Congenital adrenal hyperplasia

Published on 02/03/2015 by admin

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Last modified 02/03/2015

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CHAPTER 31

Congenital adrenal hyperplasia

1. Define congenital adrenal hyperplasia.

2. What enzyme defects can lead to CAH?

3. Describe the functions of the three hydroxylases.

4. How is CAH inherited?

5. What is the most common form of CAH?

6. Which genes encode for 21-hydroxylase?

7. What causes most of the genetic events responsible for CYP21A2 deficiencies?

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:

image Patients with no enzyme activity typically have large deletions or splicing mutations and predominantly have the salt-wasting form of the disorder.

image Patients with a nonconservative amino substitution in exon 4 usually have 1% to 2% of enzyme activity and typically have the simple virilizing form of the disease.

image Patients with a point mutation in exon 7 have 20% to 50% of normal enzyme activity and most often have the nonclassic form of the disease.

image Patients who are heterozygotes have mild abnormalities but no clinically important endocrine disorder.

9. What is the second most common cause of CAH?

10. Summarize the rarer forms of CAH.

11. How common is CAH?

12. What percentage of the population at large are heterozygote carriers of the 21-hydroxylase defect?

13. How common is 11β-hydroxylase deficiency?

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:

image Masculinization of the external genitalia of a genetic female fetus, leading to ambiguous genitalia at birth (female pseudohermaphroditism).

image Behaviors more typical of boys during childhood in terms of toy preference, rough play, and aggressiveness. (However, most females are heterosexual and their sexual identity is invariably female.)

image Rapid growth during early childhood with ultimate short stature as an adult due to early closure of epiphyses.

image Infertility in 20% of females with simple virilizing disease and approximately 40% of females with salt-wasting disease.

image Osteopenia in young adulthood in 45% of women with salt wasting.

image Obesity.

image Lower quality-of-life scores in patients with CAH than in age- and sex-matched controls.

image Variable and subtle hyperpigmentation.

17. What are other clinical consequences of CAH in males?

18. Are patients with CAH at increased risk for cardiovascular disease?

19. How do patients with 17α-hydroxylase deficiency present?