Врожденная гиперплазия надпочечников при дефиците 21-гидроксилазы: классификация, диагностика и клинические проявления.

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. 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. Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent hyperplasia of the adrenal cortex and elevation of ACTH levels. ACTH stimulates uptake of cholesterol and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17α hydroxypregnenolone, and especially 17OHP accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10 1000 times the normal concentration. Since 21 hydroxylase activity is not involved in synthesis of androgens, a substantial fraction of the large amounts of 17α hydroxypregnenolone is diverted to synthesis of DHEA, androstenedione, and other androgens of adrenal origin beginning in the third month of fetal life in both sexes. Synthesis of aldosterone is also dependent on 21 hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the placental connection allows maternal blood to "dialyze" the fetus and maintain both electrolyte balance and blood volume.

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 presents or absents, respectively. This subtyping is often not clinically meaningful, because all patients with classical form lose salt to some degree, and clinical presentations may overlap.

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 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. 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.

CAH 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 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.

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, 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.

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.

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. 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. The first questions about assignment were raised in the early 1980s when Money and others reported an unexpectedly high rate of failure to achieve normal 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 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.

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. 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 androgen "backdoor" pathway, that leads to excess of 5α dihydrotestosterone and other potent androgens. The mainstay of treatment of symptomos 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 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 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. Various variants of the CYP21A2 gene result various degrees of hyperandrogenism, some of which may be such a 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 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 in a manner similar to 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.

Conditions justifying newborn screening for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire consequence if not diagnosed early, (3) an effective treatment if diagnosed, and (4) a frequency in the population high enough to justify the expense. In the last decade more states and countries are adopting newborn screening for salt wasting CAH due to 21 hydroxylase deficiency, which leads to death in the first month of life if not recognized. For the newborn screening, levels of 17α hydroxyprogesterone (17OHP) are typically measured against predetermined cutoff, which depends on the measurement method. This is a higher rate of false positives than the screening tests for many other congenital metabolic diseases. When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. Since most infants with salt wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate. Levels of 17OHP, androstenedione, and cortisol may play a role in screening.

While 17OHP with or without ACTH stimulation is the main marker for 21 hydroxylase deficiency, other markers have been proposed, with various degrees of acceptance: However, it is not elevated in preterm infants or in other forms of congenital adrenal hyperplasia. Unlike 17OHP, 21 deoxycortisol is not produced in the gonads and is uniquely adrenal derived. Still, 21 deoxycortisol can be a key screening marker for 21 hydroxylase deficiency in newborn screening. 21 Deoxycorticosterone, also known as 11β hydroxyprogesterone (11β OHP), have been proposed as a marker in 1987. A study in 2017 has shown that in subjects with 21 hydroxylase deficiency, serum 11β OHP concentrations range from 0.012 to 3.37 ng/mL, while in control group it was below detection limit of 0.012 ng/mL. This marker did not gain acceptance due to the fact that the test for the levels of this steroid is not routinely offered by diagnostic laboratories. Progesterone levels are higher in CAH subjects. A study has revealed that serum progesterone concentrations in boys (10 days to 18 years old) with 21 hydroxylase deficiency reached levels up to 10.14 ng/mL, i. e. similar to female luteal values, while in the control group of boys average level was 0.07 ng/mL (0.22 nmol/L), with values ranging from 0.05 to 0.40 ng/mL. Cortisol is one of the two main final products of 21 hydroxylase, and the deficiency of this enzyme may lead to a certain degree of cortisol deficiency. Cortisol levels are lower in CAH subjects, on average, The selectivity offered by liquid chromatography tandem mass spectrometry (LC MS/MS) has largely overcome these limitations. As a result, the use of LC MS/MS instead of immunoassays in cortisol measurement aims to provide greater specificity. 11 Deoxycortisol is a direct product of 17α hydroxyprogesterone, with 21 hydroxylase catalyzing the reaction, and an intermediate product towards cortisol pathway. Reduced 21 hydroxylase activity leads to decreased levels of 11 deoxycortisol, but not all laboratories specify minimum reference value it, since it is mostly used as a biomarker for 11β hydroxylase deficiency, where 11 deoxycortisol levels increase dramatically, so the laboratories may only specify the maximum reference value. The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks. Theoretically, if enough glucocorticoid could be supplied to the fetus to reduce adrenal androgen biosynthesis by the 9th week, virilization could be prevented and the difficult decision about timing of surgery avoided. The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother. The first problem has not yet been entirely solved, but it has been shown that if dexamethasone is taken by a pregnant woman, enough can cross the placenta to suppress fetal adrenal function. At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl. Whether the fetus is an affected girl can be determined by chorionic villus sampling at 9–11 weeks of gestation, or by amniocentesis at 15–18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal DNA is analyzed to see if she carries one of the known abnormal alleles of the CYP21 gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1 mg daily. Administration of pre natal dexamethasone has been the subject of controversy over issues of informed consent and because treatment must predate a clinical diagnosis of CAH in the female fetus, especially because in utero dexamethasone may cause metabolic problems that are not evident until later in life; Swedish clinics ceased recruitment for research in 2010. The treatment has also raised concerns in LGBT and bioethics communities following publication of an essay posted to the forum of the Hastings Center, and research in the Journal of Bioethical Inquiry, which found that pre natal treatment of female fetuses was suggested to prevent those fetuses from becoming lesbians after birth, may make them more likely to engage in "traditionally" female identified behaviour and careers, and more interested in bearing and raising children. Citing a known attempt by a man using his knowledge of the fraternal birth order effect to avoid having a homosexual son by using a surrogate, the essayists (Professor Alice Dreger of Northwestern University's Feinberg School of Medicine, Professor Ellen Feder of American University and attorney Anne Tamar Mattis) suggest that prenatal dexamethasone treatments constitute the first known attempt to use in utero protocols to reduce the incidence of homosexuality and bisexuality in humans. Since CAH is a recessive gene, both the mother and father must be recessive carriers of CAH for a child to have CAH. Due to advances in modern medicine, those couples with the recessive CAH genes have an option to prevent CAH in their offspring through preimplantation genetic diagnosis (PGD). In PGD, the egg is fertilized outside the woman's body in a Petri dish (IVF). On the 3rd day, when the embryo has developed from one cell to about 4 to 6 cells, one of those cells is removed from the embryo without harming the embryo. The embryo continues to grow until day 5 when it is either frozen or implanted into the mother. Meanwhile, the removed cell is analyzed to determine if the embryo has CAH. If the embryo is determined to have CAH, the parents may make a decision as to whether they wish to have it implanted in the mother or not. Meta analysis of the studies supporting the use of dexamethasone on CAH at risk fetuses found "less than one half of one percent of published 'studies' of this intervention were regarded as being of high enough quality to provide meaningful data for a meta analysis. Even these four studies were of low quality  in ways so slipshod as to breach professional standards of medical ethics" and "there were no data on long term follow up of physical and metabolic outcomes in children exposed to dexamethasone".

