Alternative titles; symbols
SNOMEDCT: 703232003; ICD10CM: E26.02; ICD9CM: 255.11; ORPHA: 403; DO: 14080;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.3 | Aldosteronism, glucocorticoid-remediable | 103900 | Autosomal dominant | 3 | CYP11B1 | 610613 |
A number sign (#) is used with this entry because glucocorticoid-remediable aldosteronism (GRA), also referred to as glucocorticoid-suppressible hyperaldosteronism (GSH) or familial hyperaldosteronism type I (HALD1), is the result of an anti-Lepore-type fusion of the CYP11B2 (124080) and CYP11B1 genes (see 610613.0002).
Familial hyperaldosteronism type I (HALD1), also referred to as glucocorticoid-remediable aldosteronism (GRA), is an autosomal dominant disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol (Lifton et al., 1992). There is significant phenotypic heterogeneity, and some individuals never develop hypertension (Stowasser et al., 2000).
Genetic Heterogeneity of Familial Hyperaldosteronism
Familial hyperaldosteronism type II (HALD2; 605635) is caused by mutation in the CLCN2 gene (600570) on chromosome 3q27. Familial hyperaldosteronism type III (HALD3; 613677) is caused by mutation in the KCNJ5 gene (600734) on chromosome 11q24. Familial hyperaldosteronism type IV (HALD4; 617027) is caused by mutation in the CACNA1H gene (607904) on chromosome 16p13.
Sutherland et al. (1966) and Salti et al. (1969) described a father and son with hypertension, low plasma renin activity, and increased aldosterone secretion. The symptoms were responsive to dexamethasone treatment. Growth and sexual development were normal. The father was found to have multiple adrenocortical adenomas. New and Peterson (1967) described 2 cases in a family. Giebink et al. (1973) studied 2 brothers and their mother who had glucocorticoid-remediable aldosteronism.
Ganguly et al. (1981) reported a kindred with GRA spanning 3 generations. The presumptive diagnosis was first made in a 7-year-old boy and led to the identification in his mother and grandmother. Urinary analysis did not identify a putative 'aldosterone-stimulating factor,' suggesting that GRA is a distinct disorder from idiopathic aldosteronism. Bilateral adrenal hyperplasia was present. Ganguly et al. (1981) reported another affected family. The diagnosis of hyperaldosteronism was established by failure of saline infusion to suppress plasma aldosterone normally and by the failure of furosemide or a low sodium diet to stimulate plasma renin activity. One family had basal serum potassium levels below 3.5 mmol per liter, whereas values were normal in the second family. Ganguly et al. (1981) showed that the paradoxic decline in plasma aldosterone when the patient is in the upright posture, usually observed in aldosterone-producing adenoma, is also seen in GRA. Thus, in patients with primary aldosteronism in whom GSH is suspected on the basis of young age and family history and a postural decline in plasma aldosterone is demonstrated, treatment with glucocorticoid should be given for 4 to 6 weeks before localization procedures are begun.
Gordon (1995) reported phenotypic heterogeneity of GRA in at least 21 members of a large kindred encompassing approximately 1,000 descendants of an English convict transported to Australia in 1837 for highway robbery in Northamptonshire. Affected individuals were often normokalemic, and some remained normotensive until late in life. Gordon (1995) referred to the disorder as 'familial hyperaldosteronism type I.'
Gates et al. (1996) described 2 large pedigrees with GRA confirmed by genetic analysis. Most of the affected members, who had only mild hypertension and normal biochemistry, were clinically indistinguishable from patients with essential hypertension. The authors suggested that GRA is an underdiagnosed condition.
Stowasser et al. (1999) found that 10 normotensive individuals with GRA who did not take antihypertensive medication had normal plasma levels and normal upright aldosterone levels. However, plasma aldosterone failed to rise by at least 50% during 2 hours of upright posture in 5 of 7 subjects, or during a 1-hour infusion of angiotensin II (2 ng/kg-min) in each of 6 subjects so studied. Serial, second-hourly (day-curve) aldosterone levels correlated tightly with cortisol (r of 0.79 to 0.97, P less than 0.01 to 0.001) but not with plasma renin activity (PRA) (r of 0.13 to 0.40, not significant) levels in each of 6 subjects, and plasma aldosterone suppressed to less than 110 pmol/L during 4 days of dexamethasone administration (0.5 mg 6 hourly) in each of 2 patients studied, consistent with ACTH-regulated aldosterone production. The authors concluded that biochemical evidence of excessive, abnormally regulated aldosterone production is present not only in hypertensive individuals with GSH, but also in those who are normotensive.
