Primary Adrenal Insufficiency

Basics

Description

Deficiency in the secretion of cortisol and/or aldosterone by the adrenal glands

Epidemiology

  • Age
    • Adrenal insufficiency associated with congenital adrenal hyperplasia (CAH) presents in the newborn period.
    • Adrenal hypoplasia congenita presents in infancy or early childhood.
    • Adrenocorticotropic hormone (ACTH) unresponsiveness presents in late infancy or the toddler period.
    • Adrenoleukodystrophy typically presents late in the 1st decade of life with neurologic symptoms. Signs and symptoms of adrenal insufficiency in persons with adrenoleukodystrophy may first present at any age.
    • Addison disease is rare in children and usually presents between the ages of 20 and 50 years. In the pediatric population, it is most often seen in late childhood and adolescence.
  • Sex
    • CAH and ACTH unresponsiveness affect both sexes equally.
    • Adrenal hypoplasia congenita, an X-linked disorder, predominantly affects boys
    • Adrenoleukodystrophy, an X-linked disorder, predominantly affects boys.
    • Addison disease is more common in girls.

Risk Factors

Genetics

  • CAH: autosomal recessive inheritance associated with a gene defect in 1 of multiple adrenal steroidogenic enzymes, most commonly CYP21A2 for the 21-hydroxylase gene
  • Adrenal hypoplasia congenita: X-linked mutation in DAX1 gene
  • ACTH unresponsiveness: autosomal recessive ACTH receptor defect
  • Adrenoleukodystrophy
    • X-linked recessive disorder of very-long-chain fatty acid metabolism due to ABCD1 gene mutation
    • An autosomal recessive form of the disease exists, with presentation during infancy.
  • Addison disease
    • Autoimmune adrenal insufficiency may be isolated or part of autoimmune polyglandular syndrome (APS) type 1 or 2. Mutations in the AIRE1 gene have been identified as the cause of APS type 1. An association exists between idiopathic Addison disease and human leukocyte antigen (HLA)-B8 and DR3.

Pathophysiology

  • CAH: a group of enzymatic disorders of steroid metabolism, of which 21-hydroxylase deficiency is the most common (Appendix, Table 13)
  • Adrenal hypoplasia congenita: a defect in adrenal organogenesis
  • ACTH unresponsiveness
    • Inherited defect in the ACTH receptor, resulting in isolated glucocorticoid deficiency with hypoglycemia in infancy and hyperpigmentation
  • Adrenoleukodystrophy
    • Inherited disorders of impaired peroxisomal degradation of very-long-chain fatty acids, resulting in adrenal insufficiency and progressive neurologic deterioration
  • Addison disease
    • Primary hypoadrenalism due to bilateral destruction of the adrenal cortices; this can be due to autoimmune destruction (isolated or associated with APS), tuberculosis, hemorrhage, fungal infection, neoplastic infiltration, or AIDS.
  • Waterhouse-Friderichsen syndrome: bilateral adrenal gland hemorrhage classically associated with fulminant meningococcemia but also reported with Staphylococcus aureus and Streptococcus pneumoniae

Commonly Associated Conditions

  • Deficiencies of other hormones, including aldosterone and adrenal sex steroids
  • Adrenal hypoplasia congenita is associated with hypogonadotropic hypogonadism.
  • APSs are associated with other autoimmune disorders:
    • APS type 1: mucocutaneous candidiasis, hypoparathyroidism
    • APS type 2: autoimmune thyroid disease, type 1 diabetes
    • Both types can also present in conjunction with multiple other autoimmune disorders (e.g., primary ovarian or testicular insufficiency, celiac disease, pernicious anemia, vitiligo, autoimmune hepatitis).

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