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Introduction: Partial androgen insensitivity syndrome (PAIS) is a rare condition that is reported to be commonly associated with gynecomastia in males., Objectives: To assess the management of gynecomastia in male PAIS., Materials and Methods: Retrospective review of males with PAIS over the age of 10 years in the I-DSD registry., Results: Of the 205 eligible cases, information was available for 57 from 13 centers. An androgen receptor gene variant was confirmed in 45 (79%) with a median age at first presentation of 1.0 year (range 0.1, 26.0). Of the 45 genetically confirmed cases, gynecomastia was present in 41 (91%) with a median age at the time of gynecomastia development of 13.5 years (11.0, 29.0). In the other 4 (9%) with no gynecomastia, the median age at last assessment was 15.7 years (10.6, 17.0). In 30 cases with information available, micropenis was present at the time of gynecomastia development in 23 (77%). Of the 35 with information available, 2 (6%) exhibited spontaneous resolution between the ages of 15 and 21 years and 25 (71%) had breast surgery at a median age of 15.7 years (14.0, 23.0). Of these 25, 9 (26%) had previously received medical therapy. The median clinician score of effectiveness for medical therapy was 3 (1, 8) compared to 10 (3, 10) for surgery (P < .0001). In 31 with information available, 13 (42%) had received psychology support., Conclusion: Gynecomastia is common in PAIS but not universal. Surgical management may be more effective than medical therapy, but there is a need for further standardized and systematic studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2023. The Author(s).)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nakhleh, Saiegh, Shehadeh, Weintrob, Sheikh-Ahmad, Supino-Rosin, Alboim, Gendelman and Zloczower.)

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/m 2 [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 (R 2 = 0.253, p <0.001) - socioeconomic position index (β=0.348, p =0.003), birthweight z-score (β=-0.258, p =0.013), and duration of hydrocortisone treatment in years (β=0.048, p =0.023); systolic blood pressure percentile (R 2  = 0.166, p <0.001) - MFR z-score (β=-9.75, p <0.001); TG/HDL ratio (R 2  = 0.116, p =0.024) - MFR z-score (β=-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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ben Simon, Brener, Segev-Becker, Yackobovitch-Gavan, Uretzky, Schachter Davidov, Alaev, Oren, Eyal, Weintrob and Lebenthal.)

Objectives: To determine trends in clinical practice for individuals with DSD requiring gonadectomy., Design: Retrospective cohort study., Methods: Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019., Results: Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries., Conclusions: The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.

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.

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.

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.

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.

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., (Copyright © 2019 Endocrine Society.)

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.

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 β-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.

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

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.

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.

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.

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.

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., (© 2018 S. Karger AG, Basel.)

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., (© 2017 John Wiley & Sons Ltd.)

Background: In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking., Objective: To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of AR analysis., Methods: Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR., Results: The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different AR mutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without AR mutation, respectively (P = .9), and median current external masculinization scores were 9 and 10, respectively (P = .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P = .004). All cases with an AR mutation had gynecomastia, compared to 9% of those without an AR mutation. Of the six men who had a mastectomy, five (83%) had an AR mutation., Conclusions: Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable AR mutation. Routine genetic analysis of AR to confirm PAIS informs long-term prognosis and management.

Background and Objectives: Alpha-1 antitrypsin (AAT) has been shown to reduce pro-inflammatory markers and protect pancreatic islets from autoimmune responses in recent studies. Our aim was to evaluate its safety and tolerability in three different doses, in a pediatric population with recent onset type 1 diabetes mellitus (T1DM)., Methods: A 37-wk prospective, open-label, phase I/II interventional trial, comprised of 24 recently diagnosed subjects (12 males; age 12.9 ± 2.4 yr), who received 18 infusions of 40, 60, or 80 mg/kg/dose high-purity, liquid, ready to use AAT over 28 wk (Glassia(®) ; Kamada Ltd., Ness Ziona, Israel)., Primary Outcomes: safety and tolerability; secondary outcomes: glycemic control, C-peptide reserve, and autoantibody levels. Possible responders were defined as individuals with peak C-peptide that declined less than 7.5% below baseline., Results: No serious adverse events, diabetic ketoacidosis (DKA), or severe hypoglycemic episodes were reported. Adverse events were dose-independent and transient. Glycemic control parameters improved during the study in all groups, independent of dosage. Hemoglobin A1c (HbA1c) decreased from 8.43 to 7.09% (mean, p < 0.001). At the end of the study, 18 subjects (75%) had a peak C-peptide ≥0.2 pmol/mL. Eight subjects (33.3%) were considered possible responders and were characterized by shorter duration of T1DM at screening (54.5 ± 34.3 vs. 95.9 ± 45.7 d, p = 0.036) and greater decrease in their HbA1c during the study period (-2.94 ± 1.55 vs.-0.95 ± 1.83%, p = 0.016)., Conclusions: AAT treatment was safe and well tolerated in pediatric subjects with recently diagnosed autoimmune diabetes. Placebo-controlled studies with larger cohorts and dose range are warranted in order to assess efficacy in maintaining pancreatic beta cell reserve and glycemic control., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2016 S. Karger AG, Basel.)

