Apparent Mineralocorticoid Excess (AME) is a rare autosomal recessive syndrome characterized by plasma volume expansion, hypertension, hypokalemic acidosis, and a suppressed rennin-angiotensin-aldosterone system. Cortisol to cortisone conversion is impaired in patients, due to defects in the 11-@Beta-Hydroxysteroid Dehydrogenase, Type II (HSD11B2) enzyme. Severe deficiency of this enzyme results in markedly elevated urinary ratio of cortisol (F), tetrahydrocortisone-F (THF), and allo-THF to cortisone (E), tetrahydrocortisone (THE), and allo-THE. Typical symptoms of the condition in children include low birth weight, failure to thrive, short stature, severe hypertension, hypokalemic metabolic acidosis, muscle weakness, delayed puberty, frequent urination and thirst, renal insufficiency, and hypokalemic nephropathy, resulting in nephrocalcinosis or polycystic kidneys. A milder version of the condition is also seen in some patients, in whom the disease manifests only in adulthood, and is characterized by a decreased rate of cortisol clearance and turnover but a normal urinary ratio of THF to THE. In such patients, some residual enzyme activity may be responsible for the milder phenotype. AME is extremely rare, with only fewer than 100 cases having been reported in medical literature.
Generally, the THF+allo-THF/THE ratio is used to diagnose AME in patients with mineralocorticoid excess. AME is associated with mutations in HSD11B2 gene. Therefore, molecular analysis of the HSD11B2 gene can be employed to confirm or diagnose the condition in patients. Treatment, however, is difficult. Sort-term treatment may involve a low-sodium diet and administering spironolactone. Dexamethasone is a more effective alternative; yet, it has growth suppressing effects, and therefore, is not suitable for children over a long period of time. Prognosis in some patients may not be good despite medications, and death within a few years of being diagnosed with AME is not uncommon.
Woodhouse et al. (2003) conducted a study to investigate the possibility that familial hypertension was due to mineralocorticoid (MC) hypersecretion by using spironolactone, which selectively blocked the MC receptors. Over an 8-month period, out of 64 hypertensive patients with at least one or more affected parent or sibling, 45 patients (29 females and 16 males; mean age - 48 years; 28% being products of consanguineous marriages) had completed the therapeutic trial and had had hypertension for a range of one month to 33 years. Out of these, 22 were Omani patients. Routine serum potassium, calcium, creatinine and plasma rennin activity were determined, and renal ultrasound was performed in all patients before starting the treatment. Of 14 patients admitted for determination of rennin and aldosterone, three were diagnosed with non-mineralocorticoid induced hypertension, four with presumptive diagnosis of familial hypertension (FHII), two with FHI, four with hyper-reninemic familial hypertension (HRFH), and one with Conn's tumor (removed with laproscopy with normalization of aldosterone level and blood pressure). Woodhouse et al. (2003) indicated that inherited forms of mineralocorticoid hypertension were common, as 84% of the patients under study responded to spironolactone, and recommended that all patients with familial hypertension should undergo therapeutic trial with an MC receptor blocking agent, before undertaking expensive endocrine investigations. Since identified responders came from three continents, they postulated that MC hypertension was a worldwide problem rather than a Middle Eastern one.
Quinkler et al. (2004) investigated the molecular basis of apparent mineralocorticoid excess (AME) syndrome in nine Omani patients (5 males, 4 females) from four unrelated families from different tribes. Patients from three of these families had consanguineous parents. Other causes of endocrine hypertension were excluded by hormonal analysis. Nearly all patients had severe intrauterine growth retardation with low birth weight (when compared to their unaffected siblings). The majority of patients presented at a young age (0.2 to 3.8 years) with failure to thrive, hypokalemic metabolic alkalosis, and hypertension (90th percentile). Polyuria and polydipsia were consistent presenting features in childhood in the majority of the patients (presumably due to hypokalemic nephropathy leading to nephrogenic diabetes insipidus). Complications were seen in a few patients as five out of six (88%) had hypercalciuria (urinary calcium/creatinine molar ratio was 0.31 to 1.6), with nephrocalcinosis in three of them. Left ventricular hypertrophy was identified by echocardiography in five out of eight patients (62%), two were treated in an intensive care unit for cardiac arrest (due to hypokalemia) and respiratory insufficiency (due to muscular weakness) respectively, while a third patient suffered from congestive heart failure. On the other hand, no hypertensive retinopathy was reported in any of these patients. Genomic analysis revealed five homozygous mutations (four novel ones) which led to severely attenuated 11 beta-HSD2 enzyme activity in these patients. Two novel mutations, R74G and P75 1nt, were detected in exon 1 in one family with three affected children. These mutations generated a stop codon which yielded a truncated protein and hence a non active enzyme. In another family with one affected child, a homozygous six nucleotide deletion (L114 6nt) was detected in exon 2, leading to the loss of Leu 114 and Glu 115, and ultimately producing an 11HSDB2 enzyme with attenuated activity. The fourth mutation identified in a family with four patients was a novel missense mutation, A221V, in exon 3 compromising the pre-mRNA splicing. The last family with two patients had a novel nine nucleotide insertion, V322ins9nt, in exon 5, which added three codons encoding alanine, proline and valine leading to defective secondary structure and a severely attenuated enzyme. Quinkler et al. (2004) highlighted that an association between disease genotype and phenotype was confirmed by their group data as early and severe presentation was associated with mutations that resulted in complete loss of enzyme activity. Quinkler et al. (2004) concluded that the discovery of these new mutations in exon 1, 3 and 5 elaborated more on the role of 11 beta-HSD2 enzyme as well as this syndrome. In addition, they added that AME could be one of the common causes of hypertension in the Omani population as consanguinity is commonly present in this population.