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Apparent mineralocorticoid excess
A rare form of pseudohyperaldosteronism characterized by very early-onset and severe hypertension, associated with low renin levels and hypoaldosteronism.
ORPHA:320Classification level: Disorder
Prevalence is difficult to estimate and likely varies between populations depending on the level of consanguinity. Less than 100 cases have been reported in the literature so far.
AME is usually diagnosed within the first years of life and is characterized by polyuria and polydipsia, failure to thrive, severe hypertension with low renin and aldosterone levels, profound hypokalemia with metabolic alkalosis, and most often nephrocalcinosis. Stroke has been observed before the age of 10 years in untreated children.
AME is caused by homozygous or compound heterozygous loss-of-function mutations or deletions in the HSD11B2 gene (16q22). In all cases, these mutations lead to abolition or a marked decrease in the activity of 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2), an enzyme involved in the conversion of cortisol to cortisone.
Diagnosis should be suspected on the basis of the clinical and biochemical characteristics. Detection of a marked increase (10 to 100-fold) in the ratio of cortisol/cortisone (F/E) or of the tetrahydroxylated metabolites (THF+alloTHF/THE) in plasma and urine is a strong indication for diagnosis. However, a milder form of AME (AME2, also caused by mutations in the HSD11B2 gene) has been described with less marked hypertension and only mild abnormalities of cortisol metabolism. The diagnosis can be confirmed by genetic testing.
Differential diagnoses include pseudohyperaldosteronism (particularly Liddle syndrome; see this term), as well as other forms of early-onset childhood hypertension (particularly renal hypertension). Natural licorice consumption can result in a clinical picture that mimics AME, but this phenomenon is only rarely observed in children as it requires either a sustained and chronic, or a high and acute, exposure to cause adverse effects.
For families in which the disease-causing mutation has already been identified, prenatal diagnosis may be considered in case of a life-threatening case in a previous child.
Transmission is autosomal recessive.
Management and treatment
Early diagnosis and treatment is important to prevent end-organ damage (central nervous system, kidney, heart and retina). Two main strategies can be used to treat AME. The first is the blockade of the mineralocorticoid receptor by spironolactone (2-10 mg/kg/day), combined with thiazides to help to normalize blood pressure and reduce hypercalciuria and nephrocalcinosis. The second and complementary strategy, is the administration of exogenous corticoids to block ACTH and suppress the endogenous secretion of cortisol. This strategy has proven efficacy on blood pressure, renin and aldosterone levels but has little effect on urinary cortisol, cortisone and corticosterone concentrations. As the hypertension is severe, nonspecific antihypertensive agents (e.g. calcium antagonists) are also often required.
In the absence of treatment, the prognosis for AME is severe with malignant hypertension, stroke, cardiac and renal insufficiency. However, the prognosis for patients with appropriate treatment appears to be good.