Background and Objective: It is unclear whether the proportion of infants with a disorder of sex development who are raised as male or female has changed over time. The temporal trends in sex assignment of affected cases entered in the International Disorder of Sex Development (I-DSD) Registry were studied., Methods: Cases of disorders of sex development reported as partial androgen insensitivity syndrome (PAIS; n = 118), disorder of gonadal development (DGD; n = 232), and disorder of androgen synthesis (DAS; n = 104) were divided into those who were born before 1990, 1990-1999, and after 1999. External appearance of the genitalia was described by the external masculinization score., Results: The median (5th-95th percentile) external masculinization scores of those infants with PAIS, DGD, and DAS who were raised as boys were 6 (2-9), 6 (3-9), and 6 (1-12), respectively, and were significantly higher than in those raised as girls (2 [0-6], 2 [0-7], and 0 [0-5], respectively); this difference was maintained in the 3 temporal birth cohorts (P < .01). Of the 118 cases in the pre-1990 cohort, 41 (35%) were raised as boys; of the 148 cases in the 1990-1999 cohort, 60 (41%) were raised as boys; and of the 188 cases in the post-1999 cohort, 128 (68%) were raised as boys., Conclusions: Although there is an association between the external appearance of the genitalia and the choice of sex assignment, there are clear temporal trends in this practice pointing toward an increased likelihood of affected infants being raised as boys. The impact of this change in practice on long-term health outcomes requires additional focus., (Copyright © 2014 by the American Academy of Pediatrics.)

An androgen receptor (AR) is a transcription factor consisting of four functional regions. The transactivation region contains a highly polymorphic area characterized by a variable number of CAG trinucleotide repeats encoding a polyglutamine tract. Several in vitro studies demonstrated a negative linear relation between the lengths of CAG repeats and relative AR transactivations. Numerous clinical studies then sought associations between the described polymorphism and clinical parameters of various medical conditions characterized by hyper/hypoandrogenism. In this article, we describe some of those interesting associations. We believe such links should be investigated in any medical condition involving androgens as a key element in its pathogenesis.

Aim: To determine whether nonclassical 21-hydroxylase deficiency (NC21OHD) compromises adult height (AH), and to establish the clinical parameters affecting AH in subjects with NC21OHD., Methods: This is a multicenter, retrospective review of medical records for clinical and biochemical parameters. The corrected height (CH) standard deviation score (SDS), defined as AH SDS minus mean parental height (MPH) SDS, was calculated for each patient, where MPH SDS is the average of the father's height SDS and the mother's height SDS., Results: The study group consisted of 122 NC21OHD subjects whose median age at diagnosis was 8.7 years (range, 0.1-36). Seventy-two patients had two mild mutations, 22 had one mild and one severe mutation, 10 were heterozygous for one mild mutation, and 18 did not undergo molecular analysis. The CH SDS of the 66 patients who initiated hydrocortisone treatment during childhood was significantly lower than those who presented after achieving AH (p = 0.03). However, there was a negative correlation between age at diagnosis and AH SDS in the former group (R = -0.7, p = 0.03). Being heterozygous for one mild and one severe mutation (R = -0.7, p < 0.02) and age at diagnosis (R = -0.7, p = 0.03) were negatively associated with CH SDS. The CH SDS was significantly lower in those who had bone age advancement at diagnosis compared to those who did not (p = 0.04)., Conclusion: The main determinants of AH in patients with NC21OHD are apparently age at diagnosis and initiation of therapy, and genotype. Early diagnosis and initiation of glucocorticoids therapy may improve height outcome in those presenting during childhood., (©2013 The Author(s)/Acta Paediatrica ©2013 Foundation Acta Paediatrica.)

