Search

Context Crinecerfont, a corticotropin-releasing factor type 1 (CRF1) receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD CAH), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated ACTH. Objective To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. Design Open-label, phase 2 study (NCT04045145). Setting United States (4 centers). Participants Males and females, 14 to 17 years of age, with classic 21OHD CAH. Intervention Orally administered crinecerfont (50 mg twice daily) for 14 consecutive days with morning and evening meals. Main outcomes Change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eight participants (3 males, 5 females) were enrolled; mean age was 15 years and 88% were Caucasian/White. After 14 days of crinecerfont, median percent reductions from baseline to day 14 were as follows: ACTH, -57.1%; 17OHP, -69.5%; and androstenedione, -58.3%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. Conclusions Adolescents with classic 21OHD CAH had substantial reductions in adrenal androgens and androgen precursors after 14 days of oral crinecerfont administration. These results are consistent with a study of crinecerfont in adults with classic 21OHD CAH.

Context Intramuscular (IM) testosterone enanthate (TE) and testosterone pellets were US Food and Drug Administration approved before 1962 for pediatric use but not studied in controlled trials in adolescents. Objective An analysis using nonlinear mixed effect (NLME) modeling was designed to evaluate the adult pharmacokinetics (PK) of subcutaneous (SC) and IM TE. This model was used to simulate SC and IM TE administration in adolescents of different weight groups. Methods Data from adult male patients in a phase 2 trial were used to characterize the PK of TE using population PK modeling for SC and IM administration: Allometry was used to scale PK parameters from the adult model to simulate adolescent (aged 12 to Results The final data set included 714 samples from 15 patients receiving 100 mg SC TE and 123 samples from 10 patients receiving 200 mg IM TE. In simulated populations, average serum concentration SC:IM ratios were 0.783, 0.776, and 0.757 at steady state for weekly, EOW, and monthly dosing groups, respectively. Simulated regimens of 12.5 mg SC TE monthly produced serum testosterone levels representative of early puberty and simulated pubertal stage progression following multiple subsequent testosterone dose increases. Conclusion SC TE administration achieved a testosterone exposure-response relationship similar to IM TE in simulated adolescent hypogonadal males, which may reduce size of fluctuations in serum T and related symptoms.

Central precocious puberty (CPP) classically refers to premature activation of the hypothalamic–pituitary–gonadal axis with onset of sexual development before the age of 8 years in girls and 9 years in boys. A decrease in the age of thelarche has been reported over the past several decades; however, the tempo of pubertal progression can be slower and adult height may not be adversely affected in many of the girls who experience thelarche at 6-8 years. Outside of this secular trend in the development itself, the past several decades have also brought about advances in diagnosis and management. This includes the widespread use of an ultrasensitive luteinizing hormone assay, decreasing the need for stimulation testing and a better understanding of the genetics that govern the onset of puberty. Additionally, management of CPP using gonadotropin-releasing hormone analogs (GnRHas) has changed with the advent of new longer-acting formulations. Emerging long-term outcomes of GnRHa administration with regards to obesity, cardiovascular risk factors and fertility are reassuring. Despite these advancements, clinical care in CPP is hampered by the lack of well-designed controlled studies, and management decisions are frequently not supported by clear practice guidelines. Data in boys with CPP are limited and this article focuses on the diagnosis and management of CPP in girls, particularly, in those who present with thelarche at the age of 6-8 years.

Context Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. Objective This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. Methods This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. Results Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (–66%), 17OHP (–64%), and androstenedione (–64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. Conclusion Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Objective To estimate the effect of skin-to-skin care (SSC) on biobehavioral measures of stress (anxiety and salivary cortisol) and attachment (attachment scores and salivary oxytocin) of mothers before and after their infants’ neonatal cardiac surgery. Design A prospective interventional, baseline response–paired pilot study. Setting Cardiac center of a large, metropolitan, freestanding children’s hospital. Participants Thirty women whose infants were hospitalized for neonatal cardiac surgery. Methods Participants acted as their own controls before, during, and after SSC at two time points: once before and once after surgery. We measured the stress response of mothers, as indicated by self-reported scores of anxiety and maternal salivary cortisol, and maternal–infant attachment, as indicated by self-reported scores and maternal salivary oxytocin. Results Significant reductions in self-reported scores of anxiety and salivary cortisol were found as a result of SSC at each time point, as well as increased self-reported attachment. No significant differences were found in oxytocin. Conclusion Our findings provide initial evidence of the benefits of SSC as a nurse-led intervention to support maternal attachment and reduce physiologic and psychological stress responses in mothers of infants with critical congenital heart disease before and after neonatal cardiac surgery.

Hypertension in childhood and adolescence has increased in prevalence. Interest in the disease was raised after the 2017 clinical practice guidelines of the American Academy of Paediatrics on the definition and classification of paediatric hypertension. Among the secondary causes of paediatric hypertension, endocrine causes are relatively rare but important due to their unique treatment options. Excess of catecholamine, glucocorticoids and mineralocorticoids, congenital adrenal hyperplasia, hyperaldosteronism, hyperthyroidism and other rare syndromes with specific genetic defects are endocrine disorders leading to paediatric and adolescent hypertension. Adipose tissue is currently considered the major endocrine gland. Obesity-related hypertension constitutes a distinct clinical entity leading to an endocrine disorder. The dramatic increase in the rates of obesity during childhood has resulted in a rise in obesity-related hypertension among children, leading to increased cardiovascular risk and associated increased morbidity and mortality. This review presents an overview of pathophysiology and diagnosis of hypertension resulting from hormonal excess, as well as obesity-related hypertension during childhood and adolescence, with a special focus on management.

