Familial hyperaldosteronism

INTRODUCTION — Familial hyperaldosteronism (FH) is an uncommon subset of primary aldosteronism. Four forms of FH exist:

●FH type I or glucocorticoid-remediable aldosteronism (GRA) due to a CYP11B1/CYP11B2 chimeric gene

●FH type II caused by germline CLCN2 pathogenic variants

●FH type III caused by germline KCNJ5 pathogenic variants

●FH type IV caused by germline CACNA1H pathogenic variants

Pathogenic variants of a related calcium channel gene, CACNA1D, may cause primary aldosteronism with seizures and neurologic abnormalities (PASNA). Severe neurologic manifestations prevent reproduction in affected individuals; consequently, these genetic variants are considered de novo germline causes of primary aldosteronism that cannot manifest as FH.

FH should be suspected in individuals who are diagnosed with primary aldosteronism at age <20 years and/or those who have a family history of either early-onset hypertension or known primary aldosteronism. The diagnosis is confirmed through genetic testing. The four forms of FH and PASNA will be reviewed here. The diagnosis, clinical features, and treatment of primary aldosteronism are discussed separately. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism" and "Treatment of primary aldosteronism".)

APPROACH TO EVALUATING SUSPECTED FAMILIAL HYPERALDOSTERONISM

When to suspect familial hyperaldosteronism — Our approach to the diagnosis and treatment of familial hyperaldosteronism (FH) is largely consistent with clinical practice guidelines from the Endocrine Society [1]. In individuals with a confirmed diagnosis of primary hyperaldosteronism, FH should be suspected if one or more of the following is present (algorithm 1):

●Age <20 years

●Family history of early-onset hypertension or known primary aldosteronism

●Personal or family history of stroke at age <40 years

●Massive adrenal hyperplasia

In the absence of any of these findings, no additional evaluation for FH is needed.

Underlying FH should only be considered in individuals with established primary aldosteronism. Case detection and diagnostic confirmation for primary aldosteronism are reviewed separately. (See "Diagnosis of primary aldosteronism".)

Distinct features — If present, certain clinical features can suggest specific forms of FH.

●Vascular complications including hemorrhagic stroke suggest possible underlying FH type 1, glucocorticoid-remediable aldosteronism (GRA). (See 'Glucocorticoid-remediable aldosteronism' below.)

●Individuals with FH type II usually have a family history of primary aldosteronism in the absence of any other distinguishing features. This is likely the most common form of FH. (See 'Familial hyperaldosteronism type II' below.)

●The diagnosis of primary aldosteronism in prepubertal children suggests underlying FH type III or type IV. Massive adrenal hyperplasia may be evident in both of these forms of FH. (See 'Familial hyperaldosteronism type III' below and 'Familial hyperaldosteronism type IV' below.)

●Exceedingly rarely, children present with primary aldosteronism and severe neurologic manifestations. Such individuals may have primary aldosteronism with seizures and neurologic abnormalities (PASNA). As the neurologic sequelae of PASNA prevent reproduction, it is not technically a form of FH but rather arises exclusively from de novo pathogenic variants. (See 'Primary aldosteronism with seizures and neurologic abnormalities' below.)

Diagnostic evaluation

●Proband – In individuals with confirmed primary aldosteronism and any clinical characteristics suggesting FH, we proceed with genetic testing. Genetic testing is the preferred diagnostic strategy for all forms of FH [2], and laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry. Genetic testing may be targeted if a specific form of FH is strongly suspected. Gene panels also are available and test multiple genes simultaneously.

●Family members – As highlighted in the 2016 Endocrine Society guidelines, case-detection testing for primary aldosteronism should be performed in all hypertensive first-degree relatives of patients with primary aldosteronism [1]. (See "Diagnosis of primary aldosteronism", section on 'Initial testing'.)

GLUCOCORTICOID-REMEDIABLE ALDOSTERONISM

Clinical presentation — Glucocorticoid-remediable aldosteronism (GRA), also known as familial hyperaldosteronism (FH) type 1, is a rare cause of primary aldosteronism. In GRA, aldosterone hypersecretion can be reversed with physiologic doses of glucocorticoid [3-5]. GRA exhibits autosomal dominant inheritance; thus, a single copy of the abnormal gene is sufficient to cause the disease.

●Clinical features – The main clinical features of GRA include the following:

•Young age of onset (typically <20 years of age [3]).

•Family history of early-onset hypertension.

•Personal or family history of stroke at an early age (<40 years) – Individuals with GRA are at increased risk of vascular complications including hypertensive retinopathy, aortic dissection, and hemorrhagic stroke [6]. In the international registry for GRA, 18 percent of patients had a cerebrovascular complication, 70 percent of which were hemorrhagic strokes due primarily to ruptured intracranial aneurysms [7]. The case fatality rate was 61 percent, and the mean age at the initial event was 32 years. In comparison, no strokes occurred in GRA-negative family members.

The factors responsible for the increase in hemorrhagic stroke are uncertain, but congenital hypertension during the early stages of cerebrovascular development likely contributes. The observation of early cerebral hemorrhage in Liddle syndrome, another form of congenital hypertension, is consistent with this hypothesis [8]. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1".)

