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Objective Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. Methods Data were collected from 461 patients aged 0–18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. Results The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0–14.5) mg/m2/day at age 1–8 years and the highest dose of 14.0 (11.6–17.4) mg/m2/day at age 12–18 years. Glucocorticoid doses decreased after 2010 in patients 0–8 years (P < 0.001) and remained unchanged in patients aged 8–18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Background Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. Methods Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. Results A total of 518 children—with a median of 11 children (range 1, 53) per center—had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P Conclusions The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency–related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Context The clinical effects of classical 3β-hydroxysteroid dehydrogenase 2 (3βHSD2) deficiency are insufficiently defined due to a limited number of published cases. Objective To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3βHSD2 deficiency. Design Multicenter, cross-sectional study. Setting Nine tertiary pediatric endocrinology clinics across Turkey. Patients Children with clinical diagnosis of 3βHSD2 deficiency. Main Outcome Measures Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3βHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. Results Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ± 5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3βHSD2 activity in vitro had a non-salt–losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. Conclusions Genetically-documented 3βHSD2 deficiency includes salt-losing and non-salt–losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3βHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3βHSD2 deficiency.

Background Lipid accumulation product (LAP) is associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults. Purpose Here we evaluated the ability of LAP to predict NAFLD in obese children. Methods Eighty obese children (38 girls; age 6–18 years) were included. Anthropometric measurements and biochemical values were obtained from the patients’ medical records. LAP was calculated as [waist circumference (WC) (cm) – 58]×triglycerides (mmol/L) in girls; [WC (cm) – 65]×triglycerides (mmol/ L) in boys. The minLAP and adjLAP were described (3% and 50% of WC values, respectively) and the total/high-density lipoprotein cholesterol index (TC/HDL-C) was calculated. NAFLD was observed on ultrasound, and patients were divided into 3 groups by steatosis grade (normal, grade 0; mild, grade 1; moderate-severe, grade 2–3). The area under the curve (AUC) and appropriate index cutoff points were calculated by receiver operator characteristic analysis. Results LAP was positively correlated with puberty stage (rho=0.409; P0.005). There was a statistically significant difference between the normal and mild groups for adjLAP (P=0.043) but not between the other groups (P>0.005). There was no significant intergroup difference in minLAP (P>0.005). Conclusion LAP is a powerful and easy tool to predict NAFLD in childhood. If LAP is ≥42.7, NAFLD should be suspected. This is the first study to assess LAP diagnostic accuracy for childhood obesity.

Background: Laron syndrome (LS), which can be defined as primary growth hormone resistance or insensitivity, is a rare genetic disease inherited by an autosomal recessive trait. Although it is undistinguishable from growth hormone deficiency, LS has high levels of growth hormone, but insulin-like growth factor (IGF-1) cannot be synthesized. Mecasermin treatment is the only option for the patients who suffer from LS. This study aims to research cardiac findings of children with LS, who receive treatment with mecasermin. Methods: The study enrolled five children four males and one female, 4 M/1 F with LS, two of whom were siblings with a mean age of 6.3±2.1 years, a body weight of 13.36±4.74 kg, a height of 88±8.7 cm, and a body mass index (BMI) of 16.47±3.35. Their demographic data were obtained from their family and files. The children received mecasermin via subcutaneous injection at 0.04–0.12 μg/kg doses twice per day. The duration of mecasermin treatment was 8–53 months. All of them were examined clinically by electrocardiogram and echocardiogram. Results: Their cardiac examinations were normal, except for one case, who had systolic murmur at cardiac auscultation. Arrhythmia was not observed on their electrocardiograms. The echocardiograms did not show a significant congenital cardiac anomaly. Their cardiac measure and functions were within normal ranges. The echocardiogram of the child with the murmur showed mitral and tricuspid insufficiency. The Doppler images showed pulmonary hypertension findings. These findings were proven by angiography. The vasoreactivity test results of that patient were negative. No reason could be found for the observed pulmonary hypertension. We diagnosed this finding as a primary pulmonary hypertension and Bosentan therapy was started. Conclusions: In this study, we showed that cardiac findings were consistent with previous studies. To the best of our knowledge, the observed pulmonary hypertension in children with LS, who received treatment with or without mecasermin, is reported for first time in the literature.

3M syndrome is a rare entity characterized by severe growth retardation, dysmorphic features and skeletal changes as its major components. It is differentiated from other types of dwarfism by its clinical features and by the typical slender long bones and foreshortened vertebral bodies that can be visualized radiographically. 3M syndrome has an autosomal recessive mode of inheritance. An early diagnosis is important for genetic counseling. In this report, we present four children (3 males, 1 female) from two families who were aged between 411/12 and 1011/12 years and had clinical findings of 3M syndrome. One of these patients had received growth hormone (GH) treatment which was discontinued due to an inadequate height gain. Physicians should be aware of this entity in the differential diagnosis of children with severe short stature and mild skeletal changes. Conflict of interest:None declared.