Genotype-Specific Cortisol Reserve in a Cohort of Subjects With Nonclassic Congenital Adrenal Hyperplasia (NCCAH).

CONTEXT: Recent guidelines suggest that patients with nonclassic congenital adrenal hyperplasia (NCCAH) stop glucocorticoid therapy after achieving adult height. However, these guidelines do not differentiate between NCCAH genotype groups. OBJECTIVE: Compare ACTH-stimulated cortisol and 17-hydroxyprogesterone (17OHP) levels, and the rate of partial cortisol insufficiency in subjects with NCCAH carrying one mild and one severe (mild/severe) mutation vs subjects with biallelic mild (mild/mild) mutations. METHODS: Retrospective evaluation of the medical records of 122 patients who presented with postnatal virilization and were diagnosed with NCCAH. Patients underwent standard intravenous 0.25 mg/m2 ACTH stimulation testing. Those with stimulated 17OHP level ≥40 nmol/L were screened for the 9 most frequent CYP21A2 gene mutations followed by multiplex ligation-dependent probe amplification. A stimulated cortisol level below 500 nmol/L was defined as partial cortisol deficiency. RESULTS: Patients were subdivided into 3 genotype groups: 77 carried the mild/mild genotype, mainly homozygous for p.V281L mutation; 29 were compound heterozygous for mild/severe mutation, mainly p.V281L/p.I2Splice, and 16 were heterozygous for p.V281L, and were excluded from statistical evaluation. Stimulated cortisol levels were significantly lower in the mild/severe than in the mild/mild group (mean ± SD, 480 ± 90 vs 570 ± 125 nmol/L, P < .001). The mild/severe group exhibited a significantly higher rate of partial cortisol insufficiency (21/28, 75% vs 28/71, 39%, P = .004). Peak 17OHP was significantly higher in the mild/severe group (198 ± 92 vs 118 ± 50 nmol/L, P < .001). CONCLUSION: The high rate of partial adrenal insufficiency in the mild/severe group underscores the need to carefully consider the value of glucocorticoid therapy cessation and the importance of stress coverage in this group.

Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects.

Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY GONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.

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.

Screening for non-classic congenital adrenal hyperplasia in women: New insights using different immunoassays.

Context: The 250µg-cosyntropin stimulation test (CST) is used to diagnose non-classic congenital adrenal hyperplasia (NCCAH). The current recommendation is to perform CST when follicular 17-hydroxyprogesterone (17OHP) is 6-30 nmol/L, a cutoff derived from radioimmunoassay (RIA). Recently, enzyme-linked immunosorbent assay (ELISA) has replaced RIA. Objectives: We aimed to (1) determine the RIA and ELISA-based 17OHP cutoffs at which CST should be performed, (2) identify predictors of NCCAH. Methods: A retrospective study at an Israeli Health Maintenance Organization. Data were retrieved from women with suspected NCCAH, referred for CST during 2001-2020. NCCAH was defined as a stimulated 17OHP >30 nmol/L. Serum 17OHP levels were assayed by RIA from 1/2000-3/2015, and by ELISA from 4/2015-12/2020. ROC curves were generated and optimal 17OHP thresholds were determined. Multivariate analysis was performed. Results: CST was performed in 2409 women (1564 in RIA, 845 in ELISA). NCCAH was diagnosed in 4.7% of the RIA group and 7.5% of the ELISA group. The optimal basal 17OHP cutoff values predicting NCCAH were 6.1 nmol/L in RIA (sensitivity=93.2%, specificity=91.7%) and 8.2 nmol/L in ELISA (sensitivity=93.7%, specificity=92.3%). In multivariate analysis, higher basal 17OHP, lower LH: FSH ratio, and oligomenorrhea were predictors of NCCAH in RIA. Higher basal 17OHP, androstenedione, and total testosterone were predictors of NCCAH in ELISA. A lower LH: FSH ratio showed similar trend in ELISA. Conclusions: Optimal RIA-based basal 17OHP cutoff was comparable with that recommended in guidelines. The results suggest adopting a higher 17OHP cutoff when using ELISA. LH : FSH ratio improves the negative predictive value of basal 17OHP.

The 2021 European Training Requirements in Paediatric Endocrinology and Diabetes.