Background: A correlation between prenatal and postnatal penile and clitoral sizes has not been reported. These data would substantiate the ability of prenatal ultrasound (US) scan to predict postnatal measurements. The aims were to correlate prenatal and postnatal penile and clitoral measurements and to ascertain the possible advantage of using prenatal penile width rather than length to predict postnatal measurements., Methods: This was a longitudinal study. Fetal penis and clitoris were measured by high-resolution US between gestational weeks 14 and 29. Postnatal measurements of external genitalia were performed during the first postnatal week. All measurements were performed twice consecutively. A correlation between the measurements sets was sought., Results: Paired prenatal and postnatal measurements were performed on 46 males and 48 females. Prenatal penile and clitoral length values correlated significantly with postnatal length at p < 0.05 each., Conclusions: Prenatal US findings appear to be reliable indicators of postnatal penile and clitoral length measurements. Penile width measurement did not add new information., (Copyright © 2012 Wiley Periodicals, Inc.)

Background: The expression of the regulatory cytokines interleukin (IL)-12 and IL-18 in patients with both Th1- and Th2-mediated diseases, type 1 diabetes mellitus (T1DM) and asthma, is unknown., Objective: To investigate the in vivo and in vitro IL-12 and IL-18 secretion patterns in patients with both T1DM and asthma., Methods: Peripheral blood mononuclear cells (PBMC) were collected from 44 patients. Mean age 19.4 ± 4.7 yr (10.5-28 yr), divided into four paired groups: T1DM and asthma, asthma only, T1DM only, and healthy controls. T-cell proliferative response was assessed. IL-12 and IL-18 serum levels and expression by PBMC following in vitro stimulation by lipopolysaccharide (LPS) were determined by enzyme-linked immunosorbent assay (ELISA)., Results: Patients with T1DM and asthma had higher serum levels of both IL-12 and IL-18 compared to controls: 146.2 ± 69.2 and 109.7 ± 34.6 pg/mL, p = 0.038 and 436.1 ± 117.9, 320.2 ± 99.1 pg/mL, p = 0.028, respectively. Stimulated IL-12 secretion was significantly lower in these patients compared to those with one disease only: 809 ± 426.4, 2111.6 ± 2214.3, 3188.1 ± 2692.9 pg/mL and after 48 h: 956.3 ± 489.3, 2429.8 ± 2394.6, 3874.5 ± 2820.3 pg/mL, respectively, p < 0.03 for all. The IL-18/IL-12 serum ratio was also significantly higher in patients with both diseases compared to those with asthma only, p = 0.017., Conclusion: Patients with both T1DM and asthma display a different pattern of IL-12 and IL-18 expression compared to patients with one disease only and controls., (© 2011 John Wiley & Sons A/S.)

The aim of this study was to assess the prevalence and risk factors of AI in pediatric recipients of kidney or liver transplantation admitted because of a physiological stress episode and to identify patients that might be at risk of adrenal crises by clinical and laboratory parameters at admission. Adrenal function was prospectively evaluated by a standard (250 μg) adrenocorticotropin test in 48 recipients. Data on clinical and laboratory parameters were collected. AI was diagnosed in 11 patients: 10/32 (31.3%) children on long-term steroid treatment and 1/16 (6.25%) untreated. The only risk factor for AI was corticosteroids cumulative dose of >0.15 mg/kg/day during the last six months (p = 0.02, OR 6.67; 95% CI: 0.97-45.79). No correlation was found between clinical or laboratory signs of adrenal crisis on admission and the presence of AI. None of the patients with AI who did not receive stress dose (n = 8) developed adrenal crisis. AI is relatively common in children receiving prolonged corticosteroid treatment after kidney or liver transplantation. Clinical parameters on admission could not reliably identify patients with AI. Universal administration of a stress dose during physiological stress might not be required. However, at this point, the only method to identify patients that will benefit from a stress dose is through the ACTH test., (© 2011 John Wiley & Sons A/S.)

