Congenital adrenal hyperplasia
1. Define congenital adrenal hyperplasia.
Congenital adrenal hyperplasia (CAH) is a group of several autosomal recessive disorders all involving a deficiency or relative defect in cortisol synthesis, aldosterone synthesis, or both resulting in some degree of cortisol deficiency, aldosterone deficiency, or both.
2. What enzyme defects can lead to CAH?
Defects in any of the six enzymes required for the synthesis of cortisol from cholesterol in the adrenal cortex can lead to CAH, including steroidogenic acute regulatory (StAR) protein, which is essential in transporting cholesterol to the mitochondria; 3β-hydroxysteroid dehydrogenase, which converts the Δ5-steroids (pregnenolone, 17-hydroxypregnenolone, DHEA) to the Δ4-steroids (progesterone, 17-hydroxyprogesterone, androstenedione); P450 side-chain cleavage (CYP11A1), which is responsible for cholesterol side-chain cleavage forming progesterone; and three hydroxylases, CYP17A1 (17α-hydroxylase), CYP21A2 (21-hydroxylase), and CYP11B1 (11β-hydroxylase).
3. Describe the functions of the three hydroxylases.
CYP17A1 (17α-hydroxylase) is essential in converting progesterone to 17-hydroxyprogesterone (17-OHP) and pregnenolone to 17-hydroxypregnenolone. This enzyme also includes a 17,20-lyase activity that converts 17-hyroxypregnenlone to dehydroepiandrosterone.
All of the enzyme defects leading to CAH are autosomal recessive disorders: therefore, both copies of the involved gene must be abnormal for the condition to occur.
5. What is the most common form of CAH?
By far the most common form is 21-hydroxylase (CYP21A2) deficiency, which accounts for 90% of cases and leads to deficiencies of the salt-retaining hormones DOC and aldosterone in both sexes and/or to virilization of genetic females. Both of these forms are considered “classic” CAH.
6. Which genes encode for 21-hydroxylase?
Two genes encode for 21-hydroxylase: CYP21A1 (pseudogene) and CYP21A2, both of which are located in a 35-kb region on the long arm of chromosome 6 (6p21.3). Both genes are downstream of the gene coding for complement factor 4 (C4A and C4B). CYP21A1 and CYP21A2 genes have 98% nucleotide sequence identity, but the former has accumulated several mutations that totally inactivate its gene product. CYP21A1 is thus an inactive pseudogene, whereas the CYP21A2 gene encodes for the active 21-hydroxylase enzyme.
7. What causes most of the genetic events responsible for CYP21A2 deficiencies?
Most of the genetic events responsible for CYP21A2 deficiencies result from the similarity between CYP21A1 and CYP21A2 and are due to two types of recombination events between CYP21A2 and the pseudogene. Seventy-five percent represent deleterious mutations found in the pseudogene that are transferred to CYP21A2 during mitosis; this process is termed “gene conversion.” Twenty percent are meiotic recombinations producing a nonfunctional chimeric pseudogene. More than 60 additional mutations account for the remaining 5%.
8. What determines the patient’s phenotype for 21-hydroxylase deficiency?
Clinical manifestations of the disease are related to the degree of cortisol deficiency, aldosterone deficiency, or both, and the accumulation of precursor hormones. More than 100 CYP21A2 mutations are known. The patient’s phenotype is generally based on the specific genetic alteration of the CYP21A2 gene, and phenotypes can be grouped into the following four categories:
9. What is the second most common cause of CAH?
The second most common cause of CAH (7% of all cases) is deficiency of the 11β-hydroxylase enzyme (CYP11B1), which is an autosomal recessive defect caused by a mutation on the short arm of chromosome 8 (8q24.3). The result of this deficiency is an increased level of DOC, which may cause hypertension through activation of the mineralocorticoid receptor, leading to sodium retention and hypokalemic alkalosis. The enzyme deficiency also results in increased production of androgens and their precursors, which cause ambiguous genitalia in genetic females.
