Rev Esp Endocrinol Pediatr

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Rev Esp Endocrinol Pediatr 2010;1 Suppl(1):33-39 | Doi. 10.3266/RevEspEndocrinologPediatr.pre2010.Nov.10
Mineralocorticoid disorders

Enviado a Revisar: 6 Nov. 2010 | Accepted: 6 Nov. 2010  | En Publicación: 8 Nov. 2010
Felix G. Riepe
Division of Paediatric Endocrinology, Department of Paediatrics. Christian Albrechts University, University Hospital Schleswig-Holstein. 24105 Kiel (Germany)
Correspondencia para Felix G. Riepe, Division of Paediatric Endocrinology, Department of Paediatrics, Christian Albrechts University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
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Fluid balance, sodium and potassium homeostasis and blood pressure are regulated through the effect of aldosterone on polarized epithelial cells. Therefore, disturbances of sodium homeostasis can be caused either by insufficient biosynthesis of aldosterone in the adrenal gland or by disturbed aldosterone signalling at the polarized epithelial cells.

Aldosterone is insufficiently synthesized in various forms of congenital adrenal hyperplasia. An isolated form of aldosterone deficiency is caused by inactivating mutations of the aldosterone synthase gene CYP11B2. Through this, aldosterone is absent in the zona glomerulosa causing life threatening renal sodium loss and potassium retention. Aldosterone deficiency can be treated with 9α-fluorocortisol. Diseases caused by insufficient aldosterone signalling are called pseudohypoaldosteronism (PHA) because of the inadequately high aldosterone level.

PHA is a rare heterogenous syndrome of mineralocorticoid resistance causing insufficient potassium and hydrogen secretion. PHA type I (PHA1) is causing neonatal salt loss, failure to thrive, dehydration and circulatory shock. Two different forms of PHA1 can be distinguished on the clinical and genetic level, showing either a systemic or a renal form of mineralocorticoid resistance. Systemic PHA1 is caused by mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC). Renal PHA1 is caused by mutations of the mineralocorticoid receptor coding gene NR3C2. PHA1 can be treated with extensive sodium supplementation.

Fluid balance, sodium and potassium homeostasis and blood pressure are regulated through the effect of aldosterone on polarized epithelial cells. Therefore, disturbances of sodium homeostasis can be caused either by insufficient biosynthesis of aldosterone in the adrenal gland or by disturbed aldosterone signalling at the polarized epithelial cells. Aldosterone biosynthesis is disturbed in several form of congenital adrenal hyperplasia. These forms of steroidogenic defects are not discussed here. A small group of patients have an isolated form of aldosterone deficiency, a rare disease first described in the early 1960s causing hyponatremia (1, 2).

The aldosterone signal is transduced by the mineralocorticoid receptor (MR) inducing the amiloridesensitive epithelial sodium channel (ENaC) as the leading intracellular actor necessary for sodium conservation. Disruption of the intracellular MR signalling pathways leads to the clinical entity of pseudohypoaldosteronism (PHA).


Aldosterone is synthetized in the zona glomerulosa of the adrenal cortex by the action of four enzymes (Fig. 1). Cholesterol side chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase type 2, 21-hydroxylase and aldosterone synthase. Aldosterone synthase is a cytochrome P450 enzyme which is located in the mitochondria. Aldosterone is a bi-functional enzyme converting 11-deoxycor ticosterone in corticosterone and corticosterone via 18-OH-corticosterone in aldosterone. Aldosterone synthase shows high homology with 11ß-hydroxylase at the protein level(3). Aldosterone synthase needs the redox partner adrenodoxin as well as adrenodoxin reductase as co-factors for its steroidogenic activity.

The gene coding for aldosterone synthase is located on the long arm of chromosome 8 and is called CYP11B2(4). CYP11B2 expression is primarily controlled by angiotensin II and potassium via the angiotensin II receptor and potassium channels.


The MR acts as ligand-dependent transcription factor. MR is coded by the NR3C2 gene. The NR3C2 gene is localized on chromosome 4q31.1(5). The mature MR protein consists of 984 amino acids and can be functionally subdivided in three domains, the N-terminal domain, the DNA-binding domain and the C-terminal ligand-binding domain (LBD). The N-terminal domain contains two distinct activation function (AF) domains, referred to as AF1a and AF1b(6). In addition an inhibitory sequence was characterized. These regions are responsible for the recruitment of co-activators and co-repressors as well as a ligand-dependent interaction with the LBD(7).

The DNA-binding domain contains two zinc-fingers formed by two groups of four cyteines binding two zinc atoms. These zinc-fingers establish the sequence specific contact to the DNA(5). The crystal structure of the LBD has been studied recently(8, 9).


