Glucocorticoid-remediable Aldosteronism GRA is a rare form of primary aldosteronism in which aldosterone secretion is solely under the control of Adrenocorticotropic hormone ACTH. GRA is caused by a chimeric gene in which the ACTH- responsive 5'-promoter of the 11Beta-hydroxylase gene is fused to coding sequences of the aldosterone synthase gene. This results in ectopic expression of aldosterone synthase activity in zona fasciculata cells of the adrenal cortex under the regulation of ACTH, with resultant hyperaldosteronism and suppression of angiotensin II-stimulated aldosterone production in the zona glomerulosa. The most common presentation of GRA is the discovery of asymptomatic severe hypertension, especially in infancy or early adulthood. A strong family history of hypertension, often associated with early death of affected family members due to cerebrovascular accidents, characteristically is seen in some GRA families. An important clinical clue is the age of onset of hypertension, with GRA patients typically diagnosed with high blood pressure as children; this is in contrast to patients with other mineralocorticoid excess states, such as aldosterone producing adenomas and idiopathic hyperplasia, who usually are diagnosed in the third through sixth decades of life.

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Robert G. Dluhy, Richard P. Sutherland et al. Thirty years later, the genetic basis of this disorder is completely understood. In that description, aldosterone secretion was solely regulated by ACTH, and the syndrome was reversed by exogenous glucocorticoid therapy. A similar syndrome was subsequently reported by New and Peterson 2 1 yr later. Glucocorticoid-remediable aldosteronism GRA , alternatively called dexamethasone-suppressible hyperaldosteronism DSH or familial hyperaldosteronism type I, a mineralocorticoid-excess state characterized by low PRA, is now a well-established subset of primary aldosteronism.

However, recent evidence suggests that the full expression of the classic mineralocorticoid phenotype, such as hypokalemia, is seen in only a minority of GRA patients.

Cases of GRA have been reported worldwide. Many affected families in North America are of Celtic ancestry; no known cases are reported among blacks.

Unlike other etiologies of primary aldosteronism, which occur with increased frequency in women and are usually diagnosed in the 3rd to 5th decades of life, hyperaldosteronism in GRA is evident from birth onward. GRA is inherited as an autosomal dominant trait, occurring equally among men and women.

Under normal conditions, aldosterone production is regulated by the renin-angiotensin system and potassium balance. In GRA, aldosterone secretion is positively and solely regulated by ACTH, the renin-angiotensin system is suppressed, and there is an absence of the normal potassium-induced increase in aldosterone secretion.

This dysregulation of aldosterone secretion solely by a hormone that is not sensitive to sodium balance explains the autonomy of aldosterone production, resulting in a chronic mineralocorticoid excess state. The regulation of aldosterone by ACTH in GRA also results in a circadian pattern of aldosterone production that parallels that of cortisol. In addition, the administration of exogenous glucocorticoids that suppress ACTH secretion result in the suppression of aldosterone levels and a reversal of this mineralocorticoid excess state thus, the appellation DSH or GRA.

However, aldosterone responsiveness to Ang II can be restored by chronic therapy with exogenous glucocorticoids. Thus, glucocorticoid treatment reverses the volume expansion associated with GRA, leading to reactivation of the suppressed renin-angiotensin system and restoration of function of the previously suppressed zona glomerulosa. The adrenal cortex in GRA produces large quantities of oxygenated cortisol compounds, oxocortisol oxo-F , and hydroxycortisol OH-F , so-called hybrid steroids because they possess enzymatic features of both zona glomerulosa and zona fasciculata steroids that is, exhibiting aldosterone and hyroxylase activities, respectively 3.

Elevated levels of these compounds in a timed h urine collection provides a highly sensitive and specific test to diagnose GRA. GRA is easily distinguished from the aldosterone-producing adenoma APA; the only other condition in which there is overproduction of oxo-F and OH-F because the levels of these compounds are 20 to 30 times higher than normal in GRA compared to only modest elevations in APA.

It is not clear whether oxo-F and OH-F possess sodium-retaining properties and contribute to the phenotypic variability of this disorder. GRA is usually characterized by moderate to severe hypertension with onset early in life.

The diagnosis of hypertension in childhood or adolescence may be delayed due to failure of some clinicians to appreciate the normative blood pressure levels in these patient groups. Thus, the blood pressure levels in GRA-affected children are usually greater than the percentile of age- and sex-matched controls. Hypertension associated with GRA is often difficult to control with conventional antihypertensive agents. In addition, the blood pressure in GRA-affected subjects within and between pedigrees is often highly variable; while most are severely hypertensive, some affected individuals are normotensive whereas others have only mild hypertension.

This variability in blood pressure levels in GRA may relate to other hereditary factors that regulate blood pressure or environmental factors such as variation in dietary sodium intake. Thus, the family history in GRA does not invariably reveal a history of severe hypertension in first-degree relatives of affected subjects.