Even after diagnosis and initiation of treatment, a small percentage of children and adults with infancy or childhood onset CAH die of adrenal crisis. To prevent this, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of hydrocortisone (e. g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.

It is unclear what concentration of adrenal androgens is best for normal growth, puberty, and bone health. One of the challenging aspects of long term management is optimizing growth so that a child with CAH achieves his or her height potential because both undertreatment and overtreatment can reduce growth or the remaining time for growth. While glucocorticoids are essential for health, dosing is always a matter of approximation. In even mildly excessive amounts, glucocorticoids slow growth. On the other hand, adrenal androgens are readily converted to estradiol, which accelerates bone maturation and can lead to early epiphyseal closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone. As a consequence, average height losses of about 4 inches (10 cm) have been reported with traditional management. In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as flutamide and by reducing the conversion of testosterone to estradiol. This conversion is mediated by aromatase and can be inhibited by aromatase blockers such as testolactone. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment to enhance growth.

The outcomes and prognosis for CAH (Congenital Adrenal Hyperplasia) can vary depending on several factors, such as the specific type of CAH, its severity, early detection, and proper management. With appropriate medical care and ongoing treatment, individuals with CAH can lead healthy lives. Consistent monitoring and adherence to treatment are crucial for optimal outcomes. The incidence of nonclassical forms of CAH is 1:200 to 1:1000 based on various estimates, and is also higher in groups people with a high rate of marriage between relatives, up to 1:50. Nonclassic CAH may be identified incidentally during the assessment of oligomenorrhea, amenorrhea, and infertility in females. However, a significant proportion, approximately 90%, of women with nonclassic CAH remain undiagnosed. As for men with nonclassic CAH, their asymptomatic nature commonly leads to underdiagnosis. However, significant strides in understanding and treating the condition have been made over the years. In the early 20th Century, numerous adrenal steroids were isolated, and bioassays eventually distinguished glucocorticoids, mineralocorticoids, and androgens. In 1957, Alfred Bongiovanni noticed a defect in 21 hydroxylation in CAH, followed by defects in 3β hydroxysteroid dehydrogenase and 11β hydroxylase. Discussions around intersex conditions have evolved over time as societal understanding has progressed. There is consensus that classical CAH is an intersex condition. However, for the nonclassical CAH, there is a debate on whether it can be considered an intersex condition. Anne Fausto Sterling, an American sexologist, in a 2000 book "Sexing the Body" came up with an estimate that people with intersex conditions account for 1.7% of the general population. This estimate is cited by a number of prominent intersex advocacy organizations. Of these intersex individuals, according to Fausto Sterling, 88% have nonclassical CAH. Including nonclassical CAH in intersex prevalence estimates has been cited by Joel Best, is a professor of sociology and criminal justice, in a 2013 book "Stat Spotting: A Field Guide to Identifying Dubious Data" as an example of misleading statistical practice. Different cultural contexts may shape views on gender identity, sexuality, and medical interventions for intersex conditions. Individuals with visible differences or unique health needs associated with CAH may face social stigmatization due to a lack of awareness, prejudice, or preconceived notions about intersexuality. Activists, such as Hida Viloria, who was born with a form of CAH, advocate for compassionate care for people born intersex.

Gene therapy is an experimental therapeutic approach that aims to correct the underlying genetic defect responsible for a particular condition. In the context of CAH, caused by mutations in the CYP21A2 gene, gene replacement therapy involves introducing a functional copy of this gene into the cells where this gene is expressed. The goal is to normalize the production of 21 hydroxylase, the enzyme encoded by CYP21A2. Providing a working copy of this gene may improve adrenal hormone synthesis and subsequently normalize cortisol and aldosterone production. Currently, gene replacement therapy for CAH is still at an early stage of research and development. Various approaches are being explored, including using viral vectors carrying a healthy copy of the CYP21A2 gene to deliver it into target cells. Another approach is based on utilizing human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) to generate steroid producing cells that can potentially replace or supplement dysfunctional adrenal tissue in individuals with CAH. However, it remains unclear how new approaches can be tested, as there are even no experimental models yet for this disease for gene therapy.