No abstract

Newborn screening for congenital adrenal hyperplasia (CAH) is justified by the sometimes difficult clinical diagnosis and the risks associated with missed diagnosis, particularly the life-threatening salt-wasting crisis. In Switzerland, nationwide screening for CAH by measuring 17-hydroxyprogesterone levels in dried blood spots was introduced in 1992. At the Zurich University Children's Hospital, 50% of the population of Switzerland is screened. The aim of the study was to evaluate the efficiency of the Zurich screening program. Between January 1, 1993, and May 31, 2001, 333,221 newborns were screened for CAH. Thirty-one newborns had CAH (incidence, 1 in 10,749); 30 were detected through screening (sensitivity, 97%). A recall for suspected CAH was performed in only 60 cases, corresponding to a very low recall rate (0.0018%). In 30 recalls CAH was confirmed (positive predictive value, 50%; specificity, 99.99%). Fifteen of 31 patients profited from screening, as CAH had not been recognized clinically. The timely availability of screening results made therapy possible within the first week of life in most cases and helped in preventing salt-wasting crisis in all patients. With a sensitivity of 97%, a specificity of 99.99%, and a positive predictive value of 50%, the Zurich neonatal screening program for CAH can be considered highly reliable.

Background: P450c17 has two distinct activities: 17α-hydroxylase activity and 17,20-lyase activity. Combined 17α-hydroxylase/17,20-lyase deficiency leads to a severe defect in the production of cortisol and sex steroids. In affected males this results in impaired masculinization with ambiguous or female external genitalia. Female patients have normal genitalia but show a lack of pubertal development in adolescence. An increased production of mineralocorticoids often leads to hypertension and hypokalemia in both sexes. Methods: To better understand the mechanisms of P450c17 deficiency, we studied 2 patients (both 46,XY) with combined 17α-hydroxylase/17,20-lyase deficiency of different severity: one with complete lack of masculinization and one with ambiguous genitalia. Results: Four mutations were identified by sequencing of the CYP17A1 gene: I332T and A355T in the less severely affected patient; G111S and R440H in the patient with complete lack of masculinization. The three novel mutations were expressed in COS1 cells and all mutant proteins except I332T showed a complete loss of both enzymatic activities. I332T retained some residual 17α-hydroxylase as well as 17,20-lyase activity. Conclusion: We identified 2 patients with the phenotypical spectrum of P450c17 deficiency. Three novel mutations in the CYP17A1 gene were identified and their functional characterization provided a good phenotype-genotype correlation. The location of the mutated residues in the three-dimensional model of P450c17 gave some additional insights into its structure-function relationship.

Disorders of isolated mineralocorticoid deficiency causing potentially life-threatening saltwasting crisis early in life have been associated with gene variants of aldosterone biosynthesis or resistance, but in some patients no such variants are found. WNT/β-catenin signaling is crucial for differentiation and maintenance of the aldosterone producing adrenal zona glomerulosa (zG). We describe a highly consanguineous family with multiple perinatal deaths or infants presenting at birth with failure to thrive, severe salt-wasting crises associated with isolated hypoaldosteronism, nail anomalies, short stature, and deafness. Whole exome sequencing revealed a homozygous splice variant in the R-SPONDIN receptor LGR4 gene (c.618-1G>C) regulating WNT signaling. The resulting transcripts affected protein function and stability, and resulted in loss of Wnt/β-catenin signaling in vitro. The impact of LGR4 inactivation was analyzed by adrenal cortex specific ablation of Lgr4, using Lgr4 Flox/Flox mated with Sf1:Cre mice. Inactivation of Lgr4 within the adrenal cortex in the mouse model caused decreased WNT signaling, aberrant zonation with deficient zG and reduced aldosterone production. Thus, human LGR4 mutations establish a direct link between LGR4 inactivation and decreased canonical WNT signaling with abnormal zG differentiation and endocrine function. Therefore, variants in WNT signaling and its regulators should systematically be considered in familial hyperreninemic hypoaldosteronism.

BackgroundThyroid hormones are essential for normal growth and puberty in children and adolescents. Graves’ disease (GD) is a rare autoimmune disorder associated with thyroid hormone over-production and occurs in 0.5–2:100’000 children (mostly females) in Europe. In contrast to adults, first line treatment of GD is long-term antithyroid drug (ATD) therapy, and radioiodine ablation is usually being reserved for patients after puberty. However, treatment of acquired hyperthyroidism with ATD is difficult since 1) paediatric patients differ considerable in age, weight and diseases severity and 2) minimal ATD dose should be used to avoid mild side effects (occurring in 6–35% of patients), and rare severe side effects such as agranulocytosis and liver failure.MethodsLongitudinal clinical and laboratory data from a Swiss multicentre cohort were analysed retrospectively. Non-linear mixed effects modelling was applied to characterize dynamics of free thyroxine (FT4) during the first 3 months of treatment with carbimazole. Sex, co-medications such as propranolol, and thyroid stimulating hormone receptor antibody were tested as covariates on model parameters. Reference range for FT4 was derived from target levels in clinical practice (12–22 pmol/L).ResultsStudy cohort comprised 45 children with GD, 78% females, median age 12.2 years (IQR = [8.7,13.6])) with a total of 181 visits. FT4 baseline at diagnosis of GD was 62.3 pmol/L (IQR = [45.7, 86.7]). None of the tested factors showed significant covariate effects. The model allows individual simulations of optimal ATD dosing strategies (starting and maintenance dose) for different GD severities, ages and weights at start of therapy. Personalized dosing examples will be presented.ConclusionsDeveloped pharmacometric model is able to predict dynamics of FT4 in children with GD depending on four parameters: ATD dose/kg/d, age, weight and disease severity, and can be applied to personalize dosing regimen to avoid over- or under dosing.Disclosure(s)Nothing to disclose