Body composition in children and adolescents with non-classic congenital adrenal hyperplasia and the risk for components of metabolic syndrome: An observational study.

Background: Treated or untreated non-classic congenital adrenal hyperplasia (NCCAH) diagnosed in childhood could pose an increased risk of obesity and metabolic derangements in adolescence and early adulthood. We aimed to explore the interaction between muscle-to-fat ratio (MFR) and components of metabolic syndrome in pediatric subjects with NCCAH. Methods: This retrospective observational study was conducted in the Tel Aviv Medical Center from January 2018 to January 2022. The study group comprised 75 subjects (26 males) with NCCAH (61 hydrocortisone-treated [21 males] and 14 untreated [5 males]) and 134 healthy sex- and age-matched subjects (41 males) with normal puberty served as controls. Body composition was measured by bioelectrical impedance analysis (BIA) and muscle-to-fat ratio (MFR) z-scores were calculated. Stepwise linear regression models were applied to evaluate explanatory variables for MFR z-scores, blood pressure percentiles, lipid profiles, and glucose metabolism. Results: The median age [interquartile range] was 7.5 years [5.3, 8.8] at NCCAH diagnosis and 12.3 years [8.9, 15.4] at BIA. The median cumulative hydrocortisone dose was 7620 mg/m2 [2547, 12903]. Subjects with NCCAH had higher mean BMI z-scores and lower median MFR z-scores compared to controls [(0.47 ± 0.97 vs. -0.19 ± 1.04, p<0.001) and (-0.74 [-1.06, -0.14] vs.-0.37 [-0.99, 0.15], p=0.045), respectively]. The linear regression models dependent variables and their explanatory variables were: MFR z-score (R2= 0.253, p<0.001) - socioeconomic position index (ß=0.348, p=0.003), birthweight z-score (ß=-0.258, p=0.013), and duration of hydrocortisone treatment in years (ß=0.048, p=0.023); systolic blood pressure percentile (R2 = 0.166, p<0.001) - MFR z-score (ß=-9.75, p<0.001); TG/HDL ratio (R2 = 0.116, p=0.024) - MFR z-score (ß=-0.300, p=0.024). No significant variables were found for glucose. Conclusions: Children and adolescents with NCCAH have a body composition characterized by an imbalance between muscle and fat tissues, which may place them at increased risk for early-onset cardiometabolic derangements. It is reassuring that glucocorticoid therapy aimed to alleviate androgen overproduction does not appear to adversely affect their body composition.

Paediatricians' practices and knowledge of corticosteroids: A national survey.

AIM: To explore corticosteroid prescription practices and knowledge among paediatricians. METHODS: The Paediatricians Corticosteroids Survey, a cross-sectional, web-based survey distributed to Israeli paediatricians between February and July 2018. RESULTS: Three hundred and forty-nine paediatricians (105 general paediatricians, 207 subspecialists and 37 paediatric endocrinologists) participated. Two hundred and three (58.2%) had >10 years of paediatric clinical experience and treated >60 patients/wk on average, 175/318 (55%) prescribed corticosteroids to >10% of their patients. On knowledge items, 11/266 (4.1%) responded 'not sure' when tapering of steroids is required, 22/268 (8.2%) to what 'stress dose' meant and 27/268 (10.1%) when a stress dose is required. Multivariate linear analysis showed higher scores were associated with training in paediatric endocrinology (ß = 2.271, P = 0.032); medical practice only in a subspecialty (ß = 1.909, P = 0.041) or in both general paediatrics and a subspecialty (ß = 2.023, P = 0.014), compared to general paediatrics alone and medical studies in Israel (ß = 1.059, P = 0.035). Overall, 96.2% thought continued medical education (CME) sessions would be helpful. CONCLUSION: Our findings suggest that despite clinical experience with corticosteroid usage, respondents demonstrated gaps in knowledge for potentially life-threatening situations. Corticosteroid-based CME programs are warranted to improve paediatricians' knowledge and patient management.

