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.

Background Children with congenital adrenal hyperplasia (CAH) are at risk for early central puberty, and gonadotropin-releasing hormone analogs (GnRHa) are frequently used aiming to improve adult height. However, their effect on bone health among the CAH population has not been previously studied. GnRHa reduce sex steroid levels and delay central puberty, which may negatively affect the achievement of peak bone mass. In healthy children, bone mass increases with time, reaching its peak between the second and third decades of life. The purpose of this study was to investigate the short-term and long-term effect of GnRHa therapy on the bone mineral density (BMD) of patients with classic CAH. Methods Sixty patients with classic CAH due to 21OH deficiency were followed longitudinally at our institution with DXA scans at the time they achieved adult height. Adult height was considered attained when bone age exceeded 15 years in girls and 17 years in boys. Twenty-one patients treated with GnRHa (81% male, 57% salt wasting, treated for mean ± SD: 4.3 ±2 years) were compared to 39 patients not treated with GnRHa (49% male, 79.5% salt wasting). BMD z scores, adjusted for height and age, were evaluated at the time they reached adult height and on average 8.3 years later. Results There was no difference between GnRHa groups in total body (p=0.96), femoral neck (p=0.24), lumbar spine (p=0.59), forearm (p=0.38), and total hip (p= 0.31) z scores at adult height attainment. In multivariable analyses, there was no effect of GnRHa on BMD z scores at any site. In reduced models, increased 17-hydroxyprogesterone (17-OHP) levels correlated with higher BMD z scores for total body (p=0.003), lumbar spine (p<0.001), and forearm (p<0.001). Higher BMI (p=0.014) and no treatment with dexamethasone (p=0.022) were also associated with higher femoral BMD z score. Overall, the follow up DXA during young adulthood (n=28) showed significant decreases in z scores at total body (p=0.019), femoral neck (p=0.036), lumbar spine (p<0.001), forearm (p<0.001), and total hip (p=0.024), and use of GnRHa did not contribute. Interestingly, when adjusting for midparental height, those treated with GnRHa had lower adult height z scores than those without GnRHa (p=0.037). Conclusion Treatment with GnRHa for approximately 4 years does not impact BMD in adolescents and young adults with CAH, and exposure to adrenal androgens may play a protective role. In patients with CAH, BMD decreases with time and during the second and third decades of life, which may reflect the effect of long-term supraphysiologic glucocorticoid therapy. Although intended to preserve height, children with CAH who experience early puberty have loss of adult height, despite treatment with GnRHa. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Monday, June 13, 2022 12:54 p.m. - 12:59 p.m.