A 14-year-old Caucasian girl was referred to the endocrine clinic for evaluation of voice deepening, facial hirsutism, and acne starting 2 years previously. She had been a competitive tennis player since age 7 years, practicing for 4-6 hours daily. On physical examination she was noticed to have a masculine appearance with mild facial acne and moderate hirsutism. Tanner stage was 1 for breast tissue and 5 for pubic hair. Her androgen levels (testosterone, androstenedione, dehydroepiandrosterone sulfate) were extremely elevated. Adrenal ultrasonography revealed a round left 4.6 × 5.3-cm adrenal mass. Laparoscopic left adrenalectomy was performed. The histologic findings were compatible with a benign adrenocortical tumor. Postoperatively, androgen levels dropped to within the normal range. Breast development proceeded normally, menarche occurred 2 months after tumor resection, and menses has been regular since then. Muscle strength of the dominant and nondominant upper and lower extremities was measured 1 month before surgery and 1 year later, using an isokinetic dynamometer (Biodex Systems II, Biodex, Shirley, NY, USA). There was no significant decrease in overall muscle strength after removal of the virilizing tumor and the marked drop in circulating androgens. In addition, the patient maintained her age category, number 1, national tennis ranking. The results suggest that even extremely high levels of tumor-related circulating androgens had no evident effect on muscle strength and competitive performance in a female adolescent tennis player. The lack of beneficial effect on performance in adolescents, combined with the potentially hazardous side effects of anabolic steroids, suggests that teenage athletes should avoid their use.

Objective: To evaluate the prevalence of nonclassical 21-hydroxylase deficiency (NC-21OHD) in men with abnormal sperm parameters of unexplained etiology compared with males with normal sperm analysis., Design: Case control study., Setting: Major tertiary medical center., Patient(s): Of 484 healthy men being followed at a fertility clinic, 222 (mean age 33.8 +/- 6.1 [+/-SD] years) presented with abnormal findings on sperm analysis (1999 WHO criteria) of unknown cause and 262 (mean age 34.8 +/- 6.5 [+/-SD] years) with a normal sperm analysis., Intervention(s): Random mid-morning blood sampling to test for 17-hydroxyprogesterone (17-OHP) levels. Subjects with levels of >or= 6 nmol/L underwent a standard adrenocorticotropic hormone (ACTH) stimulation test., Main Outcome Measure(s): NC-21-OHD, defined as a stimulated ACTH level of >or=45 nmol/L., Result(s): A serum 17-OHP level of >or=6 nmol/L was detected in 11 study patients (5.0%) and 14 control subjects (5.3%). Seven study patients and 8 controls subsequently underwent ACTH stimulation test, and none had levels compatible with a diagnosis of NC-21OHD. Mean 17-OHP levels were similar in the two groups (3.3 +/- 1.4 [+/-SD] nmol/L and 3.3 +/- 1.5 [+/-SD] nmol/L, respectively). There was no correlation between sperm parameters and serum 17-OHP levels., Conclusion(s): Until larger studies are performed, the routine measurement of 17-OHP in the evaluation of male infertility is not recommended., (Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: X-linked adrenal hypoplasia congenita (AHC) is a rare disorder caused by mutations or complete deletion of the NR0B1 gene that encodes the DAX-1 protein, an orphan member of the nuclear receptor superfamily. AHC is characterized by adrenal insufficiency in infancy and early childhood. Later, hypogonadotropic hypogonadism (HH) manifests as pubertal failure., Patients and Methods: We evaluated the clinical, endocrine and molecular characteristics of 12 AHC patients from 5 families diagnosed between 1984 and 2007 in Israel., Results: Most of the boys (10/12) presented with signs of adrenal insufficiency such as salt wasting and failure to thrive during the neonatal period. Aldosterone deficiency usually preceded cortisol deficiency requiring early mineralocorticoid therapy. Serum cortisol levels in the first weeks of life varied from very low to high levels (<2.76 to >1776 nmol/l). Five boys showed signs of precocious sexual development during infancy and childhood, including enlargement of the penis and testes. In four patients the initial diagnoses were erroneous. Molecular analysis of the NR0B1 gene identified point mutations in six patients including a novel splice site mutation in one patient and his family (IVS1-1G-->C). Contiguous gene deletion was found in six patients from two families who manifested impaired mental development., Conclusions: In X-linked AHC caused by different molecular defects in NR0B1 gene, the clinical spectrum of the disease is quite variable and precocious sexual development is a prominent feature. Genetic testing is indicated in boys presenting with salt-wasting with or without cortisol deficiency if congenital adrenal hyperplasia has been ruled out.