The aims of the 2021 European Training Requirements (ETR) in Paediatric Endocrinology and Diabetes (PED) are to (1) provide standards to harmonize training programmes in PED between different European countries, (2) establish clearly defined standards of knowledge and skills required to practice PED at the tertiary care level, (3) foster the development of a network of competent tertiary care centres for PED in Europe and globally, and (4) improve the quality of care for children and adolescents requiring PED services. This ETR in PED specifies the requirements for training institutions, trainers, and trainees. It also provides the detailed syllabus/core content that trainees are expected to achieve in order to become competent independent clinicians in PED. References to consensus guidelines produced and/or endorsed by ESPE are included. The target users are trainees in PED, trainers, and all involved with quality assurance and accreditation. The process to develop and approve this 2021 ETR has been rigorous and involved trainees and consultants in paediatric and adult Endocrinology, ESPE (Syllabus Task Force, Education and Training Committee, Council), European Academy of Paediatrics (Tertiary Care Council, Assembly), European Board of Paediatrics, and Union of European Medical Specialists. Implementing the ETR will complement professional regulatory requirements for postgraduate training in PED in different countries and allow harmonizing standards across Europe. ETR is publicly available at www.eurospe.org/education/education-training-syllabus and at https://www.uems.eu/__data/assets/pdf_file/0007/133990/UEMS-2021.17-European-Training-Requirement-in-Paediatric-Endocrinology.pdf.

CHILDREN AND ADOLESCENTS WITH GENDER DYSPHORIA IN ISRAEL: INCREASING REFERRAL AND FERTILITY PRESERVATION RATES.

Objective: To describe patient characteristics at presentation, management, and fertility preservation rates among a cohort of Israeli children and adolescents with gender dysphoria (GD). Methods: We performed a retrospective chart review of 106 consecutive children and adolescents with GD (<18 years) referred to and followed at the multidisciplinary Israeli Pediatric Gender Dysphoria Clinic from March 2013 through December 2018. Results: Of the 106 patients, 10 were prepubertal (9 prepubertal transgender females), and 96 were pubertal (38 pubertal transgender females). The GD population increased 11-fold since the establishment of our clinic in 2013. The subject's median age at referral was 15.5 years (range, 4.6 to 18 years). At the time of referral, 91 (95%) of the pubertal group had completed sexual maturation in their assigned gender at birth. Thirteen (13.5%) patients had attempted suicide, and 11 (11.5%) reported having had suicidal thoughts. Fourteen (45%) pubertal transgender females and 3 (6.5%) pubertal transgender males completed fertility preservation. Gonadotropin-releasing hormone analog treatment was prescribed in 77 (80%) patients at a mean age of 15.9 ± 1.6 years. Gender-affirming hormones were prescribed in 61 (64%) patients at a mean age of 16.5 ± 1.3 years. No severe side effects were recorded. Two (2%) of the pubertal group expressed regret about medical treatment. Conclusion: Children and adolescents with GD are presenting for medical attention at increasing rates. Israeli adolescents with GD have high fertility preservation rates, perhaps attributable to cultural perspectives. Taking advantage of the option to preserve fertility can be achieved when proper counseling is both available and promoted by medical personnel. Abbreviations: GAH = gender-affirming hormone; GD = gender dysphoria; GnRHa = gonadotropin-releasing hormone analog; MHP = mental health professional.

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.

Higher C-peptide levels and glucose requirements may identify neonates with transient hyperinsulinism hypoglycemia who will benefit from diazoxide treatment.

The aim of the study was to characterize factors that may serve as clinical tools to identify neonates with transient neonatal hyperinsulinism hypoglycemia (HH) who may benefit from diazoxide treatment. This retrospective study included 141 neonates with transient HH (93 males) of whom 34 (24%) were treated with diazoxide. Diazoxide treatment was started at median age of 13 days (range 5-35) and discontinued at median age of 42 days (range 14-224). The maximal dose was 7.1 ± 2.3 mg/kg/day. Diazoxide-treated neonates required a higher glucose infusion rate (GIR) compared with non-treated neonates (16.6 ± 3.4 vs. 10.4 ± 4.0 mg/kg/min, respectively, P < .01), had a longer duration of intravenous fluids (15.9 ± 9.3 vs. 7.8 ± 6.5 days, P < .01), a longer hospitalization (32.8 ± 22.7 vs. 20.4 ± 13.4 days, P < .01), a longer duration of carbohydrate supplementation (38.9 ± 40.4 vs. 17.8 ± 21.4 days, P < .01), and higher mean C-peptide levels on "critical sample" (1.4 ± 0.9 vs. 0.8 ± 0.5 ng/ml, P < .01). Their insulin levels also tended to be higher (3.5 ± 2.9 vs. 2.2 ± 3.8 µU/ml, P = .07). A stepwise logistic regression model revealed that significant predictors of prolonged HH were maximal GIRs (odds ratio (OR) 1.56, 95%; confidence interval (CI) 1.3-1.88, P < .001) and C-peptide levels (OR 3.57, 95%; CI 1.3-12.1, P = .005).Conclusion: Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.What is Known:• Neonates with transient hyperinsulinism usually do not require treatment beyond glucose supplementation due to its self-limited clinical course, but some may benefit from diazoxide treatment.What is New:• Higher C-peptide levels and higher GIR requirements may serve as clinical tools to identify neonates with transient HH who may benefit from diazoxide treatment.• The incidence of prolonged neonatal HH is higher than the currently accepted figures.