The epithelial sodium channel (ENaC) constitutes the rate limiting step in sodium re-absorption in the apical membrane of epithelia(10). It is characterized by a high selectivity for sodium over potassium and a high affinity for the potassium-sparing diuretics amiloride and triamterene. ENaC is a heteromultimeric protein consisting of three subunits, termed α, β and γ ENaC(11). The α, β and γ ENaC subunits are coded by the SCNN1A gene on chromosome 12p13, and the SCNN1B and the SCNN1G genes on chromosome 16p12. As deduced from the crystal structure of the ENaC orthologue ASIC1 channel, ENaC is likely a trimer consisting of three homologous subunits α, β and γ(12). However, good evidence alternatively supports the presence of two α ENaC subunits in the functional channel(13). All three subunits share about 35% homology at the amino acid level and adopt the same topology, with two transmembrane α helices, a short intracellular amino- and carboxyterminal end and a large extracellular loop corresponding to about two thirds of the protein.


Filtrated sodium is reabsorbed from the glomerular filtrate and potassium is secreted through a tight epithelium in the kidney (Fig. 2). Sodium crosses the apical membrane and enters the epithelial cell through the ion selective ENaC. Sodium is actively exchanged against potassium at the basolateral membrane mediated by the Na, K-ATPase(14). This generates a lumen-negative voltage that drives potassium facilitated through a selective potassium channel (ROMK) into the lumen. Aldosterone binds to MR after passively crossing the epithelial membrane.

The ligand-bound receptor translocates into the nucleus and binds as dimer to response elements in the promoter regions of aldosterone target genes and initiates hormone-mediated gene transcription and repression(15). The sodium transport machinery is initially activated by the transcription of signalling factors. Transepithelial sodium transport is hereby enhanced without a numerical increase in transport proteins. One early induced signalling factor is serum- and glucocorticoid-induced kinase 1 (Sgk1)(16). By the activation of additional proteins ENaC accumulates at the plasma membrane what enhances the transepithelial sodium transport(17). In a later phase translation and allocation of ENaC proteins, basolateral Na+K+ATPase and apical K+ channels (ROMK) is enhanced(18, 19).


Aldosterone synthase deficiency is an autosomal recessively inherited disorder. Due to deficient adrenal zona glomerulosa aldosterone synthase activity, 11-deoxycorticosterone is not efficiently converted to aldosterone. Insufficient aldosterone secretion leads to decreased sodium reabsorption from and potassium secretion into the urine. All affected children present with frequent vomiting, failure to thrive, and severe, life-threatening salt-loss in the first weeks of life. The clinical severity of the disease decreases with age(20). Adolescents and adults may show only the abnormal steroid pattern which persists throughout life(21). The typical steroid profile in patients with aldosterone synthase deficiency consists of low to undetectable aldosterone plasma levels and elevated mineralocorticoid precursor levels. Renin secretion is increased because of poor feedback control. Patients can be categorized through the level of 18-hydroxycorticosterone (18- OH-B) into a type I and a type II deficiency. In type I deficiency 18-OH-B is decreased, whereas it is markedly elevated in type II. Treatment of aldosterone synthase deficiency consists of the substitution of 9α-fluorocortisol, a steroid with high mineralocorticoid activity. Continued mineralocorticoid replacement after childhood is not always necessary(20).

Aldosterone synthase deficiency is caused by inactivating mutations of the CYP11B2 gene(22, 23). Approximately 30 mutations have been characterized scattered over the whole gene. The two variants of aldosterone synthase deficiency are caused by different mutations within the same gene. Until now, it is not possible to explain the two different hormonal phenotypes observed in patients on the molecular level. Most likely different changes of the interaction with the redox partner adrenodoxin due to structural changes of the molecule are responsibly for these findings.


PHA is a rare heterogenous syndrome of mineralocorticoid resistance leading to insufficient potassium and hydrogen secretion. The common clinical features are hyperkalemia, metabolic acidosis and elevated plasma aldosterone levels. PHA has been classified into three distinct clinical forms (Table 1) (24). This classification includes primarily salt losing syndromes, such as PHA type 1 and PHA type 3 and the potassium retaining PHA type 2. All forms are caused by a mineralocorticoid resistance due to disturbances in the mineralocorticoid mediated signal transduction. The clinical features and the underlying pathophysiology of PHA type 1 are described in detail in the following. PHA type 2 is characterized by hyperkalemia and hypertension. It has been described by Gordon et al. as heterogenous syndrome with highly variable plasma aldosterone concentrations, suppressed plasma renin activity, various degrees of hyperchloremia and metabolic acidosis(25). Renal and adrenal functions are normal.