Aromatase inhibitors are compounds that block aromatase which converts androgens to estrogens. These compounds have been investigated for many years in a variety of conditions in which estrogen blockade is desired. During the past decade, a third generation of aromatase inhibitors has been developed with a much more potent blockade of the enzyme and less side effects. These new aromatase inhibitors are well absorbed after oral administration and, because of a long half life, are given once daily, thereby increasing compliance. The use of aromatase inhibitors is approved for the treatment of estrogen responsive breast cancer. Estrogens play a major role in bone maturation and growth plate fusion in both sexes. Therefore, inhibition of estrogen production may increase final height in a number of conditions where the final height is compromised. Due to their ability to block estrogen production, a number of clinical studies have been conducted to investigate their efficiency in a range of situations where estrogen blockade is desired. These include: peripheral precocious puberty secondary to congenital adrenal hyperplasia, familial male-dominant precocious puberty, and McCune-Albright syndrome, short stature in boys secondary to growth hormone deficiency, familial/genetic short stature, constitutional growth delay or idiopathic short stature. The use of aromatase inhibitors has been investigated also in pubertal gynecomastia. It is important to emphasize that this treatment, although it seems to be safe and encouraging, is still investigational and is not yet approved for routine usage.

Background: Besides its toll on human life, the steep rise in the rate of diabetes as the cause of end stage renal disease (ESRD), with the consequent increase in the need for renal replacement therapy has created a substantial economic burden on health care systems. Clinical trials have found angiotensin receptor blockers (ARBs) to be more beneficial than traditional antihypertensive therapy in patients with type 2 diabetic nephropathy (DN). However, in Israel, ARBs are not considered first-line therapy., Objectives: To determine the cost-effectiveness of ARB treatment for diabetic nephropathy in the Israeli health care system., Methods: A Markov model was constructed wherein utility values were assigned to each consecutive health state of diabetic nephropathy. The transition probabilities from one state to another were derived from reported clinical trials. Quality-adjusted life years (QALYs) were calculated and sensitivity analysis was performed. For the economic evaluation, the researchers used data from the Israeli health system., Results: Treatment with ARBs over a 3-year period yielded a higher QALY than conventional anti-hypertensive treatment (2.63 vs. 2.59) and a lower cost (NIS 36,678 vs. NIS 39,932). For a time horizon of 10 years, the cost difference increased to NIS 50,000, with a 20% reduction in the number of patients with ESRD. Sensitivity analysis revealed that these results were valid over a wide range of parameters., Conclusions: The use of ARBs to delay ESRD appears to be cost-effective. We recommend that ARBs be considered in Israel as first-line treatment for patients with type 2 diabetic nephropathy.

Pseudohypoparathyroidism (PHP) is a rare inherited syndrome characterized by parathyroid hormone (PTH) resistance and is frequently associated with Albright's hereditary osteodystrophy and resistance to other cAMP-mediated hormones. The usual neonatal presentation is mild primary hypothyroidism secondary to resistance to thyroid-stimulating hormone; hypocalcemia usually develops after age 3-5 years. This work describes the diversity in the clinical expression and course of PHP, with emphasis on calcium levels by age and treatment, in 8 children under long-term follow-up at our pediatric tertiary center. The calcium levels at presentation ranged from transient neonatal hypocalcemia to infantile hypercalcemia to childhood/adolescence hypocalcemia. Interestingly, relative hypocalciuria at diagnosis and during therapy, in the presence of renal PTH resistance, was the rule. These findings indicate that transient neonatal hypocalcemia associated with other clinical features or a family history of PHP may be a flag for clinicians to screen for PTH resistance later in life. In addition, PTH resistance may be missed by surveying calcium levels only; thus the PTH levels have to be checked as well. In addition, the recommendation for patients with hypoparathyroidism that strict low-normal calcium levels be maintained during therapy in order to prevent hypercalciuria is probably not applicable in PHP., (Copyright 2008 S. Karger AG, Basel.)

