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EDITORIAL |
Department of Medicine and Experimental Oncology, Division of Internal Medicine 4 and Hypertension, University of Torino, 10126 Torino, Italy
Address all correspondence and requests for reprints to: Paolo Mulatero, Medicina Interna 4, ASO San Giovanni Battista, Via Genova 3, 10126, Torino, Italy. E-mail: paolo.mulatero{at}libero.it.
Primary aldosteronism (PA) is the most frequent form of secondary hypertension accounting for up to 5–10% of all hypertensive patients (1, 2, 3). The diagnosis of this form of hypertension is fundamental because, compared with essential hypertensives with similar risk profiles, patients with PA are more prone to stroke, myocardial infarction, and atrial fibrillation (4) and display an increase in cardiovascular damage and metabolic complications (5). Two familial forms of primary aldosteronism [familial hyperaldosteronism (FH)] have been described so far, referred to as FH-I, also known as glucocorticoid-remediable aldosteronism (GRA), and FH-II (5, 6, 7).
In this issue of the Journal, Geller et al. (8) report a newly described Mendelian form of familial hyperaldosteronism with distinctive clinical and biochemical features from previously described forms.
FH-I/GRA is transmitted as an autosomal dominant disease and is characterized by hypertension, elevated ACTH-dependent aldosterone secretion, renin suppression, and high levels of the hybrid steroids, 18OHcortisol (18OHF) and 18oxo-cortisol (18oxoF). Despite the state of hyperaldosteronism, hypokalemia is uncommon (7, 9). The genetic defect leading to FH-I/GRA is an unequal genetic recombination between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase), generating a chimeric CYP11B gene containing CYP11B1 sequences (including the promoter) at its 5' end and CYP11B2 sequences at its 3' end (7, 9). Because CYP11B1 expression is regulated by ACTH, the hybrid gene encodes a chimeric enzyme with aldosterone synthase activity and ACTH-dependent expression throughout the adrenal cortex. Hence, in FH-I/GRA patients, aldosterone levels are persistently suppressed by glucocorticoid administration. Most affected individuals develop severe hypertension in early life, but patients with mild hypertension or blood pressure in the normal range are described in many families, some of them displaying a notably milder clinical phenotype (10, 11).
FH-II is a nonglucocorticoid remediable familial form of PA (6). Patients affected by FH-II present a family history of PA caused by either an adrenal adenoma or hyperplasia. Each single case of FH-II is clinically, biochemically, and morphologically indistinguishable from apparently sporadic forms of PA. In most families, a vertical transmission suggests an autosomal dominant inheritance. The diagnosis of FH-II is based on the demonstration of PA in at least two members from the same family. Unfortunately, the genetic background of FH-II remains unknown, and thus, the diagnosis is made by the finding of a consistently high Aldosterone Renin Ratio (ARR) (without interfering medications) with a positive confirmatory test (saline load ± fludrocortisone) and lack of the hybrid gene responsible for FH-I/GRA (6). This strategy of studying first-degree relatives in FH-I/GRA and FH-II families allowed the diagnosis of PA in normotensive individuals, indicating a different penetrance of the disease, even within the same family (10, 12). A linkage study involving one large Australian family demonstrated linkage between FH-II and a locus at chromosome 7p22 (13). Subsequently this locus has been shown to be in linkage with FH-II in a second Australian family, a South American family, and more recently two Italian families (12).
Recent evidence from the Framingham Offspring Study (14) has emphasized the importance of aldosterone in the development of hypertension. This study found a significant relationship between ARR and both blood pressure progression and hypertension development among Framingham study participants and significant heritability of the ARR (15). Intriguingly, in a linkage analysis that included 1225 genotyped individuals from 328 families, the most striking locus of linkage for logARR in the multivariable adjusted model was at chromosome 7p (15).
In the study by Geller et al. (8), the authors could not identify the genetic alteration responsible for the disease. However, they excluded the involvement of potential candidate genes such as CYP11B1 and CYP11B2; the angiotensin II and ACTH receptors, DAX-1, which has been implicated in congenital adrenal hypoplasia, and Ad4BP, a transcription factor essential for the transcription of steroidogenic p450 genes; and the nerve growth factor inducible factor B family members Nur77 and Nurr1, which have been implicated in adrenal zonation and potentially involved in the regulation of aldosterone synthase. This new familial form of PA, which could be called familial hyperaldosteronism type III (FH-III), is characterized by severe hypertension in early childhood associated with marked aldosteronism, hypokalemia, and significant target organ damage (8), which were resistant to aggressive antihypertensive therapy including spironolactone and amiloride, thus requiring bilateral adrenalectomy.
These clinical and biochemical features are more severe than those displayed by families with FH-I/GRA and distinctly different from those of FH-II that are usually onset in adulthood. Affected FH-III subjects not only displayed a particularly high aldosterone production but also a poor response to full doses of several classes of antihypertensive drugs, including spironolactone and amiloride: this distinguishes FH-III from the other familial forms and sporadic PA because spironolactone is usually successful in controlling blood pressure.
