Differentials
X-linked adrenal hypoplasia congenita (AHC)
SIGNS / SYMPTOMS
Presents in male infants only. Present with adrenal crisis related to both glucocorticoid and mineralocorticoid deficiency. May also have hypogonadotrophic hypogonadism which is not seen in congenital adrenal hyperplasia (CAH).
INVESTIGATIONS
In AHC, 17-hydroxyprogesterone is low or normal and in CAH this is high.
Genetic testing: deletion or mutation of DAX-1.
Genetic causes of primary adrenal insufficiency
SIGNS / SYMPTOMS
Adrenal hypoplasia can be part of syndromes, such as IMAGE or MIRAGE. They may present with adrenal crisis early in life and additional symptoms related to the specific syndrome.
In the AAA syndrome (achalasia, alacrima and adrenal insufficiency), adrenal insufficiency develops during the first or second decade of life.
Adrenal leukodystrophy presents with progressive neurological deterioration and adrenal insufficiency usually during the first decade.
In all these cases, there is no sign of virilisation in XX individuals or symptoms of androgen excess.
INVESTIGATIONS
Endocrine evaluation indicates primary adrenal insufficiency (high adrenocorticotrophic hormone concentrations in the presence of low serum cortisol levels) with or without an additional mineralocorticoid defect.
17-hydroxyprogesterone and adrenal androgens are normal.
Elevated concentrations of very-long-chain fatty acids are diagnostic of adrenal leukodystrophy.
Genetic testing can confirm the specific genetic defect.
Addison's disease
SIGNS / SYMPTOMS
Patients with Addison's disease tend to have symptoms of muscle weakness and fatigue. Similar to congenital adrenal hyperplasia (CAH), they can present with adrenal crisis with mineralocorticoid deficiency. Patients with Addison’s disease do not display signs of hyperandrogenism. As Addison’s disease is an autoimmune process, earliest presentation is in early childhood and not infancy as CAH often presents.
INVESTIGATIONS
In Addison's disease, an adrenocorticotrophic hormone stimulation test will show a poor or absent cortisol response; however, they would not show stimulation of other adrenal hormones.
Familial glucocorticoid resistance
SIGNS / SYMPTOMS
Patients have symptoms of adrenal insufficiency due to end-organ resistance to cortisol. They do not have mineralocorticoid deficiency, and in fact, may present with signs of mineralocorticoid excess due to the increased stimulation of adrenal hormone production. They can also display hyperandrogenism.
INVESTIGATIONS
Patients with familial glucocorticoid resistance have normal urea and electrolyte and mild elevation of adrenocorticotrophic hormone, cortisol and adrenal androgens.
Genetics reveals defects in the glucocorticoid receptor gene NR3C1.
Differences in sex development (DSD)
SIGNS / SYMPTOMS
DSD include a number of conditions that present with genital ambiguity. Internal reproductive organ structures and karyotype can vary.
INVESTIGATIONS
An elevated 17-OHP level along with a 46,XX karyotype differentiates classical congenital adrenal hyperplasia (CAH) from other types of DSD.
Additional evaluations may include pelvic sonogram and measurements of LH, FSH, dihydrotestosterone (DHT), testosterone and anti-Mullerian hormone (AMH). Stimulation testing (i.e., adrenocorticotrophic hormone or human chorionic gonadotrophin tests) may be performed based on the specifics of each case. Genetic analysis can confirm CAH or identify another DSD-related gene.
Renal salt-wasting
SIGNS / SYMPTOMS
Renal salt-wasting is associated with a history of diuretic use and/or uncontrolled diabetes mellitus, not typically shared by patients with congenital adrenal hyperplasia (CAH).
INVESTIGATIONS
In renal salt-wasting, 17-hydroxyprogesterone is normal and in CAH this is high.
Pseudohypoaldosteronism (PHA)
SIGNS / SYMPTOMS
PHA is a group of disorders characterised by resistance to the action of aldosterone. Presentation is that of electrolyte abnormalities with hyponatraemia, hyperkalaemia and acidosis. PHA type I can present in the newborn, and therefore, can be confused with the salt-wasting that is seen in classical congenital adrenal hyperplasia. There is no evidence of adrenal insufficiency or androgen excess.
INVESTIGATIONS
Aldosterone concentrations and plasma renin activity are elevated in PHA.
Genetics show loss of function mutations in the mineralocorticoid receptor gene (NR3C2) or the genes of the three subunits of the epithelial sodium channel (ENaC).
Aldosterone synthase deficiency
SIGNS / SYMPTOMS
Present with failure to thrive and salt-wasting without any concern for glucocorticoid deficiency as seen in congenital adrenal hyperplasia (CAH).
INVESTIGATIONS
In aldosterone synthase deficiency, 17-OHP is normal and in CAH this is high.
Polycystic ovary syndrome (PCOS)
SIGNS / SYMPTOMS
Women with PCOS can present with hyperandrogenic symptoms of hirsutism and acne with irregular menses, similar to those with non-classical congenital adrenal hyperplasia (CAH).
INVESTIGATIONS
In non-classical CAH, 17-hydroxyprogesterone (17-OHP) concentrations are elevated. Adrenocorticotropic hormone stimulation testing would reveal an elevated 17-OHP upon stimulation.
Adrenal tumour - 17-OHP producing adenoma
SIGNS / SYMPTOMS
Hypertension may present with 17-OHP (17-OHP) producing adenoma and not with 21-hydroxylase deficiency.
INVESTIGATIONS
Absence of CYP21A2 mutation.
May also have significant DHEA-S and testosterone elevations.
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