Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. During the last two decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these disorders involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense-mechanisms, and regulation of cell cycle. Adrenal hypoplasia can occur: 1) secondary to defects in transcription factors involved in pituitary development or 2) defects in ACTH synthesis and secretion; 3) as a primary defect in the development of the adrenal gland; 4) as part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive or autosomal dominant manner; and 5) in the context of chromosomal abnormalities. Early diagnosis and management are crucial because of the life-threatening nature of the condition. Depending on the etiology, adrenal crisis may occur in early infancy or could insidiously develop over the course of childhood or adolescence. Moreover, some of these conditions previously thought to occur only in childhood, may also be diagnosed later in adulthood and present with variable phenotypes, including isolated infertility or disorders of sex differentiation. The clinical manifestations of primary adrenal insufficiency (PAI) result from deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The acute presentation can be precipitated by physiologic stress, such as surgery, trauma, or an intercurrent infection. Patients may present with signs and symptoms of complete adrenal insufficiency, usually early in life, including hypoglycemic convulsions, hyponatremia, hyperkalemia, metabolic acidosis or later with hyperpigmentation, vomiting and poor weight gain. It should be remembered, that the most common cause of PAI in children is congenital adrenal hyperplasia due to 21-hydroxylase deficiency and can be excluded by measuring baseline or ACTH-stimulated 17-hydroxyprogesterone levels in serum. Screening for autoimmune Addison disease includes detection of 21-hydroxylase antibodies. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy measuring very–long-chain fatty acids concentrations in plasma. The presence of alacrima in patients with PAI should raise suspicion for Triple A syndrome, whereas the combination of PAI and hypogonadotropic hypogonadism in a male patient point towards X-linked adrenal hypoplasia congenita. To date, molecular genetic testing is commercially available for the identification of several genes involved in adrenal hypoplasia syndromes. The early identification of these diseases can have important prognostic and therapeutic implications for patients with respect to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk. Adrenal insufficiency is potentially life threatening, thus treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis. Therapy consists of life-long replacement therapy with glucocorticoids and mineralocorticoids. Hypogonadism or other associated disorders should be treated appropriately. Screening of family members for the disease or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
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