10. Summarize the rarer forms of CAH.
The rarer forms of CAH are 17α-hydroxylase and 3β-hydroxysteroid dehydrogenase deficiencies. There have been fewer than 200 cases of 17α-hydroxylase deficiency, with 40 described mutations of CYP17 that span an 8.7-kb region on the short arm of chromosome 10 (10q24.3). The consequence of this deficiency is hypertension due to sodium retention and hypokalemia due to DOC excess (associated with suppression of renin and aldosterone) along with deficiency of androgens and androgen precursors, which causes pseudohermaphroditism in genetic males and delayed puberty in both sexes (see questions 16 and 21).
CAH is one of the most common inherited diseases. The most common form of CAH, 21-hydroxylase deficiency, has an incidence of 1:10,000 to 1:20,0000 births. The prevalence of this disorder varies greatly among different ethnic groups and is highest among the Ashkenazi Jewish population of Eastern Europe. Nonclassic 21-hydroxylase deficiency occurs in approximately 0.2% of the general Caucasian population but more frequently (1%-2%) in certain populations, such as the Eastern European Ashkenazi Jews.
12. What percentage of the population at large are heterozygote carriers of the 21-hydroxylase defect?
Less than 2% of the population at large is heterozygote carriers of the 21-hydroxylase defect—that is, abnormality of one of the two copies of the 21-hydroxylase gene. Such heterozygote carriers appear normal in all respects but may have elevated 17-OHP with adrenocorticotropic hormone (ACTH) stimulation testing.
13. How common is 11β-hydroxylase deficiency?
The 11β-hydroxylase deficiency, the second most frequent form of CAH, occurs in 1:100,000 births in the general population but in 1:5000 births in Jews of Moroccan descent. CAH due to defects of the other enzymes listed here is extremely rare.
14. Explain why adrenal hyperplasia develops.
The process of adrenal hyperplasia begins in utero. Reduced production of cortisol in the fetus, due to decreased activity of one of the enzymes needed for cortisol synthesis, results in lowered levels of serum cortisol. Cortisol normally acts through a negative feedback loop to inhibit the secretion of ACTH by the pituitary gland and corticotropin-releasing hormone (CRH) by the hypothalamus. Thus, the low serum cortisol levels that occur in a person with CAH increase the secretion of CRH and ACTH in an attempt to stimulate the adrenal glands to overcome the enzyme block and return the serum cortisol level to normal. As this process continues over time, the elevations of serum ACTH stimulate growth of the adrenal glands, leading to hyperplasia. It has been shown that the adrenal volume correlates positively with 17-OHP levels.
15. What is the most serious clinical consequence of CAH?
Adrenal crisis in the newborn period is the most serious consequence of CAH. It usually occurs with genetic defects that result in severe reductions in both aldosterone and cortisol. It is especially insidious in genetic males who do not have ambiguous genitalia as a clue to the diagnosis. Overall, about two thirds of patients with 21-hydroxylase deficiency have this salt-wasting form. These patients have decreased production of DOC and aldosterone but also have increased levels of progesterone and 17-OHP, which may act as mineralocorticoid antagonists, exacerbating the effects of aldosterone deficiency. Aldosterone deficiency leads to hypotension, volume depletion, hyponatremia, hyperkalemia, and increased renin activity. Cortisol deficiency contributes to poor cardiac function, poor vascular response to catecholamines, decreased glomerular filtration rate, and increased secretion of antidiuretic hormone. Both deficiencies lead to hyponatremia, dehydration, and shock.
16. What are other clinical consequences of CAH in females?
Many of the precursors and metabolites that build up behind the blocked enzymes (21-hydroxylase, 11β-hydroxylase, and 3β-hydroxysteroid dehydrogenase) are androgens. They may cause the following conditions:
Osteopenia in young adulthood in 45% of women with salt wasting.
Lower quality-of-life scores in patients with CAH than in age- and sex-matched controls.
