Phase 3 Trial of Crinecerfont in Pediatric Congenital Adrenal Hyperplasia.

BACKGROUND: Children with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency require treatment with glucocorticoids, usually at supraphysiologic doses, to address cortisol insufficiency and reduce excess adrenal androgens. However, such treatment confers a predisposition to glucocorticoid-related complications. In 2-week phase 2 trials, patients with CAH who received crinecerfont, a new oral corticotropin-releasing factor type 1 receptor antagonist, had decreases in androstenedione levels. METHODS: In this phase 3, multinational, randomized trial, we assigned pediatric participants with CAH, in a 2:1 ratio, to receive crinecerfont or placebo for 28 weeks. A stable glucocorticoid dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0 to 10.0 mg per square meter of body-surface area per day (hydrocortisone dose equivalents), provided that the androstenedione level was controlled (≤120% of the baseline level or within the reference range). The primary efficacy end point was the change in the androstenedione level from baseline to week 4. A key secondary end point was the percent change in the glucocorticoid dose from baseline to week 28 while androstenedione control was maintained. RESULTS: A total of 103 participants underwent randomization, of whom 69 were assigned to the crinecerfont group and 34 to the placebo group; 100 (97%) remained in the trial at 28 weeks. At baseline, the mean glucocorticoid dose was 16.4 mg per square meter per day, and the mean androstenedione level was 431 ng per deciliter (15.0 nmol per liter). At week 4, the androstenedione level was substantially reduced in the crinecerfont group (-197 ng per deciliter [-6.9 nmol per liter]) but increased in the placebo group (71 ng per deciliter [2.5 nmol per liter]) (least-squares mean difference, -268 ng per deciliter [-9.3 nmol per liter]; P<0.001); the observed mean androstenedione value, obtained before the morning glucocorticoid dose, was 208 ng per deciliter (7.3 nmol per liter) in the crinecerfont group, as compared with 545 ng per deciliter (19.0 nmol per liter) in the placebo group. At week 28, the mean glucocorticoid dose had decreased (while androstenedione control was maintained) by 18.0% with crinecerfont but increased by 5.6% with placebo (least-squares mean difference, -23.5 percentage points; P<0.001). Headache, pyrexia, and vomiting were the most common adverse events. CONCLUSIONS: In this phase 3 trial, crinecerfont was superior to placebo in reducing elevated androstenedione levels in pediatric participants with CAH and was also associated with a decrease in the glucocorticoid dose from supraphysiologic to physiologic levels while androstenedione control was maintained. (Funded by Neurocrine Biosciences; CAHtalyst Pediatric ClinicalTrials.gov number, NCT04806451.).

Expanding the reproductive organ phenotype of CHD7-spectrum disorder.

CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia.

Behavioral Health Diagnoses in Youth with Differences of Sex Development or Congenital Adrenal Hyperplasia Compared with Controls: A PEDSnet Study.

OBJECTIVE: To evaluate the odds of a behavioral health diagnosis among youth with differences 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 = 1216) or CAH (n = 1647) and at least 1 outpatient encounter were extracted from the PEDSnet database and propensity-score matched on 8 variables (1:4) with controls (n = 4864 and 6588, respectively) using multivariable logistic regression. The likelihood of having behavioral health diagnoses was examined using generalized estimating equations. RESULTS: Youth with DSD had higher odds of a behavioral health diagnosis (OR, 1.7; 95% CI, 1.4-2.1; P < .0001) and neurodevelopmental diagnosis (OR, 1.7; 95% CI, 1.4, 2.0; P < .0001) compared with matched controls. Youth with CAH did not have an increased odds of a behavioral health diagnosis (OR, 1.0; 95% CI, 0.9, 1.1; P = .9) compared with matched controls but did have higher odds of developmental delay (OR, 1.8; 95% CI, 1.4, 2.4; P < .0001). CONCLUSIONS: Youth with DSD diagnosis have higher odds of a behavioral health or neurodevelopmental diagnosis compared with matched controls. Youth with CAH have higher odds of developmental delay, highlighting the need for screening in both groups.

Adolescent polycystic ovary syndrome according to the international evidence-based guideline.

