Chapter 570 Congenital Adrenal Hyperplasia and Related Disorders
Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders of cortisol biosynthesis (normal adrenal steroidogenesis is discussed in Chapter 568). Cortisol deficiency increases secretion of corticotropin (ACTH), which in turn leads to adrenocortical hyperplasia and overproduction of intermediate metabolites. Depending on the enzymatic step that is deficient, there may be signs, symptoms, and laboratory findings of mineralocorticoid deficiency or excess; incomplete virilization or premature puberty in affected males; and virilization or sexual infantilism in affected females (Figs. 570-1 and 570-2 and Table 570-1).
570.1 Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency
Etiology
More than 90% of congenital adrenal hyperplasia (CAH) cases are caused by 21-hydroxylase deficiency. This P450 enzyme (CYP21, P450c21) hydroxylates progesterone and 17-hydroxyprogesterone (17-OHP) to yield 11-deoxycorticosterone (DOC) and 11-deoxycortisol, respectively (see Fig. 568-1). These conversions are required for synthesis of aldosterone and cortisol, respectively. Both hormones are deficient in the most severe, “salt-wasting” form of the disease. Slightly less severely affected patients are able to synthesize adequate amounts of aldosterone but have elevated levels of androgens of adrenal origin; this is termed simple virilizing disease. These 2 forms are collectively termed classical 21-hydroxylase deficiency. Patients with nonclassical disease have relatively mildly elevated levels of androgens and may have signs of androgen excess after birth.
Pathogenesis and Clinical Manifestations
Aldosterone and Cortisol Deficiency
Because both cortisol and aldosterone require 21-hydroxylation for their synthesis, both hormones are deficient in the most severe, salt-wasting form of the disease. This form constitutes about 70% of cases of classical 21-hydroxylase deficiency. The signs and symptoms of cortisol and aldosterone deficiency, and the pathophysiology underlying them, are essentially those described in Chapter 569. These include progressive weight loss, anorexia, vomiting, dehydration, weakness, hypotension, hypoglycemia, hyponatremia, and hyperkalemia. These problems typically 1st develop in affected infants at approximately 10-14 days of age. Without treatment, shock, cardiac arrhythmias, and death may occur within days or weeks.
Prenatal Androgen Excess
The most important problem caused by accumulation of steroid precursors is that 17-hydroxyprogesterone is shunted into the pathway for androgen biosynthesis, leading to high levels of androstenedione that are converted outside the adrenal gland to testosterone. This problem begins in affected fetuses by 8-10 wk of gestation and leads to abnormal genital development in females (see Figs. 570-1 and 570-2).
The external genitals of males and females normally appear identical early in gestation (Chapter 576). Affected females, who are exposed in utero to high levels of androgens of adrenal origin, have masculinized external genitalia (see Figs. 570-1 and 570-2). This is manifested by enlargement of the clitoris and by partial or complete labial fusion. The vagina usually has a common opening with the urethra (urogenital sinus). The clitoris may be so enlarged that it resembles a penis; because the urethra opens below this organ, some affected females may be mistakenly presumed to be males with hypospadias and cryptorchidism. The severity of virilization is usually greatest in females with the salt-losing form of 21-hydroxylase deficiency. The internal genital organs are normal, because affected females have normal ovaries and not testes and thus do not secrete antimüllerian hormone.
Male infants appear normal at birth. Thus, the diagnosis may not be made in boys until signs of adrenal insufficiency develop. Because patients with this condition can deteriorate quickly, infant boys are more likely to die than infant girls. For this reason, many states and countries have instituted newborn screening for this condition (see Newborn Screening, later).
Postnatal Androgen Excess
Signs of androgen excess include rapid somatic growth and accelerated skeletal maturation. Thus, affected patients are tall in childhood but premature closure of the epiphyses causes growth to stop relatively early, and adult stature is stunted (see Fig. 570-1). Muscular development may be excessive. Pubic and axillary hair may appear; and acne and a deep voice may develop. The penis, scrotum, and prostate may become enlarged in affected boys; however, the testes are usually prepubertal in size so that they appear relatively small in contrast to the enlarged penis. Occasionally, ectopic adrenocortical cells in the testes of patients become hyperplastic similarly to the adrenal glands, producing testicular adrenal rest tumors (Chapter 578). The clitoris may become further enlarged in affected females (see Fig. 570-1). Although the internal genital structures are female, breast development and menstruation may not occur unless the excessive production of androgens is suppressed by adequate treatment.
Differential Diagnosis
Intersex conditions are discussed more generally in Chapter 582. The initial step in evaluating an infant with ambiguous genitals is a thorough physical examination to define the anatomy of the genitals, locate the urethral meatus, palpate the scrotum or labia and the inguinal regions for testes (palpable gonads almost always indicate the presence of testicular tissue and thus that the infant is a genetic male), and look for any other anatomic abnormalities. Ultrasonography is helpful in demonstrating the presence or absence of a uterus and can often locate the gonads. A rapid karyotype (such as fluorescence in situ hybridization of interphase nuclei for X and Y chromosomes) can quickly determine the genetic sex of the infant. These results are all likely to be available before the results of hormonal testing and together allow the clinical team to advise the parents as to the genetic sex of the infant and the anatomy of internal reproductive structures. Injection of contrast medium into the urogenital sinus of female pseudohermaphrodites demonstrates a vagina and uterus, and most surgeons utilize this information to formulate a plan for surgical management.