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.

Combined Gestational Age- and Birth Weight-Adjusted Cutoffs for Newborn Screening of Congenital Adrenal Hyperplasia.

CONTEXT: Congenital adrenal hyperplasia (CAH) was among the first genetic disorders included in newborn screening (NBS) programs worldwide, based on 17α-hydroxyprogesterone (17-OHP) levels in dried blood spots. However, the success of NBS for CAH is hampered by high false positive (FP) rates, especially in preterm and low-birthweight infants. OBJECTIVE: To establish a set of cutoff values adjusting for both gestational age (GA) and birthweight (BW), with the aim of reducing FP rates. DESIGN: This cross-sectional, population-based study summarizes 10 years of experience of the Israeli NBS program for diagnosis of CAH. Multitiered 17-OHP cutoff values were stratified according to both BW and GA. PARTICIPANTS: A total of 1,378,132 newborns born between 2008 and 2017 were included in the NBS program. RESULTS: Eighty-eight newborns were ultimately diagnosed with CAH; in 84 of these, CAH was detected upon NBS. The combined parameters-adjusted approach significantly reduced the recall FP rate (0.03%) and increased the positive predictive value (PPV) (16.5%). Sensitivity among those referred for immediate attention increased significantly (94%). There were four false negative cases (sensitivity, 95.4%), all ultimately diagnosed as simple-virilizing. Sensitivity and specificity were 95.4% and 99.9%, respectively, and the percentage of true-positive cases from all newborns referred for evaluation following a positive NBS result was 96%. CONCLUSIONS: The use of cutoff values adjusted for both GA and BW significantly reduced FP rates (0.03%) and increased overall PPV (16.5%). Based on our 10 years of experience, we recommend the implementation of this two parameter-adjusted approach for NBS of classic CAH in NBS programs worldwide.

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.

Management of Gonads in Adults with Androgen Insensitivity: An International Survey.

BACKGROUND: Complete and partial androgen insensitivity syndrome (CAIS, PAIS) are associated with an increased risk of gonadal germ cell cancer (GGCC). Recent guidelines recommend gonadectomy in women with CAIS in late adolescence. Nevertheless, many adult women prefer to retain their gonads. AIMS: This study aims to explore attitudes towards gonadectomy in AIS in centres around the world, estimate the proportion of adults with retained gonads and/or who developed GGCC, and explore reasons for declining gonadectomy. METHODS: A survey was performed among health care professionals who use the International DSD Registry (I-DSD). RESULTS: Data were provided from 22 centres in 16 countries on 166 women (CAIS) and 26 men (PAIS). In CAIS, gonadectomy was recommended in early adulthood in 67% of centres; 19/166 (11.4%) women refused gonadectomy. Among 142 women who had gonadectomy, evidence of germ cell neoplasm in situ (GCNIS), the precursor of GGCC, was reported in 2 (1.4%) out of 8 from whom pathology results were formally provided. Nine out of 26 men with PAIS (34.6%) had retained gonads; 11% of centres recommended routine gonadectomy in PAIS. CONCLUSION: Although development of GGCC seems rare, gonadectomy after puberty is broadly recommended in CAIS; in PAIS this is more variable. Overall, our data reflect the need for evidence-based guidelines regarding prophylactic gonadectomy in AIS.

Long-term safety of α-1 antitrypsin therapy in children and adolescents with Type 1 diabetes.