Stowasser et al. (2000) studied 9 GRA individuals with mild hypertension (normotensive or onset of hypertension after 15 years of age, blood pressure never greater than 160/100 mm Hg, 1 medication or less required to control hypertension, no history of stroke, age greater than 18 years when studied) and 17 GRA individuals with severe hypertension (onset before 15 years of age, or systolic blood pressure greater than 180 mm Hg or diastolic blood pressure greater than 120 mm Hg at least once, or more than 2 medications, or history of stroke). Severe hypertension was more frequent in males (11 of 13 males vs 6 of 13 females; P less than 0.05). Four subjects still normotensive after age 18 years were females. Of 10 other affected, deceased individuals (7 males and 3 females) from a single family, 6 who died before 60 years of age (4 by stroke) were males. Aldosterone was unresponsive (rose by less than 50%) to angiotensin II in all subjects. Day-curve studies (blood collected every 2 hours for 24 hours; n = 2 mild and 7 severe) demonstrated abnormal regulation of aldosterone by ACTH rather than by angiotensin II in both groups. The authors concluded that the degree of hybrid gene-induced aldosterone overproduction may have contributed to the severity of hypertension.
Mulatero et al. (2002) reported a 5-generation pedigree from Sardinia in which the presence of the chimeric gene was demonstrated in affected members of 4 generations. This family displayed a mild phenotype, with average blood pressure levels of 131/86 mm Hg for GRA patients. The occurrence of stroke was very low, and preeclampsia was not observed in 29 pregnancies from 8 GRA mothers. Mulatero et al. (2002) found a significant correlation between blood pressure and 18-hydroxycortisol, 18-oxocortisol, and plasma aldosterone levels, but not with kallikrein (KLK1; 147910). However, other biochemical or genetic parameters investigated could not explain the mild phenotype in this family.
In 8 GRA patients who were rendered normotensive for 1.3 to 4.5 years by glucocorticoid treatment, Stowasser et al. (2000) found that urinary 18-oxocortisol levels remained above normal, although they were lower than before treatment. Other biochemical findings during treatment included higher upright plasma potassium, decreased aldosterone, increased renin activity, and decreased aldosterone-to-renin ratios. However, 4 patients had uncorrected renin levels and aldosterone-to-renin ratios. For each of the 8 patients, day-curve aldosterone levels during treatment correlated more tightly with cortisol than with PRA. The findings indicated that control of hypertension by glucocorticoid treatment was associated with only partial suppression of ACTH-regulated hybrid steroid and aldosterone production. Stowasser et al. (2000) concluded that normalization of urinary hybrid steroid levels and abolition of ACTH-regulated aldosterone production may not be a requisite for hypertension control in patients with GRA and cautioned against the risk of cushingoid side effects.
By analysis of a large kindred with glucocorticoid-remediable aldosteronism, Lifton et al. (1992) demonstrated complete linkage to chromosome 8q (maximum lod score of 5.23).
In affected members of a family with GRA, Lifton et al. (1992) identified a chimeric gene in which the 5-prime regulatory sequences of the CYP11B1 gene were fused to the coding region of the CYP11B2 gene (610613.0002), resulting in ectopic expression of aldosterone synthase in the zona fasciculata. In Australian GRA patients, Miyahara et al. (1992) found that the chimeric gene encoded a fused P-450 protein consisting of the amino-terminal portion (exons 1-4) of CYP11B1 and the carboxyl-terminal part (exons 5-9) of CYP11B2.
The chimeric gene responsible for GRA is an example of an 'anti-Lepore-type fusion.' The various hemoglobins Lepore (e.g., 142000.0019) have a fusion beta-type subunit that is delta globin at the NH2 end and beta globin at the COOH end. This chimeric structure results from nonhomologous pairing and unequal crossing-over between the contiguous delta and beta globin genes. The hemoglobins Lepore result from delta-beta fusion because the delta globin gene (142000) is located upstream from the beta globin gene (141900). The hemoglobins anti-Lepore, e.g., Hb Miyada (141900.0179) and Hb P(Nilotic) (141900.0215), are the reciprocal product of nonhomologous pairing and unequal crossing-over between the HBD and HBB genes; they are beta-delta fusion globins. In GRA, the 5-prime portion of the downstream gene is the 5-prime portion of the fusion gene; hence, it is an anti-Lepore fusion.
MacConnachie et al. (1998) used a multiplex PCR protocol that allowed amplification of the control aldosterone synthase and chimeric gene to be carried out in the same tube. They described the regions of crossover in each of 10 GRA kindreds identified in Scotland. To identify crossover regions in each of the kindreds, the chimeric long PCR products were cloned and sequenced. Five crossover sites were identified ranging from intron 2 to exon 4, indicating the reliability of the method in identifying chimeric genes resulting from different sites of crossover.