Background: The primary objective of this exploratory, feasibility study was to examine the relationships of self-reported perceived stressors and psychological stress responses with measures of the biomarker cortisol in parents of infants hospitalized after neonatal cardiac surgery for critical congenital heart disease (cCHD). Methods: This was a prospective, cross-sectional study of 28 biological mother–father dyads of neonates with cCHD using consecutive enrollment. In the postoperative period after neonatal cardiac surgery, parents provided awakening and diurnal saliva samples and self-report measures on stress, anxiety, depression, dyadic adjustment, and perceived severity of illness of their neonate. Results: Evaluable data, including salivary cortisol samples, were obtained for 27 of the 28 dyads enrolled in the study. Compared to fathers, mothers exhibited significantly higher mean cortisol values at wakeup ( p = .032), 30-minute post-wakeup ( p = .024), and bedtime ( p = .010) timepoints. Anxiety and depressive symptoms were both significant predictors of awakening cortisol measures. Depressive symptoms were also a predictor of diurnal cortisol ( p < .05). Stress arising from infant appearance and behavior was found to significantly predict cortisol awakening response ( p = .0403). Conclusions: Findings suggest that cortisol may be an important biomarker in the examination of parent stress in the pediatric cardiac intensive care unit (PCICU), serving as a foundation for future study in this area. Furthermore, we have provided preliminary evidence of feasibility of including saliva collection in studies of highly stressed parents in a challenging environment.

Context Diabetes and cardiovascular diseases are common among men with Klinefelter syndrome (KS) and contribute to high morbidity and mortality. Objective To determine if cardiometabolic-related diagnoses are more prevalent among youth with KS than matched controls in a large population-based cohort. Methods Secondary data analysis of electronic health records from 6 pediatric institutions in the United States (PEDSnet). Patients included all youth with KS in the database (n = 1080) and 4497 youth without KS matched for sex, age (mean 13 years at last encounter), year of birth, race, ethnicity, insurance, site, and duration of care (mean 7 years). The main outcome measures were prevalence of 5 cardiometabolic-related outcomes: overweight/obesity, dyslipidemia, dysglycemia, hypertension, and liver dysfunction. Results The odds of overweight/obesity (OR 1.6; 95% CI 1.4-1.8), dyslipidemia (3.0; 2.2-3.9), and liver dysfunction (2.0; 1.6-2.5) were all higher in KS than in controls. Adjusting for covariates (obesity, testosterone treatment, and antipsychotic use) attenuated the effect of KS on these outcomes; however, boys with KS still had 45% greater odds of overweight/obesity (95% CI 1.2-1.7) and 70% greater odds of liver dysfunction (95% CI 1.3-2.2) than controls, and both dyslipidemia (1.6; 1.1-2.4) and dysglycemia (1.8; 1.1-3.2) were higher in KS but of borderline statistical significance when accounting for multiple comparisons. The odds of hypertension were not different between groups. Conclusion This large, population-based cohort of youth with KS had a higher odds of most cardiometabolic-related diagnoses than matched controls.

IntroductionOsteopenia and osteoporosis have been reported in adults with Complete Androgen Insensitivity Syndrome (CAIS). Little is known about changes in bone mineral density (BMD) in adolescents with CAIS and whether it is affected by early gonadectomy. Body composition data have not been reported.MethodsSingle-center, retrospective study of CAIS adolescents who underwent dual-energy x-ray absorptiometry (DXA) (Hologic, Horizon A). Body composition is presented as lean and fat mass indices (LMI, FMI). Z-scores for lumbar spine areal BMD (LBMD), total body less head (TBLH), bone mineral content (BMC), LMI, and FMI were calculated using female normative data. Results are expressed as median and min, max.ResultsSix females with genetically confirmed CAIS were identified—one with intact gonads and five with history of gonadectomy at 2–11 months. In the subject with intact gonads, LBMD-Z and TBLH BMC-Z were −1.56 and −1.26, respectively, at age 16 years. Among those with gonadectomy, LBMD-Z was −1.8 (−3.59 to 0.49) at age 15.6 years (12–16.8) and decreased in all three subjects who had longitudinal follow-up despite hormone replacement therapy (HRT). Adherence to HRT was intermittent. LMI-Z and FMI-Z were 0.1 (−1.39 to 0.7) and 1.0 (0.22 to 1.49), respectively.ConclusionsThese limited data indicate that adolescents with CAIS have bone mass deficit. Further studies are needed to understand the extent of BMD abnormalities and the effect of gonadectomy, especially early in childhood, and to establish the optimal HRT regimen for bone accrual. Data on lean mass are reassuring.

Background The use of gonadotropin-releasing hormone agonists (GnRHa) for pubertal suppression has been associated with increased body mass index (BMI) in female subjects with central precocious puberty (CPP), although results have been so far conflicting. This study examined the effects of GnRHa therapy in both genders and in subjects treated for CPP, early puberty or short stature. Methods This was a longitudinal retrospective study of subjects followed at outpatient pediatric endocrinology clinics of an academic medical center from 2005 to 2014 receiving GnRHa therapy. Results At 12 months, subjects on depot GnRHa had a statistically significant increase in BMI standard deviation score (SDS) from baseline (0.13 ± 0.35, p Conclusions Subjects with short stature, normal BMI at baseline and female sex had significant increases in BMI SDS at 12 months. This is the first study to show an increase in BMI SDS in children treated with GnRHa for short stature, and is one of the few studies to assess BMI changes in males.

Purpose To perform the largest review of the safety and clinical management practices of histrelin implantation in children. Methods A retrospective cohort study was performed including all patients (age ≤ 20) that underwent histrelin implant insertion, replacement, or removal by a single surgeon at a large pediatric tertiary care center (2008–2017). Data analyzed included patient demographics, procedure details, and complications. Results A total of 377 patients, with a mean age of 9.3 ± 2.4 years, underwent 866 unique procedures (352 insertions, 329 replacements, and 185 removals) for a diagnosis of either central precocious puberty (343 patients, 821 cases) or gender identity disorder (34 patients, 45 cases). There were 271 (72%) female patients, 72 (19%) male patients, and 34 (9%) children in gender transition. Procedures were performed in three settings: 415 (47.9%) in the outpatient clinic, 401 (46.3%) in a sedation unit, and 50 (5.8%) in the operating room. The preferred setting shifted over time to more clinic-based procedures (9.4% vs. 62.9% in the first five vs. second five years, respectively). Complications were rare (1% of cases). Conclusion Histrelin implantation in the pediatric population is safe, with minimal morbidity. Implantation and removal in the clinic setting are appropriate for the majority of patients. Level of evidence Treatment study; Level IV.

