Growth-Related Characteristics of Patients <18 Years of Age with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency (21OHD): Real World Evidence from the I-CAH Registry

Background: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a rare, autosomal recessive disease of the adrenal cortex leading to a lack of cortisol production and compensatory ACTH secretion, which drives excess androgen production. The chronic exposure to excess androgen, coupled with supraphysiologic glucocorticoid doses, can lead to advanced skeletal maturation with reduced growth in puberty, premature epiphyseal closure, and shorter final adult height. The I-CAH Registry, launched in 2007, currently has >1500 cases of CAH from 26 countries. Aim of the current study was to identify growth-related characteristics of children and adolescents with 21OHD CAH registered in the I-CAH registry and who were based in Europe. Methods: The I-CAH registry was queried on 8-Oct-2019 using the following criteria: CYP21A enzyme deficiency; European site, male or female, age <18 years; and ≥1 growth-related assessment. Descriptive analyses were conducted using data from all patient visits, with age subgroups defined as follows: 0 to <2 years (0-2yr), 2 to 11 years (2-11yr), and 12 to 17 years (12-17yr). Since I-CAH data are longitudinal, patients who aged during registry enrollment may be included in >1 subgroup. Analyses included standard deviation scores (SDS) for patients’ height for chronological age (CA), weight for CA, and height for bone age (BA) using World Health Organization growth chart data for reference values. Results: Of 232 patients in 10 European countries, 126 (54%) were female and most were from Germany (25%), United Kingdom (23%), Netherlands (14%), and Italy (11%). The 232 patients had a total of 2042 visits, with 44% (900 visits) in the 0-2yr group, 42% (860 visits) in the 2-11yr group, and 14% (282 visits) in the 12-17yr group. No discernible pattern by age group was found for height for CA based on mean/median SDS scores. For weight for CA, mean/median SDS scores showed an increasing trend in older patients: 0-2yr (0.22/-0.06 [896 visits]); 2-11yr (0.47/0.55 [855 visits]); and 12-17yr (0.55/0.66 [278 visits]). Mean/median SDS scores for height for BA decreased with age: 0-2yr (0.31/0.05 [36 visits]); 2-11yr (-0.32/-0.23 [172 visits]); and 12-17yr (-0.49/-0.26 [44 visits]). Paired BA and CA values from 259 patient visits showed a trend towards bone age being greater than CA, starting at approximately 48 months of age and leveling out around 120-130 months. Mean BA was advanced by 9.7 months compared to CA (SD: 21.2 months, 95%; CI: 7.1 to 12.3 months, [p<0.0001]). Conclusions: As previous research has indicated, I-CAH registry data suggest that children and adolescents with classic 21OHD CAH in Europe have advanced BA relative to CA, with height relative to BA tending to decrease with older age. The I-CAH registry offers the opportunity to study a variety of growth determinants and measurements with an option for subgroup analysis.