Approach to the Child and Adolescent With Adrenal Insufficiency.

Standard glucocorticoid formulations fail to replicate the physiological circadian rhythm of cortisol and do not adequately control adrenal androgen production driven by adrenocorticotropin.

• The overall goals of treatment are to prevent life-threatening adrenal crises, optimize linear growth, control androgen levels without overdosing in patients with congenital adrenal hyperplasia (CAH), and improve quality of life.
• Standard formulations cannot mimic the natural diurnal cortisol secretion pattern.
• Excess ACTH-driven androgen production remains inadequately controlled with conventional therapy.

New pharmacological strategies have been developed to best mimic physiological cortisol secretion in children and adolescents with adrenal insufficiency.

• Novel therapeutic approaches include new ways to deliver circadian cortisol replacement.
• Adjunctive therapies to reduce androgen production and/or androgen action/effects have been developed.
• These strategies aim to personalize and tailor glucocorticoid therapy to improve patient outcomes.

Three illustrative cases of adrenal insufficiency with different underlying etiologies and times of presentation were used to discuss diagnostic and management processes.

• The cases represent different etiologies of adrenal insufficiency in children and adolescents.
• Diagnostic and management processes are discussed with emphasis on treatment and outcomes.
• The cases were selected to illustrate the breadth of clinical presentations encountered in pediatric AI.

Preclinical studies are exploring restorative cell-based therapies for adrenal insufficiency.

• Cell-based therapies are at the preclinical stage of investigation.
• These approaches are being explored as potential restorative treatments for adrenal insufficiency.
• Such therapies represent an emerging frontier beyond current hormonal replacement strategies.

A first recombinant adeno-associated virus-based gene therapy is being developed in humans with congenital adrenal hyperplasia.

• This represents the first gene therapy approach being tested in human subjects with CAH.
• The therapy is based on a recombinant adeno-associated virus (AAV) vector.
• Gene therapy development marks a significant step toward potential curative treatment for CAH.

The paper provides the most up-to-date evidence for tailored management of children and adolescents with adrenal insufficiency.

• The review covers personalized approaches to glucocorticoid replacement therapy.
• Both established and emerging treatment strategies are reviewed in the context of pediatric AI.
• Management emphasis includes optimizing linear growth and quality of life alongside crisis prevention.