Context Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is typically treated with lifelong supraphysiologic doses of glucocorticoids (GCs). Tildacerfont, a corticotropin-releasing factor type-1 receptor antagonist, may reduce excess androgen production, allowing for GC dose reduction. Objective Assess tildacerfont safety and efficacy. Design and Setting Two Phase 2 open-label studies. Patients Adults with 21OHD. Intervention Oral tildacerfont 200 to 1000 mg once daily (QD) (n = 10) or 100 to 200 mg twice daily (n = 9 and 7) for 2 weeks (Study 1), and 400 mg QD (n = 11) for 12 weeks (Study 2). Main Outcome Measure Efficacy was evaluated by changes from baseline at 8 am in adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), and androstenedione (A4) according to baseline A4 ≤ 2× upper limit of normal (ULN) or A4 > 2× ULN. Safety was evaluated using adverse events (AEs) and laboratory assessments. Results In Study 1, evaluable participants with baseline A4 > 2× ULN (n = 11; 19-67 years, 55% female) had reductions from baseline in ACTH (−59.4% to −28.4%), 17-OHP (−38.3% to 0.3%), and A4 (−24.2% to −18.1%), with no clear dose response. In Study 2, participants with baseline A4 > 2× ULN (n = 5; 26-63 years, 40% female) had ~80% maximum mean reductions in biomarker levels. ACTH and A4 were normalized for 60% and 40%, respectively. In both studies, participants with baseline A4 ≤ 2× ULN maintained biomarker levels. AEs (in 53.6% of patients overall) included headache (7.1%) and upper respiratory tract infection (7.1%). Conclusions For patients with 21OHD, up to 12 weeks of oral tildacerfont reduced or maintained key hormone biomarkers toward normal.

Context Klinefelter syndrome (KS) is the most common sex aneuploidy in men. Affected males have hypogonadism, and, as a result, face an increased risk for osteoporosis and fractures. Androgen therapy is standard in adolescents and adults with KS but has not been used earlier in childhood. Objective To determine the effects of androgen treatment on bone mass in children with KS. Methods Randomized, double-blind, placebo-controlled clinical trial of oxandrolone (OX; 0.06 mg/kg daily; n = 38) versus placebo (PL; n = 40) for 2 years in boys with KS (ages 4-12 years). Changes in bone mass were examined by digital x-ray radiogrammetry, which determines the Bone Health Index (BHI) and standard deviation score (SDS). Results BHI SDS was similar between groups at baseline (–0.46 ± 1.1 vs –0.34 ± 1.0 OX vs PL, P > .05) and higher in the OX group at 2 years (–0.1 ± 1.3 vs –0.53 ± 0.9, OX vs PL, P Conclusion Bone mass using BHI SDS is reduced in some children with KS and improves with OX. Since these individuals are at risk for osteoporosis, age-appropriate androgen replacement and future studies on bone health in children with KS should be further explored.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

To determine the effect of skin-to-skin care on stress, pain, behavioral organization, and physiologic stability of infants with critical congenital heart disease before and after neonatal cardiac surgery.A baseline response-paired design was used, with infants acting as their own controls before, during, and after skin-to-skin care at two distinct time points: once in the preoperative period (T1) and once in the postoperative period (T2).Cardiac ICU and step-down unit in a large metropolitan freestanding children's hospital.Convenience sample of 30 infants admitted preoperatively for critical congenital heart disease.Eligible infants were placed into skin-to-skin care for 1 hour with their biological mothers once each at T1 and T2.Measurements of stress (salivary cortisol), pain and behavior state (COMFORT scale), and physiologic stability (vital signs) were assessed immediately before skin-to-skin care, 30 minutes into skin-to-skin care, and 30 minutes after skin-to-skin care ended.At both T1 and T2, infant pain scores were significantly decreased (p0.0001) and infants moved into a calmer behavior state (p0.0001) during skin-to-skin care as compared to baseline. At T1, infants also had significantly reduced heart rate (p = 0.002) and respiratory rate (p0.0001) and increased systolic blood pressure (p = 0.033) during skin-to-skin care. At both T1 and T2, infant cortisol remained stable and unchanged from pre-skin-to-skin care to during skin-to-skin care (p = 0.096 and p = 0.356, respectively), and significantly increased from during skin-to-skin care to post-skin-to-skin care (p = 0.001 and p = 0.023, respectively). Exploratory analysis revealed differences in cortisol reactivity for infants with higher baseline cortisol (0.3 μg/dL) versus lower (≤ 0.3 μg/dL) prior to skin-to-skin care. Infants with higher baseline cortisol at T2 experienced significantly reduced cortisol during skin-to-skin care (p = 0.025). No significant differences in demographics or baseline variables were found between infants in either group.Skin-to-skin care is a low-cost, low-risk intervention that promotes comfort and supports physiologic stability in infants before and after neonatal cardiac surgery.

