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.

Pierpont syndrome is a rare disorder characterized mainly by global developmental delay, unusual facial features, altered fat distribution in the limbs, and hearing loss. A specific mutation (p.Tyr446Cys) in TBL1XR1, encoding a WD40 repeat-containing protein which is a component of the SMRT/NCoR corepressor, has been reported as the genetic cause of Pierpont syndrome. Here we used CRISPR-cas9 technology to generate a mutant mouse with the Y446C mutation in Tbl1xr1 which is also present in Pierpont syndrome. Several aspects of the phenotype were studied in the mutant mice: growth, body composition, hearing, motor behavior, thyroid hormone state and lipid and glucose metabolism. The mutant mice (Tbl1xr1Y446C/Y446C) displayed delayed growth, altered body composition with increased relative lean mass, and impaired hearing. Expression of several genes involved in fatty acid metabolism differed in white adipose tissue, but not in liver or muscle of mutant mice compared to wild type mice (Tbl1xr1+/+). No difference in thyroid hormone plasma concentrations was observed. Tbl1xr1Y446C/Y446C mice can be used as a model for distinct features of Pierpont syndrome which will enable future studies on the pathogenic mechanisms underlying the various phenotypic characteristics.

Antibodies against the so called 'second colloid antigen' (CA2 antibodies) occurred in 51% of the mothers of hypothyroid children detected by screening for neonatal congenital hypothyroidism in Quebec (N = 49) and in The Netherlands (N = 26). In The Netherlands where corresponding neonatal serum was available, 31% (8 of 26) of the infants with congenital hypothyroidism were positive for antibodies against the second colloid antigen. When during follow-up, 3 to 5 years after diagnosis, the mothers and their children were investigated, 46% (7 of 15) of the mothers were positive for antibodies against the second colloid antigen, whereas 29% (4 of 14) of the hypothyroid children were also positive. Various control groups did not show more than a 12% positivity. This presence of thyroid-reactive antibodies in a proportion of the hypothyroid children 3 to 5 years after diagnosis is not compatible with a mere transplacental passage; it indicates that the antibodies must be produced by the mothers and by the children themselves. We conclude that a thyroid autoimmune response occurs in a considerable part of infants with congenital hypothyroidism and their mothers and that this immune response seems to persist in both of them for years.In 1985 were reported the presence of immunoglobulins (Igs) blocking TSH-induced thyroid growth in the sera of about 50% of mothers giving birth to infants with sporadic congenital hypothyroidism (CH). Sera of the infants also contained the growth blocking Igs (1,2). These results suggested a trans¬ placental passage of maternal Igs influencing TSHinduced processes of thyroid growth which might be important in the pathogenesis of sporadic CH. Later Peters et al. (3) and recently Bogner et al. (4) also reported the presence of thyroid-reactive Igs in sera of CH children and their mothers; they de¬ scribed both growth blocking, in approximately 50% of maternal and infant sera, and thyroid cyto¬ toxic antibodies, in approximately 25% of maternal and infant sera. As early as in 1961 Balfour et al. (5) demonstrated an autoimmune involvement in CH.These authors discovered a new kind of thyroid autoantibodies directed towards a colloidal antigen, called 'second colloid antigen' (CA2). They showed in absorption and precipitation experi¬ ments that these antibodies were distinct from autoantibodies against the first colloidal antigen, thyroglobulin. CA2 antibodies were found in the sera of 4 out of 11 mothers of'athyreotic cretins' as well as in sera of patients with nowadays well estab¬ lished thyroid autoimmune disorders such as Ha¬ shimoto's thyroiditis (95-100%), atrophie thyroiditis (35-45%) and Graves' disease (40-50%).Since the initial report of Balfour et al., the antigen specificity and clinical relevance of CA2 antibodies have only scarcely been studied. Yet it has become clear that CA, antibodies are not pres¬ ent only in well-established thyroid autoimmune diseases but that they also occur in de Quervain's subacute thyroiditis. In this putatively viral disor-

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