INTRODUCTION:Hypogonadism has been reported in patients with X-linked adrenoleukodystrophy (ALD), but little is known about prevalence and characteristics. We aimed to further characterize hypogonadism in males with ALD. METHODS:We conducted a retrospective chart review and a prospective study of male children and adults with ALD followed in a multidisciplinary clinic at a tertiary academic center. Serum gonadotropin and testosterone levels defined presence of hypogonadism in adults. Data on symptoms were collected in a survey. RESULTS:We included 94 males: 56 adults, 32 adolescents and 6 infants. Seven of the 56 adults studied retrospectively (13%) had central hypogonadism. Five of the 49 adults with normal testosterone studied retrospectively (10%), and 7 of the 11 adults studied prospectively (64%) had elevated serum luteinizing hormone and normal testosterone levels, indicative of subclinical compensated primary testicular dysfunction. Adolescents and infants showed no evidence of testicular dysfunction, with normal anti-Müllerian hormone and inhibin levels. Erectile dysfunction was present in 25 of adults with ALD and normal serum testosterone levels (51%), likely reflecting neurologic dysfunction. CONCLUSIONS:Adult males with ALD are at risk of developing central hypogonadism and compensated primary hypogonadism. Adolescents and infants had normal testicular function, suggesting that testicular dysfunction ensues later in life as the disease progresses. Larger prospective studies of ALD cohorts are needed to fully characterize the prevalence and natural history of pituitary-gonadal dysfunction in this population.

Context Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. Objective To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. Design We conducted a retrospective medical chart review of pediatric patients with ALD. Setting All patients were seen in a leukodystrophy clinic in an academic medical center. Patients We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). Main Outcome Measures We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. Results Thirty-one (27%) patients were diagnosed with ALD by NBS, and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9, 12.12] months vs 6.05 [3.74, 8.35] years) (P < .001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. Conclusions Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD.

Brief summary: This paper describes consensus expert recommendations for the diagnosis and management of patients with Adrenoleukodystrophy.

Pathogenic variants in the ABCD1 gene cause adrenoleukodystrophy (ALD), a progressive metabolic disorder characterized by 3 core clinical syndromes: a slowly progressive myeloneuropathy, a rapidly progressive inflammatory leukodystrophy (cerebral ALD), and primary adrenal insufficiency. These syndromes are not present in all individuals and are not related to genotype. Cerebral ALD and adrenal insufficiency require early detection and intervention and warrant clinical surveillance because of variable penetrance and age at onset. Newborn screening has increased the number of presymptomatic individuals under observation, but clinical surveillance protocols vary. We used a consensus-based modified Delphi approach among 28 international ALD experts to develop best-practice recommendations for diagnosis, clinical surveillance, and treatment of patients with ALD. We identified 39 discrete areas of consensus. Regular monitoring to detect the onset of adrenal failure and conversion to cerebral ALD is recommended in all male patients. Hematopoietic cell transplant (HCT) is the treatment of choice for cerebral ALD. This guideline addresses a clinical need in the ALD community worldwide as the number of overall diagnoses and presymptomatic individuals is increasing because of newborn screening and greater availability of next-generation sequencing. The poor ability to predict the disease course informs current monitoring intervals but remains subject to change as more data emerge. This knowledge gap should direct future research and illustrates once again that international collaboration among physicians, researchers, and patients is essential to improving care.

Purpose of review The current article will review the newest diagnostic tools, genetic causes, and treatment of adrenal insufficiency in children. Recent findings It is common practice to perform an adrenocorticotropin hormone (ACTH) stimulation test when adrenal insufficiency is suspected. The indications for use of a high-dose or low-dose of synthetic ACTH in children have been refined. In addition, newer studies propose adding 15 and 30-min serum or salivary cortisol levels to the low-dose ACTH stimulation test to correctly identify adrenal insufficiency. Recent identification of genetic mutations in children with non-classic steroidogenic acute regulatory protein and other mutations associated with primary and secondary adrenal insufficiency have expanded the cause and pathophysiology of monogenic adrenal insufficiency. In addition, newer hydrocortisone formulations and delivery methods and medications to use in combination with hydrocortisone are being explored to improve treatment for children with adrenal insufficiency. Summary Improved diagnostic aids, detection of newer genetic mutations, and better treatment options and delivery systems will help correctly identify and manage children with adrenal insufficiency to improve health outcomes and quality of life. Video abstract

Purpose of review The current article will review the newest diagnostic tools, genetic causes, and treatment of adrenal insufficiency in children. Recent findings It is common practice to perform an adrenocorticotropin hormone (ACTH) stimulation test when adrenal insufficiency is suspected. The indications for use of a high-dose or low-dose of synthetic ACTH in children have been refined. In addition, newer studies propose adding 15 and 30-min serum or salivary cortisol levels to the low-dose ACTH stimulation test to correctly identify adrenal insufficiency. Recent identification of genetic mutations in children with non-classic steroidogenic acute regulatory protein and other mutations associated with primary and secondary adrenal insufficiency have expanded the cause and pathophysiology of monogenic adrenal insufficiency. In addition, newer hydrocortisone formulations and delivery methods and medications to use in combination with hydrocortisone are being explored to improve treatment for children with adrenal insufficiency. Summary Improved diagnostic aids, detection of newer genetic mutations, and better treatment options and delivery systems will help correctly identify and manage children with adrenal insufficiency to improve health outcomes and quality of life. Video abstract http://links.lww.com/COE/A21

