Survival without treatment of patients with classic and non-classic 21-hydroxylase deficiency

CONTEXT: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is characterized by cortisol and aldosterone deficiency and hyperandrogenism. Historically, patients have been classified into salt-wasting (SW), simple-virilizing (SV), and the less severe non-classic (NC) form. Standard treatment for patients with classic 21OHD (SW and SV) consists of glucocorticoid and sometimes mineralocorticoid replacement to prevent adrenal crises. Interestingly, some patients were untreated due to delayed diagnosis or stopped treatment and survived without overt signs of adrenal insufficiency. OBJECTIVE: Describe a cohort of patients with 21OHD who survived without glucocorticoid treatment, with particular focus on sickness, surgical interventions, and adrenal crises. DESIGN: Observational study. SETTING: Multicenter retrospective open cohort study. PATIENTS: Patients with classic (SW, n=29; SV, n=23) and NC (n=24) 21OHD, with a median age of 11.0 and 21.7 years, respectively. RESULTS: Patients with classic and NC 21OHD were untreated with glucocorticoid for 8.7 years (IQR 4.7-14.3) and 28.1 years (IQR 12.2-39.0), respectively (p<0.001). Of patients with classic 21OHD, 48% never received glucocorticoid treatment. Remarkably, 71% of them did not experience adrenal crises during the untreated period, even during illness or surgical interventions. In the NC 21OHD group, 21% was never treated with glucocorticoid, two patients (8.3%) experienced an adrenal crisis, both had an I2 splice/P31L genotype. All adrenal crises, except one, were reported before the age of 7 years. CONCLUSIONS: Study on untreated patients with 21OHD provides valuable opportunity to further explore mechanisms that influence glucocorticoid activity and elucidate disease variability in 21OHD.