WOMEN WITH NONCLASSIC CONGENITAL ADRENAL HYPERPLASIA HAVE GENDER, SEXUALITY, AND QUALITY-OF-LIFE FEATURES SIMILAR TO THOSE OF NONAFFECTED WOMEN.

Objective: Females with the severe classic forms of congenital adrenal hyperplasia reportedly have a higher frequency of atypical gender identity, nonheterosexual sexual relationships, and cross-gender role behavior. Comparable data and quality-of-life measures among those with the milder, more prevalent form, nonclassic congenital adrenal hyperplasia, are scarce. We aimed to assess health-related quality of life, gender identity, role, and sexual orientation in women with nonclassic congenital adrenal hyperplasia via a prospective, questionnaire-based, case-control study. Methods: Thirty-eight women with nonclassic congenital adrenal hyperplasia (median age 34 years; range, 18 to 44 years) and 62 age-matched female controls were recruited. Outcome measures included the Multi-Gender Identity, Sexuality, and World Health Organization (WHO) quality-of-life questionnaires. Results: Sociodemographic parameters (marital status, number of children, and educational level) were similar for both groups, as were most measures of the Multi-Gender Identity, Sexuality, and WHO quality-of-life questionnaires. However, "sometimes-feeling-as-a-man and sometimes-feeling-as-a-woman" were more frequently reported in the study group compared to the controls (7/38 [18.4%] vs. 3/62 [4.8%], respectively; P = .02). Furthermore, more nonclassic congenital adrenal hyperplasia women reported first falling in love with a woman (4/37 [10.8%] vs. 0/58 [0%]; P = .02). Conclusion: Our findings suggest possible subtle differences in gender identity and sexual orientation between adult nonclassic congenital adrenal hyperplasia females and controls. Quality of life was not impaired in individuals within the study group. The impact of exposure to mildly elevated androgen levels during childhood and adolescence on the female brain warrants more in-depth assessment in further studies. Abbreviations: CAH = congenital adrenal hyperplasia; Multi-GIQ = Multi-Gender Identity Questionnaire; NCCAH = nonclassic congenital adrenal hyperplasia; QoL = quality of life.

HEALTH-RELATED QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS WITH NONCLASSIC CONGENITAL ADRENAL HYPERPLASIA.

Objective: Nonclassic congenital adrenal hyperplasia (NCCAH) is a late-onset milder form of congenital adrenal hyperplasia that differs dramatically from the classic form. Health-related quality of life (HRQOL) in pediatric patients with the sole diagnosis of NCCAH has not been determined; therefore, in this study, we aimed to determine whether HRQOL is compromised in comparison to the general population. Methods: Single-center, cross-sectional, case-control study. Twenty-three hydrocortisone-treated children and adolescents (7 males) diagnosed with NCCAH by cosyntropin stimulation test and CYP21A2 gene mutation analysis were recruited to this study; 6 healthy siblings were also recruited. HRQOL was assessed by the child and parent-proxy PedsQL Inventory and compared between NCCAH subjects and healthy siblings. HRQOL scores of NCCAH subjects were compared with known standards from the U.S. and Israeli general healthy populations. Anthropometric measurements of children and parents were performed and compared between NCCAH subjects and healthy siblings. Pearson correlation coefficients were calculated. Results: HRQOL scores of the participants and parents did not differ between NCCAH subjects and healthy siblings. The HRQOL emotional domain scores of the NCCAH patients and parent were significantly lower than the healthy U.S. pediatric population (P = .046) but not different from established standards of the healthy Israeli population (P = .583). Anthropometric measurements were within the normal range and did not differ between NCCAH subjects and their siblings. Total, school functioning, and psychosocial HRQOL domain scores were positively correlated with body mass index-standard deviation score in NCCAH subjects. Conclusion: HRQOL was not adversely affected by NCCAH among adequately treated children and adolescents. Abbreviations: BMI = body mass index; CAH = congenital adrenal hyperplasia; HRQOL = health-related quality of life; NCCAH = nonclassic congenital adrenal hyperplasia; PedsQL = Pediatric Quality of Life Inventory; SDS = standard deviation score.

