Severe, early onset<unk> -hydroxylase deficient CAH The two most serious neonatal consequences of<unk> -hydroxylase deficiency occur: life-threatening salt-wasting crises in the first month of life (for male and female infants alike) and severe virilization of female infants. The subdivision of the early onset CAH into salt-wasting and simple-virilizing forms, which is based on the capacity of the<unk>  to produce small amounts of aldosterone in the simple-virilizing form, is often not clinically meaningful, because clinical presentations overlap and all patients lose salt to some degree. Salt-wasting crises in infancy The excessive amounts of<unk>  testosterone produce little effect on the genitalia of male infants with severe CAH. If a male infant with CAH is not detected by newborn screening, he will appear healthy and normal and be quickly discharged home to his family. However, the lack of aldosterone results in a high rate of sodium loss in the urine. Urinary sodium concentrations may exceed 50 mEq/L. With this rate of salt loss, the infant cannot maintain blood volume, and hyponatremic dehydration begins to develop by the end of the first week of life. Potassium and acid excretion are also impaired when mineralocorticoid activity is deficient, and hyperkalemia and metabolic acidosis gradually develop. Ability to maintain circulation is further limited by the effect of cortisol deficiency. The early symptoms are spitting and poor weight gain, but most infants with severe CAH develop vomiting, severe dehydration, and circulatory collapse (shock) by the second or third week of life. When brought to a hospital, the 1- to 3-week-old infant will be both underweight and dehydrated by appearance. Blood pressure may be low. Basic chemistries will reveal hyponatremia, with a serum Na+ typically between 105 and 125 mEq/L. Hyperkalemia in these infants can be extreme—levels of K+ above 10 mEq/L are not unusual—as can the degree of metabolic acidosis. Hypoglycemia may be present. This is termed a salt-wasting crisis and rapidly causes death if not treated. As ill as these infants can be, they respond rapidly to treatment with hydrocortisone and intravenous saline and dextrose quickly restores blood volume, blood pressure, and body sodium content, and reverses the hyperkalemia. With appropriate treatment, most infants are out of danger within 24 hours. Virilization of female infants It is the<unk> -hydroxylase enzyme that is essential in conversion of progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol, respectively. This process is done through hydroxylation at C-21 position. It was described in at least 1953 that impaired steroid hydroxylation at C-21 position happens in<unk><unk>  hyperplasia and is accompanied by excessive amounts of 17α-hydroxyprogesterone that leads to virilism. In the insufficiency of<unk> -hydroxylase to participate in the biosynthesis of cortisol, the<unk> -hydroxylation in the zona fasciculata of the<unk>  cortex is impaired, so 17α-hydroxyprogesterone and progesterone will not be properly converted into 11-deoxycortisol and 11-deoxycorticosterone, respectively − the precursors for cortisol and aldosterone. As the plasma concentration of cortisol and aldosterone decreases, ACTH levels increase, leading to excessive production and accumulation of cortisol precursors (especially 17α-hydroxyprogesterone), which are eventually transferred to androsterone and testosterone. Other androgens may be additionally produced from 17α-hydroxyprogesterone, due to its elevated levels, that leads, inter alia, to its 5α-reduction. These additional androgens are produced via the so-called "backdoor pathway". For example, in this "backdoor" pathway, 5α-dihydrotestosterone is produced with roundabout of testosterone as an intermediate product. Some of the androgens produced by the backdoor pathway are those that cannot be converted to estrogens by aromatase, causing prenatal virilization, and making them the dominant androgens in classic<unk> -hydroxylase deficiency. Virilization of genetically female (XX) infants usually produces obvious genital ambiguity. Inside the pelvis, the ovaries are normal and since they have not been exposed to testicular antimullerian hormone (AMH), the uterus, fallopian tubes, upper vagina, and other mullerian structures are normally formed as well. However, the high levels of testosterone in the blood can enlarge the phallus, partially or completely close the vaginal opening, enclose the urethral groove so that it opens at the base of the phallus, on the shaft or even at the tip like a boy. Testosterone can cause the labial skin to become as thin and rugated as a scrotum, but cannot produce palpable gonads (i.e., testes) in the folds. Thus, depending on the severity of hyperandrogenism, a female infant can be mildly affected, obviously ambiguous, or so severely