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< 21 or > 45 days (> 1 to < 3 years post-menarche); cycles < 21 or > 35 days (> 3 years post-menarche) and primary amenorrhea by age 15 or > 3 years post-thelarche. Irregular menstrual cycles (< 1 year post-menarche) represent normal pubertal transition. (2) Hyperandrogenism defined as hirsutism, severe acne and/or biochemical hyperandrogenaemia confirmed using validated high-quality assays. (3) Pelvic ultrasound not recommended for diagnosis of PCOS within 8 years post menarche. (4) Anti-Müllerian hormone levels not recommended for PCOS diagnosis; and (5) exclusion of other disorders that mimic PCOS. For adolescents who have features of PCOS but do not meet diagnostic criteria an 'at risk' label can be considered with appropriate symptomatic treatment and regular re-evaluations. Menstrual cycle re-evaluation can occur over 3 years post menarche and where only menstrual irregularity or hyperandrogenism are present initially, evaluation with ultrasound can occur after 8 years post menarche. Screening for anxiety and depression is required and assessment of eating disorders warrants consideration. Available data endorse the benefits of healthy lifestyle interventions to prevent excess weight gain and should be recommended. For symptom management, the combined oral contraceptive pill and/or metformin may be beneficial. CONCLUSIONS: Extensive international engagement accompanied by rigorous processes honed both diagnostic criteria and treatment recommendations for PCOS during adolescence.

Skin-to-Skin Care Is a Safe and Effective Comfort Measure for Infants Before and After Neonatal Cardiac Surgery.

OBJECTIVES: 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. DESIGN: 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). SETTING: Cardiac ICU and step-down unit in a large metropolitan freestanding children's hospital. SUBJECTS: Convenience sample of 30 infants admitted preoperatively for critical congenital heart disease. INTERVENTIONS: Eligible infants were placed into skin-to-skin care for 1 hour with their biological mothers once each at T1 and T2. MEASUREMENTS AND MAIN RESULTS: 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 (p < 0.0001) and infants moved into a calmer behavior state (p < 0.0001) during skin-to-skin care as compared to baseline. At T1, infants also had significantly reduced heart rate (p = 0.002) and respiratory rate (p < 0.0001) 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. CONCLUSIONS: 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.

Endocrine Management of Ovotesticular DSD, an Index Case and Review of the Literature.

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.

Health supervision for people with Bloom syndrome.

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.

Cortisol Correlates with Severity of Illness and Poorly Reflects Adrenal Function in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVE: To test the association between random cortisol and severity of illness in a "real-world" application of current guidelines. STUDY DESIGN: 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 cortisol < 18 and ≥ 18 µg/dL, and hydrocortisone use and outcomes compared. RESULTS: Of 357 children with ARDS, 155 (15 nonsurvivors; 10%) had vasopressors initiated with cortisol drawn before possible hydrocortisone use. Patients with cortisol < 18 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. CONCLUSIONS: 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 cortisol < 18 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.

Menstrual Bleeding as a Manifestation of Mini-Puberty of Infancy in Severe Prematurity.

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.

Guidelines for the Standard Monitoring of Patients With Thalassemia: Report of the Thalassemia Longitudinal Cohort.

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.

Bone health in children and adolescents with chronic diseases that may affect the skeleton: the 2013 ISCD Pediatric Official Positions.

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.

Salivary Diurnal Cortisol Predicts Post-Traumatic Stress Symptoms in Parents of Infants With Congenital Heart Disease.

BACKGROUND: Parents of infants born with congenital heart disease (CHD) who require open heart surgery after birth are at risk for prolonged psychological distress. Even after their infants are discharged, parents may experience anxiety, depressive, and post-traumatic stress (PTS) symptoms; yet, it is unclear which parents are at greater risk for ongoing symptoms. The purpose of this study was to explore whether measures of the biomarker cortisol in parents during their infants' postoperative period were associated with subsequent psychological distress symptoms at three-month post discharge. METHODS: This was a prospective, longitudinal exploratory study of 40 parents of infants with CHD after open heart surgery using consecutive enrollment. Parents provided diurnal saliva samples for two consecutive days in the postoperative period. Six predictors were summarized and generated including waking cortisol, bedtime cortisol, cortisol awaking response, area under curve with respect to the ground (AUCg), cortisol index, and cortisol slope. Self-report outcome measures on anxiety, depressive, and PTS symptoms were collected three-months post-discharge. Linear mixed models examined the associations between each predictor and each outcome while accounting for within-dyad variance using an unstructured covariance matrix. RESULTS: Cortisol AUCg was a predictor of PTS at three-months post-discharge (ß = .34, p = .03, Cohen's d = 2.05). No significant relationships were found with the other cortisol measures. CONCLUSIONS & IMPLICATIONS: Findings suggest that cortisol area under curve may help to identify parents at risk for increased PTS in the months following their infants' hospitalization for cardiac surgery, serving as a foundation for future study in this area.