Context Patients with classic congenital adrenal hyperplasia (CAH) often require supraphysiologic glucocorticoid doses to suppress adrenocorticotropic hormone (ACTH) and control androgen excess. Nevanimibe hydrochloride (ATR-101), which selectively inhibits adrenal cortex function, might reduce androgen excess independent of ACTH and thus allow for lower glucocorticoid dosing in CAH. 17-hydroxyprogesterone (17-OHP) and androstenedione are CAH biomarkers used to monitor androgen excess. Objective Evaluate the efficacy and safety of nevanimibe in subjects with uncontrolled classic CAH. Design This was a multicenter, single-blind, dose-titration study. CAH subjects with baseline 17-OHP ≥4× the upper limit of normal (ULN) received the lowest dose of nevanimibe for 2 weeks followed by a single-blind 2-week placebo washout. Nevanimibe was gradually titrated up if the primary outcome measure (17-OHP ≤2× ULN) was not met. A total of 5 nevanimibe dose levels were possible (125, 250, 500, 750, 1000 mg twice daily). Results The study enrolled 10 adults: 9 completed the study, and 1 discontinued early due to a related serious adverse event. At baseline, the mean age was 30.3 ± 13.8 years, and the maintenance glucocorticoid dose, expressed as hydrocortisone equivalents, was 24.7 ± 10.4 mg/day. Two subjects met the primary endpoint, and 5 others experienced 17-OHP decreases ranging from 27% to 72% during nevanimibe treatment. The most common side effects were gastrointestinal (30%). There were no dose-related trends in adverse events. Conclusions Nevanimibe decreased 17-OHP levels within 2 weeks of treatment. Larger studies of longer duration are needed to further evaluate its efficacy as add-on therapy for CAH.

Introduction: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD CAH) is a rare autosomal recessive disease that results in impaired cortisol synthesis and excess androgen production. Compounds that inhibit adrenocorticotropic hormone (ACTH) release could reduce adrenal androgen production and thus the amounts of exogenous glucocorticoids needed to decrease these androgen levels. This study evaluated the effect of crinecerfont (NBI-74788), a novel, non-steroidal, and selective corticotropin-releasing factor-1 (CRF1) receptor antagonist on adrenal androgens and precursors in adults with 21OHD CAH. Methods: This open-label, multiple-dose study enrolled men and women (18–50 years old) with 21OHD CAH. A sequential-cohort design evaluated 4 crinecerfont oral dosing regimens: 50 mg QHS (Cohort 1); 100 mg QHS (Cohort 2); 100 mg QD (Cohort 3); and 100 mg alternative dosing (Cohort 4). Each regimen was administered for 14 consecutive days. ACTH, 17-hydroxy-progesterone (17OHP), and androstenedione (A4) were measured serially over a 24-hour period, at baseline and after 14 days of dosing. Results: Analyses included 23 participants: Cohort 1 (4 women, 4 men: mean age 31.1 years); Cohort 2 (5 women, 2 men: mean age 32.9 years); and Cohort 3 (3 women, 5 men: mean age 30.9 years). Cohort 4 is ongoing. At baseline, median plasma ACTH, serum 17OHP, and serum A4 levels were as follows: Cohort 1 (ACTH, 151 pg/mL; 17OHP, 5352 ng/dL; A4, 270 ng/dL); Cohort 2 (ACTH, 232 pg/mL; 17OHP, 12821 ng/dL; A4, 597 ng/dL); and Cohort 3 (ACTH, 470 pg/mL; 17OHP, 6451 ng/dL; A4, 299 ng/dL). After 14 days of once-daily crinecerfont 50 mg, Cohort 1 patients had median percent reductions from baseline in plasma ACTH (-54%), serum 17OHP (-60%), and serum A4 (-21%). Median percent reductions were generally larger with 100 mg in Cohort 2 (ACTH, -67%; 17OHP, -75%; A4, -47%) and Cohort 3 (ACTH, -69%; 17OHP, -55%; A4, -43%), consistent with a dose-related response. Adverse events were mostly mild; no clinically significant findings from routine laboratory tests, vital signs, or electrocardiograms were noted. Conclusions: Results of this Phase 2 study of crinecerfont, a novel, orally administered, selective CRF1-receptor antagonist, indicated clinically meaningful reductions of elevated ACTH, 17OHP, and A4 in adults with 21OHD CAH after 14 days of treatment. Further studies are warranted to evaluate the effects of chronic crinecerfont therapy on maintenance of adrenal steroid production, clinical endpoints of disordered steroidogenesis, and reductions in GC exposure in both adult and pediatric patients with 21OHD CAH.

STUDY QUESTION: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference?SUMMARY ANSWER: International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS.WHAT IS KNOWN ALREADY: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist.STUDY DESIGN, SIZE, DURATION: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength.PARTICIPANTS/MATERIALS, SETTING, METHODS: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels.MAIN RESULTS AND THE ROLE OF CHANCE: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management.LIMITATIONS, REASONS FOR CAUTION: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided.WIDER IMPLICATIONS OF THE FINDINGS: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program.STUDY FUNDING/COMPETING INTEREST(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.

OBJECTIVE: To evaluate the odds of a behavioral health diagnosis among youth with a difference of sex development (DSD) or congenital adrenal hyperplasia (CAH) compared with matched controls in the PEDSnet database. STUDY DESIGN: All youth with a diagnosis of DSD (n=1,216) or CAH (n=1,647) and at least one outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) to controls (n=4,864 and 6,588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. RESULTS: Youth with a DSD had higher odds of a behavioral health diagnosis (OR: 1.7 [95% CI: 1.4, 2.1], p

Summary Background Children with congenital adrenal hyperplasia (CAH) are at risk for adrenal crises in the perioperative period and require higher doses of glucocorticoids. However, there are no specific protocols detailing the appropriate stress dosing required for children with CAH undergoing surgery with anesthesia. Objective To evaluate CAH patients using our current hydrocortisone stress dose surgical protocol. We hypothesized that current clinical protocols may overestimate the endogenous response to perioperative stress. Study design 14 children with CAH scheduled to have genital surgery and a control group of 10 unaffected children scheduled to have cardiac or urologic surgery (of a similar duration) were evaluated in a prospective observational study. Urinary free cortisol (UFC) and urinary 17-hydroxycorticosteroids (17-OHCS) per body surface area were measured in the postoperative period. Results UFC levels were significantly higher in CAH patients (115.8 ± 24.6 nmol/m2) than in controls (26.5 ± 12.2 nmol/m2), P Conclusion In the immediate postoperative period, urinary cortisol and its metabolites are significantly higher in pediatric CAH patients receiving stress dose corticosteroids compared to controls. Results suggest that the amount of hydrocortisone given during our stress dose protocol may be higher than physiologic needs. Future dynamic studies are needed to determine appropriate perioperative and postoperative cortisol requirements in pediatric CAH patients in order to develop optimal stress dose regimens. Download : Download high-res image (137KB) Download : Download full-size image Summary Figure . Urinary free cortisol per body surface area.

