Glucocorticoid-remediable aldosteronism 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 ... Glucocorticoid-remediable aldosteronism 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 (605635) has been mapped to chromosome 7p22. Familial hyperaldosteronism type III (613677) is caused by mutation in the KCNJ5 gene (600734) on chromosome 11q24.
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 ... 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.
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 ... 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 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 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.