17. What are other clinical consequences of CAH in males?
Newborn males with CAH due to deficiency of 21-hydroxylase or 11β-hydroxylase do not have ambiguous genitalia. Because of the typical normal physical appearance, it is often difficult to detect an affected male, especially when symptoms of salt wasting occur after the first week of life.
Later in childhood or early adulthood, males with CAH may present with the following features:
Variable and subtle hyperpigmentation
Advanced height in early childhood with ultimate short stature
Testicular enlargement due to adrenal rests, which may produce adrenal-specific hormones
Oligospermia and/or infertility
Lower quality-of-life scores than age- and sex-matched controls
18. Are patients with CAH at increased risk for cardiovascular disease?
Studies have shown that patients with CAH have higher body mass index (BMI), higher blood pressures, and more insulin resistance than age-matched controls. They also have endothelial dysfunction similar to that in other obese patients. Further studies are needed to determine whether they have higher rates of cardiovascular events but, given the increased risk factors, patients with CAH should receive lifestyle counseling at an early age.
19. How do patients with 17α-hydroxylase deficiency present?
In 17α-hydroxylase deficiency, the enzyme defect blocks synthesis of androgens, thus precluding masculinization or ambiguity of the external genitalia. Patients present at puberty with the following features:
Primary (or rarely, secondary) amenorrhea
Hypokalemia (because of increased mineralocorticoid production)
20. How do patients with nonclassic CAH present?
Patients with nonclassic CAH (also called late-onset CAH) produce normal amounts of cortisol and aldosterone at the expense of mild to moderate overproduction of sex hormone precursors. The prevalence of nonclassic CAH in women presenting with hyperandrogenic symptoms has been shown to be 2.2%. Thus, a follicular phase 17-OHP test should be included in the evaluation of any female patient with hyperandrogenic symptoms. Usually these patients are asymptomatic, with normal external genitalia, but they may present with the following features:
Severe cystic acne—occurring in 33% of patients
Hirsutism—most common symptoms occurring in 60% of symptomatic females
Oligomenorrhea and polycystic ovaries—second most common, occurring in 54% of patients
21. Summarize the relationship between adrenal “incidentalomas” and CAH.
Adrenal incidentalomas are more common in patients with CAH and in heterozygotes. Conversely, 60% of patients with incidentalomas have exaggerated 17-OH progesterone responses to ACTH.
22. Describe the presentation of males with CAH due to deficiencies of other enzyme activity.
During fetal development, males with CAH due to deficient activity of 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, or cholesterol side-chain cleavage enzymes are unable to produce the androgens that are necessary for the formation of male external genitalia. As a consequence, they may have the following features:
External genitalia at birth are only partially masculinized.
23. Describe the clinical features that suggest the possibility of CAH.
Adrenal crisis or severe salt wasting in the newborn period suggests the possibility of CAH. CAH also must be considered prominently in the differential diagnosis of any newborn with ambiguous genitalia. Because adrenal crisis and salt loss in CAH may be fatal if not treated, the finding of ambiguous genitalia in a newborn should trigger a rapid attempt to confirm or exclude CAH. Most males with CAH do not have ambiguous genitalia; consequently, many cases go unrecognized at birth, unless there is a documented family history of the disorder.
24. What clinical clues help support or refute the diagnosis of CAH in a newborn with ambiguous genitalia?
The overwhelming majority of genetic males with CAH have unambiguous external genitalia at birth; conversely, CAH is an uncommon cause of ambiguous genitalia in a genetic male. Thus, determination that the infant with ambiguous genitalia is a genetic male makes CAH unlikely and decreases the diagnostic urgency, because the disorders giving rise to ambiguous genitalia in genetic males are rarely associated with a fatal outcome. For example, the finding of palpable gonads in the scrotal or inguinal area suggests that the infant is a genetic male because such palpable gonads are almost always testes. Conversely, the detection of a uterus in an infant with ambiguous genitalia, on either physical examination or ultrasound, strongly suggests that the infant is a genetic female, thus heightening the possibility of CAH.
