Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

The Prevalence of Obesity Among Children With Type 2 Diabetes: A Systematic Review and Meta-analysis.

Importance: The childhood obesity epidemic is presumed to drive pediatric type 2 diabetes (T2D); however, the global scale of obesity in children with T2D is unknown. Objectives: To evaluate the global prevalence of obesity in pediatric T2D, examine the association of sex and race with obesity risk, and assess the association of obesity with glycemic control and dyslipidemia. Data Sources: MEDLINE, Embase, CINAHL, Cochrane Library, and Web of Science were searched from database inception to June 16, 2022. Study Selection: Observational studies with at least 10 participants reporting the prevalence of obesity in patients with pediatric T2D were included. Data Extraction and Synthesis: Following the Meta-analysis of Observational Studies in Epidemiology reporting guideline, 2 independent reviewers in teams performed data extraction and risk of bias and level of evidence analyses. The meta-analysis was conducted using a random-effects model. Main Outcomes and Measures: The primary outcomes included the pooled prevalence rates of obesity in children with T2D. The secondary outcomes assessed pooled prevalence rates by sex and race and associations between obesity and glycemic control and dyslipidemia. Results: Of 57 articles included in the systematic review, 53 articles, with 8942 participants, were included in the meta-analysis. The overall prevalence of obesity among pediatric patients with T2D was 75.27% (95% CI, 70.47%-79.78%), and the prevalence of obesity at diabetes diagnosis among 4688 participants was 77.24% (95% CI, 70.55%-83.34%). While male participants had higher odds of obesity than female participants (odds ratio, 2.10; 95% CI, 1.33-3.31), Asian participants had the lowest prevalence of obesity (64.50%; 95% CI, 53.28%-74.99%), and White participants had the highest prevalence of obesity (89.86%; 95% CI, 71.50%-99.74%) compared with other racial groups. High heterogeneity across studies and varying degrees of glycemic control and dyslipidemia were noted. Conclusions and Relevance: The findings of this systematic review and meta-analysis suggest that obesity is not a universal phenotype in children with T2D. Further studies are needed to consider the role of obesity and other mechanisms in diabetes genesis in this population.

Is there a secular trend regarding puberty in children with down syndrome?

Introduction: There are very few studies on the age of onset and end of puberty in children with Down syndrome (DS). Also, data regarding the course of puberty in these children compared to their healthy peers is limited. Moreover, there is limited information regarding the effects of factors such as obesity and hypothyroidism on the puberty process in children with DS. Our aim in our study is to determine whether the pubertal development of children with DS differs from their healthy peers and from previous studies conducted with DS children. Methods: The medical records of DS children were examined retrospectively. The anthropometric measurements and the age of onset of pubertal stages, and menarche were recorded. The patients' age at puberty onset, the puberty processes, and age at menarche were compared with their healthy peers and previously published data on children with DS. Results: Of the 140 Down syndrome patients followed in our clinic, 51 of whom with puberty constituted the study group. The mean age of onset of puberty was 10.3 ± 1.0 years in our group (10.0 ± 0.8 years for girls, 10.6 ± 1.2 years for boys, respectively). Obesity occurred in 46% of pubertal girls with DS. The age of menarche in girls with DS was 11.8 ± 0.7 years. The menarche age of girls with DS was significantly different from healthy girls. In the DS boys, only the Tanner V stage ages were different from the healthy children. True- precocious-puberty was detected in three children. Conclusion: Although breast development begins later in females with DS than in their healthy peers; menarche is detected earlier than in their peers and a tendency towards obesity in the whole population. While the age of pubertal onset was similar to healthy children in male patients, our findings suggest that their puberty duration is longer.

Increased Severe Cases and New-Onset Type 1 Diabetes Among Children Presenting With Diabetic Ketoacidosis During First Year of COVID-19 Pandemic in Turkey.