Ketoacidosis is a serious complication of diabetes mellitus, especially type 1, and its secondary consequences account for a large proportion of diabetes-related hospitalizations and mortality in children with type 1 diabetes. Our understanding of the pathophysiology of ketoacidosis has increased considerably, together with methods and means of management. Nevertheless, its incidence has remained constant in most parts of the western world, as has the incidence of cerebral edema, the main cause of death due to ketoacidosis. Therefore, a major goal of clinical teams is to prevent ketoacidosis by early diagnosis of diabetes in new patients, and by appropriate treatment of intercurrent disease in patients with known diabetes, combined with family involvement and psychosocial interventions, as necessary. Although studies of the risk factors for the development of cerebral edema in this setting have yielded discrepant findings, there is a wide consensus regarding ketoacidosis treatment. The accepted protocol consists of slow rehydration with isoosmotic fluids, without bicarbonate solution except in rare cases, with continuous attention to glucose, sodium and potassium levels and the patient's neurological state. The aim of this survey is to present guidelines for the treatment of diabetic ketoacidosis (DKA) in children and to recommend preventive measures.

Background: While regular yearly screening for diabetic retinopathy and nephropathy is well established in patients with diabetes mellitus, there are no standardized diagnostic tests for diabetic peripheral neuropathy (DPN). In the present study, we compared the bedside neuropathy disability score (NDS) with quantitative sensory testing (QST) for screening for DPN in youth with type 1 diabetes mellitus., Methods: One hundred sixty-six patients aged 10 to 34 years (median 21 years) were evaluated for DPN by the NDS and QST. Quantitative sensory testing was also done in 43 healthy, age-matched controls. Diabetic peripheral neuropathy grade by both methods was correlated with disease-related variables., Results: On QST, the diabetic group had significantly higher mean scores for vibration (P<.001) and warm sensation (P<.01) than controls, and lower scores for cold sensation (P<.05); however, there was a great degree of overlap. The NDS significantly correlated with the vibration threshold, but not with the warm and cold thresholds. The NDS significantly correlated with age at testing, diabetes duration, and long-term and current HbA1c levels (P<.001), and with the presence of microalbuminuria and diabetic retinopathy (P<.001). Analysis of the QST variables yielded significant correlations of vibration and warm sensation with age at testing (P<.001, P<.05, respectively) and of vibration with diabetes duration (P<.001) and retinopathy (P=.05); none of the quantitative tests correlated with glycemic control., Conclusions: The stronger association of the NDS with glycemic control and other microvascular complications compared to the perception thresholds, and its shorter time of performance and lack of costly equipment, may make the NDS the preferred method for measuring DPN in this population.

Objective: Type 1 diabetes mellitus (DM1) and asthma are mediated by opposite arms of the cellular immune system, namely T helper (Th)1 and Th2 CD4+ cells, respectively. It is not known whether their coexistence affects their clinical manifestations., Methods: The number of asthma exacerbations, frequency of hypoglycemic events, HbA1c levels, diabetes associated autoantibody status and diabetes associated late complications were determined in three paired groups of patients (n = 11) matched by gender and age: DM1 and asthma, asthma only, and DM1 only., Results: Patients with both diseases had a higher prevalence of hypoglycemic events per month compared to patients with DM1 only: 5.67 +/- 4.27 vs 1.45 +/- 2.06, respectively (p = 0.008). The co-existence of the two diseases did not modify the remaining clinical and laboratory parameters., Conclusion: Patients with both DM1 and asthma have similar clinical characteristics to patients with only one of these diseases apart from a higher rate of hypoglycemic events compared to patients with DM1 without asthma.

The V281L mutation in the CYP21 gene, responsible for non classical CAH, was studied in patients of different Israeli ethnic groups and compared to the data on healthy population. The Israeli population consists of many ethnic groups which can be divided into three main entities: Ashkenazi, Non Ashkenazi and Israeli Arabs. The frequency of V281L mutation in the patients of the different ethnic groups varied and was a reflection of the frequency found in the healthy population namely: very high in the Ashkenazi (74%) , lower in the non Ashkenazi (39%) and very low in the Israeli Arabs (2.9%) . The phenomenon of strong association between the HLA B14 allele and the V281L mutation found in our population study, as well as in other studies, confirmed by linkage found in patient families, can be used to distinguish between homozygote and hemizygote carrying the V281L mutation, when no family study is available. The relevance of this finding is especially important in cases of genetic counseling when a carrier of a severe mutation is involved.