PHA type 2 shows an autosomal dominant mode of inheritance. Deletions and mutations of two members of the WNK serine-threonine kinase family (WNK1 and WNK4) have been identified as disease causing(26). Gordon syndrome can be treated with thiazide diuretics(27). PHA type 3 comprises transient and secondary forms of salt-losing states caused by various pathologies of the kidney, intestine tract or sweat glands. Nephropathies such as urinary tract infections and obstructive uropathies are the most frequent cause(28-31). Contrary to PHA1 and PHA2, the glomerular filtration rate is decreased in these cases. The mechanism resulting in transient mineralocorticoid resistance is not clear.


PHA1 is characterized by neonatal salt loss resistant to mineralocorticoid treatment(32). Laboratory findings are hyponatremia, hyperkalemia and metabolic acidosis. Plasma renin and aldosterone concentrations are highly elevated, reflecting a peripheral resistance of the kidney and other tissues to mineralocorticoids. The medical treatment of PHA1 consists of sodium supplementation. In addition ion exchange resins may be necessary in order to lower elevated potassium levels. Two forms of PHA1 can be distinguished at the clinical and genetic level (33). The severity of the disease and the phenotype of the two genetically different PHA1 forms vary noticeable.


Isolated renal resistance to aldosterone, leading to renal salt loss, hyponatremia, hyperkalemia, metabolic acidosis, failure to thrive, elevated plasma renin and aldosterone concentrations are the characteristics of autosomal dominant PHA1 (adPHA1) (33, 34). The leading clinical sign is insufficient weight gain due to chronic dehydration. Hyperkalemia is generally mild and metabolic acidosis is not always detectable. The patients mainly manifest in early infancy. Medical treatment consists of sodium supplementation what is usually sufficient to lower the elevated potassium levels. Sodium supplementation becomes generally unnecessary by 1 to 3 years of age(32, 35), what is explained by the maturation of the renal salt conservation abilities by the replacement of distal sodium reabsorption through proximal parts of the tubulus. Overall adPHA1 is the milder PHA1 form as the salt-loss is strictly restricted to the kidney. The clinical spectrum ranges from healthy unaffected patients, patients without electrolyte disturbances but elevated plasma renin and aldosterone levels to patients with clinically manifest renal salt loss(36). Elevated aldosterone levels are the only biochemical marker of adPHA1 in adulthood(37). However, reports from several families suggest that adult carriers of causative mutations might also have normal levels of aldosterone(38).

The underlying cause of adPHA1 is an inactivation of the human MR through mutations of the coding gene NR3C2(34). A considerable amount of de novo mutations are found in NR3C2 in affected individuals( 36). Familial NR3C2 gene mutations can cause a very heterogenous disease expression within one family. The reason for the incomplete penetrance of the phenotype is not known. More than 50 different mutations in the human NR3C2 gene causing adPHA1 have been described. These mutations are spread throughout the gene. The first NR3C2 mutations were identified in the late 1990s(34).


The systemic arPHA1 follows an autosomal recessive trait of inheritance. The clinical manifestation is most often within the neonatal period with severe dehydration and hyponatremia due to systemic salt loss, including kidneys, colon and sweat and salivary glands. Elevated sodium concentration in sweat and absent nasal or rectal transepithelial voltage differences can be used as diagnostic tools.

Hyponatremia and hyperkalemia are combined with elevated plasma renin and aldosterone concentrations reflecting end organ resistance. Children suffering from arPHA1 often show pulmonary affections due to reduced sodium-dependent liquid absorption( 39). On clinical grounds cough, tachypnea, fever and wheezing can be recollected(39-42). Interestingly, no neonatal respiratory distress syndromes are reported in arPHA1 patients. In addition phenotypes showing cholelithiasis, skin rashes mimicking milia rubra or dermal infections, salt loss via the Meibomian glands or polyhydramnios are reported(24, 43-45). The arPHA1 is a livelong disease showing no improvement over time(46). Patients are prone to lifethreatening salt loosing crises combined with severe hyperkalemia and dehydration. Medical management consists of extensive salt supplementation.

Additional measures may include the use of potassium lowering agents like ion exchangers. The systemic form of PHA1 is caused by inactivating mutations of the ENaC subunit genes SCNN1A (chromosome 12p13.31), SCNN1B (chromosome 16p12.1) and SCNN1G (chromosome 16p12.1). Various SCNN1A, SCNN1B and SCNN1G mutations are reported to date. The majority of mutations are frameshift or nonsense mutations leading to truncated or completely abnormal proteins, which are nonfunctional. The first missense mutations were reported by Chang et al. in five consanguineous kindreds originating from the Near-East(47).

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