Impact of Growth-promoting Therapies on Puberty, Growth, and Final Height in Classical 21-hydroxylase Deficiency

Abstract

Context: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OHD) poses significant growth challenges, including accelerated bone maturation, precocious puberty, and compromised final height (FH). Data on pubertal growth in large 21-OHD cohorts remain limited.

Objective: To assess puberty timing, duration, height gain, FH outcomes, and the effects of growth-promoting therapies (GPTs), including GnRH analog, aromatase inhibitors, and cyproterone acetate, in a large cohort with genetically confirmed classical 21-OHD.

Design and setting: A multicenter, retrospective, longitudinal analysis of 284 patients (46,XX: 160; 46,XY: 124).

Methods: Data on puberty, growth, and treatments were collected from clinical records. Growth curves were plotted based on GPT use.

Results: Median age at diagnosis was 0.1 years (interquartile range [IQR]: 0.03-1.1), and at last visit, 12.1 years (IQR: 7.0-17.0). Median FH was 154.0 cm (IQR: 147.3-158.2) in 46,XX (menarche at 13.0 years) and 167.0 cm (IQR: 160.0-170.0) in 46,XY. In the total cohort, 63.4% were pubertal/postpubertal, and the ratio of GPTs used alone or in combination was 41.1%. GnRH analogs, cyproterone acetate, and aromatase inhibitors were administered in 21.8% (n = 62), 8.1% (n = 23), and 5.3% (n = 15) of the cohort, respectively. The median FH-MPH difference improved from -6.7 cm to -2.3 cm in boys without and with GPT, respectively, whereas in girls it declined from -3.7 cm to -6.6 cm.

Conclusion: Patients with 21-OHD had diminished FH despite early diagnosis. Puberty in classical 21-OHD had an earlier onset, slower tempo, and prolonged duration, especially in girls, in which GPTs are less effective in promoting height. The management of pubertal growth needs a personalized approach in patients with classical 21-OHD.

Keywords: CYP21A2; classical 21-hydroxylase deficiency; congenital adrenal hyperplasia; growth; puberty.