Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.
The condition is classified as an inherited metabolic disorder. CAH is an autosomal recessive condition since it results from inheriting two copies of the faulty CYP21A2 gene responsible for 21-hydroxylase enzyme deficiency. The most common forms of CAH are: classical form, usually diagnosed at birth, and nonclassical, late onset form, typically diagnosed during childhood or adolescence, although it can also be identified in adulthood when seeking medical help for fertility concerns or other related issues, such as PMOS or menstrual irregularities. Carriers for the alleles of the nonclassical forms may have no symptoms, such form of CAH is sometimes called cryptic form. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency in all its forms accounts for over 95% of diagnosed cases of all types of congenital adrenal hyperplasia. Unless another specific enzyme is mentioned, CAH in most contexts refers to 21-hydroxylase deficiency. CAH is one of the most common autosomal recessive genetic diseases in humans.
Due to the loss of 21-hydroxylase function, patients are unable to efficiently synthesize cortisol. As a result, ACTH (adrenocorticotropic hormone) levels increase, leading to adrenocortical hyperplasia and overproduction of cortisol precursors, which are used in the synthesis of sex steroids, which can lead to signs of androgen excess, including ambiguous genitalia in newborn girls and rapid postnatal growth in both sexes. In severe cases of CAH in females, surgical reconstruction may be considered to create more female-appearing external genitalia. However, there is ongoing debate regarding the timing and necessity of surgery. The way CAH affects the organism is complicated, and not everyone who has it will show signs or have symptoms. Individuals with CAH may face challenges related to growth impairment during childhood and fertility issues during adulthood. Psychosocial aspects such as gender identity development and mental health should also be taken into consideration when managing individuals with CAH. Overall prognosis for individuals with appropriate medical care is good; however, lifelong management under specialized care is required to ensure optimal outcomes.
Treatment for CAH involves hormone replacement therapy to provide adequate levels of glucocorticoids and mineralocorticoids. Regular monitoring is necessary to optimize hormone balance and minimize potential complications associated with long-term glucocorticoid exposure.
Presentation 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.
Salt-wasting crises in infancy Excessive levels of androgens of adrenal origin have little effect on the genitals of male infants with classical CAH. If a male infant with CAH goes undetected during newborn screening, he will exhibit normal health and physical appearance upon examination, leading to his timely discharge from the hospital.
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. The blood pressure may be abnormally low. Basic laboratory analyses will indicate low levels of sodium (hyponatremia), typically falling between 105 and 125 mEq/L Na+ in serum samples. These infants may also experience severe hyperkalemia with potassium (K+) levels exceeding 10 mEq/L, along with significant metabolic acidosis. Hypoglycemia (low blood sugar) might also be observed. This collection of manifestations is referred to as a "salt-wasting crisis" which poses an imminent risk of fatal consequences if left untreated.
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 CAH is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.
Production of cortisol begins at week 8 of fetal life.
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. Impaired steroid hydroxylation at the C-21 position in congenital adrenal hyperplasia, accompanied by excessive amounts of 17OHP that leads to virilism, was described as early as 1953.
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. Other androgens may be additionally produced from 17OHP, due to its elevated levels, that leads, among other things, to its 5α-reduction. 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, visibly 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 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 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