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Key Points

  • Disease summary:

    • Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive inherited disorders of steroidal biosynthesis caused by a variety of enzymatic defects (Fig. 64-1).

    • Most cases of CAH can be accounted for by deficiencies in 21-hydroxylase (21-GHO): 90% to 95% of cases and 11β-hydroxylase (OHO): 3% to 8%.

    • Deficiencies in 21-hydroxylase and 11β-hydroxylase cause decreased cortisol production, that lead to a lack of negative inhibition of adrenocorticotropic hormone (ACTH) and oversecretion of ACTH. This increase in ACTH drives the adrenal glands to attempt to produce more cortisol but this increase is blocked by enzyme deficiencies. Adrenal precursors are thus shunted into the androgen pathway resulting in increased androgen synthesis, which does not require these enzymes.

    • Phenotypes can range widely depending on the degree of enzyme deficiency.

    • Hyperandrogenism is a key feature seen in 21-OHD and 11β-OHD.

  • Hereditary basis:

    • These are autosomal recessive genetic disorders; thus both parents are typically carriers of CYP21A2 or affected with 21-hydroxylase deficiency for the fetus to be affected.

    • Though less common, new mutations can arise in CYP21A2.

  • Differential diagnosis:

    • In 46,XX, maternal androgen exposure, P450 oxoreductase deficiency (POR), ovotesticular disorder of sexual differentiation (DSD), mixed gonadal dysgenesis

    • In 46,XY, incomplete androgenization of genitals, 5α-reductase deficiency, nonclassic StAR

Figure 64-1

Schematic of Steroid Synthesis in CAH.

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria for CAH

Diagnostic evaluation should include

  • Newborn screen for 21-hydroxylase deficiency in all children born in the United States.

  • All patients born with ambiguous genitalia must have a detailed hormonal and genetic evaluation.

  • Genotyping is necessary as each mutation can cause a different phenotype.

  • Hormonal determination

    • The gold standard for establishing hormonal diagnosis of 21-hydroxylase deficiency (21-OHD) is the corticotropin stimulation test (250 μg cosyntropin intravenously), measuring levels of 17-OHP at baseline and 60 minutes. These values can then be plotted on a nomogram to ascertain disease severity (Fig. 64-2). There is significant overlap between carriers and unaffected.

    • Assessment of fertility potential.

  • Electrolytes should be monitored closely for hyponatremia and hyperkalemia and treated immediately; salt-wasting is present in 75% of patients with classic 21-OHD and can be life threatening. Plasma renin and aldosterone ratio is elevated.

  • Extra doses of corticosteroids must be given during illness, trauma, and surgery to avoid crisis and death.

Figure 64-2

Nomogram Relating Baseline to 60’ ACTH-Stimulated Serum Concentrations of 17-Hydroxyprogesterone. The coordinates are logarithmic. A regression line for all data points is shown.

Clinical Characteristics

Clinical Features of CAH

Hyperandrogenism is a clinical feature consistent in both 21-OHD and 11β-OHD.

46,XX females: Genital virilization occurs only in the androgen-responsive external genitalia. Since ...

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