Ovotesticular Differences in Sexual Development (OT-DSD) is a rare subset of DSD with great phenotypic variability characterized by the presence of both testicular and ovarian tissue in the same individual. Here, we describe the case of 46,XX, SRY-negative baby with ambiguous genitalia and ovotestis discovered during laparoscopy. As the family decided on female gender of rearing, the testicular component of the ovotestis was removed while the ovarian component was preserved. Stemming from this case, we review the clinical presentation of OT-DSD throughout ages, the role of genetics and risk for gonadal tumors when making decisions about prophylactic gonadectomy. Finally, we summarize the most recent information of the spontaneous endocrine function, with or without conservative therapy, and fertility potential of people with OT-DSD.

Background Diagnosing polycystic ovary syndrome (PCOS) during adolescence is challenging because features of normal pubertal development overlap with adult diagnostic criteria. The international evidence-based PCOS Guideline aimed to promote accurate and timely diagnosis, to optimise consistent care, and to improve health outcomes for adolescents and women with PCOS. Methods International healthcare professionals, evidence synthesis teams and consumers informed the priorities, reviewed published data and synthesised the recommendations for the Guideline. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied to appraise the evidence quality and the feasibility, acceptability, cost, implementation and strength of the recommendations. Results This paper focuses on the specific adolescent PCOS Guideline recommendations. Specific criteria to improve diagnostic accuracy and avoid over diagnosis include: (1) irregular menstrual cycles defined according to years post-menarche; > 90 days for any one cycle (> 1 year post-menarche), cycles 45 days (> 1 to 35 days (> 3 years post-menarche) and primary amenorrhea by age 15 or > 3 years post-thelarche. Irregular menstrual cycles ( Conclusions Extensive international engagement accompanied by rigorous processes honed both diagnostic criteria and treatment recommendations for PCOS during adolescence.

Background Children with congenital adrenal hyperplasia (CAH) because of 21 hydroxylase deficiency (21OHD) are at risk for early or precocious puberty and a short adult height compared to population means and midparental height. The effect of histrelin in suppressing puberty and improving growth in these children has not been reported. Methods Retrospective cohort analysis of all patients (age ≤ 20) at our institution who underwent histrelin implantation between 2008 and 2017. Treated patients with CAH (classic and nonclassic forms of 21OHD) were identified and their growth data analyzed. Results Fifteen children with CAH were treated with histrelin for a median of 3 years (range 2–5; age at first implantation 7.7 ± 1.5 years). Bone age (BA) to chronologic age (CA) decreased from 1.57 ± 0.4 to 1.25 ± 0.25 (P < .01), while predicted adult height (PAH) increased by 7.1 ± 6.6 cm (P < .01). A subgroup of 10 children reached adult height. Similar changes in BA/CA and PAH were observed with therapy (P = .02). Adult height z improved compared to pretreatment PAH z (–1.42 ± 0.9 vs. –1.96 ± 1.1 respectively, P < .01), but remained lower than midparental height z (P = .01). Conclusion In this retrospective cohort study of children with CAH due to 21OHD and early or precocious puberty, histrelin implantation resulted in a decrease in BA progression compared to CA and an improvement in PAH. In the subgroup who completed growth, adult height remained significantly lower than midparental. These results need to be confirmed with prospective controlled studies.

Background: Congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency (21OHD) causes cortisol insufficiency and androgen excess. A phase 2 trial of crinecerfont, a CRF1 receptor antagonist, in 18 adults with 21OHD showed prominent decreases in ACTH, 17-hydroxyprogesterone, and androstenedione (A4), and in women, testosterone (T), after 14 days of treatment. In men with 21OHD, T derives from both adrenals and testes; in poor disease control, A4/T ratio is elevated due to disproportionately increased adrenal A4 production and decreased testicular T production. We sought to determine the impact of crinecerfont on both adrenal and gonadal androgen production in men with 21OHD in this phase 2 trial. Methods: A4 and T data were analyzed for 7 men who completed 1 or more of 4 oral dosing regimens: Cohort 1, 50 mg QHS, n=4; Cohort 2, 100 mg QHS, n=2; Cohort 3, 100 mg QPM, n=5; and Cohort 4, 100 mg BID, n=3 (14 total treatment periods). Mean 0600-1000 4-hour morning window (M4hMW) and mean 24-hour (M24h) A4, T, and A4/T ratios were analyzed from serial serum samples at baseline and on day 15. Results: Dose-dependent reductions in M4hMW A4 were observed [median (range)] in men, consistent with previously presented data in all subjects:Cohort 1: -21% (-84 to -12%);Cohort 2: -37% (-51% to -23%);Cohort 3: -43% (-85% to +140%);Cohort 4: -62% (-90% to -33%). In contrast, M4hMW T showed inconsistent changes [median (range)]: Cohort 1: +18% (-40% to +82%);Cohort 2: -4% (-4.3% to -3.8%);Cohort 3: +9% (-11 to +24%);Cohort 4: +9% (-3% to +27%). Thus, M4hMW A4/T ratios decreased with dose. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 0.9 (0.3–2.6), 0.6 (0.1–2.1), -26% (-91% to +23%);Cohort 2: 5.0 (4.8–5.2), 3.3 (2.5–4.2), -35% (-49% to -20%);Cohort 3: 0.6 (0.1–6.9), 0.3 (0.1–2.7), -54% (-85% to +178%);Cohort 4: 3.9 (0.6–5.9), 0.4 (0.3–2.1), -65% (-92% to -31%). M24h A4/T ratios similarly declined in all cohorts. Values at baseline, on day 15, and percent changes [median (range)] were, respectively:Cohort 1: 1.0 (0.3–2.3), 0.4 (0.1–1.9), -33% (-92% to +2%);Cohort 2: 4.3 (3.8–4.9), 2.7 (2.4–3.0), -36% (-51% to -22%);Cohort 3: 0.5 (0.1–4.7), 0.4 (0.1–2.4), -59% (-78% to +310%);Cohort 4: 3.2 (0.4–4.1), 0.4 (0.3–1.7), -58% (-89% to -31%). Conclusions: Following crinecerfont therapy, A4 and A4/T decreased in a dose-dependent manner in men with 21OHD. In contrast to reductions in T observed in women with 21OHD, T did not change consistently and rose in some men. Preserved T values despite marked A4 reductions suggests testicular T production increased during crinecerfont therapy, perhaps due to release of gonadotropin suppression from adrenal-derived androgens. Long term studies are needed to determine if crinecerfont treatment improves additional measures of testicular function in men with 21OHD. Reference: RJ Auchus, et al. J Endocr Soc 2020;4(Suppl 1):OR25-03.