Adrenal crises in children with adrenal insufficiency: epidemiology and risk factors.

The aim of the study was to assess the epidemiology and risk factors of adrenal crises (AC) in children with adrenal insufficiency (AI). Children diagnosed with AI between 1990 and 2017 at four Israeli pediatric endocrinology units were studied. Demographic and clinical data were retrieved retrospectively from their files. The study population consisted of 120 children (73 boys, 47 girls) and comprised 904 patient years. Median age at diagnosis was 0.3 years (0-17.5). Thirty-one AC events in 26 children occurred during the study period, accounting for a frequency of 3.4 crises/100 patient years. Fifty-two percent of AC events occurred at presentation. The significant risk factors for developing AC were the following: younger age at diagnosis (P = 0.003), primary AI vs. secondary AI (P = 0.016), specific diagnosis of autoimmune AI, adrenal hypoplasia congenita and salt wasting congenital adrenal hyperplasia (P < 0.001), mineralocorticoid treatment (P < 0.001), and recurrent hospital admissions (P > 0.001). After applying a stepwise logistic regression model, only the group of diagnoses, including salt wasting CAH, AHC, and Addison's disease, remained significant predictor of AC (OR 17.5, 95% CI 4.7-64.9, P < 0.001). There was no AC-associated mortality during the study period.Conclusions: Since significant percent of AC events occurred at presentation, measures to increase the awareness to signs and symptoms of AI among primary care physicians should be taken. Efforts to prevent AC should be focused on younger patients, especially those with primary AI. What Is Known: • Diagnosis and long-term management of pediatric patients with adrenal insufficiency (AI) remain a challenge. • Adrenal crises (AC) pose life-threatening emergencies in affected youngsters. Studies on the rate and risk factors of AC in children with AI are scarce, and they were done mainly on children with congenital adrenal hyperplasia (CAH). What Is New: • The rate of AC was relatively low and there was no AC-associated mortality during the study period. • Children with primary AI were at higher risk for AC than children with secondary AI. Specifically, children with salt wasting CAH, adrenal hypoplasia congenita, and Addison's disease at the highest risk.

Pregnancy in women with nonclassic congenital adrenal hyperplasia: Time to conceive and outcome.

OBJECTIVE: Nonclassic congenital adrenal hyperplasia (NCAH) is common among Ashkenazi Jews (1:400). It is associated with various degrees of postnatal virilization, irregular menses and infertility. Therapy of symptomatic subjects consists of physiologic doses of glucocorticoids. The objective of this study was to evaluate the effect of glucocorticoid treatment on fertility and on pregnancy outcome in women with NCAH. DESIGN, SETTING AND PATIENTS: This retrospective study included 75 women diagnosed with NCAH who were followed in our clinic and sought fertility between 2008 and 2015. RESULTS: Seventy-two women succeeded in conceiving (187 pregnancies). Time to conception was 4.0 ± 7 months without and 3.3 ± 3 months with glucocorticoid therapy (P = .43). Seventeen pregnancies were achieved by glucocorticoid therapy after failure to conceive spontaneously. Time to conception before therapy initiation was 10.2 ± 11.4 months compared to 3.3 ± 3.4 months after therapy initiation (P = .02). Of 187 pregnancies, 135 (72%) resulted in live births, 38 (20.3%) ended in spontaneous miscarriages during the first trimester, seven (3.7%) were electively terminated, three (1.6%) were ectopic and four (2.1%) were ongoing during the study with similar rate in glucocorticoid treated and untreated pregnancies. CONCLUSIONS: The 96% pregnancy rate among our cohort of NCAH females was similar to the 95% rate reported for the normal population. Glucocorticoid therapy may shorten the time to conceive in a subgroup of women with NCAH. Glucocorticoid therapy did not affect the rate of first trimester miscarriage. Our 77% live birth rate was similar to the 72% live birth rate in the current healthy US population.

