CAH can occur in various forms. The clinical presentation of each form is different and depends to a large extent on the kind of the underlying 21-hydroxylase enzyme defect. Classical forms appear in infancy, and
nonclassical forms appear in late childhood. The presentation in patients with classical CAH can be further subdivided into two forms: salt-wasting and simple-virilizing, depending on whether mineralocorticoid deficiency is present or absent, respectively. This subtyping is often not clinically meaningful, because all patients with classical form lose salt to some degree, and clinical presentations may overlap.
Severe, early onset 21-hydroxylase deficient CAH The two most serious neonatal consequences of
21-hydroxylase deficiency are the following: life-threatening salt-wasting crises in the first month of life (for male and female infants alike) and severe virilization of female infants which can cause genital ambiguity. The subdivision of the early onset CAH into salt-wasting and simple-virilizing forms, which is based on the capacity of the adrenal 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. have little effect on the genitals of male infants with classical CAH. Aldosterone insufficiency in salt-wasting CAH results in a significant loss of sodium in the urine. Urinary sodium concentrations may exceed 50 mEq/L. Due to the loss of salt at that rate, the infant is unable to maintain proper
blood volume and begins to suffer from
dehydration due to
hyponatremia 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. When there's not enough cortisol in the body due to the classical CAH, it becomes harder to have proper blood circulation. Inadequate circulation can cause problems like spitting and difficulty gaining weight in babies. Furthermore, infants with salt-wasting CAH may experience even worse symptoms like vomiting, and extreme dehydration, and their circulation can suddenly fail (which is called
circulatory shock) within two or three weeks after birth. Upon admission to a medical facility, the infant between the ages of 1 and 3 weeks will exhibit signs of both underweight and dehydration. Despite the severity of this condition, affected infants respond swiftly to treatment involving hydrocortisone administration along with intravenous infusion of saline solution and dextrose supplementation. Consequently, normal blood volume is promptly restored alongside stabilization of blood pressure and restoration of appropriate body sodium levels, leading to a reversal of hyperkalemia. With prompt and apt management measures in place, most infants are no longer at risk within a span of approximately 24 hours.
Virilization of female infants through testosteroneCAH is a genetic disorder characterized by impaired production of cortisol in the adrenal glands. The
21-hydroxylase enzyme is essential in conversion of
progesterone and
17OHP 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 congenital adrenal hyperplasia and is accompanied by excessive amounts of 17OHP that leads to virilism. In the insufficiency of 21-hydroxylase to participate in the biosynthesis of cortisol, the 21-hydroxylation in the
zona fasciculata of the adrenal cortex is impaired, so 17OHP 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 17OHP), which are eventually transferred to
androsterone that is a feedstock for other androgens. These additional androgens are produced via the so-called "
backdoor pathway" (see red arrows on the diagram). 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 21-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
anti-Müllerian hormone (AMH), the
uterus,
fallopian tubes, upper
vagina, and other Müllerian 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 rugate 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, 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 the female sex is 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 is the rare, completely virilized genetic female (Prader stage 5), who presents the most challenging assignment and surgery dilemmas. When the degree of ambiguity is obvious, corrective surgery is usually offered and performed, but reconstructive surgery on infant genitalia has controversies.
Reduced fertility Testicular adrenal rest tumors Infertility observed in adult males with classical CAH has been associated with testicular adrenal rest tumors (TART) that may originate during childhood. Delayed diagnosis of CAH was associated with a higher risk of developing TART, which may be attributable to poor disease control early in life, emphasizing the need of early detection and management of CAH, and, once CAH is detected, detection and management of TART. TART in prepubertal males with classical 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. Early glucocorticoid therapy may be beneficial to the reduction of TART. Early detection and management of TART in CAH patients is important for preserving testicular function and preventing long-term complications that may impact fertility. Subsequently, male subjects with nonclassic CAH rarely present with TARTs, and even though these tumors do not affect fertility and do not require regular ultrasound examination of the scrotum.
Female fertility Women with classical 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 the
nonclassical form of CAH, the live birth is 63–90%, similar to the age-matched control groups.
Sex assignment Classical CAH leads to female
pseudohermaphroditism at birth, and is the most common cause of sex ambiguity, the second one is mixed
gonadal dysgenesis. Most commonly, at birth, the phallus enlarges, so it is larger than a normal female but smaller than a normal male. Instead of separate urethral and vaginal openings, there is a
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. Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities are 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 New Zealand American psychologist
John Money and other influential psychologists and physicians to conclude that gender identity was (1) unrelated to chromosomes, (2) primarily a result of social learning, and (3) could not be easily changed after infancy. The first questions about assignment were raised in the early 1980s when Money and others reported an unexpectedly high rate of failure to achieve expected adult sexual relationships (i.e., heterosexual orientation, marriage, and children) in grown women with CAH (though all had female gender identities). However, the sample was small, and results seemed interpretable in many ways:
selection bias, early hormone effects on orientation, or
sexual dysfunction created by residual body abnormalities or by the genital surgery itself. From a perspective two decades later, the report was one of the first pieces of evidence that the standard management paradigm was not always producing hoped-for outcomes. Despite these concerns, no significant opposition to standard management arose until the mid-1990s, when a confluence of evidence and opinion from several sources led to a re-examination of outcomes. Several
intersex support and advocacy groups (e.g., the
Intersex Society of North America) began to publicly criticize infant genital surgery based on unsatisfactory outcomes of some adults who had been operated on as infants. Their complaints were that they had a reduced ability to enjoy sexual relations or that they resented not having had the choice of gender assignment or surgical reconstruction left until they were old enough to participate. In 1997, influential articles by Reiner,
Diamond, and Sigmundson advocated
consideration of (1) male sex assignment in the unambiguously male XX infants (most of whom are considered male until the CAH is recognized at 1–2 weeks of age), and (2) delaying reconstructive surgery until the patient is old enough to participate in the decision.
