Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in ... Apparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type II (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone (review by Ferrari, 2010).
Werder et al. (1974) reported a 3-year-old girl with low birth weight, short stature, polydipsia, polyuria, and hypertension in the absence of genital anomalies. Laboratory studies showed hypernatremia, hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone. Urinary steroid ... Werder et al. (1974) reported a 3-year-old girl with low birth weight, short stature, polydipsia, polyuria, and hypertension in the absence of genital anomalies. Laboratory studies showed hypernatremia, hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone. Urinary steroid profile showed low tetrahydrocortisone, although plasma cortisol was normal. Dexamethasone and spironolactone resulted in alleviation of the hypertension. The findings were consistent with mineralocorticoid excess. Atanasov et al. (2007) provided follow-up of the patient reported by Werder et al. (1974), who reappeared at age 40 years with subarachnoid hemorrhage and end-stage renal failure resulting from untreated hypertension. In 2 unrelated patients, Ulick et al. (1979) described a disorder in the peripheral metabolism of cortisol, manifested by hypertension, hypokalemia, low plasma renin activity, and responsiveness to spironolactone. Aldosterone levels were subnormal. Although the features suggested primary mineralocorticoid excess, no overproduction of mineralocorticoid could be demonstrated. One of the patients, who had been reported by New et al. (1977), was a 3-year-old Zuni Indian girl with hypertension, hypokalemia, and decreased secretion of all known sodium-retaining corticosteroids. The second patient was a boy of Middle Eastern parentage who had a stroke with residual left hemiparesis at age 7, and was first found to be hypertensive at age 9 (blood pressure as high as 250/180 mm Hg). Other findings included growth retardation, grade III retinopathy, hypokalemia, and hyposthenuria. Biochemical studies indicated a decreased rate of conversion of active cortisol to cortisone, and the authors postulated a defect in 11-beta-hydroxy oxidation of cortisol. Ulick et al. (1979) suggested the term 'apparent mineralocorticoid excess.' Monder et al. (1986) studied 3 children, including 2 sibs, with AME. There was hypertension and hypokalemic alkalosis in the presence of low plasma renin activity and subnormal levels of aldosterone and other known mineralocorticoids. The symptoms responded to spironolactone administration or a low sodium diet, suggesting that they are mediated by the mineralocorticoid receptor. Metyrapone was also effective, indicating that the steroid occupying the receptor is 11-beta-hydroxylated. Administration of cortisol or of ACTH exacerbated the hypertension. Stewart et al. (1988) investigated the first adult patient with AME. Nikkila et al. (1993) reported 4 patients with AME. One presented at 18 months with hypertension, hypokalemia, and low renin and aldosterone levels, and at age 5 years had evidence of left ventricular hypertrophy and an old infarct of the left cerebellum on brain MRI. Another patient presented at 4 years of age with similar manifestations. At age 10.5 years, this patient had developed complications of hypertension, including grade I hypertensive retinopathy and left ventricular hypertrophy. Li et al. (1998) reported a large consanguineous Sardinian kindred with AME. Affected individuals were more than 30 years of age and had both mineralocorticoid hypertension and evidence of impaired metabolism of cortisol to cortisone. The heterozygote state was phenotypically normal, but was associated with subtle defects in cortisol metabolism. Wilson et al. (1998) reported a patient from a consanguineous Mennonite family with a mild form of AME due to a homozygous mutation in the HSD11B2 gene (P227L; 614232.007). She had low-renin hypertension, but did not demonstrate the typical features of AME. Biochemical analysis revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared to 0 to 6% in patients with typical AME (the normal conversion is 90 to 95%). The parents and sibs were heterozygous for this mutation. Because approximately 40% of patients with essential hypertension demonstrate low renin, Wilson et al. (1998) suggested that such patients should undergo genetic analysis of the HSD11B2 gene. In an extensive review of steroid disorders in children, specifically congenital adrenal hyperplasia and apparent mineralocorticoid excess, New and Wilson (1999) provided further information concerning what they alleged was the first reported patient with a mild form of AME. Asymptomatic hypertension was diagnosed at age 12.5 years during a sports physical. The parents were consanguineous Mennonites of Prussian descent (Alexanderwohl Church). The only family member with hypertension was the maternal grandmother. Although the patient lacked hypokalemia and low birth weight and had only mild hypertension, New and Wilson (1999) established the diagnosis for AME genetically.
Nunez et al. (1999) identified 4 novel and 3 previously reported HSD11B2 mutations in 4 patients with AME. Transfection experiments showed that 2 of the mutations abolished activity in whole cells, but that 3 others retained significant activity. ... Nunez et al. (1999) identified 4 novel and 3 previously reported HSD11B2 mutations in 4 patients with AME. Transfection experiments showed that 2 of the mutations abolished activity in whole cells, but that 3 others retained significant activity. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, which was demonstrated in whole cells, with cortisol as the substrate. The parameters included the ratio of urinary cortisone to cortisol metabolites, age at presentation, and birth weight. Approximately 5% conversion of cortisol to cortisone was predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly HSD11B1. In a review, Ferrari (2010) noted that patients with HSD11B2 mutations showed varying degrees of severity in terms of clinical and biochemical features, according to the residual in vivo activity of the mutant enzyme. Mutations can cause a spectrum of disease, ranging from life-threatening disease in early childhood to a milder form diagnosed only in adults as isolated hypertension.
In 9 patients from 8 families with apparent mineralocorticoid excess and hypertension, Mune et al. (1995) identified 7 different mutations in the HSD11B2 gene (see, e.g., 614232.0001 and 614232.0002). All patients were homozygous or compound heterozygous for the ... In 9 patients from 8 families with apparent mineralocorticoid excess and hypertension, Mune et al. (1995) identified 7 different mutations in the HSD11B2 gene (see, e.g., 614232.0001 and 614232.0002). All patients were homozygous or compound heterozygous for the mutations. In vitro functional expression studies showed that the mutant enzymes had decreased or undetectable enzyme activity compared to controls. In affected members of a large consanguineous Sardinian pedigree with AME, Li et al. (1998) found a homozygous mutation in the HSD11B2 gene (R279C; 614232.0006). Expression of the HSD11B2 mutant cDNA resulted in an enzyme with reduced maximum velocity, but similar substrate affinity, compared to activity of the wildtype cDNA. In the patient reported by Werder et al. (1974), Atanasov et al. (2007) identified compound heterozygosity for 2 mutations in the HSD11B2 gene (614232.0012 and 614232.0013).