Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) is a genetic disorder characterized by impaired production of cortisol in the adrenal glands.
83-568: 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
166-610: A heme cofactor binding loop. Each subunit in the human enzyme consists of a total of 13 α-helices and 9 β-strands that folds into a triangular prism-like tertiary structure . The iron(III) heme group that defines the active site resides in the center of each subunit. The human enzyme binds one substrate at a time. In contrast, the well-characterized bovine enzyme can bind two substrates. The human and bovine enzyme share 80% amino acid sequence identity, but are structurally different, particularly in loop regions, and also evident in secondary structure elements. Variations of
249-406: A pediatric urologist for a reconstructive vaginoplasty and clitoral reduction or recession—surgery to create or enlarge a vaginal opening and reduce the size or protrusion of the clitoris. This approach was designed to preserve fertility for both sexes and remains the standard management, but two aspects of this management have been challenged: assignment of completely virilized genetic females and
332-668: A 25% chance of having the disease, a 50% chance of being a carrier like the parents, and a 25% chance of having two normal genes. It is possible to test for heterozygosity by measuring 17OHP elevation after ACTH stimulation. More than 200 disease-causing variants within the CYP21A2 gene have been identified so far that lead to 21-hydroxylase deficiency. Most patients have at least two of these variants present as compound heterozygous . There are some mild disease-causing variants that seem to exert dominant negative effects on enzymatic activity, even if present as single heterozygous. One example
415-452: A backdoor pathway and 11-oxygenated androgens. 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. Unlike testosterone and androstenedione, 11-oxygenated androgens are not known to be aromatized to estrogens in
498-654: A certain disease or condition. If the primers are not designed carefully, they may bind to both the CYP21A2 and the CYP21A1P pseudogene, or to different segments of the RCCX cluster, resulting in false-positive or false-negative results. Therefore, PCR for the CYP21A2 requires the use of locus-specific primers that can distinguish between the gene and the pseudogene, and between different RCCX modules. Moreover, PCR may not be able to detect complex variants such as large gene conversions , deletions , or duplications , which are frequent in
581-658: 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
664-440: A disturbance in the development of the enzyme, leading to congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Gene conversion events involving the functional gene and the pseudogene account for many cases of steroid 21-hydroxylase deficiency. CAH is an autosomal recessive disorder . There are multiple forms of CAH, defined as classical and nonclassical forms based on the amount of enzyme function still present in
747-494: 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
830-486: A manner similar to the effect of progestogen contraceptives, interferes with the normal menstrual cycle, which can lead to oligomenorrhea or amenorrhea and impairs sperm penetration. 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. Late onset CAH
913-533: A module count is two or more, there is only one copy of each functional gene rest being non-coding pseudogenes with the exception of the C4 gene which always has active copies. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene and the complexity of the RCCX locus, it is difficult to perform molecular diagnostics for CYP21A2 . The pseudogene can have single-nucleotide polymorphisms (SNP) that are identical or similar to those in
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#1732863286265996-470: A product of a reaction catalyzed by CYP21, as their primary glucocorticoid hormone with mineralocorticoid properties. This suggests the presence of a complex and highly specific corticosteroid signaling pathway that emerged at least half a billion years ago during early vertebrate evolution. In vertebrates, such as fish, amphibians, reptiles, birds, and mammals, Cyp21 participates in the biosynthesis of glucocorticoids and mineralocorticoids, therefore, Cyp21
1079-409: A span of approximately 24 hours. 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
1162-542: Is a member of the cytochrome P450 family of monooxygenase enzymes, the protein has 494 amino acid residues with a molecular weight of 55,000. This enzyme is at most 28% homologous to other P-450 enzymes that have been studied. Structurally, the protein contains an evolutionarily conserved core of four α-helix bundles (the importance of such genetic conservation is in demonstrating the functional importance of this aspect of this protein's structure). In addition, it has two additional alpha helices, two sets of β-sheets , and
1245-513: Is a point mutation in exon 7 of CYP21A2 , (p.V281L), which is commonly found in LOCAH-associated alleles. Carriers for this mutation retain 20%–50% of 21-hydroxylase activity, but are at higher risk of symptoms of androgen excess than carriers of the severe mutations, and had higher adrenocorticotropic hormone (ACTH) stimulated 17OHP, suggesting that the mutant protein V281L enzyme co-expressed with
1328-478: Is almost exclusively expressed in the adrenal gland. As of 2023, the main subcellular location for the encoded protein in human cells is not known, and is pending cell analysis. The enzyme, steroid 21-hydroxylase hydroxylates steroids at the C21 position. Steroids are a group of naturally occurring and synthetically produced organic compounds, steroids all share a four ring primary structure. The enzyme catalyzes