Introduction: There have been some significant changes regarding healthcare utilization during the COVID-19 pandemic. Majority of the reports about the impact of the COVID-19 pandemic on diabetes care are from the first wave of the pandemic. We aim to evaluate the potential effects of the COVID-19 pandemic on the severity of diabetic ketoacidosis (DKA) and new onset Type 1 diabetes presenting with DKA, and also evaluate children with DKA and acute COVID-19 infection. Methods: This is a retrospective multi-center study among 997 children and adolescents with type 1 diabetes who were admitted with DKA to 27 pediatric intensive care units in Turkey between the first year of pandemic and pre-pandemic year. Results: The percentage of children with new-onset Type 1 diabetes presenting with DKA was higher during the COVID-19 pandemic (p < 0.0001). The incidence of severe DKA was also higher during the COVID-19 pandemic (p < 0.0001) and also higher among children with new onset Type 1 diabetes (p < 0.0001). HbA1c levels, duration of insulin infusion, and length of PICU stay were significantly higher/longer during the pandemic period. Eleven patients tested positive for SARS-CoV-2, eight were positive for new onset Type 1 diabetes, and nine tested positive for severe DKA at admission. Discussion: The frequency of new onset of Type 1 diabetes and severe cases among children with DKA during the first year of the COVID-19 pandemic. Furthermore, the cause of the increased severe presentation might be related to restrictions related to the pandemic; however, need to evaluate the potential effects of SARS-CoV-2 on the increased percentage of new onset Type 1 diabetes.

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Psychometric Properties of the Turkish Version of the Diabetes Strengths and Resilience Measure for Adolescents with Type 1 Diabetes

Objective: Resilience in diabetes refers to the capacity overcome diabetes-related challenges to achieve favorable psychosocial and health outcomes. Despite the known benefits of resilience in adolescents with type 1 diabetes mellitus (T1DM), there tends to be more emphasis on risk factors in research and practice. This study evaluated the psychometric properties of the Diabetes Strengths and Resilience Measure for Adolescents with Type 1 Diabetes (DSTAR-Teen) in Turkey. Methods: This descriptive, methodological study was conducted between October 2020 and May 2021. The Turkish DSTAR-Teen was administered to 120 adolescents with T1DM, and the data were evaluated using Cronbach's alpha coefficients, factor analyses, test-retest correlation, and item-total score correlations. Results: The Turkish DSTAR-Teen has 12 items in two factors that explained 50.64% of the total variance. Confirmatory factor analysis revealed goodness-of-fit and comparative fit indices of 0.92 and 0.95, respectively. The total Cronbach's alpha value of the scale was 0.85. Item-total score correlations ranged from 0.49 to 0.74 (p<0.001). Conclusion: Our analyses showed that the Turkish DSTAR-Teen is a valid and reliable instrument in Turkish adolescents with T1DM. The Turkish DSTAR-Teen can be used to evaluate strengths and resilience associated with diabetes management in adolescents with T1DM in Turkey.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

Surgical Practice in Girls with Congenital Adrenal Hyperplasia: An International Registry Study.

In this article international trends in surgical practice in girls with congenital adrenal hyperplasia (CAH) are evaluated. All cases that had been classified in the I-CAH/I-DSD registry as 46,XX CAH and who were born prior to 2017 were identified. Centers were approached to obtain information on surgical decision making. Of the 330 included participants, 208 (63.0%) presented within the first month of life, and 326 (98.8%) cases were assigned female. Genital surgery had been performed in 250 (75.8%). A total of 64.3, 89.2, and 96.8% of cases residing in Europe, South America and Asia, respectively, had at least one surgery. In a logistic regression model for the probability of surgery before the second birthday (early surgery) over time an increase of probability for early vaginal surgery could be identified, but not for clitoral surgery or both surgeries combined. Genitoplasty in girls with CAH remains controversial. This large international study provides a snapshot of current practice and reveals geographical and temporal differences. Fewer surgeries were reported for Europe, and there seems to be a significant trend towards aiming for vaginal surgery within the first 2 years of life.

Gonadectomy in conditions affecting sex development: a registry-based cohort study.

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.

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

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

Hypogonadism: Is It Always Hypogonadotropic in an Adolescent With a Cleft Palate? A Surprising Case of Klinefelter Syndrome.