Promising findings of α-1 antitrypsin (AAT) intervention in mice models of Type 1 diabetes (T1D) led researchers to investigate AAT as a therapeutic modality for ß-cell preservation in recent-onset T1D patients. Our prospective, open-label Phase I/II extension study demonstrated that the administration of multiple repeated AAT infusions (up to 36) to AAT-sufficient pediatric T1D patients is safe and well-tolerated. Long-term surveillance of participants (up to 5 years) from diabetes onset revealed normal growth and pubertal progression through adolescence to attainment of full puberty and near adult height. No serious adverse events, clinical or laboratory abnormalities were reported. Given its safety profile, AAT may be an individualized-tailored innovative immunotherapy in AAT-sufficient pediatric patients with diverse immune-related medical conditions. ClinicalTrials.gov Identifier: NCT01661192.

Correction: The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities.

[This corrects the article DOI: 10.1371/journal.pone.0195046.].

The effect of CAG repeats length on differences in hirsutism among healthy Israeli women of different ethnicities.

PURPOSE: Variations in the degree of hirsutism among women of different ethnic backgrounds may stem from multiple etiologies. Shorter length of the polymorphic CAG repeats of the androgen receptor (AR) gene may be associated with increased activity of the receptor leading to hirsutism. We hypothesized that there are ethnic differences in the degree of hirsutism that is unrelated to androgen levels among Israeli women, and that the CAG repeats length may contribute to these differences. Anti-androgenic therapies, such as spironolactone, could be suggested if a shorter CAG repeats length is found to affect the difference in the degree of hirsutism between the ethnic groups. METHODS: Healthy Israeli Jewish women aged 18-45 years of Ashkenazi and non-Ashkenazi origin were invited to participate. Hirsutism was assessed using the simplified Ferriman-Gallwey (sFG) score, and serum total testosterone levels were measured as well. The CAG repeats length was determined by PCR. Methylation-sensitive methods were used to detect the fractional activity of each allele, and the weighted mean was calculated for the CAG repeats length. RESULTS: One-hundred and eight women were recruited (49 Ashkenazi and 59 non-Ashkenazi). The Ashkenazi women had a significantly lower degree of hirsutism (P<0.01), lower mean BMI (P = 0.003), total testosterone levels (P = 0.017), and longer weighted bi-allelic CAG repeats mean (P = 0.015) compared to non-Ashkenazi women. For the group as a whole, there was a significant negative correlation between the number of CAG repeats in the AR gene and the sFG score, while the number of repeats was not related to testosterone levels. Stepwise logistic regression revealed that ethnic origin and the CAG repeats length were the strongest factors affecting hirsutism (P<0.001, P = 0.03, respectively). CONCLUSIONS: There is a significant difference in the degree of hirsutism between Ashkenazi and non-Ashkenazi women in Israel that is partially explained by CAG repeats length.

SERUM FREE CORTISOL DURING GLUCAGON STIMULATION TEST IN HEALTHY SHORT-STATURED CHILDREN AND ADOLESCENTS.

OBJECTIVE: The total cortisol (TC) response may be measured during the glucagon stimulation test (GST) for growth hormone (GH) reserve in order to assess the integrity of the hypothalamic-pituitary-adrenal (HPA) axis. Measurements of TC are unreliable in conditions of albumin and cortisol-binding globulin (CBG) alterations (e.g., hypoproteinemia or CBG deficiency). We aimed to measure the serum free cortisol (sFC) response to the GST in children and adolescents and determine whether it could predict the GH response to glucagon stimulation. METHODS: Infants and children with either short stature or growth attenuation who were referred for evaluation of GH reserve underwent the GST. RESULTS: The study population consisted of 103 subjects (62 females), median age 3.9 years (range, 0.5-14). The mean basal and peak TC levels were 13.3 ± 6.7 µg/dL and 29.6 ± 8.8 µg/dL, respectively. The mean basal and peak sFC levels were 0.7 ± 0.8 µg/dL and 1.7 ± 1.1 µg/dL, respectively. There was a negative correlation between peak TC and age ( r = -0.3, P = .007) but not between peak sFC and age ( r = -0.09, P = .36). Ninety-five percent of the patients had peak TC levels >15.8 µg/dL and peak sFC levels >0.6 µg/dL. CONCLUSION: Our results on a cohort of healthy short-statured children can serve as reference values for the sFC response during GST. Based on these results, we propose peak TC levels >15.8 µg/dL and peak sFC levels >0.6 µg/dL for defining normalcy of the HPA axis during the GST in children and adolescents. ABBREVIATIONS: ACTH = adrenocorticotrophic hormone BMI = body mass index CBG = cortisol-binding globulin GH = growth hormone GST = glucagon stimulation test HPA = hypothalamic-pituitary-adrenal SDS = standard deviation score sFC = serum free cortisol TC = total cortisol.

