Current Insights Into Adrenal Insufficiency in the Newborn and Young Infant

Abstract

Adrenal insufficiency (AI) is a potentially life-threatening condition that can be difficult to diagnose, especially if it is not considered as a potential cause of a child's clinical presentation or unexpected deterioration. Children who present with AI in early life can have signs of glucocorticoid deficiency (hyperpigmentation, hypoglycemia, prolonged jaundice, poor weight gain), mineralocorticoid deficiency (hypotension, salt loss, collapse), adrenal androgen excess (atypical genitalia), or associated features linked to a specific underlying condition. Here, we provide an overview of causes of childhood AI, with a focus on genetic conditions that present in the first few months of life. Reaching a specific diagnosis can have lifelong implications for focusing management in an individual, and for counseling the family about inheritance and the risk of recurrence.

Keywords: Addison's disease; DAX-1; MIRAGE syndrome; adrenal hypoplasia; adrenal insufficiency; congenital adrenal hyperplasia; genetic testing; glucocorticoid.

Figure 1

Genetic mechanisms of pediatric adrenal insufficiency (AI) along the hypothalamo-pituitary-adrenal (HPA) axis. Key genes are shown in white boxes. (A) Genetic causes of AI as they relate to the mature HPA axis. These genes are required for a multitude of key enzymatic and biochemical processes occurring within the nucleus, mitochondria, and cytoplasm. Disruption of these genes gives rise to the clinical phenotypes discussed in the text. OMM, outer mitochondrial membrane; IMM, inner mitochondrial membrane. (B) Overview of adrenal development and key genes associated with adrenal hypoplasia. Adrenal hypoplasia is mediated by disruption of key genes required for normal fetal adrenal development. These genes are involved in transcription, signaling, and growth/cell cycle processes.