In 8 patients with idiopathic hyperaldosteronism, a positive dexamethasone suppression test, and a negative genetic test for the chimeric CYP11B1/CYP11B2 gene, Fardella et al. (2001) did not find any abnormalities in exons 3 through 9 of CYP11B1. The authors suggested that a positive dexamethasone suppression test could lead to an incorrect diagnosis of GRA.
White (1989) noted that an enzyme required for aldosterone synthase can be recovered from the zona granulosa of rats that have been sodium-deprived and potassium-loaded. He suggested that glucocorticoid-suppressible hyperaldosteronism might be due to abnormal regulation of CYP11B2 or abnormal structure, such as gene conversion, of CYP11B1.
In glucocorticoid-suppressible hyperaldosteronism, CYP11B2 activity is under the control of ACTH (which normally regulates CYP11B1), which results from an unequal crossing-over involving the CYP11B1 and CYP11B2 genes. These genes are normally in the following orientation: 5-prime--CYP11B2--CYP11B1--3-prime; the hybrid anti-Lepore gene lies between CYP11B2 and CYP11B1 and has B1 sequence at its 5-prime end and B2 sequence at its 3-prime end. The breakpoints of the various hybrid genes that have been studied have been found to be 5-prime of intron 4. Pascoe et al. (1992) demonstrated that hybrid cDNAs containing 5-prime sequences from CYP11B1 and 3-prime sequences from CYP11B2, when transfected into COS-1 cells, resulted in aldosterone synthesis at near normal levels when the constructs contained up to the first 3 exons of CYP11B1, while those with 5 or more exons from CYP11B1 produced no detectable aldosterone.
Pascoe et al. (1995) studied a French kindred in which 7 members had GSH; of the 7, 2 also had adrenal tumors and 2 other members of the family had micronodular adrenal hyperplasia. RT-PCR and Northern blot analysis of 1 of the adrenal tumors and the surrounding adrenal tissue showed that the hybrid CYP11B1/CYP11B2 gene causing the disease was expressed at higher levels than either CYP11B1 or CYP11B2 in the adrenal cortex. In situ hybridization showed that both CYP11B1 and the hybrid chain were expressed in all 3 zones of the cortex. Cell culture experiments demonstrated that hybrid gene expression was stimulated by ACTH, leading to increased production of aldosterone and the hybrid steroids characteristic of GSH. The genetic basis of the tumors and hyperplasia in this family was not known, but may have been related to the duplication causing the hyperaldosteronism.
In glucocorticoid-suppressible hyperaldosteronism, there are increased levels of 18-hydroxycortisol and 18-oxocortisol due to exposure of cortisol to abnormal CYP11B2 activity in the zona fasciculata. These products have been implicated as having a local inhibitory effect on 11-beta-hydroxylase activity (Jamieson et al., 1996). However, in Chinese hamster ovary cells transfected with human CYP11B1 and CYP11B2, Fisher et al. (2001) found that neither 18-hydroxycortisol nor 18-oxocortisol affected the 11-beta-hydroxylase activity of either enzyme. By contrast, 18-hydroxydeoxycorticosterone significantly reduced the conversion rate of 11-deoxycorticosterone to corticosterone and that of 11-deoxycortisol to cortisol by both enzymes, and increased the production rate of 18-hydroxycorticosterone and aldosterone by CYP11B2. Aldosterone synthase was also able to convert 18-hydroxydeoxycorticosterone to 18-hydroxycorticosterone and aldosterone, although its affinity for this substrate was much lower (4.76 micromol/liter) than that for 11-deoxycorticosterone (0.11 micromol/liter).
Mulrow (1981) speculated that the primary defect in GSH resides in the anterior pituitary gland. Experiments in animals had suggested the existence of another aldosterone-regulating hormone, possibly originating in the pituitary. Mulrow (1981) asked: 'Is it possible that in the familial disorder of glucocorticoid-suppressible hyperaldosteronism, the pituitary gland is synthesizing or processing a more potent form of (a fragment of proopiomelanocortin, POMC; 176830) that enhances the response of the adrenal glomerulosa cell to normal concentrations of ACTH?' This hypothesis later proved to be untrue.
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Fisher, A., Friel, E. C., Bernhardt, R., Gomez-Sanchez, C., Connell, J. M. C., Fraser, R., Davies, E. Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11-beta-hydroxylase. J. Clin. Endocr. Metab. 86: 4326-4329, 2001. [PubMed: 11549669] [Full Text: https://doi.org/10.1210/jcem.86.9.7797]
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