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:
