The salient features of classical simple virilizing 21-OHD are prenatal virilization and progressive postnatal masculinization with accelerated growth and advanced bone ages but no evidence of mineralocorticoid deficiency.

Diagnosis at birth of a female with simple virilizing CAH usually is made immediately because of the apparent genital ambiguity. As differentiation of the external genitalia is not affected in newborn males, only hyperpigmentation may suggest increased ACTH secretion and cortisol deficiency. Diagnosis at birth in males usually depends on prenatal or newborn screening. If glucocorticoid replacement therapy does not begin postnatally, female genitalia may continue to virilize because of excess adrenal androgens, and pseudoprecocious puberty can occur. Signs of hyperandrogenism in children affected with CAH include early onset of facial, axillary, and pubic hair, adult body odor, and rapid somatic growth. This early growth spurt is accompanied by premature epiphyseal maturation and closure, resulting in a final height that is below that expected from parental heights. (7-11) CAH patients are tall children but short adults. In adolescents and adults, signs of hyperandrogenism may include temporal balding, severe acne, irregular menses, hirsutism, and infertility. Poor control of the disease in males with both simple virilizing and salt-wasting CAH has been associated with reduced sperm counts. (10, 12-14) Gonadal dysfunction usually occurs because the excess adrenal androgens are aromatized peripherally to estrogens, which suppress pituitary gonadotropins and impair the growth and function of the testes.

When classical CAH is diagnosed and adequately treated in infancy, the onset of puberty in both girls and boys usually occurs at the expected chronological age. (15, 16) However, physiologic secretion of gonadotropins may be abnormal. Studies suggest that excess adrenal androgens (aromatized to estrogens) inhibit the pubertal pattern of gonadotropin secretion by the hypothalamic-pituitary axis. (12, 17)

Although the expected age of menarche may be delayed in females with classical CAH, (18) many who are adequately treated have regular menses after menarche. (8, 16) Menstrual irregularity and secondary amenorrhea with or without hirsutism occur in a subset of postmenarchal females, especially those in poor hormonal control. (8, 19-21) Primary amenorrhea or delayed menarche can occur if a woman with classical CAH is untreated, inadequately treated, or over treated with glucocorticoids. Short stature in patients who are over treated result from glucocorticoid induced growth suppression.(15)

Fertility problems in females with classical CAH arise for various reasons including anovulation, secondary polycystic ovarian syndrome, irregular menses, non- suppressible serum progesterone levels, and inadequate introitus. (22, 23) However, there have been several reports of treated women who have had successful pregnancies with the delivery of healthy, full-term infants. (16, 24, 25) Adequacy of glucocorticoid therapy is probably an important variable with respect to fertility outcome. As inadequate vaginal introitus may affect a third of classical CAH adult females, (22) it has been the practice to delay vaginoplasty until sexual intercourse is regular or when the patient can be expected to assume responsibility for vaginal dilatation.

Successfully treated male patients with CAH may have normal pubertal development, normal testicular function, and normal spermatogenesis and fertility. (10, 19, 26, 27) However, in some adequately treated patients as well as those in poor hormonal control, the presence of gonadal abnormalities in adult males with 21-hydroxylase deficiency has been reported in the form of testicular nodules, testicular atrophy, azoospermia, and the suppression of gonadotropin secretion. (10, 12-14, 28) Testicular nodules caused by expanding adrenal rests are another frequently reported complication in postpubertal boys with classical CAH and inadequate hormonal control. (29-32) These nodules develop during periods of sustained elevations of ACTH and decrease in size during administration of glucocorticoids. (30, 31, 33) Regular testicular examination and periodic testicular ultrasonography are recommended for early detection of testicular lesions.

 

 

Inadequate secretion of the mineralocorticoid aldosterone causes salt wasting in approximately three-quarters of all classical CAH patients. Aldosterone secretion is insufficient for the reabsorption of sodium by the distal renal tubule resulting in salt wasting, characterized by hyponatremia, hyperkalemia, inappropriate natriuresis, and low serum and urinary aldosterone with concomitantly high plasma renin activity (PRA). In addition, hormonal precursors of 21-hydroxylase may act as mineralocorticoid antagonists and provoke salt wasting. (34, 35) Untreated infants with renal salt-wasting have poor feeding, weight loss, and dehydration which can progress to azotemia, vascular collapse, shock and death. Adrenal crises occur in the newborn period as early as one to seven weeks of life.

It is important to recognize that the extent of virilization in an affected female may be the same in simple virilizing and salt-wasting CAH. Thus, even a mildly virilized newborn with 21-hydroxylase deficiency should be observed carefully for signs of a potentially life-threatening crisis within the first few weeks of life.