1411-400: Is approximately 1.3 x 10 M s at 37 °C. This makes it the most catalytically efficient P450 enzyme of those reported to date, and catalytically more efficient than the closely related bovine steroid 21-hydroxylase enzyme. C-H bond breaking to create a primary carbon radical is thought to be the rate-limiting step in the hydroxylation. Genetic variants in the CYP21A2 gene cause
1494-560: Is associated with mild and clinically silent cortisol impairment, but an excess of androgens post-puberty. Non-classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (NCCAH) is a milder and late-onset congenital adrenal hyperplasia. Its prevalence rate in different ethnic groups varies from 1 in 1000 to 1 in 50 . Some people affected by the condition have no relevant signs and symptoms, while others experience symptoms of hyperandrogenism . Women with NCCAH usually have normal female genitalia at birth. In later life,
1577-634: 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
1660-415: 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
1743-422: Is essential for the biosynthesis of cortisol and aldosterone . Steroid 21-hydroxylase is a cytochrome P450 enzyme that is notable for its substrate specificity and relatively high catalytic efficiency . Like other cytochrome P450 enzymes, steroid 21-hydroxylase participates in the cytochrome P450 catalytic cycle and engages in one-electron transfer with NADPH - P450 reductase . Steroid 21-hydroxylase
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#17328632862651826-453: Is essential for the regulation of stress response, electrolyte balance and blood pressure, immune system, and metabolism in vertebrates. Cyp21 is relatively conserved among mammals, and shows some variations in its structure, expression, and regulation. Rhesus macaques and orangutans possess two copies of Cyp21 , while chimpanzees have three, still, a pseudogene ( CYP21A1P ) is only present in humans among primates. Steroid 21-hydroxylase
1909-448: 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. CAH can occur in various forms. The clinical presentation of each form
1992-410: Is highly specific for hydroxylation of progesterone and 17-hydroxyprogesterone. This is in marked contrast to the evolutionarily and functionally related P450 enzyme 17-hydroxylase , which has a broad range of substrates. The chemical reaction in which steroid 21-hydroxylase catalyzes the addition of hydroxyl (-OH) to the C21 position of progesterone , 17α-hydroxyprogesterone and 21-desoxycortisone
2075-545: 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
2158-478: Is localized in microsomes of endoplasmic reticulum membranes within adrenal cortex . It is one of three microsomal steroidogenic cytochrome P450 enzymes, the others being steroid 17-hydroxylase and aromatase . Unlike other enzymes of the cytochrome P450 superfamily of enzymes that are expressed in multiple tissues, with most abundant expression in the liver, in adult humans steroid 21-hydroxylase, along with steroid 11β-hydroxylase and aldosterone synthase ,
2241-444: 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
2324-433: 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
2407-512: 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
2490-597: 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
2573-569: 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. Most patients that have the nonclassic form do not require any glucocorticoid replacement therapy, as cortisol synthesis impairment is mild but clinically silent. Patients usually have the same baseline but lower peak cortisol levels comparing to healthy controls. The exact degree of cortisol synthesis impairment depends on genotype. An important aspect of management of nonclassic CAH
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - Misplaced Pages Continue
2656-561: Is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the testes are pubertal in size, or that androgens of adrenal origin remain elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by leuprolide . As outlined above, recent additions to treatment to preserve growth include aromatase inhibition to slow bone maturation by reducing
2739-504: Is the most complex gene cluster in the human genome. The number of RCCX segments varies between one and four in a chromosome , with the prevalence of approximately 15% for monomodular, 75% for bimodular ( STK19-C4A-CYP21A1P-TNXA-STK19B-C4B-CYP21A2-TNXB ), and 10% for trimodular in Europeans. The quadrimodular structure of the RCCX unit is very rare. In a monomodular structure, all of the genes are functional i.e. protein-coding , but if
2822-442: Is unable to detect the junction sites of chimeras. The CYP21A2 gene is prone to mismatch and rearrangement, producing different types of complex variations that include copy number variants , large gene conversions , small insertions / deletions , and single-nucleotide (SNP) variants. Southern blotting is not capable of detecting all these types of variants simultaneously. Besides that, southern blotting requires genetic analysis of
2905-584: 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
2988-562: The Tenascin X gene TNXB and STK19 . MHC class III is the most gene-dense region of the human genome, containing many genes that have, as of 2023 - unknown functions or structures. Inside the MHC class III , CYP21A2 is located within the RCCX cluster (an abbreviation composed of the names of the genes RP (a former name for STK19 serine/threonine kinase 19), C4 , CYP21 and TNX ), which
3071-424: The chemical reaction in which the hydroxyl group (-OH) is added at the C21 position of the steroid biomolecule . This location is on a side chain of the D ring. The enzyme is a member of the cytochrome P450 superfamily of monooxygenase enzymes. The cytochrome P450 enzymes catalyze many reactions involved in drug metabolism and synthesis of cholesterol , steroids and other lipids . Steroid 21-hydroxylase
