Premature adrenarche in Prader-Willi syndrome is associated with accelerated pre-pubertal growth and advanced bone age

Objectives: Prader-Willi syndrome (PWS) is characterized by obesity, growth hormone deficiency, hypogonadism, and a high prevalence of premature adrenarche despite reported hypothalamic-pituitary-adrenal axis dysfunction. While idiopathic premature adrenarche is associated with accelerated pre-pubertal growth and advanced bone age, the consequences of elevated adrenal androgens on growth and bone maturation in PWS remain unknown. This study therefore sought to describe age-related changes in dehydroepiandrosterone sulfate (DHEAS) and their effects on growth and bone maturation in PWS. Methods: This retrospective observational study included 62 children with PWS. Simple and multiple regression models were constructed to relate age and BMI-SDS with DHEAS levels. Height velocity was compared to age and sex-based norms with t-tests and two-way ANOVA. Patterns in bone age Z- scorewere examinedwith two- way ANOVA, and the contributions of age, BMI-SDS, and DHEAS to bone age Z-score were analyzed with multiple regression. Results: DHEAS levels rose earlier and were less strongly correlated with age in males and females with PWS (R-2=0.12 and 0.30) compared to healthy controls (R2=0.89 and 0.88) in a pattern unrelated to BMI- SDS (adjusted R-2=0.076, p=0.10 for age, and 0.29 for BMI-SDS). Mid- childhood height velocity was increased in males and preserved in females with PWS before declining at the age of expected puberty (p<0.0001). Peri-adrenarchal bone age was advanced in a manner associated with DHEAS but not BMI-SDS (p<0.0001; adjusted R-2=0.48, p=0.0014 for DHEAS, and 0.78 for BMI-SDS). Conclusions: An obesity-independent increase in adrenal androgens is associated with accelerated mid-childhood growth and bone maturation in PWS.