25. Discuss the role of molecular biology techniques in the diagnosis of CAH.
Molecular biology techniques can rapidly confirm the genetic sex of a newborn without the prolonged wait for a traditional chromosome analysis. Because of the potentially severe consequences of CAH, it is probably prudent to assume that any genetic female with ambiguous genitalia has CAH until proven otherwise. Furthermore, it is probably best to wait to assign gender until molecular testing is done, because gender misassignment may cause long-term psychological problems for the families of such children. Early diagnosis and appropriate therapy also allow one to avoid the progressive effects of excess adrenal androgens, which cause short stature, gender confusion in girls, and psychosexual disturbances in both boys and girls.
26. How is the diagnosis of CAH confirmed?
Because one does not know which enzyme is deficient in a newborn with suspected CAH (unless the family has a documented history of a particular enzyme defect), serum levels of all steroids that may be in the affected biosynthetic pathway can be measured before and after the administration of 250 μg of synthetic ACTH. Urinary measurement of these steroids by gas chromatography/mass spectroscopy has become economically feasible. Plasma renin activity and aldosterone levels should also be measured to assess the adequacy of aldosterone synthesis. Determination of which steroid levels are supranormal and which are low facilitates localization of the exact enzyme block.
27. How are specific genetic defects confirmed?
Specific genetic defects may be confirmed with molecular genetic testing. Polymerase chain reaction (PCR) amplification for the rapid simultaneous detection of the 10 mutations that are found in approximately 95% of 21-hydroxylase deficiency alleles is used for rapid results. Molecular genetic analysis of CYP21 is not essential for diagnosis but may be helpful to:
28. What should be done when nonclassic CAH is suspected in older patients?
When nonclassic CAH is suspected in the preteen, teenage, or adult patient, obtain an early morning 17-OHP measurement, and if the level is greater than 200 ng/dL, proceed with ACTH stimulation testing. ACTH stimulation testing should be done with 250 μg (not 1 μg) of synthetic ACTH; measurement of 17-OHP, 17-OH pregnenolone, and cortisol should be done before and 60 minutes after injection. Stimulated levels of 17-OHP with classic CAH are typically greater than 20,000 ng/dL, whereas patients with nonclassic CAH usually have 17-OHP levels in the range of 1500 to 10,000 ng/dL. Hyperandrogenism can be assessed in women by measuring serum levels of testosterone, androstenedione, and 3α-androstanediol glucuronide.
29. Describe the test used for newborn screening.
The screening process for newborns is divided into first-tier screening and second-tier screening tests. First-tier screening tests for CAH focus on the rapid detection of classic 21-hydroxylase deficiency on Guthrie cards (filter paper on which blood samples are collected, dried, and transported) measured by automated time-resolved dissociation-enhanced lanthanide fluoroimmunoassay. This screening method measures 17-OHP. Basal 17-OHP usually exceeds 10,000 ng/dL in affected infants, whereas the levels in normal infants are below 100 ng/dL. For the test to have a high level of sensitivity, cutoff values are set low in order to have 1% of all test results reported as positive, thus leading to several false-positive results. Infants who are premature, sick, or stressed have higher levels of 17-OHP. Second-tier testing includes molecular genetic testing or biochemical testing that measures steroid ratios by liquid chromatography followed by mass spectrometry. As of 2009, all 50 states in the United States and at least 12 other countries screen for CAH.
30. What other tests may be used?
If CAH is suspected and newborn filter paper screening is not available, ACTH stimulation with steroid precursor measurements should be done after the first 24 hours of life. Adrenal ultrasonography can also be used as a potential screening test for CAH in neonates with ambiguous genitalia and/or salt-losing crisis by detecting an adrenal limb width greater than 4 mm.