We report 2 infants with severe prematurity who presented with uterine bleeding at age 6 months (approximately 2.5 months corrected for gestational age). Mini-puberty of infancy should be considered in the differential diagnosis of girls who present with uterine bleeding during the first 6 months of life.

Bloom Syndrome (BSyn) is an autosomal recessive disorder that causes growth deficiency, endocrine abnormalities, photosensitive skin rash, immune abnormalities, and predisposition to early-onset cancer. The available treatments for BSyn are symptomatic, and early identification of complications has the potential to improve outcomes. To accomplish this, standardized recommendations for health supervision are needed for early diagnosis and treatment. The purpose of this report is to use information from the BSyn Registry, published literature, and expertise from clinicians and researchers with experience in BSyn to develop recommendations for diagnosis, screening, and treatment of the clinical manifestations in people with BSyn. These health supervision recommendations can be incorporated into the routine clinical care of people with BSyn and can be revised as more knowledge is gained regarding their clinical utility.

Individuals with congenital adrenal hyperplasia have reduced fertility. However, reproductive outcomes have improved over the years. This review provides an update on the multiple pathologic processes that contribute to reduced fertility in both sexes, from alterations of the hypothalamic-pituitary-gonadal axis to the direct effect on gonadal function by elevated circulating adrenal androgens. In addition, elevated serum progesterone concentrations may hinder ovulation and embryo implantation in women, whereas in men testicular adrenal rest tumors can be a major cause of infertility. Suppression of adrenal androgen secretion represents the first line of therapy toward spontaneous conception in both sexes.

Context Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed medications to treat depression and anxiety. SSRIs exert their effects by inhibiting the serotonin transporter and modulating extracellular serotonin levels, a neurotransmitter that has been shown to affect bone metabolism in animals. Studies in adults suggest a negative association between SSRI use and bone mineral density (BMD), greater rates of bone loss with SSRI use and increased risk of fractures. However, the results on bone mass have been inconsistent. Furthermore, there is a dearth of studies examining an association between SSRI use and bone mass in the pediatric and adolescent age group. Objective To investigate associations between SSRI use and bone mass in adolescents. Design Cross-sectional analysis of data from the 2005–2010 National Health and Nutrition Examination Study (NHANES). Participants 4303 NHANES participants aged 12–20 years. The mean age was 15.65 ± 2.42 years. Main outcomes Total femur, femoral neck and lumbar spine bone mineral content (BMC) and BMD assessed via dual-energy X-ray absorptiometry (DXA). Results 62 out of 4303 subjects used SSRIs. SSRI use was an independent predictor of bone mass after adjusting for age, gender, height and weight Z score, socioeconomic status, physical activity, serum cotinine level and race/ethnicity. After multivariable adjustment, total femur BMC was 8.8% lower among SSRI users versus non-users (mean difference 2.98 g, SE ± 0.105 g, p = 0.0006), while total femur BMD was 6.1% lower (mean difference 0.06 g/cm2, SE ± 0.002 g/cm2, p = 0.016). Femoral neck BMC and BMD and lumbar spine BMC were similarly negatively associated with SSRI use. Compared to nonusers, lumbar spine BMC was 7% lower among SSRI users (mean difference 0.97 g, SE ± 0.048 g, p = 0.02) and BMD was 3.2% lower (mean difference 0.03 g/cm2, SE ± 0.015 g/cm2, p = 0.09). Sub-analysis of those individuals treated for more than 6 months yield similar results. Finally, the association of SSRIs with bone mass persisted after excluding individuals with Body Mass Index (BMI) less than 5th percentile thus accounting for the possible confounding effect of anorexia nervosa, which can be treated with SSRIs. Conclusion In this NHANES study, adolescents treated with SSRIs had lower DXA measurements of the total femur and lumbar spine compared to SSRI non-users. These findings support the need for future prospective studies to examine the effects of SSRI use on bone mass in adolescents.

Heterozygous de novo or inherited pathogenic variants in the PCDH19 gene cause a spectrum of neurodevelopmental features including developmental delay and seizures. PCDH19 epilepsy was previously known as "epilepsy and mental retardation limited to females", since the condition almost exclusively affects females. It is hypothesized that the co-existence of two populations of neurons, some with and some without PCDH19 protein expression, results in pathologically abnormal interactions between these neurons, a mechanism also referred to as cellular interference. Consequently, PCDH19-related epilepsies are inherited in an atypical X-linked pattern, such that hemizygous, non-mosaic, 46,XY males are typically unaffected, while individuals with a disease-causing PCDH19 variant, mainly heterozygous females and mosaic males, are affected. As a corollary to this hypothesis, an individual with Klinefelter syndrome (KS) (47,XXY) who has a heterozygous disease-causing PCDH19 variant should develop PCDH19-related epilepsy. Here, we report such evidence: - a male child with KS and PCDH19-related epilepsy - supporting the PCDH19 cellular interference disease hypothesis.