virilized as to appear to be a male. Andrea Prader devised the following Prader scale as a way of describing the degree of virilization. * An infant at stage 1 has a mildly large clitoris and slightly reduced vaginal opening size. This degree may go unnoticed or may be simply assumed to be within normal variation. * Stages 2 and 3 represent progressively more severe degrees of virilization. The genitalia are obviously abnormal to the eye, with a phallus intermediate in size and a small vaginal opening. * Stage 4 looks more male than female, with an empty scrotum and a phallus the size of a normal penis, but not quite free enough of the perineum to be pulled onto the abdomen toward the umbilicus (i.e., what is termed a chordee in a male). The single small urethral/vaginal opening at the base or on the shaft of the phallus would be considered a hypospadias in a male. X-rays taken after dye injection into this opening reveal the internal connection with the upper vagina and uterus. This common opening can predispose to urinary obstruction and infection. * Stage 5 denotes complete male virilization, with a normally formed penis with the urethral opening at or near the tip. The scrotum is normally formed but empty. The internal pelvic organs include normal ovaries and uterus, and the vagina connects internally with the urethra as in Stage 4. These infants are not visibly ambiguous, and are usually assumed to be ordinary boys with undescended testes. In most cases, the diagnosis of CAH is not suspected until signs of salt-wasting develop a week later. When the genitalia are determined to be ambiguous at birth, CAH is one of the leading diagnostic possibilities. Evaluation reveals the presence of a uterus, extreme elevation of 17OHP, levels of testosterone approaching or exceeding the male range but low AMH levels. The karyotype is that of an ordinary female: 46,XX. With this information, the diagnosis of CAH is readily made and female sex confirmed. Evaluation of ambiguous genitalia is described in detail elsewhere. In most cases it is possible to confirm and assign female sex within 12–36 hours of birth. The exception are the rare, completely virilized genetic females (Prader stage 5), who present the most challenging assignment and surgery dilemmas, discussed below. When the degree of ambiguity is obvious, corrective surgery is usually offered and performed. As reconstructive surgery on infant genitalia has become a focus of controversy, the issues are described in more detail below. Reduced fertility Testicular<unk>  rest tumors Infertility observed in adult males with<unk><unk>  hyperplasia (CAH) has been associated with testicular<unk>  rest tumors (TART) that may originate during childhood. TART in prepubertal males with classic CAH could be found during childhood (20%). Martinez-Aguayo et al. reported differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control. Female fertility Women with classic CAH have statistically reduced fertility, especially those with the salt-losing form. Live birth rate is 33%-50% in simple virilized form of CAH, and 0%-10% in most severe salt-wasting form. In nonclassic form of CAH the live birth is 63%-90%, similar to the age-matched control groups. Sex assignment issues and controversies Classical CAH leads to female pseudohermaphroditism at birth, and is the most common case of sex ambiguity, the second one is mixed gonadal dysgenesis. Most commonly, at birth, the phallus enlarges, so it is larger than normal female but smaller than normal male. Instead of separate urethral and vaginal openings, there is an urogenital sinus that is often covered by tissue resulting from the posterior fusion of the labioscrotal ridges. Therefore, different degrees of external genital abnormalities can be found, ranging from normal perineum to penile urethra. There are no difficulties assigning appropriate sex for most infants with CAH. Genetic males have normal male genitalia and gonads and simply need hormone replacement. Most virilized females are assigned and raised as girls even if their genitalia are ambiguous or look more male than female. They have normal ovaries and uterus and potential fertility with hormone replacement and surgery. However, the dilemmas surrounding sex assignment of the most severely virilized XX infants have helped shape our understanding of gender identity and sexual orientation, and continue to be a subject of debate. Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities congruent with their sex of rearing. In a few cases of male rearing, a sex reassignment was attempted in mid-childhood when newly discovered karyotyping revealed "female" chromosomes. These reassignments were rarely successful, leading John Money and other influential psychologists and physicians to conclude that gender
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