3154-427: 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. Another treatment option is oral contraceptive pills. The CYP21A2 gene for
3237-835: 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
3320-581: The mouse genome , the Cyp21a2 is a pseudogene and the Cyp21a1 is a functional gene. In the chicken and quail , there is only a single Cyp21 gene, which locus is located between complement component C4 and TNX gene, along with Cenpa . CYP21A2 in humans is located in chromosome 6 , in the major histocompatibility complex III (MHC class III) close to the Complement component 4 genes C4A and C4B ,
3403-495: The 5′ region of the CYP21A2 gene, but also all of the C4B gene and 3′ regions of the CYP21A1P pseudogene. Duplications of CYP21A1P pseudogene and C4B gene are often associated with nonclassic 21-hydroxylase deficiency. Due to the high degree of homology between the CYP21A2 gene and the CYP21A1P pseudogene, and the complexity of the locus, research on the molecular level is difficult. Differences in residual enzyme activity of
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency - Misplaced Pages Continue
3486-593: The P450c21 enzyme (also known as 21-hydroxylase ) is at 6p21.3, amid genes HLA B and HLA DR coding for the major human histocompatibility loci ( HLA ). The protein-coding CYP21A2 gene may be accompanied with one or several copies of the nonfunctional pseudogene CYP21A1P . Scores of abnormal alleles of CYP21A2 have been documented, most arising from recombinations of homologous regions of CYP21A2 and CYP21A1P . The 21-hydroxylase deficiency may be caused by macrodeletions of about 30 Kb, which includes not only most of
3569-483: 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
3652-696: 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
3735-410: 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
3818-493: The case of the CYP21A2 . Southern blotting , a method used for detecting and quantifying a specific DNA sequence in DNA samples, also has limitations in analyzing CYP21A2 . This method is time-consuming and requires a large amount of good-quality DNA, which makes it less applicable in routine diagnostic settings. This method comes with a radioactive biohazard, which poses safety concerns and makes it labor-intensive. Southern blotting
3901-456: The chromosome 6p21.3. That's why CYP21A2 genotyping, interpretation of the results, and adequate genetic counseling for patients and their families requires deep understanding of CYP21A2 genetics. CYP21A2 Steroid 21-hydroxylase is a protein that in humans is encoded by the CYP21A2 gene . The protein is an enzyme that hydroxylates steroids at the C21 position on the molecule. Naming conventions for enzymes are based on
3984-408: 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
4067-513: The disease is detected. A diagnosis of nonclassical CAH is usually confirmed by discovering extreme elevations of 17OHP along with moderately high testosterone levels. A cosyntropin stimulation test may be needed in mild cases, but usually the random levels of 17OHP are high enough to confirm the diagnosis. Elevated 17OHP may activate androgen "backdoor" pathway, that leads to excess of 5α-dihydrotestosterone and other potent androgens. The mainstay of treatment for symptoms of hyperandrogenism
4150-425: 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. Excessive levels of androgens of adrenal origin have little effect on the genitals of male infants with classical CAH. If
4233-412: 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
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#17328632862654316-577: 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
4399-555: The enzyme may cause congenital adrenal hyperplasia . Steroid 21-hydroxylase is a member of the cytochrome P450 family of monooxygenase enzymes that use an iron-containing heme cofactor to oxidize substrates. In humans, the enzyme is localized in endoplasmic reticulum membranes of cells in adrenal cortex , and is encoded by the CYP21A2 gene which is located near the CYP21A1P pseudogene that has high degree of sequence similarity. This similarity makes it difficult to analyze
4482-629: 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
4565-426: 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,
4648-520: The functional gene, making it difficult to distinguish between them. The pseudogene can also recombine with the functional gene, creating hybrid genes that have features of both. This can result in false-positive or false-negative results when testing for SNPs in the CYP21A2 . The whole genome sequencing technology relies on breaking the DNA into small fragments, sequencing them, and then assembling them back together based on their overlaps. However, because of
4731-456: The gene at the molecular level, and sometimes leads to loss-of-function mutations of the gene due to intergenic exchange of DNA . 4Y8W ,%%s 2GEG 1589 13079 ENSG00000235134 ENSMUSG00000024365 P08686 Q08AG9 P03940 NM_000500 NM_001128590 NM_009995 NP_001122062.3 NP_034125 Steroid 21-hydroxylase in humans is encoded by the CYP21A2 gene that may be accompanied by one or several copies of
4814-456: 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.,
4897-429: The high homology and variability of the CYP21A2 and its pseudogene, the fragments cannot be mapped unambiguously to either copy of the gene. This can lead to errors or gaps in the assembly, or missing some variants that are present in the gene. Polymerase chain reaction (PCR) molecular diagnostics uses selective primers to amplify specific segments of the DNA sequence that are relevant for diagnosing or detecting
4980-419: The human body. 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
5063-418: 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
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#17328632862655146-1009: 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
