The syndrome of apparent mineralocorticoid excess (AME) arises from non-functional mutations in 11β hydroxysteroid dehydrogenase type2 enzyme (11beta-HSD2), an enzyme that inactivates cortisol and confers aldosterone specificity on the mineralocorticoid receptor. The imapaired conversion of cortisol (compound F) to cortisone (compound E) has been associated with low renin, low aldosterone hypertension with hypokalemia in children. The hypertension in the syndrome is presumed to arise from volume expansion secondary to renal sodium retention. This disorder is potentially fatal but treatable and hence early diagnosis is required to prevent the mortality.

Case-1: A one year old Kuwaiti girl, product of a consanguineous marriage; delivered by LSCS; IUGR with birthweight of 1.7 kg was admitted to our hospital with the history of polyuria and polydypsia for one week duration. On examination, the child’s weight and height were both below 3rd centile. Her blood pressure was high (130/88 mmHg) at the time of admission. She had marked dystrophic squint and other systemic examination was unremarkable. Biochemical findings indicated hypokalemia with metabolic alkalosis. With this clinical and biochemical presentation Bartter syndrome was suspected, but the patient was further investigated to rule out other possibilities. Her plasma renin activity was low (<0.2 pmol/L/mL/h); serum aldosterone was low (<75 pmol/L); low serum renin and aldosterone level were against the diagnosis of Bartter syndrome. Chromatographic determination of urinary steroid metabolites showed an abnormal elevation of tetrahydrocortisol (THF) and allo-tetrahydrocortisol compared to tetrahydrocortisone (THE). High ratio of cortisol to cortisone metabolites was suggestive of defect in 11β hydroxysteroid dehydrogenase type 2 enzyme. Renal ultrasound revealed the presence of bilateral nephrocalcinosis. Genetic study proved homozygous missense mutation c.710C>T;p.A273V in HSD11B2 gene confirming the diagnosis of apparent mineralocorticoid excess (AME) syndrome. Patient responded well to spironolactone along with amiloride, with good control of blood pressure and electrolytes. Patient is being followed regularly in pediatric endocrinology and nephrology clinics.

Case 2. A 8-month-old girl (sister of above mentioned patient), product of a consanguineous marriage; full term delivered by LSCS with birth weight of 2.5 kg with uneventful neonatal period was admitted as a case of acute bronchiolitis. On examination, the child’s weight and height were both below 3rd centile. Her blood pressure was high (114/78 mmHg) at the time of admission. Her systemic examination was unremarkable except for wheezes on auscultation of chest. Biochemical findings indicated hypokalemia (serum potassium-2.8 mmol/L) and normal sodium (136 mmol/L) with metabolic alkalosis; keeping in mind of the diagnosis of apparent mineralocorticoid excess (AME) syndrome in her elder sister, she was screened for the same too. Chromatographic determination of urinary steroid metabolites showed an abnormal elevation of tetrahydrocortisol (THF) and allo-tetrahydrocortisol compared to tetrahydrocortisone. High ratio of cortisol to cortisone metabolites was suggestive of defect in 11β hydroxysteroid dehydrogenase type 2 enzyme. Renal ultrasound revealed the presence of bilateral nephrocalcinosis. Genetic study proved homozygous missense mutation c.710C>T;p.A273V in HSD11B2 gene confirming the diagnosis of apparent mineralocorticoid excess (AME) Syndrome. Patient responded well to spironolactone along with amiloride and is currently under regular follow-up.

The syndrome of apparent mineralocorticoid excess of AME is a form of low-renin hypertension that is caused by congenital deficiency in the activity of the enzyme HSD11β 2. 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 [1,2]. Stroke has been observed before the age of 10 years in untreated children. Transmission is autosomal recessive and AME is caused by homozygous or compound heterozygous loss-of-function mutations or deletions in the　HSD11B2　gene (16q22) [3,4]. 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 [5,6]. 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.　Differential diagnoses include pseudohyperaldosteronism (particularly Liddle syndrome), as well as other forms of early-onset childhood hypertension (particularly renal hypertension) [7,8]. For families in which the disease-causing mutation has already been identified, prenatal diagnosis may be considered in case of a life-threatening event in a previous child. 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 [9]. 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. The loss of functional epithelial sodium channel (ENaC) explains why amiloride is only an effective means of long term blood pressure control [8,10]. 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.

10. Khosla N, Hogan D. Mineralocorticoid hypertension and hypokalemia. Semin Nephrol. 2006;26:434-40.