The adrenal gland is an endocrine organ that sits on top of the kidney and it produces hormones that have widespread effects on the regulation and response of the body. The adrenal gland is part of the hypothalamic-pituitary-adrenal axis, which is the control center for most of the body's hormonal systems. This three-gland system is the most complicated control system in the body and in the pediatric population each one of the three can be involved in adrenal insufficiency. According to Nelson's, "Textbook of Pediatrics," there are more than 60 diseases and/or disease subtypes that can cause adrenocortical hypofunction, and depending on the particular system and specific pathology, the symptoms may be severe or mild, appear abruptly or insidiously, begin in infancy or later, and be permanent or temporary.
Understanding the Adrenal System
The adrenal cortex is composed of three areas, the outer area (Zona glomerulosa) produces mineralocorticoids (primarlily aldosterone), the larger inner area (Zona fasciculata) produces glucocorticoids (cortisol), and the smaller inner area (Zona reticularis) produces androgens and anabolic steroids (testosterone and dehydroepiandrosterone). Mineralocorticoids regulate blood volume, water and salt balance; and, glucocorticoids regulate cell energy balance and maintain cardiovascular, metabolic and immune equilibrium. Androgens and anabolic steroids regulate primary and secondary sexual characteristics. Pediatric adrenal insufficiency can be classified congenital or acquired, and primary or secondary. Congenital diseases are present at birth and most are due to a lack of one of the components of the hypothalamic-pituitary-adrenal axis resulting from a genetic defect. Acquired diseases develop after birth may also be from a genetic defect. Primary adrenal insuffiency has to do with a disease or defect of the adrenal gland itself, while secondary are disease or defects of other components of the system, primarily the hypothalamus and pituitary glands.
Congenital Adrenal Hyperplasia
Congenital Adrenal Hyperplasia (CAH) is the most common cause of pediatric adrenal insufficiency and is a group of autosomal recessive disorders with identified gene mutations, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both. The three enzymes are 21-hydroxylase, 11-beta-hydroxylase and 17-alpha-hydroxylase. Deficiency of 21-hydroxylase, which accounts for 90 percent of all cases, is clinically divided into three phenotypes: salt wasting, simple virilizing and non-classic. Severe deficiency of 21-hydroxylase causes salt-wasting CAH, which is life-threatening. Moderate deficiency causes simple virilizing CAH, and non-classic or late onset CAH is the mildest form and may not present until late childhood or early adulthood.
Congential Adrenal Hypoplasia
Congential adrenal hypoplasia is a rare cause of primary adrenal insufficiency. The cortex portion of the adrenal gland fails to form which results in the reduced or absent production of cortisol. X-linked and autosomal recessive variations are known.
3-beta--hydroxysteroid dehydrogenase (3BHSD) deficiency
The 3-beta--hydroxysteroid dehydrogenase (3BHSD) deficiency is a rare genetic disorder of steroid biosynthesis that results in decreased production of all three groups of adrenal steroids, including mineralocorticoids, glucocorticoids and sex steroids. There is great variation in the clinical presentation of this disorder, as well as in older patients who present with a milder or so-called late-onset variant.
Familial Glucocorticoid Deficiency
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by glucocorticoid deficiency, elevated plasma adrenocorticotropic hormone (ACTH) levels and preserved aldosterone secretion.
Hypopituitarism
The anterior pituitary gland releases ACTH with is the stimulus for the adrenal cortex to release glucocorticoid (cortisol). Hypopituitarism that includes the anterior pituitary gland results in secondary adrenal insufficiency. Congenital causes of hypopituitarism are birth trauma or asphyxia, midline defect syndromes and genetic mutation, while acquired hypopituitarism results from hydrocephalus, major head trauma, tumors or vascular abnormalities in the hypothalamic-pituitary region and radiation to the head and neck. The onset can occur in children or adults and clinical presentation varies considerably.
Pseudohypoaldosteronism
Pseudohypoaldosteronism (PHA) is group of disorders of electrolyte metabolism characterized by an unresponsiveness or resistance to the action of aldosterone. Since the kidney does not respond to the elevated levels of adrenal cortex produced aldosterone, the symptoms are of adrenal insufficiency.
Adrenoleukodystrophy and Adrenomyeloneuropathy
Adrenoleukodystropy and adrenomyeloneuropathy are genetic diseases associated with the accumulation of very long chain fatty acids in the adrenal cortex and nervous system white matter. Adrenoleukodystrophy (X-ALD) (also known as "Addison-Schilder Disease," "Siemerling-Creutzfeldt Disease" and "Schilder's disease") is a rare, X-linked disease that leads to progressive brain damage, failure of the adrenal glands and eventually death. Adrenomyeloneuropathy (AMN) is a rare, milder form of X-linked adrenoleukodystrophy (X-ALD). In adrenoleukodystrophy, young children generally exhibit cerebral dysfunction, with rapid progression to dementia and quadriparesis. Adrenomyeloneuropathy progresses more slowly, with patients first showing symptoms of weakness and spasticity in adolescence or adulthood. Patients also develop adrenal insufficiency. ALD is one disease in a group of inherited disorders called leukodystrophies.
Lipoid Congenital Adrenal Hyperplasia
Lipoid congenital adrenal hyperplasia is one of the rarer forms of CAH and results from defects in the steps from cholesterol to pregnenolone which are precursors to cortisol and sex hormones. This results in the catastrophic loss of most or all steroid hormones in the body. This inherited disease is autosomal recessive.
Wolman Disease
Wolman disease is extremely rare, autosomal recessive form of adrenal insufficiency. Wolman disease is marked by accumulation of a transport form of cholesterol and triglycerides that can build up significantly and cause damage in the cells and tissues. It is a universally fatal by age one with no known cure.
Other Cause of Adrenal Insufficiency
Infectious adrenalitis, also called Waterhouse-Friderichsen syndrome, is a rare form of adrenal insufficiency and is generally related to tuberculosis or HIV infections. Adrenal hemorrhage is also seen as a cause of adrenal insufficiency in the neonate secondary to birth trauma or sponatenously. In older children adrenal hemmorage is generally secondary to major trauma. Polyglandular autoimmune (PGA) syndromes and polyglandular failure syndromes are constellations of multiple endocrine gland insufficiencies that are associated with adrenal insufficiency. Deficiency of corticotropin releasing hormone (CRH) from the hypothalmus has been occasionally reported. Iatrogenic (literally translated as caused by a Physician) causes include abrupt cessation of corticosteroids or corticotropin; removal of an functioning adrenal tumor; adrenalectomy for Cushing disease; and the drugs, ketoconazole, Mitotane, aminoglutethimide, metyrapone. A very rare cause of adrenal hypofunction is adrenal tumor. Finally, fetal adrenal supression can occur from maternal increase in steriods either from endogenous causes or therapeutic.
References
- "Nelson's Textbook of Pediatrics;" Richard E. Behrman, M.D., et. al. eds.; 1992
- Textbook of Endocrinology 11th ed. Philadelphia, PA: Saunders; 2008
- Perry R, Kecha O, Paquette J, Huot C, Van Vliet G, Deal C. Primary adrenal insufficiency in children: twenty years experience at the Sainte-Justine Hospital, Montreal. J Clin Endocrinol Metab. Jun 2005
