Investigations
1st investigations to order
serum 17-hydroxyprogesterone (17-OHP)
Test
Diagnosis of 21-OHD is confirmed by hormonal evaluation. A very high concentration of 17-OHP, the steroid precursor that accumulates in 21-OHD, is diagnostic of classical disease.
17-OHP can also be elevated in healthy neonates during the first 1 to 2 days of life and in premature and ill neonates.[2] These levels should be measured at least 24 hours after birth to prevent false-positive testing. One must also ensure there has not been recent steroid exposure which might cause false-negative test results.
While 17-OHP levels are often diagnostic in the classical form, values may be insufficiently elevated in non-classical disease. False-positive and false-negative results are common if samples are obtained immediately after birth.[14] In such cases, the adrenocorticotrophic hormone stimulation test is crucial in establishing the diagnosis of the non-classical form.
Result
elevated for age in patients with 21-hydroxylase deficiency (21-OHD)
adrenocorticotrophic hormone (ACTH) stimulation test
Test
A stimulation test should be performed if the diagnosis is suspected and if baseline morning levels of 17-hydroxyprogesterone (17-OHP) are not diagnostic. While 17-OHP levels are often diagnostic in the classical form, values may be insufficiently elevated in non-classical disease. False-positive and false-negative results are common if samples are obtained immediately after birth.[14]
An intravenous injection of cosyntropin is given and 17-OHP and delta-4-androstenedione levels are measured at baseline and then 60 minutes later. These values can then be plotted on a published nomogram to ascertain disease severity.[15]
In individuals with borderline 17-OHP levels, after a cosyntropin stimulation test we recommend obtaining a measurement of additional steroids, such as 11-deoxycorticosterone, dehydroepiandrosterone (DHEA) and 17-OH pregnenolone to differentiate 21-hydroxylase deficiency from other rare forms of congenital adrenal hyperplasia.
Result
classical form - basal 17-hydroxyprogesterone: high (10,000 to 100,000 ng/dL), post-ACTH stimulation 17-hydroxyprogesterone: high (25,000 to 100,000 ng/dL), delta-4 androstenedione: high (250 to 1000 ng/dL); non-classical form - basal 17-hydroxyprogesterone: lower than classical level, post-ACTH stimulation 17-hydroxyprogesterone: 2000-10,000 ng/dL
serum cortisol
Test
Full adrenal profile should be obtained after the rapid adrenocorticotrophic hormone stimulation test.[14]
Result
classical form: low concentrations consistent with adrenal insufficiency; non-classical form: normal
serum chemistry
Test
Particularly useful for newborns (after the first day of life) and for infants with atypical genitalia or at risk for 21-hydroxylase-deficient congenital adrenal hyperplasia.[2] In a salt-wasting crisis, results often indicate severe dehydration, hyponatraemia, hyperkalaemia, and metabolic acidosis; however, this would not be expected until 1 to 2 weeks of life.[17] Haemolysed blood gives rise to a false-positive result (i.e., elevated potassium). Results may reflect haemoconcentration.
Result
hyponatraemic, hyperkalaemic, metabolic acidosis; azotaemia
genetic analysis
Test
If there is a family history of the disease or one of the future parents has the disease, genetic analysis is strongly recommended. Both parents should also have genetic testing to determine if they carry a mutation. Genotyping may also be helpful if the results of the adrenocortical profile after a rapid adrenocorticotrophic hormone stimulation test are equivocal.[14]
Gene analysis of CYP21A2 that detects the most common mutations is established in commercially available laboratories.
Result
mutation and autosomal recessive inheritance pattern
karyotype or fluorescence in situ hybridisation (FISH) for X and Y chromosome detection
Test
Indicated for newborns and infants with ambiguous genitalia.
Result
XX or XY
Investigations to consider
measurement of additional steroids
Test
In individuals with borderline 17-hydroxyprogesterone levels, after a cosyntropin stimulation test we recommend obtaining a measurement of additional steroids, such as 11-deoxycorticosterone, DHEA and 17-OH pregnenolone to differentiate 21-hydroxylase deficiency from other rare forms of congenital adrenal hyperplasia (CAH).
Result
elevated for age in patients with rare forms of CAH
plasma renin activity/plasma renin measurement
Test
Plasma renin activity measurement is recommended in patients suspected of classical salt-wasting congenital adrenal hyperplasia (CAH).[14] Unfortunately, a high plasma renin in untreated CAH is not diagnostic of salt-wasting CAH given that 17-hydroxyprogesterone (17-OHP), at high concentrations, has mineralocorticoid receptor antagonistic properties. Thus, high 17-OHP increases the plasma renin. Renin may also be elevated in states of volume depletion, heart failure and other critical illness. The use of steroid medicines can lower the renin level. High plasma renin activity levels indicate aldosterone deficiency and potential hypovolaemia.
Note that normal values are higher during the newborn period. Results in a newborn with CAH need to be interpreted taking into account normal ranges in the neonate.
Result
classical CAH: high values indicate salt-wasting, aldosterone deficiency and potential hypovolaemia; low or suppressed values during CAH treatment, especially if associated with hypokalaemia, may indicate excessive treatment with fludrocortisone
pelvic and adrenal ultrasound
Test
Indicated for newborns and infants who have ambiguous genitalia.[2] The presence or absence of a uterus and adnexa on pelvic ultrasound can be rapidly ascertained while awaiting karyotype to confirm chromosomal sex.
Result
uterus and adnexa seen in 46XX females with classical congenital adrenal hyperplasia; enlarged adrenal glands and adrenal densities (calcification). Enlarged adrenals with large benign masses (myelolipomas) can be seen in adults with classical disease and a history of poor adrenal control.
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