Early, often fatal, cerebrovascular complications in GRA patients were sporadically reported by earlier investigators. The mean age at the time of the initial event was 32 yr, and the underlying mechanism was intracranial aneurysm. Accordingly, screening of asymptomatic GRA patients with magnetic resonance angiography is recommended, beginning at puberty and every 5 yr thereafter similar to the recommendations for patients with adult polycystic kidney disease, where there is a similar frequency of aneurysm.

Normokalemia in GRA-affected patients was first described by Grim and Weinberger 4A , but it was believed to be uncommon. A prospective study by Rich et al. Other investigators screening at-risk relatives in GRA families have corroborated this finding.

Thus, serum potassium lacks sensitivity as a screening test for this mineralocorticoid-excess state. The mechanism s for the absence of hypokalemia in GRA are unknown, but there does not seem to be an impairment in renal responsiveness to potassium loading or florinef administration. GRA is inherited as an autosomal dominant trait that follows classic Mendelian genetics. Lifton et al.

This gene duplication results in ectopic expression of aldosterone synthase activity in the cortisol-producing zona fasciculata. As a result, aldosterone and the novel steroids OH-F and 18 oxo-F are produced ectopically in the zona fasciculata under the regulation of adrenocorticotropin from cortisol and cortisol steroid precursors. In 11 additional GRA pedigrees all subjects proved to have chimeric gene duplications, but in these subjects a minimum of eight independent mutations with five different sites of crossing over were identified 7.

Confirmation of the presence of such chimeric gene mutations was subsequently reported in another study of four additional patients from unrelated GRA pedigrees by Pascoe et al.

DNA sequence analyses of the chimeric genes from unrelated pedigrees indicate that the sites of fusion are variable, but in all cases are upstream of exon 5, suggesting that encoded amino acids in exon 5 of aldosterone synthase are essential for aldosterone synthase enzymatic function.

Expression of various chimeric gene constructs in vitro has demonstrated that when these genes are fused after exon 3 the expressed product retains aldosterone synthase enzymatic activity, whereas when the fusion is after exon 5 aldosterone synthase enzymatic activity is undetectable.

These results suggest that a gene conversion involving exons 5 and 6, in which these residues are encoded, could cause a novel form of GRA. However, to date, no conversions of the CYP11B1 gene expected to cause GRA involving exons 4, 5, and 6 from CYP11B2 have been found in a sample of low renin hypertensive patients, patients with primary aldosteronism, and 90 normotensive individuals Jamieson et al.

Individuals inheriting the chimera from their mothers also had significantly higher basal mean arterial pressure and basal aldosterone levels compared with individuals with a paternal source of the chimeric gene.

The authors speculated that chronic exposure of the developing fetus to high mineralocorticoid levels could alter the expression of the genes that regulate aldosterone synthesis.

However, they were not able to show a difference in basal plasma aldosterone concentrations between affected and unaffected GRA siblings to support this hypothesis, but the numbers of normal siblings studied was small. GRA can masquerade as essential hypertension because most affected subjects are normokalemic and their blood pressures can range from mildly to severely elevated 5.

Many patients are refractory to conventional antihypertensive agents but may become hypokalemic if potassium-wasting diuretics are administered. However, a careful medical history can be revealing. The diagnosis of GRA should be considered in a patient with hypertension of early onset especially children or a history of early onset hypertension in first-degree relatives. Another clue is a prominent family history of mortality or morbidity from early hemorrhagic stroke. PRA will be suppressed unless mineralocorticoid antagonists such as spironolactone or amiloride have been used as therapeutic agents.

Aldosterone blood levels or urinary aldosterone excretion rates are usually normal or mildly elevated, but the levels may be inappropriate for the intake of sodium since production is solely regulated by ACTH. Although most patients show a significant improvement in blood pressure levels following DST, PA levels or aldosterone excretion rates have been the primary end points of this test.

A fall in aldosterone to nearly undetectable levels after low-dose DST 0. Test length variability can be a cause of misinterpretation because DST of short duration can result in false positive results, whereas longer duration tests may yield false negative results as aldosterone levels return to the normal range subsequent to reactivation of the renin-angiotensin system.

However, autonomous production of aldosterone in APA accounts for the failure of aldosterone levels to fall to very low or nearly undetectable levels. It was with these observations in mind that the late Dr. Stanley Ulick favored the term GRA over DSH for the disorder that he biochemically characterized by the measurement of unique steroid metabolites 3.

Urinary excretion of the oxygenated cortisol corresponds OH-F and oxo-F are markedly elevated in GRA and provide a sensitive and highly specific test to diagnose this disorder. However, measurement of urinary OH-F and oxo-F necessitates a h collection, but, more importantly, the assay is usually not available to most practicing clinicians.

The above reasons, combined with the inconvenience of DST, support the use of direct genetic testing for the chimeric gene to diagnose GRA. After DNA extraction the hybrid or chimeric gene can be detected by the Southern blot approach [developed by Lifton et al. The advantage of the long-PCR method is that it is considerably faster and cheaper than Southern blotting.