Objective: To compare by age and glycemic control continuous subcutaneous insulin infusion with multiple daily injections in youth with type 1 diabetes., Methods: The files of 279 patients who had type 1 diabetes and switched from multiple daily injections to continuous subcutaneous insulin infusion between 1998 and 2003 were reviewed for glycemic control, body mass index standard deviation score, and adverse events. Patients were divided by age as follows: 23 prepubertal (median age: 5.4; range: 1.6-8.6 years), 127 adolescent (median age: 13.7; range 9-17 years), and 129 young adult (median age: 22.8; range: 17-40 years). The data were compared between the 12 months of multiple daily injections that preceded continuous subcutaneous insulin infusion and the period after the start of continuous subcutaneous insulin infusion for the whole cohort and by age group., Results: A significant decrease in hemoglobin A1c was demonstrated after the start of continuous subcutaneous insulin infusion use for the entire cohort (-0.51%) and for the prepubertal (-0.48%), adolescent (-0.26%), and young adult (-0.76%) groups. There was a significant interaction between the change in hemoglobin A1c level and hemoglobin A1c value at initiation of pump therapy (-1.7% for patients with hemoglobin A1c > or = 10%; 0.2% for patients with hemoglobin A1c < or = 7%). The rate of severe hypoglycemic episodes decreased significantly in the adolescent group, from 36.5 to 11.1 events per 100 patient-years, and in the young adult group, from 58.1 to 23.3. There was no significant change in the rate of diabetic ketoacidosis between the 2 periods. The young adults showed a significant decrease in body mass index standard deviation scores (-0.08 +/- 0.37)., Conclusions: Continuous subcutaneous insulin infusion improves glycemic control in youth with type 1 diabetes, especially in those with a history of poor glycemic control. This improvement is associated with a decrease in the rate of severe hypoglycemia in the absence of weight gain.

Background and Objective: T1DM and asthma are mediated by opposite arms of the cellular immune system namely T helper (Th)1 and Th2 CD4(+) cells, respectively. Our aim was to characterize the Th1/Th2 cytokine balance in patients with both T1DM and asthma., Methods: Forty-four patients, mean age 19 years were matched by gender and age, to 4 paired groups: T1DM and asthma, asthma only, T1DM only and healthy controls. Peripheral blood mononuclear cells (PBMC) were stimulated in vitro with disease-specific recombinant antigens; glutamic acid decarboxylase and house dust mite (Der p1 antigen) for T1DM and asthma, respectively, and non-specific mitogens; phytohemaglutinin (PHA), tetanus toxin and anti-CD3 mAb. ELISPOT and ELISA technique were used to determine INF-gamma, IL-2, IL-4, IL-13 and IL-10 expression., Results: Patients with T1DM and asthma demonstrated a similar cytokine pattern but lower Th1/Th2 ratio compared to patients with T1DM only. The Th2 cytokines response to Der p1 was enhanced in patients with both diseases compared to controls. The IL-10 overall secretion was higher in patients with both diseases compared to one disease only., Conclusion: The Th1 and Th2 secretory pattern of patients with T1DM and asthma combines features of both diseases suggesting a unique Th1/Th2 balance.

Objective: Previous studies suggested that in patients with thalassemia major, initiating deferoxamine (DFO) therapy before puberty can prevent iron-induced failure of growth and puberty. However, early initiation of chelation has also been associated with DFO toxicity. The aim of this retrospective study was to determine the prevalence rates of endocrine complications and DFO bone toxicity in our thalassemia major patients and to correlate them with the degree of iron chelation., Methods: Thirty-nine patients with thalassemia major were followed for a median of 16.3 yr (range 2-28). Individual mean serum ferritin level during the study period was calculated using repeated annual measurements. Bone DFO toxicity was assessed by wrist and spine radiographs; endocrine dysfunction by anthropometric measurements and pubertal stage; and hypogonadotropic hypogonadism by lack of luteinizing hormone response to gonadotropin-releasing hormone., Results: Chelation therapy was initiated at median age 4.9 yr. Mean serum ferritin level during the study period was 2698 +/- 1444 ng/mL. Hypogonadism was noted in 59% of the patients who reached pubertal age, and short stature was found in 36% of patients who reached final height. Mean ferritin level of 2500 ng/mL during puberty was the cut-off for hypogonadism, and ferritin level of 3000 ng/mL during prepuberty was the cut-off for final short stature. None of the patients who attained final height had signs of DFO bone toxicity., Conclusions: High serum ferritin levels during puberty are a risk factor for hypogonadism, and high serum ferritin levels during the first decade of life predict final short stature. It remains to be determined whether improving chelation by earlier initiation of DFO or by the combined use of DFO and deferiprone will lead to better growth and sexual development without DFO toxicity., ((c) Blackwell Munksgaard 2005)