Pituitary hormone deficiencies may occur in children with midline defects; in these cases, hypogonadism is usually hypogonadotropic. Herein, we report a boy at the age of 13.8 years with mild mental retardation, previously operated for complete cleft palate (isolated) and presented with hypoglycemia due to isolated secondary adrenal insufficiency, who further had a decrease in testicular size with increased follicle-stimulating hormone level (hypergonadotropic hypogonadism) and diagnosed with Klinefelter syndrome. Klinefelter syndrome in childhood is rarely diagnosed and cases are observed in a wide spectrum. Although some regional duplications of the X chromosome also show midline defects such as spina bifida-neural tube defects, mental retardation, hypopituitarism (mostly growth hormone deficiency); coexistence of Klinefelter syndrome and isolated secondary adrenal deficiency/midline defect in our case may also be coincidental. However, to our knowledge, this is the first case in literature with this association in a patient with a 47, XXY karyotype.

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Molecular Analysis of CYP27B1 Mutations in Vitamin D-Dependent Rickets Type 1A: c.590G > A (p.G197D) Missense Mutation Causes a RNA Splicing Error.

CONTEXT: Vitamin D-dependent rickets type 1A (VDDR1A) is a rare autosomal recessively inherited disorder due to loss-of-function mutations in the CYP27B1 gene. CYP27B1 encodes an enzyme of 25-hydroxyvitamin D-1α-hydroxylase for converting inactive 25-OHD to biologically active 1,25-(OH)2D. OBJECTIVE: To identify underlying genetic defects in patients with VDDR1A. METHODS: Twelve patients from 7 Turkish and 2 Saudi families were investigated. The coding exons and intron-exon boundaries of the CYP27B1 gene were amplified by Polymerase Chain Reaction (PCR) from peripheral lymphocyte DNA. PCR products were directly sequenced. The consequences of c.590G > A mutation were analyzed by in silico and functional analysis. RESULTS: CYP27B1 mutations were identified in all the patients. Two novel mutations were identified in two separate families: c.171delG (family 7) and c.398_400dupAAT (family 8). The intra-exon deletion of c.171delG resulted in a frameshift and premature stop codon 20 amino acids downstream from the mutation (p.L58Cfs∗20). The intra-exon duplication of c.398_400dupAAT generated a premature stop codon at the mutation site (p.W134∗). A missense c.590G > A (p.G197D) mutation was found in a patient from family 4 and caused a defect in pre-mRNA splicing. As a result, two populations of transcripts were detected: the majority of them with intron 3 retention (83%), and the minority (17%) being properly spliced transcripts with about 16% of wild-type enzymatic activity. The remaining nine patients from six families carried a previously reported c.1319_1325dupCCCACCC (F443Pfs∗24) mutation. Clinically, all the patients need continued calcitriol treatment, which was consistent with inactivation of 25-hydroxy vitamin D1α-hydroxylase activity. CONCLUSION: Two novel frameshift CYP27B1 mutations were identified and predicted to inactivate 25-hydroxyvitamin D-1α-hydroxylase. The loss of enzymatic activity by c.590G > A missense mutation was mainly caused by aberrant pre-mRNA splicing.

Idiopathic infantile hypercalcemia: mutations in SLC34A1 and CYP24A1 in two siblings and fathers.

Objectives Both CYP24A1 and SLC34A1 gene mutations are responsible for idiopathic infantile hypercalcemia, whereas loss-of-function mutations in CYP24A1 (25-OH-vitamin D-24-hydroxylase) lead to a defect in the inactivation of active 1.25(OH)2D; mutations in SLC34A1 encoding renal sodium phosphate cotransporter NaPi-IIa lead to primary renal phosphate wasting combined with an inappropriate activation of vitamin D. The presence of mutations in both genes has not been reported in the same patient until today. Case presentation Hypercalcemia was incidentally detected when a 13-month-old boy was being examined for urinary tract infection. After 21 months, hypercalcemia was detected in his six-month-old sister. High dose of vitamin D was not given to both siblings. Both of them also had hypophosphatemia and decreased tubular phosphate reabsorption. Intensive hydration, furosemide and oral phosphorus treatment were given. Bilateral medullary nephrocalcinosis was detected in both siblings and their father. Serum Ca and P levels were within normal limits at follow-up in both siblings. Siblings and their parents all carry a homozygous stop codon mutation (p.R466*) in CYP24A1. Interestingly, both siblings and the father also have a heterozygous splice-site mutation (IVS6(+1)G>A) in SLC34A1. The father has nephrocalcinosis. Conclusions A biallelic loss-of-function mutation in the CYP24A1 gene was identified as responsible for hypercalcemia, hypercalciuria and nephrocalcinosis. In addition, a heterozygous mutation in the SLC34A1 gene, although not being the main pathogenic factor, might contribute to the severe phenotype of both patients.