Establishing Normal Ranges of Basal and ACTH-Stimulated Serum Free Cortisol in Children.

BACKGROUND: Normative data have been established for stimulated serum total cortisol in children but not for serum free cortisol. METHODS: Children who were referred for ACTH testing to rule out adrenal insufficiency were enrolled. Only children with normal response and normal androgen levels were included. Total cortisol was determined by a chemiluminescence method, and free cortisol was measured by the same method following equilibrium dialysis. RESULTS: The study group consisted of 85 subjects (28 male; 57 female) with a median age of 8.5 years (range 0.6-17.7). The mean basal and peak total cortisol levels were 11.5 ± 5.7 and 32.9 ± 6.2 µg/dl, respectively. The mean basal and peak free cortisol levels were 0.4 ± 0.3 and 1.8 ± 0.6 µg/dl, respectively. There was a negative correlation between peak total cortisol and age but not between peak free cortisol and age. The 3rd and 97th percentile values for peak free cortisol were 0.94 µg/dl (26 nmol/l) and 2.97 µg/dl (82 nmol/l), respectively. CONCLUSIONS: Measurement of free cortisol has the advantage of being independent of cortisol-binding globulin levels. This study provides reference ranges for stimulated free cortisol in children, with a cutoff value of 0.9 µg/dl (25 nmol/l) as a normal response to a standard ACTH test.

Medical Clowns and Cortisol levels in Children Undergoing Venipuncture in the Emergency Department: A Pilot Study.

BACKGROUND: Medical clowns are increasingly used for diminishing pain and anxiety during painful procedures being performed on children in the hospital setting. Cortisol levels rise as a response to emotional distress. OBJECTIVES: To investigate whether medical clown-assisted interventions to reduce child's distress during venipuncture have an effect on cortisol levels. METHODS: During a 1 year period, children requiring blood work or intravenous access in the pediatric emergency department were prospectively randomized to either the presence or absence of a medical clown during the procedure. The child's distress was evaluated using the Faces Pain Scale - revised (FPS-R) for the 4-7 year age group and the visual analog scales (VAS) for those aged 8-15 years. Serum cortisol levels were measured in blood samples obtained by venipuncture. RESULTS: Fifty-three children aged 2-15 years were randomly assigned to the study group (with medical clown, n=29) or to the control group (without medical clown, n=24). Combined pain scores of the study group and control group were 2.2 and 7.5 respectively (P < 0.001). No difference in mean cortisol levels was found between the study group and the control group at all ages (16.4 µg/dl vs. 18.3 µg/dl, P = 0.65). CONCLUSIONS: In this pilot study, medical clowns reduced the distress from venipuncture in children. No effect on cortisol levels was observed.

The accuracy of C-reactive protein, procalcitonin, and s-TREM-1 in the prediction of serious bacterial infection in neonates.

UNLABELLED: In this prospective study, we examined the usefulness of C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cells (s-TREM-1), and procalcitonin (PCT), in identifying serious bacterial infection (SBI) among neonates. Infants younger than 3 months with suspected SBI were included and serum concentrations of CRP, PCT, and s-TREM-1 were determined. RESULTS: A total of 112 patients (19 with SBI and 93 with negative cultures) were evaluated. There were no statistical differences between the 2 groups regarding age, presence of fever, and serum concentrations of the different biomarkers. Performance of the different biomarkers were as follows: The sensitivities were 45%, 55%, and 82% for CRP, PCT, and s-TREM-1, respectively, whereas the specificities we 82%, 75%, and 48% for CRP, PCT, and s-TREM-1, respectively. The areas under the receiver operating characteristic curve were 0.6, 0.63, and 0.61, for CRP, PCT, and s-TREM-1, respectively. CONCLUSIONS: In real-life pediatric practice, none of the tested biomarkers was sufficiently accurate to serve as a reliable indicator for the identification of SBI in neonates.