Another distinct feature of FH-III is the enormous production of 18OHF and 18oxoF. These two steroids are produced at high levels in FH-I/GRA patients and results from the hybrid CYP11B2/CYP11B1 enzyme activity ectopically expressed in the zona fasciculata-reticularis using cortisol as substrate (7, 9). Patients with sporadic PA (and also FH-II patients), sustained by an aldosterone-producing adenoma, also have an increased production of 18OHF and 18oxoF (3–4 times the normal), although it is less than patients with FH-I/GRA (10 times the normal). However, the levels of 18OHF and 18oxoF in the FH-III family are 10 times and 1000 times higher, respectively, compared with those described in FH-I/GRA families. Furthermore, in the newly described form of FH, FH-III, the responses of aldosterone and cortisol to the dexamethasone suppression test (DST) were markedly different from those observed in the other forms of familial hyperaldosteronism as well as from normal subjects: in fact, when DST was performed, FH-III patients displayed a paradoxical increase of aldosterone to twice basal levels and a lack of suppression of cortisol levels, which despite being within the normal range, indicated a defective regulation and inappropriate production.
This finding further distinguishes FH-III from other forms of FH and sporadic PA. When DST is performed in FH-I/GRA patients, aldosterone is suppressed to undetectable levels (7, 9). This is not the case for patients with FH-II or sporadic PA, in which aldosterone can be partially and temporarily suppressed by dexamethasone, although not to undetectable levels (6). However, some patients with sporadic PA have been described with complete suppression of aldosterone levels during DST, without carrying the chimeric gene, and despite extensive studies, the alteration responsible has not been demonstrated (16, 17, 18). Recently a knockout TWIK-related acid-sensitive potassium channel 1–/– (potassium channel subfamily K member 3) mouse model has been described with a phenotype of glucocorticoid-remediable aldosteronism (19) that, in the adult, was restricted to females. It is conceivable that some patients with abnormal aldosterone suppression after DST that do not carry the chimeric gene could have an alteration in the TASK1 channel.
An opposite situation has been described in a patient carrying the chimeric gene but with aldosterone that was not suppressible with dexamethasone administration (20). This condition could be due to an alteration in the ACTH-responsive elements in the promoter of the chimeric gene due to point mutations or to a gene conversion between CYP11B1 and CYP11B2 genes; however, if this were the case, the pathophysiological basis for the increased aldosterone production and the response to the unilateral adrenalectomy described in that patient is unclear (20).
The paradoxical increase of aldosterone levels during DST are reminiscent of the cortisol increase during dexamethasone administration observed in patients affected by the Cartney complex syndrome and primary pigmented nodular adrenocortical disease (21). In FH-III patients, the adrenal glands are markedly enlarged (3–6 times the normal weight) with a diffuse hyperplasia of the zona fasciculata and atrophy of the zona glomerulosa but without evidence of nodularity. FH-III patients also display normal but autonomous cortisol production that is not suppressed by dexamethasone. It could be speculated that cortisol is within the normal range because it is used as a substrate for the production of 18OHF and 18oxoF.
Two previous manuscripts reported conditions that display some similarities with this syndrome (22, 23); however, the biochemical and pathological phenotypes were not well defined, so they cannot be identified as FH-III, and comparison between the different cases is not possible.
The description of this new form of familial hyperaldosteronism is highly relevant and should be of great interest for the readers of the Journal. In the past, the identification of Mendelian forms of hypertension and the identification of responsible genes offered scientists a unique opportunity of understanding complex mechanisms underlying the pathophysiology of blood pressure regulation, even in the wide population of so-called essential hypertensives and sporadic PA. It should be highlighted that most genetic alterations that have been identified as being responsible for monogenic forms of hypertension involve in some way sodium reabsorption, often through an increased stimulation or activity of the mineralocorticoid receptor (5, 24). The future challenge therefore will be the identification of the genes responsible for FH-II and FH-III. Much work has been done by the Brisbane group in the hunt for the gene(s) responsible for FH-II: linkage studies have excluded linkage with the AT1, CYP11B2, and MEN1 as well as candidates within the 7p22 locus, such as RBaK, PMS2, and GNA12 (25). In the case of FH-III, it is conceivable that, rather than genes involved in aldosterone synthesis, regulation, and secretion, the causative gene would be involved in the control of cell growth. It can be hypothesized that mutations predisposing to adrenal cortical hyperplasia and neoplasia may be responsible for some cases of sporadic PA and FH-II, which displays genetic heterogeneity. The identification of the genetic causes of FH-II and FH-III will allow the development of genetic tests that, like the long-PCR test and the Southern blot in FH-I/GRA (7, 9), will permit the study and the diagnosis in a large population of patients, avoiding more cumbersome and less reliable biochemical methods. The early diagnosis in infant patients and preclinical situations will allow the timed institution of a specific therapy, thus preventing the development of target organ damage.
Footnotes
Disclosure Summary: P.M. has nothing to declare.
Abbreviations: ARR, Aldosterone Renin Ratio; DST, dexamethasone suppression test; FH, familial hyperaldosteronism; GRA, glucocorticoid-remediable aldosteronism; 18OHF, 18Ohcortisol; 18oxoF, 18oxo-cortisol; PA, primary aldosteronism.
Received June 9, 2008.
Accepted June 10, 2008.
References
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