Associated clinical abnormalities among patients with Turner syndrome.

OBJECTIVE: The early diagnosis of Turner syndrome (TS) is often difficult because of the various clinical features. This study aimed to investigate clinical features and identify associated abnormalities in a group of patients with TS. METHODS: Retrospective data of presenting clinical features collected from the medical records of the 37 patients with TS. All patients were examined for associated clinical abnormalities. RESULTS: Mean age at diagnosis was 9.3±4.1 years. The main reason for referral was short stature and/or delayed puberty. All of the patients had at least one dysmorphic sign. Skeletal system abnormalities (57%) were the most common associated abnormality, which was followed by gastrointestinal system problems (40%). Cardiac defects occurred in 32%. Urinary system abnormalities occurred in 27%. Dermatological problems were detected in 32% of the patients. The pathology of the hearing was found in 19%. Autoimmune thyroid disease was detected in 24% of the patients, and celiac disease was detected in 5.4% of the patients. CONCLUSION: Phenotypic variability often leads to a delay in the diagnosis of TS. Early diagnosis can initiate effective management in patients with TS.

Different Potent Glucocorticoids, Different Routes of Exposure but the Same Result: Iatrogenic Cushing's Syndrome and Adrenal Insufficiency

Objective: Potent glucocorticoids (GC) cause iatrogenic Cushing's syndrome (ICS) due to suppression of hypothalamo-pituitary-adrenal (HPA) axis and may progress to adrenal insufficiency (AI). The aim was to review the clinical and laboratory findings of patients with ICS and to investigate other serious side effects. Methods: The possibility of AI was investigated by low-dose adrenocorticotrophic hormone test. Hydrocortisone was started in patients with adrenal failure. Results: Fourteen patients (five boys) with ages ranging from 0.19 to 11.89 years were included. The duration of GC exposure ranged from 1 to 72 months. Ten patients were prescribed topical GC and the rest had oral exposure. Moon face and abdominal obesity were detected in all patients. At presentation, 12 of 14 had AI and two infants had hypercalcemia and nephrocalcinosis. Of 11 patients, ultrasonography revealed hepatosteatosis in five. A cream for diaper dermatitis was used in one infant and the active ingredient was listed as panthenol. However, blood and urine steroid analyses revealed that all endogenous steroids were suppressed. Median (range) time to normalization of HPA axis function was 60 (30-780) days. Conclusion: The majority (85%) of patients had life-threatening AI and two patients had hypercalcemia. These results highlight the serious side-effects of inappropriate use of potent GCs, especially in infants. The recovery of the HPA axis in children might take as long as three years. Parents should be informed regarding the possibility of some products containing unlisted synthetic GC and to be aware of their side effects.

Revisiting Classical 3ß-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases.

CONTEXT: The clinical effects of classical 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency are insufficiently defined due to a limited number of published cases. OBJECTIVE: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3ßHSD2 deficiency. DESIGN: Multicenter, cross-sectional study. SETTING: Nine tertiary pediatric endocrinology clinics across Turkey. PATIENTS: Children with clinical diagnosis of 3ßHSD2 deficiency. MAIN OUTCOME MEASURES: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3ßHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. RESULTS: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ±â€…5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3ßHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. CONCLUSIONS: Genetically-documented 3ßHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3ßHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3ßHSD2 deficiency.