5229-470: 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
5312-423: The nonfunctional pseudogene CYP21A1P , this pseudogene shares 98% of the exonic informational identity with the actual functional gene. Pseudogenes are common in genomes, and they originate as artifacts during the duplication process. Though often thought of as "junk DNA", research has shown that retaining these faulty copies can have a beneficial role, often providing regulation of their parent genes. In
5395-467: The parents, which is not always feasible or practical. Therefore, to analyze the CYP21A2 gene accurately, a more specialized and sensitive method is needed, such as targeted long-read sequencing , which can sequence longer DNA fragments and capture more information about the gene structure and variation. However, this method is not widely available or affordable for clinical use. Steroid 21-hydroxylase,
5478-537: The patient. The classical forms occur in approximately 1 in 10 000 to 1 in 20 000 births globally, and includes both the salt-wasting (excessive excretion of sodium via the urine causing hyponatremia and dehydration) and simple-virilizing forms. Complete loss of enzymatic activity causes the salt-wasting form. Variations in the structure of steroid 21-hydroxylase are related to the clinical severity of congenital adrenal hyperplasia. Cortisol and aldosterone deficits are associated with life-threatening sodium loss, as
5561-410: 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
5644-493: 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
5727-503: 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. While testosterone levels can appear normal, ignoring the alternative androgen pathways may lead to diagnostic errors since hyperandrogenism may be caused by potent androgens such as DHT produced by
5810-400: 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
5893-513: The signs and symptoms of the condition may include acne , hirsutism , male-pattern baldness, irregular menstruation, and infertility. Fewer studies have been published about males with NCCAH comparing to those about females, because males are generally asymptomatic. Males, however, may present with acne and early balding. While symptoms are usually diagnosed after puberty, children may present with premature adrenarche . Hyperkalemia Too Many Requests If you report this error to
5976-541: 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
6059-503: The steroid 21-hydroxylase can be found in all vertebrates . Cyp21 first emerged in chordates before the speciation between basal chordates and vertebrates. The sea lamprey , an early jawless fish species that originated over 500 million years ago, provides valuable insights into the evolution and emergence of Cyp21 . Sea lampreys lack the 11β-hydroxylase enzyme responsible for converting 11-deoxycortisol to cortisol as observed in mammals. Instead, they rely on 11-deoxycortisol,
6142-413: The steroids play roles in regulating sodium homeostasis . Simple-virilizing CAH patients (~1-2% enzyme function) maintain adequate sodium homeostasis, but exhibit other symptoms shared by the salt-wasting form, including accelerated growth in childhood and ambiguous genitalia in female neonates . The nonclassical form is the mildest condition, retaining about 20% to 50% of enzyme function. This form
6225-530: The substrate acted upon and the chemical process performed. Biochemically, this enzyme is involved in the biosynthesis of the adrenal gland hormones aldosterone and cortisol , which are important in blood pressure regulation , sodium homeostasis and blood sugar control . The enzyme converts progesterone and 17α-hydroxyprogesterone into 11-deoxycorticosterone and 11-deoxycortisol , respectively, within metabolic pathways which in humans ultimately lead to aldosterone and cortisol creation—deficiency in
6308-495: 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. Although the standard management approach remains "standard", more time and consideration are being given in many cases to explaining alternatives to parents and a small number of XX children with unambiguously male external genitalia are again being raised as boys. In
6391-546: The value and age of corrective surgery. 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
6474-474: The various alleles account for the various degrees of severity of the disease. Inheritance of all forms of 21-hydroxylase CAH is autosomal recessive , except some mild disease-causing variants such as p.V281L that seem to exert dominant negative effects on enzymatic activity. Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually heterozygotes (or carriers ). When both parents carry an abnormal allele, each child has
6557-451: The wild-type (healthy) enzyme resulted in an apparent dominant negative effect on the enzymatic activity. There is a good correlation between the genotype and phenotype. As a result, the CYP21A2 genotyping has high diagnostic value. However, the genotyping of the CYP21A2 gene is prone to errors, especially due to the closely located and highly homologous pseudogene CYP21A1P and the complex duplications, deletions and rearrangements within
6640-413: 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
6723-490: 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 −
6806-434: Was first described in 1952. Studies of the human enzyme expressed in yeast initially classified 17-hydroxyprogesterone as the preferred substrate for steroid 21-hydroxylase, however, later analysis of the purified human enzyme found a lower K M and greater catalytic efficiency for progesterone over 17-hydroxyprogesterone. The catalytic efficiency of steroid 21-hydroxylase for conversion of progesterone in humans
6889-652: Was originally characterized in 1957 by French biochemist Jacques Decourt, 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
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