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Author: Abdollah Sadeghi-Nejad, M.D.
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1. Goals

Understand how inherited disorders of steroid hormone biosynthesis may result in excess or deficient synthesis of adrenal cortex steroid hormones including cortisol, aldosterone and testosterone resulting in ambiguous genitalia and disorders of salt metabolism.

2. Learning Objectives

  • Enzymatic defects in the synthetic pathway reduce cortisol synthesis and results in increased ACTH secretion
  • If the defect also inhibits aldosterone synthesis, the disorder is associated with salt-wasting
  • ACTH stimulation results in build up of steroid hormone precursors at the step before the enzymatic defect
  • Clinical features vary depending on the block and result from a deficiency or excess of a particular hormone
  • The most common form of CAH is a 21-hydroxylase deficiency that results in excess 17 hydroxyprogesterone

3. Introduction

A group of inherited disorders of steroid biosynthesis caused by a deficiency of one of several enzymes. The adrenal cortex synthesizes and secretes glucocorticoid (Cortisol), mineralocorticoids (Aldosterone) and sex steroids (Testosterone). Adrenocorticotropic hormone (ACTH) stimulates adrenal steroid synthesis by enhancing conversion of cholesterol to pregnenolone. Hydrocortisone (Cortisol) inhibits the secretion of corticotropic releasing hormone by the hypothalamus and of ACTH by the pituitary (negative feedback). In congenital adrenal hyperplasia enzymatic block diminishes secretion of cortisol which impairs the negative feedback system and results in increased secretion of ACTH. Clinical features vary depending on the block and result from a deficiency or excess of a particular hormone.

4. Desmolase Deficiency

  1. Defect in first step of conversion of cholesterol to pregnenolone by removal of sidechain
    1. Extremely rare
    2. Both adrenal and testis affected with absent formation of adrenal steroids and testicular androgens
    3. Males do not masculinize
  2. Salt loss
  3. Large lipid filled adrenal glands

5. 3β Hydroxysteroid Dehydrogenase Deficiency

  1. Failure to convert pregnenolone to progesterone
  2. Extremely rare
  3. Both adrenal and testis affected
  4. Partial masculinization of males and females
    • Salt loss

6. 17 Hydroxylase Deficiency

  1. Extremely rare
  2. Females lack estrogens -males lack androgens
  3. Ambiguous genitalia in males, no secondary sex development in females
  4. Overproduction of corticosterone, desoxycorticosterone and, potentially, aldosterone
  5. Hypertension and hypokalemia

7. 11 Hydroxylase Deficiency

  1. Less than 5 percent of patients
  2. Salt retention with hypertension
  3. Virilization in females
  4. Treatment as in non-salt losing 21 hydroxylase deficiency

8. 21 Hydroxylase Deficiency

  1. Incidence 1:5000-15,000 (Caucasians), 1:70-100 in Yupic Eskimos
  2. Most common type of congenital adrenal hyperplasia
  3. Most common cause of ambiguous genitalia
  4. Autosomal recessive
  5. Gene coding located on chromosome 6 near HLA gene
  6. Within a family all affected members have the same HLA
  7. Females have enlarged clitoris and fusion of labia at birth
  8. High ACTH level and hyperpigmentation
  9. May become hypoglycemic
  10. Salt wasting in 5-7 days with low serum sodium and high potassium.
  11. May develop vomiting and weight loss. High serum 17 hydroxyprogesterone concentration
  12. Treatment is replacement of glucocorticoid and mineralocorticoid
  13. Adequacy of therapy monitored by growth rate, bone age and 17 hydroxyprogesterone concentration
  14. Prenatal diagnosis by amniotic fluid 17 hydroxyprogesterone and cell HLA typing
  15. In late onset of 21 hydroxylase deficiency the patients are normal at birth but have virilization years later. Females may develop hirsutism and enlargement of clitoris
  16. Patients with cryptic 21 hydroxylase deficiency have the biochemical abnormality but do not have virilization
    21 Hydroxylase Deficiency

Newborn Phenotype

Deficiency Genotype: XX Genotype: XY Post-natal Virilization Salt Loss Hypertension
20,22-Desmolase Female Female - + -
3β-Dehydrogenase Ambiguous or Female Ambiguous +/- + -
17-Hydroxylase Female Female - - +
11-Hydroxylase Ambiguous Male + - +
21-Hydroxylase Ambiguous Male + +(50-80%)
- (20-50%)
-

9. References

  • Carlson AD, Obeid JS, Kanellopoulou N, Wilson RC, New MI. Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J Steroid Biochem Mol Biol 69 (1999) pp. 19-29.
  • New MI, Ghizzoni L and Speiser PW. Update on congenital adrenal hyperplasia. In: Litshitz F, Ed. Pediatric Endocrinology. 3rd Ed. Marcel Dekker, New York. 1996.
  • Speiser PW. Congenital adrenal hyperplasia. In: Becker KL et al Eds. Principles and Practice of Endocrinology and Metabolism. 2nd. Ed. JB Lippincott, Philadelphia. 1995.