Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy.

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.

International Recommendations for the Diagnosis and Management of Patients With Adrenoleukodystrophy: A Consensus-Based Approach.

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.

Adrenal insufficiency updates in children.

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.

Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue.

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.

Establishing the incidence and timing of hypoglycemia at a residential diabetes camp.

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 ±â€¯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.

Bone mineral density and body composition in children with congenital adrenal hyperplasia.

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 TBMDHAZ Z-scores (-0.51 vs -0.01, P = .001) than controls. In CAH cases, TBMD and TBMDHAZ 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.

Health-related quality of life in children with congenital adrenal hyperplasia.

BACKGROUND: Children with congenital adrenal hyperplasia (CAH) require life-long glucocorticoid replacement and have daily intermittent hyper/hypocortisolemia and hyperandrogenemia. Health-related quality of life (HRQL) is important for understanding the impact the disease and therapy have on physical, mental, emotional, and social functioning. Little is known about HRQL in CAH. We compared HRQL in children with CAH to healthy norms and examined how these scores related to physiologic variables. METHODS: A cross-sectional study examined 45 patients (mean age 8.2(4.5) years). Thirty-two self-reported their quality of life (QoL) on the PedsQL™ Generic Core Scale and PedsQL™ Fatigue Scale, and 44 parents completed a parent report. Bone age Z-scores were calculated from the most recent bone age. RESULTS: Children with CAH did not report lower QoL than healthy norms. However, their parents reported lower overall QoL and fatigue scores than parents of healthy norms. Children with CAH rated sleep poorer than their parents. QoL scores did not differ by sex or CAH subtype and were not associated with total daily hydrocortisone dose. Bone age Z-scores were negatively associated with child-reported emotional health and cognitive fatigue. CONCLUSIONS: Parents of children with CAH reported a negative impact of disease on their children's QoL, but their children did not. The negative associations between bone age Z-scores and emotional health and cognitive fatigue suggest an impact from chronic hypocortisolemia and hyperandrogenemia.