Multicenter Analysis of Cardiometabolic-Related Diagnoses in Youth with Congenital Adrenal Hyperplasia: a PEDSnet study.

CONTEXT: Small cohorts of youth with congenital adrenal hyperplasia (CAH) demonstrate increased risk of obesity and poor cardiometabolic health. OBJECTIVE: To determine the odds of cardiometabolic-related diagnoses in youth with CAH compared to matched controls in a cross-sectional analysis in a large, multisite database (PEDSnet). DESIGN: Electronic health record data (2009-2019) were used to determine odds of cardiometabolic-related outcomes based on diagnosis, anthropometric and laboratory data using logistic regression among youth with CAH vs. controls. SETTING: Six PEDSnet sites. PATIENTS OR OTHER PARTICIPANTS: Youth with CAH and >1 outpatient visit in PEDSnet (n=1,647) were propensity-score matched on 8 variables to controls (n=6,588). A subset of youth with classic CAH (n=547, with glucocorticoid and mineralocorticoid prescriptions) were matched to controls (n=2,188). INTERVENTION(S): N/A. MAIN OUTCOME MEASURE(S): Odds of having cardiometabolic-related diagnoses among youth over 2 years with CAH compared to matched controls. RESULTS: Outcomes were calculated for all individuals with CAH (median age at last visit 12.9 years [7.3, 17.6]) and a subset with classic CAH (median age at last visit 11.6 years [4.7, 17.5]) compared to their matched controls. All patients with CAH had higher odds of overweight/obesity (odds ratio [95% confidence interval] 3.63 [3.24,4.07]), hypertension (3.07 [2.60,3.64]), dysglycemia (1.95 [1.35,2.82], dyslipidemia (2.28 [1.79,2.91]) and liver dysfunction (2.30 [1.91,2.76]) compared to matched controls. Patients with classic CAH had higher odds of overweight/obesity (3.21 [2.61,3.93]), hypertension (8.22 [6.71,10.08]), and liver dysfunction (2.11 [1.55,2.89]) compared to matched controls. CONCLUSIONS: Overall, youth with CAH are at increased risk of diagnoses related to worse cardiometabolic health.

Approach to the Patient: Central Precocious Puberty.

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.

Allometric Scaling of Testosterone Enanthate Pharmacokinetics to Adolescent Hypogonadal Males (IM and SC Administration).

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 < 18 years) serum testosterone levels at body weights of 30, 40, 50, and 60 kg after weekly, every-other-week (EOW), and monthly SC and IM administration of 12.5, 25, 50, 75, and 100 mg TE regimens. 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.

Information needs and health status in adolescents and young adults with differences of sex development or sex chromosome aneuploidies.

INTRODUCTION: When and how to provide condition-related information to adolescents and young adults (AYAs) with differences of sex development or sex chromosome aneuploidies (DSDs or SCAs) is largely based on anecdotal experience and lacks informed guidance. For AYAs with a DSD or SCA, having accurate information is critical for attaining optimal adjustment and well-being, participating in decision making related to treatment options, and transitioning successfully to adult health care, yet prior studies have focused exclusively on parental perspectives and not on the views of adolescents themselves. OBJECTIVE: The objective of this study was to describe unmet information needs in AYAs with a DSD or SCA and examine associations with perceived global health. METHODS: Participants were recruited from specialty clinics at Children's Hospital of Philadelphia (n = 20) and Children's Hospital Colorado (n = 60). AYAs ages 12-21 years with a DSD or SCA and a parent completed a survey assessing perceived information needs across 20 topics, importance of those topics, and global health using the PROMIS Pediatric Global Health questionnaire (PGH-7). RESULTS: AYAs had diagnoses of Klinefelter syndrome (41%), Turner syndrome (25%), and DSD (26%) and were 16.7 years (SD = 2.56) and 44% female. Parent participants were primarily mothers (81%). AYAs perceived that 48.09% of their information needs were unmet (SD = 25.18, range: 0-100). Parents perceived that 55.31% of AYAs' information needs were unmet (SD = 27.46 range: 5-100). AYAs and parents across conditions reported unmet needs related to information about transition to adult health care, financial support for medical care, and how the condition might affect the AYA's health in the future. While AYA-reported PGH-7 scores were not associated with percentage of AYA unmet information needs, parent-reported PGH-7 scores were (r = -.46, p < .001), such that lower parent-reported global health was associated with higher percentage of AYA unmet information needs. DISCUSSION/CONCLUSION: On average, parents and AYAs perceived that half of AYAs' information needs were unmet, and a higher percentage of AYA unmet information needs was associated with lower perceived global health. The frequency of unmet needs in this sample of AYAs reflects an opportunity for improvement in clinical care. Future research is needed to understand how education to children and AYAs unfolds as they mature and to develop strategies to address the information needs of AYAs with a DSD or SCA, promote well-being, and facilitate AYA engagement in their own health care.

