Gonadotropin-Releasing Hormone Agonist Therapy and Longitudinal Bone Mineral Density in Congenital Adrenal Hyperplasia.

CONTEXT: Children with congenital adrenal hyperplasia (CAH) are at risk for early puberty. Gonadotropin-releasing hormone analog (GnRHa) is frequently used and can decrease bone mineral density (BMD). OBJECTIVE: Our aim was to investigate the effect of GnRHa therapy on BMD in a longitudinal study of patients with CAH spanning both childhood and adulthood. DESIGN AND SETTING: Sixty-one patients with classic CAH due to 21-hydroxylase deficiency (20 treated with GnRHa) were followed with dual-energy X-ray absorptiometry (DXA) scans at puberty onset, attainment of adult height, and during early adulthood. MAIN OUTCOME MEASURES: Whole body, lumbar spine, femoral neck, total hip, and distal radius BMD z-score at adult height. Longitudinal BMD and adult height were also assessed. RESULTS: Twenty patients received GnRHa for an average of 4.5 ± 2 years. There were no differences in BMD between GnRHa-treated and -untreated groups at adult height for all sites. Overall, the follow-up DXA during early adulthood showed decreases in BMD z-scores for whole body (P = .01), lumbar spine (P < .0001), femoral neck (P = .06), total hip (P = .009), and distal radius (P = .05). GnRHa treatment correlated with improved height outcomes compared to predicted height at puberty onset after adjusting for midparental height (P = .02). Patients in both groups achieved similar adult height. CONCLUSION: In children with CAH, GnRHa does not compromise BMD. However, BMD decreases with time and during the second and third decades of life is a possible effect of chronic supraphysiologic glucocorticoids. Children with CAH who experience early puberty benefit from GnRHa treatment as evidenced by the positive effect on height.

Course of COVID-19 infection in patients with congenital adrenal hyperplasia.

Context: Patients with primary adrenal insufficiency due to congenital adrenal hyperplasia (CAH) are at risk for adrenal crisis during infectious illnesses. Increased risk of infection including COVID-19 has been variably reported. Objective: To evaluate COVID-19 illness outcomes and stress dose practices in a large cohort of patients with CAH during the first two years of the pandemic and compare observations of COVID-19 infection in patients with CAH to the general USA population. Methods: Between March 2020 and November 2022, patients with CAH followed at the National Institutes of Health Clinical Center were queried about COVID-19 infection during their routine visits. Cases of COVID-19 were compared to controls. COVID-19 infection rates and symptoms were compared to general USA population data from the Centers for Disease Control and Prevention. Results: Of 168 patient visits, there were 54 (32%) cases of COVID-19 infection, and 15 (28%) were pediatric. Overall an association was found between acquiring COVID-19 and obesity (p=0.018), and adults acquiring COVID-19 were on lower doses of fludrocortisone (p=0.008). Fewer cases of COVID-19 infection were reported in those receiving hydrocortisone or modified-release hydrocortisone compared to longer acting glucocorticoids (p=0.0018). In our CAH population, the pattern of COVID-19 infection rates and COVID-related symptomatology were similar to those observed in the general USA population. Most patients with the presumed alpha variant reported anosmia and ageusia, while gastrointestinal symptoms were commonly reported during the delta and omicron waves. Stress dosing occurred in 30/54 cases, and 7 received parenteral hydrocortisone. Two hospitalizations occurred; one pediatric and one adult, both with co-morbidities. There were 5 emergency room visits and no reported deaths. Conclusion: Patients with CAH with close follow-up do not appear to be at increased risk of acquiring COVID-19 or to have a more severe course of COVID-19 compared to the general USA population. Obesity may increase risk of acquiring COVID-19 in patients with CAH, and overall infection risk may be lower in those receiving short-acting and circadian glucocorticoid replacement therapy. Established age-appropriate guidelines for stress dosing during infectious illnesses should be used for patients with CAH and COVID-19. COVID-19 specific guidelines are not indicated. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT00250159.

CAHQL: A patient reported outcome instrument to assess health-related quality of life in congenital adrenal hyperplasia.

CONTEXT: Measuring health-related quality of life (HRQoL) is a crucial aspect of evaluating health care outcomes. Patients with congenital adrenal hyperplasia (CAH) often self-report deficiencies in HRQoL. OBJECTIVE: The aim of our study was to develop a disease-specific patient reported outcome (PRO) instrument to evaluate the HRQoL of patients >16 years old with classic congenital adrenal hyperplasia (CAH). DESIGN, SETTING AND OUTCOMES: Following the FDA guidelines for developing PRO instruments, we developed a conceptual framework for the instrument. A preliminary instrument was created after interviewing a representative sample of 12 patients with CAH between 16 to 68 years old and 3 parents, and obtaining expert feedback from 4 endocrinologists. The instrument was edited after cognitive interviews with 6 patients. Internal consistency of the instrument was evaluated using Cronbach's alpha. Validity was assessed by comparing the scores of our instrument with scores from widely used validated instruments for HRQoL and PRO not specific to CAH. RESULTS: Sixty-nine patients 16 to 75 years old participated in validating our preliminary instrument. The final questionnaire consists of 44 questions within 7 domains: General Health, Adrenal Insufficiency, Glucocorticoid Excess, Physical Functioning, Mental Health and Cognition, Social Functioning, and Sexual Functioning, with acceptable internal consistency (Chronbach's alpha≥0.6) and validity (r = -0.350 to 0.866). CONCLUSION: CAHQL is the first validated PRO instrument to capture disease specific HRQoL outcomes in CAH. In addition to its anticipated use in the clinical setting, the instrument could be used to assess the efficacy of novel treatments in development.

Congenital adrenal hyperplasia due to two rare CYP21A2 variant alleles, including a novel attenuated CYP21A1P/CYP21A2 chimera.

BACKGROUND: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (21OH) deficiency is an autosomal recessive inborn error of cortisol biosynthesis, with varying degrees of aldosterone production. There is a continuum of phenotypes which generally correlate with genotype and the expected residual 21OH activity of the less severely impaired allele. CYP21A1P/CYP21A2 chimeric genes caused by recombination between CYP21A2 and its highly homologous CYP21A1P pseudogene are common in CAH and typically associated with salt-wasting CAH, the most severe form. Nine chimeras have been described (CH-1 to CH-9). AIMS: The aim of this study was to genetically evaluate two variant alleles carried by a 22-year-old female with the non-salt-wasting simple virilizing form of CAH and biallelic 30-kb deletions. METHODS: The haplotypes of the CYP21A2 heterozygous variants, as well as the chimeric junction sites, were determined by Sanger sequencing TA clones of an allele-specific PCR product. RESULTS: Genetic testing revealed two rare CYP21A1P/CYP21A2 chimeras: allele 1 matches the previously described CAH CH-1 chimera but without the P30L variant, and allele 2, termed here as novel CAH CH-10, has a junction site between c.293-37 and c.29314, which is expected to retain partial 21OH activity. CONCLUSION: These two variant alleles further document the complex nature of RCCX modules and highlight that not all CYP21A1P/CYP21A2 chimera severely impair 21OH activity.