Plasma Renin Measurements are Unrelated to Mineralocorticoid Replacement Dose in Patients With Primary Adrenal Insufficiency.

CONTEXT: No consensus exists for optimization of mineralocorticoid therapy in patients with primary adrenal insufficiency. OBJECTIVE: To explore the relationship between mineralocorticoid (MC) replacement dose, plasma renin concentration (PRC), and clinically important variables to determine which are most helpful in guiding MC dose titration in primary adrenal insufficiency. DESIGN: Observational, retrospective, longitudinal analysis. PATIENTS: A total of 280 patients (with 984 clinical visits and plasma renin measurements) with primary adrenal insufficiency were recruited from local databases and the international congenital adrenal hyperplasia (CAH) registry (www.i-cah.org). Thirty-seven patients were excluded from the final analysis due to incomplete assessment. Data from 204 patients with salt-wasting CAH (149 adults and 55 children) and 39 adult patients with Addison disease (AD) were analysed. MAIN OUTCOME MEASURES: PRC, electrolytes, blood pressure (BP), and anthropometric parameters were used to predict their utility in optimizing MC replacement dose. RESULTS: PRC was low, normal, or high in 19%, 36%, and 44% of patients, respectively, with wide variability in MC dose and PRC. Univariate analysis demonstrated a direct positive relationship between MC dose and PRC in adults and children. There was no relationship between MC dose and BP in adults, while BP increased with increasing MC dose in children. Using multiple regression modeling, sodium was the only measurement that predicted PRC in adults. Longitudinally, the change in MC dose was able to predict potassium, but not BP or PRC. CONCLUSIONS: The relationship between MC dose and PRC is complex and this may reflect variability in sampling with respect to posture, timing of last MC dose, adherence, and concomitant medications. Our data suggest that MC titration should not primarily be based only on PRC normalization, but also on clinical parameters such as BP and electrolyte concentration.

Lipid accumulation product is a predictor of nonalcoholic fatty liver disease in childhood obesity.

BACKGROUND: Lipid accumulation product (LAP) is associated with the presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults. PURPOSE: Here we evaluated the ability of LAP to predict NAFLD in obese children. METHODS: Eighty obese children (38 girls; age 6-18 years) were included. Anthropometric measurements and biochemical values were obtained from the patients' medical records. LAP was calculated as [waist circumference (WC) (cm) - 58]×triglycerides (mmol/L) in girls; [WC (cm) - 65]×triglycerides (mmol/ L) in boys. The minLAP and adjLAP were described (3% and 50% of WC values, respectively) and the total/high-density lipoprotein cholesterol index (TC/HDL-C) was calculated. NAFLD was observed on ultrasound, and patients were divided into 3 groups by steatosis grade (normal, grade 0; mild, grade 1; moderate-severe, grade 2-3). The area under the curve (AUC) and appropriate index cutoff points were calculated by receiver operator characteristic analysis. RESULTS: LAP was positively correlated with puberty stage (rho=0.409; P<0.001), fasting insulin (rho= 0.507; P<0.001), homeostasis model assessment of insulin resistance (rho=0.470; P<0.001), uric acid (rho=0.522; P<0.001), and TC/HDL-C (rho=0.494; P<0.001) and negatively correlated with HDL-C (rho=-3.833; P<0.001). LAP values could be used to diagnose hepatosteatosis (AUC=0.698; P=0.002). The LAP, adjLAP, and minLAP cutoff values were 42.7 (P=0.002), 40.05 (P=0.003), and 53.47 (P= 0.08), respectively. For LAP, the differences between the normal and mild groups (P=0.035) and the normal and moderate-severe groups were statistically significant (P=0.037), whereas the difference between the mild and moderate-severe groups was not (P>0.005). There was a statistically significant difference between the normal and mild groups for adjLAP (P=0.043) but not between the other groups (P>0.005). There was no significant intergroup difference in minLAP (P>0.005). CONCLUSION: LAP is a powerful and easy tool to predict NAFLD in childhood. If LAP is ≥42.7, NAFLD should be suspected. This is the first study to assess LAP diagnostic accuracy for childhood obesity.

Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.