Diagnostic Criteria

Suggestive Findings

21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH) should be suspected in the following individuals:

Source: GeneReviews — "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"

Differential Diagnosis

The production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps. Congenital adrenal hyperplasia (CAH) results from deficiency in any one of these enzymes; impaired cortisol synthesis leads to chronic elevations of ACTH and overstimulation of the adrenal cortex resulting in hyperplasia. The five forms of CAH are summarized in . Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to a unique combination of retained precursors and deficient products. The most common enzyme deficiency, accounting for more than 90% of all CAH, is 21-hydroxylase deficiency (21-OHD). Table 5. Enzyme Deficiencies Resulting in CAH

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with 21-hydroxylase-deficient congenital adrenal hyperplasia (21-OHD CAH), the following evaluations are recommended:

To assess for salt wasting

• Plasma renin activity (PRA)

• Serum electrolytes

To distinguish classic from non-classic forms of 21-OHD CAH

• Baseline 17-OHP, 4-androstenedione, cortisol, and aldosterone

• ACTH stimulation test to compare stimulated concentration of 17-OHP to the baseline level

To assess the degree of prenatal virilization in females

• Careful physical examination of the external genitalia and its orifices

• Vaginogram to assess the anatomy of urethra and vagina

To assess the degree of postnatal virilization in both males and females

• Bone maturation assessment by bone age

Clinical Guidance

Physical stress such as febrile illness, gastroenteritis with dehydration, surgery accompanied by general anesthesia, and major trauma can precipitate an adrenal crisis in individuals with classic CAH. Increased doses of glucocorticoids are recommended in these situations.

Source: GeneReviews — "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"

Therapies Under Investigation

Affected female fetus with genital ambiguity. Through molecular genetic testing of fetal DNA, defects in 21-OHD CAH synthesis can be diagnosed in utero. Genital ambiguity in female fetuses may be reduced or eliminated by suppressing fetal androgen production through administration of dexamethasone to the mother beginning early in gestation and continuing until delivery. Prenatal treatment should continue to be considered experimental and should only be used within the context of a formal IRB-approved clinical trial. Noninvasive prenatal diagnostic methods for earlier diagnosis of affected female fetuses have been developed and may eliminate the unnecessary prenatal treatment of males and unaffected females . Treatment of short stature.

Source: GeneReviews — "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"

Surveillance Guidelines

The following evaluations should be performed every three to four months when children are actively growing. Evaluation may be less often thereafter. The frequency of evaluation should vary depending on individual needs . Efficacy of glucocorticoid replacement therapy is monitored by measurement of the following:

• Early-morning serum concentrations of 17-OHP, 4-androstenedione, and testosterone approximately every three months during infancy and every three to six months thereafter. (In some instances, measurement of urinary pregnantriols and 17 ketosteroids in a 24-hour urine sample may help assess hormonal control. However, the process of urine collection makes it less practical than a simple blood draw.)

• Linear growth, weight gain, pubertal development, and clinical signs of cortisol and androgen excess

• Bone age to assess osseous maturation (at 6- to 12-month intervals)

Efficacy of mineralocorticoid replacement therapy is monitored by measurement of the following:

• Blood pressure

• Early morning plasma renin activity or direct renin assay in a controlled position (usually upright)

Monitoring for testicular abnormalities in males. Periodic imaging of the testes either by ultrasonography or MRI should begin after puberty and be repeated every three to five years. Monitoring fertility and metabolic risks in adults. In affected adults, periodic measurements and/or monitoring of the following should be performed:

Source: GeneReviews — "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia"