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).

Figure 570-1 A, A 6-yr-old girl with congenital virilizing adrenal hyperplasia. The height age was 8.5 yr, and the bone age was 13 yr. B, Notice the clitoral enlargement and labial fusion. C, Her 5-yr-old brother was not considered to be abnormal by the parents. The height age was 8 yr, and the bone age was 12.5 yr.

Figure 570-2 Three virilized females with untreated congenital adrenal hyperplasia. All were erroneously assigned male sex at birth, and each had a normal female sex-chromosome complement. Infants A and B had the salt-wasting form and received the diagnosis early in infancy. Infant C was referred at 1 yr of age because of bilateral cryptorchidism. Notice the completely penile urethra; such complete masculinization in females with adrenal hyperplasia is rare; most of these infants have the salt-wasting form.

Table 570-1 DIAGNOSIS AND TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA

570.1 Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Perrin C. White

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.

Epidemiology

Classical 21-hydroxylase deficiency occurs in about 1 in 15,000-20,000 births in most populations. Approximately 70% of affected infants have the salt-losing form, whereas 30% have the simple virilizing form of the disorder. In the USA, CAH is less common in African-Americans compared with white children (1 : 42,000 vs 1 : 15,500). Nonclassical disease has a prevalence of about 1 in 1,000 in the general population but occurs more frequently in specific ethnic groups such as Ashkenazi Jews and Hispanics.

Genetics

There are 2 steroid 21-hydroxylase genes—CYP21P (CYP21A1P, CYP21A) and CYP21 (CYP21A2, CYP21B)—which alternate in tandem with 2 genes for the 4th component of complement (C4A and C4B) in the human leukocyte antigen (HLA) major histocompatibility complex on chromosome 6p21.3 between the HLA-B and HLA-DR loci. Many other genes are located in this cluster. CYP21 is the active gene; CYP21P is 98% identical in DNA sequence to CYP21 but is a pseudogene due to 9 different mutations. More than 90% of mutations causing 21-hydroxylase deficiency are recombinations between CYP21 and CYP21P. Approximately 20% are deletions generated by unequal meiotic crossing-over between CYP21 and CYP21P, whereas the remainder is nonreciprocal transfers of deleterious mutations from CYP21P to CYP21, a phenomenon termed gene conversion.

The deleterious mutations in CYP21P have different effects on enzymatic activity when transferred to CYP21. Several mutations completely prevent synthesis of a functional protein, whereas others are missense mutations (they result in amino acid substitutions) that yield enzymes with 1-50% of normal activity. Disease severity correlates well with the mutations carried by an affected individual; for example, patients with salt-wasting disease usually carry mutations on both alleles that completely destroy enzymatic activity. Patients are frequently compound heterozygotes for different types of mutations (i.e., 1 allele is less severely affected than the other), in which case the severity of disease expression is largely determined by the activity of the less severely affected of the 2 alleles.

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.

CAH differs from other causes of primary adrenal insufficiency in that precursor steroids accumulate proximal to the blocked enzymatic conversion. Because cortisol is not synthesized efficiently, ACTH levels are high, leading to hyperplasia of the adrenal cortex and levels of precursor steroids that may be hundreds of times normal. In the case of 21-hydroxylase deficiency, these precursors include 17-hydroxyprogesterone and progesterone. Progesterone and perhaps other metabolites act as antagonists of the mineralocorticoid receptor and thus may exacerbate the effects of aldosterone deficiency in untreated patients.

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.

Prenatal exposure of the brain to high levels of androgens may influence subsequent sexually dimorphic behaviors in affected females. Girls tend to be interested in masculine toys such as cars and trucks and often show decreased interest in playing with dolls and demonstrate aggressive play behavior. Women may have decreased interest in maternal roles. There is an increased frequency of homosexuality in affected females. Nonetheless, most function heterosexually and do not have gender identity confusion or dysphoria. It is unusual for affected females to assign themselves a male role.

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

Untreated or inadequately treated children of both sexes develop additional signs of androgen excess after birth. Boys with the simple virilizing form of 21-hydroxylase deficiency often have delayed diagnosis because they appear normal and rarely develop adrenal insufficiency.

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.

Adrenomedullary Dysfunction

Development of the adrenal medulla requires exposure to the extremely high cortisol levels normally present within the adrenal gland. Thus patients with classic CAH have abnormal adrenomedullary function, as evidenced by blunted epinephrine responses, decreased blood glucose and lower heart rates with exercise. Ability to exercise is unimpaired and the clinical significance of these findings is uncertain. Adrenomedullary dysfunction may exacerbate the cardiovascular effects of cortisol deficiency in untreated or undertreated patients.

Laboratory Findings (See Table 570-1)

Patients with salt-losing disease have typical laboratory findings associated with cortisol and aldosterone deficiency, including hyponatremia, hyperkalemia, metabolic acidosis, and often hypoglycemia, but these abnormalities can take 10-14 days or longer to develop after birth. Blood levels of 17-hydroxyprogesterone are markedly elevated. However, levels of this hormone are high during the 1st 2-3 days of life, even in unaffected infants and especially if they are sick or premature. After infancy, once the circadian rhythm of cortisol is established, 17-hydroxyprogesterone levels vary in the same circadian pattern, being highest in the morning and lowest at night. Blood levels of cortisol are usually low in patients with the salt-losing type of disease. They are often normal in patients with simple virilizing disease but inappropriately low in relation to the ACTH and 17-hydroxyprogesterone levels. In addition to 17-hydroxyprogesterone, levels of androstenedione and testosterone are elevated in affected females; testosterone is not elevated in affected males because normal infant males have high testosterone levels compared with those seen later in childhood. Levels of urinary 17-ketosteroids and pregnanetriol are elevated but are now rarely used clinically because blood samples are easier to obtain than 24-hr urine collections. ACTH levels are elevated but have no diagnostic utility over 17-hydroxyprogesterone levels. Plasma levels of renin are elevated, and serum aldosterone is inappropriately low for the renin level. However, renin levels are high in normal infants in the 1st few weeks of life.

Diagnosis of 21-hydroxylase deficiency is most reliably established by measuring 17-hydroxyprogesterone before and 30 or 60 min after an intravenous bolus of 0.125-0.25 mg of cosyntropin (ACTH 1-24). Nomograms exist that readily distinguish normals and patients with nonclassical and classical 21-hydroxylase deficiency. Heterozygous carriers of this autosomal recessive disorder tend to have higher ACTH-stimulated 17-hydroxyprogesterone levels than genetically unaffected individuals, but there is significant overlap between subjects in these 2 categories. However, in infants with frank electrolyte abnormalities or circulatory instability, it may not be possible or necessary to delay treatment to perform this test, as levels of precursors will be sufficiently elevated on a random blood sample to make the diagnosis.

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.