31. How is CAH treated in neonates?
The most important goal of treatment is to prevent salt loss and adrenal crisis in the newborn period. This goal requires the prompt administration of glucocorticoids and, in many cases, mineralocorticoids as well as careful monitoring of salt intake. This treatment not only replaces the deficient hormones but also suppresses serum ACTH elevations, thereby reducing adrenal production of androgenic precursors and metabolites. Such treatment may be given presumptively during the wait for the results of definitive laboratory tests and then discontinued if the results are not confirmatory.
32. What is the appropriate hydrocortisone formulation in infants and children unable to take a tablet?
The hydrocortisone tablet and suspension are not bioequivalent, and the suspension may have uneven distribution. Infants and children unable to take a tablet should take crushed hydrocortisone tablets in liquid.
33. When is surgical correction of ambiguous genitalia carried out?
Surgical correction of ambiguous genitalia in girls consists of genitoplasty of the clitoris and labia and vaginoplasty. Single-stage surgery is now implemented between 2 and 6 months of life. Patients so treated may have variable degrees of impairment of psychosexual functioning as adults, depending on the method and timing of the surgery and the underlying mutation. Evidence has shown that patients with more severe mutations have lower sexual function scores, a lower satisfaction with their sexual lives, and more surgical complications.
34. Describe the treatment of CAH in children.
The preferred glucocorticoid for long-term replacement is hydrocortisone in doses of 10 to 15 mg/m2/day in three divided doses. Hydrocortisone is preferred because of its short half-life, which minimizes growth suppression. It is sometimes extremely difficult or impossible to find a dosage of glucocorticoid that normalizes production of androgens and maintains normal growth and weight gain. In such situations, mineralocorticoids (fludrocortisone) and/or spironolactone/flutamide (androgen receptor blockers that prevent virilization) in combination with the aromatase inhibitor testolactone (which prevents estrogen-induced epiphyseal fusion) may be useful adjunctive therapy in combination with nonsuppressive replacement doses of glucocorticoids. Rarely, adrenalectomy has been used for difficult-to-control cases, because treatment of adrenal insufficiency is relatively much simpler. All patients with salt-wasting CAH should be treated with fludrocortisone, the recommended dosing being 0.05 to 0.2 mg/day given once or twice a day.
35. How is CAH treated in adolescents and adults?
The use of growth hormone, gonadotropin-releasing hormone analogs (GNRHas), anti-androgens, and aromatase inhibitors—alone or in various combinations—may improve the final predicted height, particularly in those whose predicted height is 2.25 standard deviations or less below normal. However, such treatment should be done under the auspices of an institutional review board (IRB)–approved protocol, because both the necessity and the long-term consequences of such an approach have yet to be determined. Prednisone (5-7 mg daily in two divided doses) or dexamethasone (0.25-0.5 mg daily) may be used once growth has been completed. Because of the potency of dexamethasone, intermediate doses can be achieved by using liquid dexamethasone (1 mg/mL), which is generally used for other conditions in infants and children. Patients should be monitored carefully for signs of iatrogenic Cushing syndrome, and sonography should be used in males to detect testicular adrenal rests.
36. What is the role of glucocorticoid treatment in nonclassic CAH?
Glucocorticoid therapy has been shown to be effective in improving acne and irregular menstruation. There is also evidence that women with nonclassic CAH undergoing glucocorticoid therapy have a lower miscarriage rate than women not receiving glucocorticoids. Glucocorticoid therapy may therefore benefit women with infertility or those with a history of miscarriage. Testicular adrenal rest tumors are rare in male patients with nonclassic CAH; thus, glucocorticoid therapy is not indicated in males.
37. What factors favor the achievement of predicted adult height?
Lower doses of hydrocortisone in the first year of life
Use of hydrocortisone rather than prednisone or dexamethasone during the pubertal growth spurt
38. What changes in therapy are necessary as a result of medically significant stress?
Patients with CAH who have been undergoing steroid therapy should wear a medical alert bracelet or necklace and should be provided with an emergency kit of hydrocortisone or dexamethasone for intramuscular use. For medically significant stress, the following measures are recommended:
Triple the oral dose of glucocorticoids.