Objective: To compare glycemic patterns by mode of therapy in children with type 1 diabetes mellitus using the Continuous Glucose Monitoring System (CGMS)., Design: Open randomized crossover comparing 3(1/2) months of multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)., Setting: Tertiary care, university-affiliated medical center. Patients Twenty-three children and adolescents with type 1 diabetes mellitus., Interventions: The CGMS was applied for 72 hours after 1 month and at the end of each study arm., Main Outcome Measures: Hemoglobin A(1c) levels and glucose level profiles were compared between the 2 study arms and the 2 sensor applications for each arm., Results: The arms were similar for mean (SD) hemoglobin A(1c) levels (CSII, 8.0% [0.8%]; and MDI, 8.2% [0.8%]) and glucose levels. Areas under the curve were significantly larger during MDI for nocturnal and 24-hour hypoglycemia (P =.01 and.04, respectively) and for postprandial hypoglycemia and hyperglycemia (P =.03 and.05, respectively). The rate of hyperglycemia increased during CSII (P =.03), but 24-hour duration and area under the curve for hyperglycemia were similar. Compared with the first CGMS reading in each arm, the second had a longer mean duration of postprandial within-target glucose levels (P =.04), tendency for lower rate of diurnal hypoglycemic events (P =.1), shorter duration of nocturnal hypoglycemia (P =.05), and smaller 24-hour area under the curve for hypoglycemia (P =.04)., Conclusions: Intensive treatment with CSII seemed to be associated with slightly better prebreakfast, postprandial, and within-target glucose profiles than MDI, as well as a smaller area under the curve for hypoglycemia. Lower hypoglycemia-related variables in the second sensor reading in each arm indicate that the CGMS may serve as an educational tool to decrease the rate and magnitude of hypoglycemia.

CSII is a feasible, safe and well-accepted mode of therapy for many children with type 1 diabetes. For a significant number of patients and parents, it serves as a much easier means of coping with the huge daily burden of diabetes. Therefore, we believe that both CSII and MDI should be made available to the diabetic team and the patients to better tailor therapy, improve satisfaction and decrease the fear of hypoglycemia.

Objective: To compare the efficacy and feasibility of continuous subcutaneous insulin infusion (CSII) with multiple daily insulin injections (MDI) in children with type 1 diabetes., Methods: The study sample included 23 children (10 males) aged 9.4 to 13.9 years with type 1 diabetes. An open randomized crossover design was used to compare 3.5 months of CSII to 3.5 months of MDI therapy for the following variables: diabetic control, incidence of adverse events, daily insulin requirement, body mass index standard deviation scores, treatment satisfaction, and quality of life., Results: The changes in HbA(1c) and fructoseamine values were similar in the 2 arms over time. At the end of the study, mean HbA(1c) level measured 8.05 +/- 0.78%. There were no differences between the treatment modes in frequency of symptomatic hypoglycemic or hyperglycemic events. There was 1 event of severe hypoglycemia during pump therapy and 3 during MDI, yielding a rate of 0.26 events per patient-year. There were no episodes of diabetic ketoacidosis. Body mass index standard deviation scores decreased during CSII and increased during MDI, as did mean insulin dose. Patients expressed a higher treatment satisfaction from CSII than MDI, although there was no difference in quality of life between the 2 modes., Conclusions: Intensive insulin therapy by either insulin pump or MDI is safe in children and young adolescents with type 1 diabetes, with similar diabetes control and a very low rate of adverse events. We suggest that both modes be available to the diabetic team to better tailor therapy.