The Natural History of Metabolic Comorbidities in Turner Syndrome from Childhood to Early Adulthood: Comparison between 45,X Monosomy and Other Karyotypes.

OBJECTIVE: Patients with Turner syndrome (TS) are at increased risk for metabolic disorders. We aimed to delineate the occurrence and evolution of metabolic comorbidities in TS patients and to determine whether these differ in 45,X monosomy and other karyotypes. METHODS: A longitudinal and cross-sectional retrospective cohort study was conducted in a tertiary pediatric endocrine unit during 1980-2016. Ninety-eight TS patients, 30 with 45,X monosomy were followed from childhood to early adulthood. Outcome measures included weight status, blood pressure (BP), glucose metabolism, and lipid profile. RESULTS: Longitudinal analysis showed a significant change in body mass index (BMI) percentiles over time [F(3,115) = 4.8, P = 0.003]. Age was associated with evolution of elevated BP [systolic BP: odds ratio (OR) = 0.91, P = 0.003; diastolic BP: OR = 0.93, P = 0.023], impaired glucose metabolism (HbA1c: OR = 1.08, P = 0.029; impaired glucose tolerance: OR = 1.12, P = 0.029), and abnormal lipid profile (cholesterol: OR = 1.06, P = 0.01; low-density lipoprotein cholesterol: OR = 1.07, P = 0.041; high-density lipoprotein cholesterol: OR = 1.07, P = 0.033). The occurrence of metabolic comorbidities was similar in 45,X monosomy and other karyotypes. Coexistence of multiple metabolic comorbidities was significantly higher in 45,X monosomy [F(1,72) = 4.81, P = 0.032]. BMI percentiles were positively correlated with metabolic comorbidities (occurrence and number) in each patient (r = 0.35, P = 0.002 and r = 0.383, P = 0.001, respectively). CONCLUSION: Our longitudinal study provides unique insights into the evolution of weight gain and metabolic disorders from childhood to early adulthood in TS patients. Since overweight and increasing age aggravate the risk for metabolic comorbidities, careful surveillance is warranted to prevent and control obesity already from childhood. The more prominent clustering of metabolic comorbidities in 45,X monosomy underscores the importance of a more vigorous intervention in this group.

Ketoacidosis in Newly Diagnosed Type 1 Diabetes in Children and Adolescents in Israel: Prevalence and Risk Factors.

BACKGROUND: Diabetic ketoacidosis (DKA) as the first presentation of type 1 diabetes mellitus (T1DM) is a serious complication that is preventable. OBJECTIVES: To identify risk factors for DKA at presentation of T1DM to delineate high-risk Israeli populations that could benefit from preventative measures. METHODS: Data for this multicenter retrospective study were collected from the medical files of three pediatric diabetes centers representing three districts in Israel. Inclusion criteria were diagnosis of T1DM, age at diagnosis ≤ 17 years, permanent residency in Israel, and documentation of the presence or absence of DKA at presentation. RESULTS: The study population included 607 patients of whom 438 met the inclusion criteria. The mean age at diagnosis was 9.1 ± 4.5 years. DKA was present at diagnosis in 156/438 patients (35.6%). The incidence of DKA was different among the three diabetes centers (P = 0.04). The DKA group was significantly younger than the non-DKA group (8.4 ± 4.5 vs. 9.5 ± 4.4, respectively, P = 0.008). DKA was significantly associated with maternal origin (Ashkenazi Jewish origin [lower] vs. non-Ashkenazi, P = 0.04) and with paternal education level (academic [lower] vs. non-academic education, P = 0.04). Stepwise logistic regression showed that maternal Ashkenazi Jewish origin has a protective effect on DKA (odds ratio [OR] 0.4, 95% confidence interval [95%CI] 0.21-0.74, P = 0.004) and that younger age is an independent risk factor (OR 1.06, 95%CI 1.01-1.1, P = 0.02). CONCLUSIONS: A diabetes educational program targeting high-risk population groups may reduce the prevalence of DKA nationwide.

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.