39. What changes in therapy are necessary during pregnancy in patients with CAH?
Use hydrocortisone or prednisone instead of dexamethasone, which passes through the placenta unmetabolized.
Adjust the steroid dose according to the clinical status.
Keep testosterone and free testosterone values in the normal range for pregnancy.
40. How is treatment monitored?
The goals of treatment are to prevent symptoms of adrenal insufficiency and to suppress ACTH and adrenal androgen production. For the second goal, it is most appropriate to monitor the levels of the key precursors immediately behind the blocked enzyme (e.g., 17-OHP and androstenedione in the case of 21-hydroxylase deficiency). The goal is not to normalize the 17-OHP level since this will lead to iatrogenic Cushing syndrome. Monitoring should be done every 3 months initially and then every 4-12 months. The levels of 17-OHP can be kept between 400-1200 ng/dL (normal less than 150 in children) and the androstenedione level should be appropriate for the patient’s age and sex.
41. What other monitoring tools may be beneficial?
Androgen levels should be monitored during treatment. These include testosterone, androstenedione, and 3α-androstanediol glucuronide. In addition, plasma renin activity should be monitored in patients with salt-wasting CAH. Children must undergo annual bone age determinations, and their height should be carefully monitored. Because patients with CAH have a higher number of risk factors for cardiovascular disease, they should be routinely monitored and treated for cardiovascular disease, which may begin at an earlier age than normal. Adult men with CAH are prone to development of testicular adrenal rests and may have reduced fertility. This can be monitored by serial ultrasound and semen analysis, if appropriate.
42. What genetic counseling is appropriate for a couple who previously had a child with CAH?
Because all forms of CAH are autosomal recessive disorders, both parents of a child with CAH are obligate heterozygote carriers of the gene defect. Consequently, the chance that another child of the same couple will have CAH is one in four; 50% of the children will be heterozygote carriers. Genetic counseling should be given to all parents who have a child with CAH. Modern genetic techniques and chorionic villus sampling of fetal DNA at 9 weeks of gestation allow the diagnosis of CAH during the first trimester of pregnancy. The other use for genotypic identification includes the prediction of the phenotype (i.e., severity of the disease). There appears to be a good relationship between genotype and phenotype in classic but not in nonclassic CAH.
43. Are any prenatal treatments available for the fetus with CAH?
Glucocorticoid treatment of the fetus with 21-hydroxylase should be regarded as experimental at this time and only be done in the context of an IRB-approved protocol. Earlier recommendations for such treatment were based on small and uncontrolled studies. The potential adverse effects of glucocorticoid therapy in this setting may outweigh any benefits.
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KEY POINTS 1: CONGENITAL ADRENAL HYPERPLASIA
1. Congenital adrenal hyperplasia (CAH), the most common inherited disease, is a group of autosomal recessive disorders, the most frequent of which is 21-hydroxylase deficiency.
2. The most serious consequences of CAH are neonatal salt wasting, ambiguous genitalia in females at birth, premature puberty, and, ultimately, short stature.
3. CAH is diagnosed through measurement of cortisol precursors before and 1 hour after the intravenous administration of 250 μg of synthetic corticotropin (ACTH).
4. Predicted adult height can be achieved through early diagnosis, lower doses of corticosteroids in the first year of life and during puberty, and the use of fludrocortisone even in those who have salt wasting on genetic but not clinical grounds.
5. CAH is a rare cause of ambiguous genitalia in a genetic male.
6. The most common symptom in nonclassic CAH in females is hirsutism.
7. Prenatal treatment with dexamethasone and height-enhancing treatment with growth hormone and/or gonadotropin-releasing hormone analogs (GNRHas) should be done only under institutional review board–approved protocols in centers of excellence that are part of multicenter studies.
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