Late onset (nonclassical) CAH In the milder,
nonclassical form of CAH, the
androgen excess is subtle enough that
virilization is not apparent or goes unrecognized at birth and in early childhood. However, androgen levels are above normal and slowly rise during childhood, producing noticeable effects between 2 and 9 years of age. The appearance of
pubic hair in mid-childhood is the most common feature that leads to evaluation and diagnosis of the
late onset (nonclassical) CAH. Other accompanying features are likely to be tall stature and accelerated
bone age (often 3–5 years ahead). Often present are increased muscle mass,
acne, and adult
body odor. In boys, the
penis will be enlarged. Mild
clitoral enlargement may occur in girls, and sometimes a degree of prenatal virilization is recognized that may have gone unnoticed in infancy. The principal goals of treatment of nonclassical CAH are to preserve as much growth as possible and to prevent central
precocious puberty if it has not already been triggered. These are more difficult challenges than in CAH detected in infancy because moderate levels of
androgens will have had several years to advance bone maturation and to trigger central
puberty before the disease is detected. Elevated 17OHP may activate the androgen "backdoor" pathway, that leads to an excess of
5α-dihydrotestosterone and other potent androgens. The mainstay of treatment for symptoms of hyperandrogenism is suppression of androgens of adrenal origin by a
glucocorticoid such as
hydrocortisone. Mineralocorticoid is only added in cases where the plasma
renin activity is high. The exact degree of cortisol synthesis impairment depends on the genotype. As outlined above, recent additions to treatment to preserve growth include
aromatase inhibition to slow bone maturation by reducing the amount of testosterone converted to
estradiol, and the use of blockers of estrogen for the same purpose. Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness or injury. Many variants of the
CYP21A2 gene result in various degrees of hyperandrogenism, some of which may be so mild that they may not even cause problems in males and may not be recognized until adolescence or later in females. Mild androgen effects in young women may include
hirsutism, acne, or
anovulation (which in turn can cause
infertility). Testosterone levels in these women may be mildly elevated, or simply above average. Despite the prevailing notion that
testosterone and
5α-dihydrotestosterone (DHT) are the primary human androgens, this notion only applies to healthy men. Although testosterone has been traditionally used as a biomarker of hyperandrogenism, it correlates poorly with clinical measurements of androgen excess. It may be that
11-ketotestosterone is the main androgen in women since it circulates at a similar level to testosterone and may or may not decline with age as testosterone does. While
11-ketodihydrotestosterone (11KDHT) is equipotent to DHT, circulating levels of 11KDHT are lower than DHT. These clinical features are those of
polycystic ovary syndrome (PCOS), and a small percentage of women with PCOS are found to have late-onset CAH when investigated. Late-onset CAH is often misdiagnosed as PCOS. Late-onset CAH is often diagnosed in the context of infertility assessment in women. Diagnosis of late-onset CAH may be suspected from a high 17OHP level, but some cases are so mild that the elevation is only demonstrable after
cosyntropin stimulation. Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation. During the follicular phase of the menstrual cycle,
progesterone accumulates along with
17OHP which can thin the endometrium and change cervical mucus like the effect of
progestogen contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or
amenorrhea Abnormal endometrial development leads to decreased uterine receptivity, which also contributes to infertility. Once attempting to conceive, most women with late-onset CAH will become pregnant within a year with or without treatment, but they have an increased risk of miscarriage. but the association with mild 21-hydroxylase deficiency called nonclassical 21-hydroxylase deficiency, which is characterized by diverse hyperandrogenic symptoms appearing postnatally in males and females, was first described in 1979 by
Maria New. New since then have studied ways to reduce androgen excess and found out that treatment with
dexamethasone 0.25 mg orally every evening reversed acne and irregular menstruation in 3 months, but hirsutism required up to 30 months. Dexamethasone has glucocorticoid activity, and potent
ACTH-suppression properties within the
hypothalamic–pituitary–adrenal axis. Lower ACTH leads to reduced production of all the steroids, including androgens. According to 2018 Clinical Practice Guideline, glucocorticoid treatment is not recommended in asymptomatic individuals, however, if the symptoms of androgen excess are sufficient, dexamethasone treatment may be prescribed. ==Genetics==