Background/Aims: Factors in congenital adrenal hyperplasia (CAH) that may affect quality of life (QOL) include the need for lifelong medication, the risk of adrenal crisis, and hyperandrogenic symptoms. The objectives were to evaluate health-related QOL (HRQOL) in children with CAH, and whether CAH poses an additional burden compared to other endocrine disorders. Methods: The validated PedsQL 4.0 generic core scales were administered to subjects (8-18 years) with CAH and hypothyroidism and their parents. The minimal clinically important difference (MCID) was determined for each scale score, allowing a comparison with the healthy population. A score of >1 standard deviation below the population mean was considered at risk for impaired HRQOL. Results: In CAH, the mean total HRQOL scores were >1 MCID below the population mean, and a higher percentage than expected had scores considered at risk. Conclusion: Compared to subjects with hypothyroidism, subjects with CAH self-reported lower school domain scores. CAH subjects more frequently reported peers not wanting to be friends.

Although vitamin D toxicity is rare in children, increased use of vitamin D formulations, re-examination of optimal vitamin D levels, and use of higher doses lend potential for an increased incidence of vitamin D toxicity.A PubMed search was conducted through May 2013 for cases of vitamin D intoxication and vitamin D trials in pediatrics. Safety data were collected and reviewed.A small number of pediatric studies tested vitamin D doses at or above the currently recommended upper tolerable intake. In children and adolescents, vitamin D excess was rare and usually asymptomatic. Recent cases of intoxication relate to errors in manufacturing, formulation, or prescription; involve high total intake in the range of 240,000 to 4,500,000 IU; and present with severe hypercalcemia, hypercalciuria, or nephrocalcinosis. However, mild hypercalcemia and hypervitaminosis using currently recommended doses have been reported in infants with rickets.Although rare, cases of vitamin D intoxication that present with dramatic life-threatening symptoms still occur in children. Moreover, recent studies in infants raise a potential need for monitoring vitamin D levels when doses at or above the currently recommended upper range are used. Further studies are needed to clarify these findings. The Drugs and Therapeutics Committee of the Pediatric Endocrine Society suggests obtaining serum 25-hydroxyvitamin D levels in infants and children who receive long-term vitamin D supplementation at or above the upper level intake that is currently recommended.

The aim of this Task Force was to review the use of dual-energy X-ray absorptiometry (DXA) in children and adolescents with underlying chronic diseases that pose risk factors for compromised bone health, such as inflammation, glucocorticoid therapy, or decreased mobility. The Task Force systematically analyzed more than 270 studies, with an emphasis on those published in the interval since the original 2007 Position Statements. Important developments over this period included prospective cohort studies demonstrating that DXA measures of areal bone mineral density (aBMD) predicted incident fractures and the development of robust reference data and strategies to adjust for bone size in children with growth impairment. In this report, we summarize the current literature on the relationship between DXA-based aBMD and both fracture (vertebral and non-vertebral) outcomes and non-fracture risk factors (e.g., disease characteristics, ambulatory status, and glucocorticoid exposure) in children with chronic illnesses. Most publications described the aBMD profile of children with underlying diseases, as well as the cross-sectional or longitudinal relationship between aBMD and clinically relevant non-fracture outcomes. Studies that addressed the relationship between aBMD and prevalent or incident fractures in children with chronic illnesses are now emerging. In view of these updated data, this report provides guidelines for the use of DXA-based aBMD in this setting. The initial recommendation that DXA is part of a comprehensive skeletal healthy assessment in patients with increased risk of fracture is unchanged. Although the prior guidelines recommended DXA assessment in children with chronic diseases at the time of clinical presentation with ongoing monitoring, this revised Position Statement focuses on the performance of DXA when the patient may benefit from interventions to decrease their elevated risk of a clinically significant fracture and when the DXA results will influence that management.

To test the association between random cortisol and severity of illness in a "real-world" application of current guidelines.We performed a secondary analysis of a prospective observational cohort of acute respiratory distress syndrome (ARDS). Children with ARDS and vasopressor-dependent shock were identified and random cortisol levels before potential hydrocortisone initiation recorded. The cohort was dichotomized to cortisol18 and ≥ 18 μg/dL, and hydrocortisone use and outcomes compared.Of 357 children with ARDS, 155 (15 nonsurvivors; 10%) had vasopressors initiated with cortisol drawn before possible hydrocortisone use. Patients with cortisol18 μg/dL had lower severity of illness scores, fewer organ failures, and lower vasopressor scores (all rank-sum P .05). No benefit was seen with hydrocortisone in either the entire cohort, or when dichotomized by a cortisol cutoff of 18 μg/dL. In patients with cortisol ≥ 18 μg/dL, hydrocortisone was associated with increased mortality after adjustment for either organ dysfunction or vasopressor score.In children with ARDS with vasopressor-dependent shock, low cortisol correlated with lower severity of illness. Random cortisol was a poor method of diagnosing adrenal insufficiency, and a strategy of hydrocortisone replacement for cortisol18 μg/dL did not target a population likely to benefit from hydrocortisone. Future guidelines should reconsider using random cortisol levels alone for assessing adrenal function.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β(2) -microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Summary This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Adults with beta thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, > or =6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X-ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty-one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1-75 yr), were studied. Spine and femur BMD Z-scores < -2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty-six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.

Purpose of review The purpose of this review is to provide a comprehensive synopsis of pediatric bone density. Osteoporosis of the adult is a well established clinical problem, and algorithms to diagnose and treat this disease are recognized throughout the medical community. Osteoporosis or ‘low bone mass’ in pediatrics, on the other hand, is a rather new and evolving area, with certain unique diagnostic and clinical challenges. Recent findings Recent findings in the literature include benefits and limitations of pediatric bone densitometry techniques, proper interpretation of the results of these various techniques, efforts to establish standards and guidelines for diagnosing low bone mass in children and adolescents, optimization of bone growth and mineral accrual for life, pediatric bone mineral density and fracture risk prediction, as well as a clearer awareness of bone fragility in children. Summary Throughout the last decade, great strides have been made in our understanding of pediatric metabolic bone disease. These will be the focus of this review.