The gratifying reduction in blood pressure in response to directed monotherapy see below underscores the importance of making the diagnosis of GRA. To date, randomized studies have not been performed that compare various pharmacological treatment regimens in GRA. Suppression of the hypothalamic-pituitary-adrenal axis does not always result in normalization of blood pressure in GRA.

This may relate to the duration of hypertension, end-organ injury from poorly treated hypertension, concomitant essential hypertension, or, rarely, autonomous production of aldosterone in patients with longstanding GRA. Target blood pressure in children should be guided by age-specific blood pressure percentiles.

Children should be followed by physicians who have experience in administering glucocorticoid therapy; linear growth should be monitored with a stadiometer to detect any slowing as a result of overtreatment. Another side effect of glucocorticoid suppression is hypoaldosteronism with salt wasting, hypotension, and hyperkalemia immediately after treatment is initiated.

This occurs because aldosterone levels fall to nearly undetectable levels and the zona glomerulosa remains acutely hypofunctional as a result of chronic suppression of the renin-angiotensin system. Spironolactone, a competitive antagonist of aldosterone for the mineralocorticoid receptor, is often very effective as monotherapy in treating GRA patients.

Potassium-wasting diuretics Spironolactone also has antiandrogenic actions with chronic usage commonly resulting in erectile dysfunction, decreased libido, and gynecomastia in adult men; menstrual irregularities are seen in women. Gastrointestinal symptoms such as nausea may be ameliorated if the drug is taken with food. Amiloride blocks the aldosterone-regulated sodium epithelial channel in the distal nephron and is an alternative to spironolactone treatment.

Like spironolactone, it usually restores normokalemia in subjects with low serum potassium, but may require the addition of other diuretics or antihypertensive agents to normalize blood pressure. Divided dosing should be used starting at 5 mg twice daily, with a maximum dose of 15 mg twice daily. Triamterene, an alternative treatment to amiloride, also acts to inhibit the distal nephron sodium epithelial channel.

Adverse effects of this drug include rash and abnormalities of liver enzymes. The extended-release formulation of the dihydropyridine calcium channel blocker nifedipine has also been advocated in the medical management of primary aldosteronism because this agent has also been shown to inhibit aldosterone biosynthesis in vitro. However, the antihypertensive response to nifedipine as monotherapy in various etiologies of primary aldosteronism has been generally disappointing. However, the antihypertensive response to dihydropyridine calcium channel blockers, such as amlodipine and nifedipine, can be gratifying in patients with GRA Dluhy R.

Can Med Assoc J. Google Scholar. J Clin Endocrinol Metab. Ann Intern Med. Nat Genet. Nat Struct Biol. Clin Sci Colch. Aust NZ J Med. Oxford University Press is a department of the University of Oxford.


A Case of Glucocorticoid Remediable Aldosteronism and Thoracoabdominal Aneurysms

Robert G. Dluhy, Richard P. Sutherland et al. Thirty years later, the genetic basis of this disorder is completely understood.


The International Registry For Glucocorticoid-Remediable Aldosteronism

Glucocorticoid remediable aldosteronism also describable as aldosterone synthase hyperactivity , is an autosomal dominant disorder in which the increase in aldosterone secretion produced by ACTH is no longer transient. It is a cause of primary hyperaldosteronism. Patients with GRA may be asymptomatic , but the following symptoms can be present:. Aldosterone synthase is a steroid hydroxylase cytochrome P oxidase enzyme involved in the generation of aldosterone.


Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism. Glucocorticoid-remediable aldosteronism GRA is a monogenic form of human hypertension that predisposes to cerebral hemorrhage. As a result of a chimeric gene duplication, aldosterone is ectopically synthesized in the cortisol-secreting zona fasciculata of the adrenal gland under the control of adrenocorticotropin ACTH. Hypertension frequently has its onset during childhood and is usually refractory to standard anti-hypertensives such as ACE inhibitors and b -blockers. Hypokalemia can develop in those treated with a potassium-wasting diuretic, but random potassium levels are usually normal. Diagnosis has been facilitated by the availability of a genetic test.


Glucocorticoid remediable aldosteronism

Glucocorticoid remediable aldosteronism GRA is rare familial form of primary aldosteronism characterized by a normalization of hypertension with the administration of glucocorticoids. We present a case of GRA and thoracoabdominal aneurysm complicated by multiple aortic dissections requiring complex surgical and endovascular repairs. Registry studies have shown a high rate of intracranial aneurysms in GRA patients with high case fatality rates. The association of thoracoabdominal aneurysms with GRA has not been described, thus far, in literature. Studies have shown that high tissue aldosterone levels concomitant with salt intake have a significant role in the pathogenesis of aneurysms and this may explain the formation of aneurysms in the intracranial vasculature and aorta. The association of GRA with thoracic aortic aneurysms needs to be further studied to develop screening recommendations for early identification and optimal treatment.

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