other health professionals, and education of the child and family about CH. Harmonization of diagnostics, treatment, and follow-up will optimize patient outcomes. Lastly, all individuals with CH are entitled to a well-planned transition of care from pediatrics to adult medicine. Conclusions: This consensus guidelines update should be used to further optimize detection, diagnosis, treatment, and follow-up of children with all forms of CH in the light of the most recent evidence. It should be helpful in convincing health authorities of the benefits of neonatal screening for CH. Further epidemiological and experimental studies are needed to understand the increased incidence of this condition.

contributed equally to this work Steroid receptor co-activator 1 (SRC-1) is a transcription co-factor that enhances the hormone-dependent action, mediated by the thyroid hormone (TH) receptor (TR) and other nuclear receptors. In vitro studies have shown that SRC-1 is necessary for the full expression of TH effect. SRC-1 knockout mice (SRC-1 -/-) provide a model to examine the role of this co-activator on TH action in vivo. At baseline, SRC-1 -/-mice display resistance to TH (RTH) as evidenced by a 2.5-fold elevation of serum TSH levels, despite a 50% increase in serum free TH levels as compared with wild-type (SRC-1 ϩ/ϩ ) mice. When mice were made hypothyroid, TSH levels increased, obliterating the difference between SRC-1 ϩ/ϩ and SRC-1 -/-mice observed at baseline. In contrast, the decline of TSH by treatment with L-triiodothyronine was severely blunted in SRC-1 -/-mice. These data indicate that SRC-1 is not required for the upregulation of TSH in TH deficiency. However, SRC-1 enhances the sensitivity of TSH downregulation by TH. This is the first demonstration of RTH caused by a deficient co-factor other than TR. It supports the hypothesis that a putative defect in the SRC-1 gene or another co-factor could be the cause of RTH in humans without mutations in the TR genes.

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We report an improved heterologous radioimmunoassay (RIA) for the measurement of thyrotropin (TSH) in mouse serum. The assay components are: antirat thyrotropin (rTSH) serum from the National Hormone and Pituitary Program, a commercial [125I]-labeled rTSH and mouse thyrotropin (mTSH) serum standards produced by dilution of a serum pool from hypothyroid mice with high TSH with a serum pool from mice treated with excess levothyroxine (LT4) (mTSH-0). Sensitivity was increased by reducing the amount of antibody and tracer and by taking advantage of the disequilibrium technique. Accuracy was greatly improved by the preparation of mouse serum TSH standards. TSH in serial dilutions of individual mice with high TSH of different etiologies paralleled the mTSH standard curve but not that of rTSH or a crude mouse TSH/luteinizing hormone (LH) reference preparation. The high-mTSH-serum standard contained 20 mU TSH per milliliter, measured in a bioassay utilizing a cell line stably transfected with human TSH receptor cDNA, and a relative TSH concentration of 40 ng/mL. The sensitivity of the RIA is 0.01 to 0.02 ng/mL, depending on the quality of the tracer and the preparation of mTSH-0 serum. The intra-assay and interassay coefficients of variations were, respectively: 16% and 27% at 0.04 ng/mL; 6.3% and 8.2% at 0.4 ng/mL; 5.4% and 9.8% at 1.7 ng/mL; 10% and 24% at 4.0 ng/mL. The mean TSH concentration in serum of 60-80-day-old male mice was four-fold higher than that in females of the same age. The assay was able to distinguish differences in serum TSH concentrations in five different strains of mice. Baseline serum TSH concentrations (mean +/- SD) of 70-day-old male mice were: 0.143 +/- 0.065 ng/mL in the CD-1 strain; 0.229 +/- 0.042 ng/mL in C57BL/6 mice; 0.084 +/- 0.017 ng/mL in SWR/J mice; 0.133 +/- 0.057 ng/mL in NOD SCID mice, and 0.266 +/- 0.122 ng/mL in FVB mice. Mean serum thyroxine (T4) concentrations were also significantly different among the mouse strains but did not correlate with the serum TSH level. Administration of levotriiodothyronine (LT3) suppressed the serum TSH to a greater degree in mice with higher baseline TSH values. Suppression of the thyroidal radioiodide uptake with LT3 correlated with that of serum TSH.

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