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Purpose: Graves' orbitopathy (GO) is a rare condition in children often considered to be a less severe condition than at an older age. The aim of our study was to analyse if there are any factors that distinguish paediatric from adult GO in order to provide guidelines for assessing and managing paediatric GO. Methods: Study design is a multicentre retrospective observational case series; 115 paediatric patients diagnosed with GO who visited our university medical centres in the Netherlands and Iran between 2003 and 2019 were submitted for complete ophthalmological examinations, serological testing and/or orbital imaging. Main outcome measures focussed on the natural course and clinical picture as well as medical and surgical treatment in paediatric GO. Results: Clinical findings included proptosis (n = 97; 84.3%), eyelid retraction (n = 77; 67%) and diplopia (n = 13; 11.3%). Ninety‐two patients (80%) presented with mild disease, 21 (18.3%) with moderate‐severe disease and two (1.7%) with severe GO. Five patients (4.3%) underwent intravenous glucocorticoids and 25 patients underwent orbital decompression surgery. Strabismus surgery due to primary involvement of extraocular muscles was performed in two patients (1.7%). Overall, rehabilitative surgical treatment was planned in 31 patients (26.9%) with inactive disease. Two patients experienced reactivation of the disease. Conclusion: Despite the fact that paediatric and adult GO are considered two separate entities, they might be the same disease with two different clinical phenotypes. Paediatric GO population presents with a comparable clinical picture regarding both soft tissue involvement and proptosis, which may require surgical intervention. Proptosis was present in the majority of paediatric GO patients. Orbital decompression was performed in 21.7% of patients. [ABSTRACT FROM AUTHOR]

Congenital adrenal hyperplasia (CAH) is a rare, inherited disorder of adrenal steroid synthesis. In many countries it is part of the neonatal screening program enabling early diagnosis and treatment. In case of an abnormal neonatal screening result or when other differences of sexual development (DSD) are suspected, measurement of serum steroid hormones using liquid chromatography coupled to mass spectrometry (LC-MS/MS) is needed for further diagnosis. However, reliable age- and sex-specific reference intervals (RIs) for serum steroid hormones during the neonatal period are missing. We therefore aimed to establish LC-MS/MS based RIs for serum steroid hormones in neonates.Serum was obtained from healthy term neonates at two time points: 130 samples at day 3–8 (T1, time of the neonatal screening) and 126 samples at day 13–15 (T2, two weeks old). Concentrations of cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) were measured using LC-MS/MS.RIs (in nmol/L) were established for T1 and T2: cortisone (19.3–215;18.0–212), cortisol (10.0–407;8.4–446), corticosterone (<31;<50), 11-deoxycortisol (0.73–4.6;0.70–3.6), 17-OHP (<4.9;<5.1), androstenedione (0.3–1.8;0.3–2.7), 11-deoxycorticosterone (<0.2;<0.2), and 21-deoxycortisol (<1;<1), respectively. Testosterone differed between boys and girls: RIs at T1 and T2 for boys were 0.27–4.3 and 0.63–13.9, and for girls<0.30 and <0.47, respectively.We established LC-MS/MS based RIs for cortisol, cortisone, corticosterone, 11-deoxycortisol, 21-deoxycortisol, 11-deoxycorticosterone, testosterone, androstenedione, and 17-OHP in neonates in the first and second week of life. [ABSTRACT FROM AUTHOR]

Humans with the mutation Y509C in transducin beta like 1 X-linked (TBL1X HGNC ID HGNC:11585) have been reported to present with the combination of central congenital hypothyroidism and impaired hearing. TBL1X belongs to the WD40 repeat-containing protein family, is part of NCoR and SMRT corepressor complexes, and thereby involved in thyroid hormone signaling. In order to investigate the effects of the Y509C mutation in TBL1X on cellular thyroid hormone action, we aimed to generate a hemizygous male mouse cohort carrying the Tbl1x Y459C mutation which is equivalent to the human TBL1X Y509C mutation using CRISPR/Cas9 technology. Hemizygous male mice were small at birth and inactive. Their life span (median life span 93 days) was very short compared with heterozygous female mice (survived to >200 days with no welfare issues). About 52% of mice did not survive to weaning (133 mice). Of the remaining 118 mice, only 8 were hemizygous males who were unable to mate whereby it was impossible to generate homozygous female mice. In conclusion, the Tbl1x Y459C mutation in male mice has a marked negative effect on birth weight, survival, and fertility of male mice. The present findings are unexpected as they are in contrast to the mild phenotype in human males carrying the equivalent TBL1X Y509C mutation. [ABSTRACT FROM AUTHOR]

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 (silencing mediator retinoid and thyroid hormone receptors/nuclear receptor corepressors), 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., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Congenital hypothyroidism (CH) is one of the most common preventable forms of mental retardation and since the implementation of neonatal screening programs in the mid-1970s, early detection and treatment have proven to be very successful in preventing brain damage. CH may be of thyroidal (= primary) or of hypothalamic-pituitary (= central) origin. Primary CH may be due to abnormal thyroid gland formation (dysgenesis) or defective thyroid hormone syntheses by a structurally normal gland (dyshormonogenesis). While thyroid dysgenesis is the most common form of CH, accounting for approximately 85% of cases, genetic defects are only found in a very low proportion of patients. On the other hand, thyroid dyshormonogenesis is less common, but is usually a genetic condition with autosomal recessive inheritance. In this review we provide an overview of all known monogenetic causes of primary CH, including promising new candidate genes. In addition, alternative genetic mechanisms are discussed., (Copyright© of YS Medical Media ltd.)

We present a 15-year-old girl and an 11-year-old boy who were prescribed dexamphetamine for treatment of Attention Deficit Hyperactivity Disorder (ADHD), and who subsequently presented with symptoms indicative of Cushing's syndrome. It turned out that both children had taken high doses of dexamethasone instead of dexamphetamine due to an error made by the pharmacist. The diagnosis of exogenous Cushing's syndrome is easily made. However, it is a serious condition with possibly severe and persistent complications. The substitution of dexamethasone for dexamphetamine has been described before. Both doctors and pharmacists should be aware of this possible error.