•Normokalemia – The plasma potassium concentration is normal in most individuals with GRA who are not treated with diuretics [3,9]. One possible explanation for this absence of hypokalemia is that aldosterone release in GRA is primarily under the influence of corticotropin (ACTH); with the normal circadian rhythm of ACTH release, aldosterone hypersecretion may be transient rather than sustained.

•Thiazide-induced hypokalemia – Profound hypokalemia may develop due to diuretic-induced increases in sodium delivery to the aldosterone-sensitive potassium secretory site in the cortical collecting tubule.

●Prevalence – In a study of 300 consecutive patients with primary aldosteronism, only two patients were diagnosed with GRA (prevalence = 0.66 percent) [10].

Pathophysiology

●Normal physiology – In normal physiology, aldosterone is synthesized in the zona glomerulosa, which lacks the 17-hydroxylase enzyme required for cortisol synthesis. Aldosterone synthesis does not occur in the ACTH-sensitive zona fasciculata, which lacks the enzymes required to add an aldehyde to corticosterone at the 18-carbon position. (See "Adrenal steroid biosynthesis".)

Two isozymes of 11-beta-hydroxylase encoded by two genes on chromosome 8 are responsible for the biosynthesis of aldosterone and cortisol (figure 1):

•The isozyme in the zona glomerulosa (CYP11B2, aldosterone synthase, P450as) catalyzes the conversion of deoxycorticosterone to corticosterone and of 18-hydroxycorticosterone to aldosterone.

•The isozyme in the zona fasciculata (CYP11B1, P450c11) catalyzes the conversion of 11-deoxycortisol to cortisol and does not contribute to aldosterone synthesis.

●GRA – GRA is caused by a chimeric CYP11B1/CYP11B2 gene (figure 2) [11,12]. The pathogenic variant (discovered 26 years after GRA was initially described in a single family in 1966) results from fusion of the promoter region of the CYP11B1 gene and the coding sequences of CYP11B2. This chimeric gene causes ACTH-dependent activation of aldosterone synthase, leading to production of cortisol, corticosterone, aldosterone, and cortisol precursors (figure 2) [12,13].

•Aldosterone synthesis in the zone fasciculata – Due to the chimeric gene, ACTH-sensitive aldosterone production occurs in the zona fasciculata rather than the zona glomerulosa, and plasma aldosterone levels decline at night when ACTH levels are low. Location of aldosterone synthesis in the zona fasciculata may also explain why, unlike normal physiology, plasma aldosterone levels do not increase in response to potassium loading [9]. The blunted aldosterone response to potassium and the dependence of aldosterone secretion on ACTH may contribute to the milder degree of hyperaldosteronism with less severe potassium wasting compared with other forms of primary aldosteronism. Also, because aldosterone production occurs in the zona fasciculata, individuals with GRA are biochemically unique in having markedly increased levels of 18-oxocortisol and 18-hydroxycortisol [3,12,13].

•Phenotypic variability – Intrafamily variability is apparent with GRA, suggesting variable regulation of the chimeric gene and/or significant effects of modifier genes. For example, in one family with GRA, only one of three individuals with the chimeric gene had classic features of GRA, whereas the other two had normotension with normal plasma renin activity and aldosterone levels [14].

Diagnosis

●Whom to test – GRA is a rare subtype of primary aldosteronism, and genetic testing should be performed only in selected patients [15]. Indications include primary aldosteronism patients with onset at a young age (eg, <20 years), or a family history of primary aldosteronism or stroke at a young age (eg, <40 years) (algorithm 1) [16]. Similar to other forms of primary aldosteronism, the plasma aldosterone is elevated and plasma renin activity is suppressed, but the aldosterone-renin ratio is typically not as high as with primary aldosteronism caused by an aldosterone-producing adenoma. (See "Diagnosis of primary aldosteronism".)

●Diagnostic confirmation (genetic testing preferred) – In individuals with suspected GRA, we suggest genetic testing rather than dexamethasone suppression testing due to the higher specificity of genetic testing. The laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry. Genetic testing entails molecular biologic techniques to detect the chimeric gene.

Whereas dexamethasone suppression testing previously was used for diagnosis [3], genetic testing is now preferred [17,18]. In a study of 117 patients with primary aldosteronism, no patients had the chimeric GRA gene, but six patients (one with an adenoma and five with idiopathic hyperaldosteronism) had false-positive results on dexamethasone suppression testing [19].

Management — Management entails either glucocorticoid treatment or mineralocorticoid receptor antagonist therapy. Treatment is titrated principally to normalize blood pressure. Glucocorticoid therapy or mineralocorticoid receptor blockade may also have a role in normotensive GRA patients, as hyperaldosteronism can confer end-organ damage independent of hypertension. (See "Treatment of primary aldosteronism", section on 'Treatment goals'.)