Aims: To establish the incidence and timing of hypoglycemia at a week-long residential diabetes camp for children. We hypothesized that hypoglycemia would occur more frequently during the first two days of camp and following evening all-camp games. Methods: 225 children (mean age 12.0 +/- 2.3 years, 56% female, mean hemoglobin A1c 8.4% [71.6 mmol/mol]) had blood glucose (BG) levels obtained before meals, at bedtime, and as needed to detect hypoglycemia. Insulin adjustments were made by medical staff according to camp protocol and at the discretion of medical staff during camper check-in. Results: Mild hypoglycemia (BG 50-69 mg/dL [3.9 mmol/L]) occurred >= 1 time in 90% of campers while 43% had >= 1 episode of BG < 50 mg/dL (2.8 mmol/L). No episodes of hypoglycemia requiring glucagon occurred. More campers experienced >= 1 overnight hypoglycemia event during the first 48 hours of camp compared to later in the week (p = 0.01). Evening all-camp games did not impact hypoglycemia rates overnight. Conclusions: Nocturnal hypoglycemia occurred more frequently during the first two nights, establishing this period as high risk and supporting implementation of a standard protocol to lower insulin doses. Rates of hypoglycemia were unaffected by all-camp games, indicating current practices are effective at minimizing hypoglycemia. (C) 2019 Elsevier B.V. All rights reserved.

OBJECTIVE:Anastrozole, an aromatase inhibitor, has been used off-label in males with short stature to delay bone maturation. No studies have examined anastrozole's effect on bone mineral density (BMD) or body composition in children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Our objective was to evaluate anastrozole's effect on BMD and visceral adipose tissue (VAT) in children with CAH.DESIGN:Total body BMD (TBMD) and L2-L4 BMD Z-scores were adjusted for height-for-age Z-scores (TBMDHAZ and L2-L4HAZ ). Hydrocortisone doses (mg/m2 /d) were averaged over the previous year. Comparison of treated vs not treated with anastrozole used linear regression adjusting for age, pubertal status, sex, CAH type, years on hydrocortisone, BMI Z-scores and bone age Z-scores.PATIENTS:We compared 25 children with CAH treated with anastrozole (mean age 11.3 [SD 3.0] years, 56% males) vs 31 children with CAH not treated with anastrozole (13.5 [SD 4.6], 29%). Participants underwent a pubertal exam, bone age X-ray and dual X-ray absorptiometry (DXA) scan.RESULTS:Average bone age Z-score of 4.3 SDs on beginning anastrozole decreased to 1.9 SDs at time of DXA exam (P = 0.0004) 5.2 (SD 2.2) years later. TBMD Z-scores (P = 0.51), L2-L4 BMD Z-scores (P = 0.66), VAT (P = 0.38), TBMDHAZ Z-scores (P = 0.66) and L2-L4HAZ Z-scores (P = 0.41) did not differ between children treated vs not treated with anastrozole.CONCLUSION:Anastrozole significantly reduced bone age advancement in children with CAH and advanced bone age (>2SDs) without adverse effects on BMD or VAT. Longitudinal studies of anastrozole in children with CAH are needed to validate these findings.

Summary Objective Children with congenital adrenal hyperplasia (CAH) are exposed to fluctuating cortisol and androgen levels. The effects these hormonal states have on bone mineral density (BMD) and body composition are not well studied. The study’s objective was to compare BMD and body composition, including visceral adipose tissue (VAT) and Android:Gynoid (A:G) ratio, in children with CAH vs healthy age‐matched, sex‐matched and BMI‐matched controls. Design Total body BMD (TBMD) Z‐scores were adjusted for height‐for‐age Z‐scores (TBMDHAZ). Hydrocortisone dose (mg/m2/d) was averaged over the past year. Bone age Z‐scores were used as a surrogate for long‐term androgen exposure in cases. Statistical analyses comparing cases and controls accounted for matched groups using mixed linear models. Patients Forty‐two cases with CAH (average age 12.3 years [SE 3]; 17 males) and 101 controls underwent a dual‐energy X‐ray absorptiometry scan. Results Children with CAH had lower TBMD (0.81 vs 1.27, P = .003) and TBMD HAZ Z‐scores (−0.51 vs −0.01, P = .001) than controls. In CAH cases, TBMD and TBMD HAZ Z‐scores were positively correlated with bone age Z‐scores ( r = .63, P < .0001; r = .51, P = .001, respectively) but were not associated with HC dose. VAT and the A:G ratio did not differ significantly between children with CAH and controls and neither was associated with HC dose. VAT was not associated with bone age Z‐score. Conclusion Lower BMD was observed in CAH cases compared with controls although no differences in body composition were identified. Among CAH cases, increased chronic androgen exposure, as measured by bone age Z‐scores, was associated with higher BMD but was not associated with VAT .

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.