Crinecerfont, a CRF1 Receptor Antagonist, Lowers Adrenal Androgens in Adolescents With Congenital Adrenal Hyperplasia.

CONTEXT: Crinecerfont, a corticotropin-releasing factor type 1 receptor antagonist, has been shown to reduce elevated adrenal androgens and precursors in adults with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a rare autosomal recessive disorder characterized by cortisol deficiency and androgen excess due to elevated adrenocorticotropin. OBJECTIVE: To evaluate the safety, tolerability, and efficacy of crinecerfont in adolescents with 21OHD CAH. METHODS: This was an open-label, phase 2 study (NCT04045145) at 4 centers in the United States. Participants were males and females, 14 to 17 years of age, with classic 21OHD CAH. Crinecerfont was administered orally (50 mg twice daily) for 14 consecutive days with morning and evening meals. The main outcomes were change from baseline to day 14 in circulating concentrations of ACTH, 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: 8 participants (3 males, 5 females) were enrolled; median 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%; 17OHP, -69%; and androstenedione, -58%. In female participants, 60% (3/5) had ≥50% reduction from baseline in testosterone. CONCLUSION: 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.

Bone loss caused by iron overload in a murine model: importance of oxidative stress.

Osteoporosis is a frequent problem in disorders characterized by iron overload, such as the thalassemias and hereditary hemochromatosis. The exact role of iron in the development of osteoporosis in these disorders is not established. To define the effect of iron excess in bone, we generated an iron-overloaded mouse by injecting iron dextran at 2 doses into C57/BL6 mice for 2 months. Compared with the placebo group, iron-overloaded mice exhibited dose-dependent increased tissue iron content, changes in bone composition, and trabecular and cortical thinning of bone accompanied by increased bone resorption. Iron-overloaded mice had increased reactive oxygen species and elevated serum tumor necrosis factor-α and interleukin-6 concentrations that correlated with severity of iron overload. Treatment of iron-overloaded mice with the antioxidant N-acetyl-L-cysteine prevented the development of trabecular but not cortical bone abnormalities. This is the first study to demonstrate that iron overload in mice results in increased bone resorption and oxidative stress, leading to changes in bone microarchitecture and material properties and thus bone loss.

An after-school dance and lifestyle education program reduces risk factors for heart disease and diabetes in elementary school children.

BACKGROUND: Forty-three percent of New York City's (NYC) school-age children are overweight or obese, placing them at risk for heart disease and type 2 diabetes mellitus (T2DM). OBJECTIVE: The objective of this study was to determine if an intensive after-school dance and lifestyle education program would reduce risk factors for heart disease, T2DM, and improve lifestyle choices. SUBJECTS: Subject include 64 fourth- and fifth-grade students at an elementary school in NYC. METHODS: Students received freestyle dance and lifestyle classes for 16 weeks and were evaluated for changes in body composition, endurance, biochemical measurements, and lifestyle choices. RESULTS: Significant improvements in BMI percentiles were found among children in the overweight and obese categories as well as in endurance and biochemical measurements that reflect heart disease and diabetes risk. Improvement was also reported in lifestyle choices. CONCLUSION: An intensive after-school dance and lifestyle education program can reduce risk factors for heart disease and T2DM and improve lifestyle choices among elementary school children.

The Associations of Psychologic and Physiologic Manifestations of Parental Stress in Critical Congenital Heart Disease.

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.