Cognitive and Behavioral Aspects of Congenital Adrenal Hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a family of genetic disorders involving enzyme defects in the synthesis of cortisol in the adrenal gland (for reviews and additional information, see Grumbach, Hughes, and Conte 2003; Merke and Bornstein 2005; Speiser 2001). The most common defect is in 21-hydroxylase (21-OH), which accounts for 90% of cases of CAH and results in physical signs of androgen excess. Congenital adrenal hyperplasia is heterogeneous, with the phenotype usually classified as nonclassic (NC), a mild, often late-onset form, or classic, a severe form. Classic CAH consists of the salt-wasting (SW) and simple-virilizing (SV) forms, which reflect degree of aldosterone deficiency (mineralocorticoid disturbance), with a SW:SV ratio of approximately 2:1. It is likely that the three forms of CAH (NC, SV, SW) reflect an underlying continuum. Individuals with classic CAH due to 21-OH deficiency are unable to produce enough cortisol to suppress the release of adrenocorticotropic hormone (ACTH). This results in an accumulation of cortisol precursors, leading to increased production of androgen from the adrenal gland beginning early in gestation and continuing until the disorder is diagnosed and treated with cortisol replacement, usually in the newborn period. Classic CAH is usually detected through newborn screening in the United States and in some other countries (Therrell 2001). Untreated classic CAH causes rapid growth (and ultimately short stature), precocious puberty, and physical virilization. Aldosterone deficiency can cause hypoglycemia, and potentially life-threatening episodes of hyponatremia and hyperkalemia. The defects in CAH also have consequences for behavior and cognition, as will be discussed throughout this chapter. Individuals with nonclassic CAH due to 21-OH deficiency do not have the significant cortisol deficiency characteristic of classic CAH. Nevertheless, they do have increased androgen, usually beginning in childhood or in adulthood. The excess androgen is associated with an increased likelihood of early puberty, infertility, and in women, hirsutism, menstrual irregularities, and polycystic ovaries. Classic CAH is one of the most common inborn errors of metabolism and the most common cause of ambiguous genitalia. Data from newborn screening show the incidence to be approximately 1 in 15,000 live births with some variations across countries and ethnic groups (Therrell 2001).