Endocrine Hypertension:
Apparent Mineralocorticoid
Excess (AME) (HSD11B2)

Loss-of-function mutations in the enzymes 11ß-hydroxylase or 17α-hydroxylase lead to accumulation of deoxycorticosterone, a precursor of aldosterone with weak mineralocorticoid activity (10).

Glucocorticoid Remediable Aldosteronism (GRA)
Fusion of the genes for 11ß-hydroxylase and for aldosterone synthetase places aldosterone synthesis under the control of the regulatory elements for glucocorticoid synthesis, leading to overproduction of aldosterone in a renin-independent manner (11).

Familial Glucocorticoid Resistance
Loss-of-function mutations in the glucocorticoid receptor disrupt feedback inhibition of cortisol synthesis, leading to cortisol overproduction. Excess cortisol saturates 11ßHSD2 activity, allowing cortisol to bind to and activate the MR (12).

Liddle Syndrome
Gain-of-function mutations in the proteins forming sodium channels (ENaC) through the apical membrane of the cells lining the distal kidney tubules allow increased sodium re-absorption to persist after the PRA has dropped and the MR is no longer activated (13, 14).

Geller Syndrome
Gain-of-function mutations in the MR lead to partial activation of the receptor in the absence of aldosterone (15).

Pseudohypoaldosteronism Type II
Mutations in either the WNK1 or the WNK4 serine-threonine kinase can lead to hypertension and hyperkalemia (16).

AME is characterized by hypertension, hypokalemia, and metabolic alkalosis in the presence of low renin and low serum aldosterone (4). It usually presents in infancy, with low birth weight, failure to thrive, hypertension, hypercalciuria, and, secondary to hypokalemia, polyuria and polydipsia. AME may lead to end-organ damage such as nephrocalcinosis or renal insufficiency, hypertensive retinopathy, or left ventricular hypertrophy of the heart at a young age. Due to cardiovascular disease, individuals with AME are prone to dying of stroke during childhood or adolescence.

The severity of AME symptoms can vary widely, depending on the effect of the HSD11B2 mutation on the enzymatic activity of 11ßHSD2. Milder, late onset forms of AME – originally thought to reflect a different type of AME (AME type II) – are now recognized to be part of a continuous disease spectrum caused by mutations in HSD11B2 (5, 17, 18). Since mild forms of AME may not present with hypokalemia or metabolic alkalosis, they may be mistaken for low-renin essential hypertension.

Diagnosis of AME is currently based on detection of hypertension, low PRA, low aldosterone levels, and an excess of free urinary cortisol over free urinary cortisone in 24-hour urine samples (8). Excess of urinary metabolites of cortisol over urinary metabolites of cortisone is also diagnostic of AME.

Genetic testing can help identify AME based on a single blood draw. In addition, genetic testing can identify heterozygous carriers of an AME-associated mutation in HSD11B2, which may predispose individuals to late-onset hypertension.

AME is usually treated with the MR antagonist spironolactone for hypertension, thiazide diurectics for hypercalciuria and nephrocalcinosis, and potassium supplements for hypokalemia (4). Dexamethasone and potassium-sparing diuretics such as triamterene and amiloride have also been successfully used.

A follow-up study in patients with AME showed significant improvement in or even reversion of earlier end-organ damage after 2 to 10 years of treatment (7).

Congenital AME is caused by loss-of-function mutations in HSD11B2 in an autosomal recessive manner (2). Heterozygous carriers of an AME-associated mutation in HSD11B2 may develop mild hypertension, with or without hypokalemia, later in life (5, 6).

It has been suggested that mutations in HSD11B2 may also play a role in salt-sensitivity (19) and pre-eclampsia (20)

The Endocrine Hypertension (HSD11B2) Evaluation detects mutations in HSD11B2, the gene coding for 11-ß-hydroxysteroid dehydrogenase type 2. Loss-offunction mutations in HSD11B2 have been associated with apparent mineralocorticoid excess (AME), which is characterized by often severe, early onset hypertension and hypokalemia. Prompt diagnosis of AME is critically important, since targeted treatment can prevent or even reverse damage to kidneys, eyes, and the cardiovascular system and decrease the risk of death due to stroke during childhood or adolescence. In relatives of AME-patients, genetic testing can detect heterozygosity for a pathogenic mutation in HSD11B2, which may predispose individuals to late-onset hypertension.