Medical condition
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.
It 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 PCOS or menstrual irregularities. Carriers for the alleles of the nonclassical forms may have no syptoms, 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, and different mutations related to enzyme impairment have been mapped on protein structures of the enzyme. It is one of the most common autosomal recessive genetic diseases in humans.
Due to loss of 21-hydroxylase function, patients are unable to efficiently synthesize cortisol. As a result, ACTH 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 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 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, 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 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.
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. Other androgens may be additionally produced from 17OHP, due to its elevated levels, that leads, inter alia, 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, 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.
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.
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 classica 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, To avoid long-term complications in male patients with CAH, regular ultrasound examination of the scrotum is recommended, especially in patients presenting with the most profound phenotypes of CAH and suboptimal endocrine regulation of the condition. 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 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. The complex issues encountered in appropriate sex assignment for severely virilized XX infants have contributed to a deeper understanding of gender identity and sexual orientation. Consequently, this matter remains an ongoing subject of debate within medical discourse.
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 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.
By the 1960s, CAH was well understood, karyotyping was routine, and standard management was to assign and raise all children with CAH according to their gonads and karyotypes, no matter how virilized. Markedly virilized girls were usually referred to a pediatric surgeon, often a pediatric urologist for a reconstructive vaginoplasty and clitoral reduction or recession—surgery to create or enlarge a vaginal opening