Background: Premature pubarche (PP) is defined as the appearance of pubic hair before 8 years in girls and 9 years in boys, without other signs of puberty. In the USA the prevalence of childhood overweight tripled between 1980 and 2000. An association between overweight and PP has been identified. Methods: We conducted a chart review to identify patients with the diagnosis of PP who were evaluated from July 2000 to October 2005. 38 patients, 29 females and 9 males, were studied. 16 were Caucasian, 11 African-American, 10 Hispanic, and 1 Arab. Age range was 4.3–9.8 years. Auxological features were analyzed. Results: Of the 38, 20 (52.6%) had a BMI >85th percentile. Increased weight was more common among females (62%) and Hispanics (80%). The study group was taller than expected Z = 1.11 ± 0.95 (TH Z = 0.34 ± 0.86). Among the 18 children who had bone age advancement >1.5 years, 10 (56%) had a predicted height Conclusions: In this study we confirmed the correlation between weight gain and PP. We also found that when the bone age was advanced >1.5 years, the predicted adult height was affected.

The Task Force focusing on the use of dual energy X-ray absorptiometry (DXA) in children and adolescents with diseases that may affect the skeleton reviewed over 300 articles to establish the basis for the Official Positions. A significant number of studies used DXA-based outcome measures to assess the effects of specific interventions and charted the natural history of incremental changes in bone size and mass in specific disease states in children. However, the utility of DXA in clinical practice has not been evaluated systematically, in large part due to the lack of a workable definition for childhood osteoporosis. Thus, in combination with the Official Positions addressing the diagnosis of osteoporosis in children, and the reporting of DXA results in children, this document presents clear guidelines from which clinicians and researchers alike can work. This report delineates a set of disorders in which it is appropriate to use DXA as part of the comprehensive assessment of skeletal health in children and adolescents, and provides guidance concerning the initiation of assessment and the frequency of monitoring. Importantly, this document also highlights significant gaps in our knowledge, emphasizing areas for future research.

Increased fragility has been described in humans with polycythemia vera (PV). Herein, we describe an osteoporotic phenotype associated with decreased osteoblast activity in a mouse model of PV and another mouse of polycythemia and elevated circulating erythropoietin (EPO). Our results are important for patients with PV or those treated with recombinant EPO (rEPO). INTRODUCTION: PV and other myeloproliferative syndromes have been recently associated with an increased risk for fractures. However, the presence of osteoporosis in these patients has not been well documented. EPO, a hormone primarily known to stimulate erythropoiesis, has been shown recently to regulate bone homeostasis in mice. The aim of this study was to examine the bone phenotype of a mouse model of PV and compare it to that of animals with polycythemia caused by elevated circulating EPO. METHODS: Bone mass and remodeling were evaluated by micro-computed tomography and histomorphometry. The JAK2(V617F) knock-in mouse, a model of human PV, manifests polycythemia and low circulating EPO levels. Results from this mouse were compared to wild type (wt) controls and the tg6 transgenic mouse that shows polycythemia caused by increased constitutive expression of EPO. RESULTS: Compared to wt, both JAK2(V617F) and tg6 mice had a decrease in trabecular bone mass. Tg6 mice showed an additional modest decrease in cortical thickness and cortical bone volume per tissue volume (P

Individuals with congenital adrenal hyperplasia have reduced fertility. However, reproductive outcomes have improved over the years. This review provides an update on the multiple pathologic processes that contribute to reduced fertility in both sexes, from alterations of the hypothalamic-pituitary-gonadal axis to the direct effect on gonadal function by elevated circulating adrenal androgens. In addition, elevated serum progesterone concentrations may hinder ovulation and embryo implantation in women, whereas in men testicular adrenal rest tumors can be a major cause of infertility. Suppression of adrenal androgen secretion represents the first line of therapy toward spontaneous conception in both sexes.

Chronic transfusion therapy has played a central role in extending life expectancy for patients with hemoglobinopathies such as thalassemia. However, this life-saving therapy is associated with numerous complications that now comprise the bulk of management considerations for patients with thalassemia. This review reports on the experience of the Thalassemia Longitudinal Cohort and reviews available literature to establish guidelines for the management of patients with thalassemia.

1. Susan R. Rose, MD* 2. Maria G. Vogiatzi, MD† 3. Kenneth C. Copeland, MD‡ 1. *Professor of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio 2. †Assistant Professor of Pediatrics, New York Presbyterian Hospital/Weill College of Cornell University, New York, NY 3. ‡Professor of Pediatrics, University of Oklahoma Health Science Center, Oklahoma City, Okla After completing this article, readers should be able to: 1. Describe the most critical test for evaluating the growth of a child. 2. Discuss the implications of decreased growth velocity after age 3 years. 3. Name the two most common normal variations resulting in short stature during childhood. 4. Characterize the growth velocities of children who have constitutional delay of growth and adolescence or familial short stature during the first 2 or 3 years after birth. 5. Recognize what a low weight-for-height ratio suggests. 6. List clues suggestive of syndromic or genetic disorders. 7. Describe how children who have congenital growth hormone deficiency may present in the newborn period. Achild’s growth pattern is a strong indicator of his or her general health. However, it may be difficult to distinguish between normal and abnormal growth. The purpose of this review is to highlight differences between growth patterns seen in normal variations of growth and those seen in pathologic conditions. In this review, growth patterns associated with normal variations or pathologic conditions are presented in the context of growth velocity, weight-for-height, and dysmorphic physical features. The most critical factor in evaluating the growth of a child is determining growth velocity (regardless of the absolute height). The simplest method of identifying whether a growth velocity is normal for age is to observe whether the child’s height pattern is “crossing” percentile lines on a linear growth curve. (The most up-to-date growth curves can be found on the Web site of the Centers for Disease Control and Prevention at www.cdc.gov/growthcharts .) Accurate height measurements performed at 6-month intervals and plotted to the year and month of age on the growth curve are an inexpensive means of identifying whether growth velocity is normal. Still more precise determinations of growth rate can be determined by using growth velocity charts. In addition to growth velocity, …