●Glucocorticoid treatment (preferred strategy) – We suggest exogenous administration of physiologic doses of a glucocorticoid (such as prednisone, prednisolone, dexamethasone, or hydrocortisone) as the first-line therapy. An intermediate-acting glucocorticoid is preferred for more effective ACTH lowering. Glucocorticoid treatment corrects the overproduction of aldosterone by diminishing ACTH release and will usually reduce or normalize blood pressure and correct hypokalemia (if present) [4,20]. Achieving partial suppression of ACTH is adequate for managing hypertension and helps avoid complications of glucocorticoid overtreatment [20].

The lowest effective dose of an intermediate-acting glucocorticoid (eg, prednisone, prednisolone) should be administered at bedtime to suppress the early morning surge in ACTH. Target blood pressure in children should be guided by age-specific blood pressure percentiles. Children should be monitored by pediatricians with expertise in glucocorticoid therapy, with careful attention paid to avoiding retardation of linear growth by overtreatment.

Patient education and safety precautions for individuals on chronic glucocorticoid therapy are reviewed in detail separately. (See "Treatment of adrenal insufficiency in adults", section on 'Patient education and safety' and "Treatment of adrenal insufficiency in children", section on 'Stress conditions'.)

●Mineralocorticoid receptor antagonist (alternative strategy) – An alternative approach is treatment with mineralocorticoid receptor antagonists, which may be just as effective and avoids the potential disruption of the hypothalamic-pituitary-adrenal axis and risk of iatrogenic side effects [6]. Mineralocorticoid receptor agonist treatment requires initial, close monitoring of serum potassium and creatinine levels, and spironolactone may confer endocrine side effects, including gynecomastia in males and menstrual irregularity in females. The choice of mineralocorticoid receptor agonist in individuals with primary aldosteronism is reviewed separately (algorithm 2). (See "Treatment of primary aldosteronism", section on 'First line: Mineralocorticoid receptor antagonists'.)

●Assessment of stroke risk (controversial) – Some experts suggest that all patients with genetically confirmed GRA should undergo screening magnetic resonance (MR) angiography at puberty and every five years thereafter [7]. However, the benefit of this approach has not been proven and must be weighed against the risk of prophylactic surgery for small aneurysms that might not rupture. The frequency of aneurysm rupture in GRA is somewhat higher than that reported in autosomal dominant polycystic kidney disease, another disorder in which hemorrhagic stroke can occur at a young age. This issue is discussed in detail elsewhere. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

FAMILIAL HYPERALDOSTERONISM TYPE II

Clinical presentation — Familial hyperaldosteronism (FH) type II may be the most common form of FH. It is inherited as an autosomal dominant trait.

●Clinical features – FH type II is the familial occurrence of aldosterone-producing adenoma or bilateral idiopathic hyperplasia, or both, in the same kindred. Biochemically and morphologically, FH type II is indistinguishable from nonfamilial primary aldosteronism.

The presence of FH type II should be suspected in individuals with primary aldosteronism and a positive family history of early-onset hypertension or primary aldosteronism. Intrafamily variability is common, with some kindred members having aldosterone-producing adenomas and others bilateral idiopathic hyperplasia. Except for familial occurrence, FH type II has no unique features or risks beyond those known for primary aldosteronism. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism" and "Treatment of primary aldosteronism".)

●Prevalence – In a series of 199 families with at least one member who had primary aldosteronism, 12 were diagnosed with FH type II (6 percent). The clinical and biochemical phenotypes of FH type II did not differ from those of sporadic primary aldosteronism [10]. A second series generated similar results [21].

Pathophysiology — In a report of a family with FH type II and 80 additional probands with early-onset primary aldosteronism of unknown etiology, a germline CLCN2 chloride channel pathogenic variant was found in eight of the probands [22]. All relatives with early-onset primary aldosteronism carried the CLCN2 pathogenic variant found in the proband. The CLCN2 gene encodes a voltage-gated chloride channel expressed in adrenal glomerulosa cells [23]. In these cells, pathogenic variants in CLCN2 cause greater chloride efflux which, in turn, increases cell depolarization, calcium influx, and aldosterone secretion. Pathogenic variants in the CLCN2 chloride channel may be responsible for all presentations that are classified as FH type II [24]. Alternatively, pathogenic variants in other genes may be identified in the future.

Diagnosis — The laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)

Until more is learned about specific genetic variants that cause FH type II, the subtype evaluation of these patients should be identical to the evaluation in patients with apparent sporadic primary aldosteronism (algorithm 3) [25]. (See "Diagnosis of primary aldosteronism", section on 'Subtype classification'.)

Management — The treatment of FH type II is identical to that of sporadic primary aldosteronism (algorithm 2). (See "Treatment of primary aldosteronism".)

FAMILIAL HYPERALDOSTERONISM TYPE III

Clinical presentation — Familial hyperaldosteronism (FH) type III is rare and inherited as an autosomal dominant trait.

●Clinical features – The presence of FH type III should be suspected in children with primary aldosteronism and in patients with primary aldosteronism and massive adrenal hyperplasia. Most patients with germline KCNJ5 pathogenic variants present with polyuria, polydipsia, and refractory hypertension in childhood. However, age at presentation exhibits some heterogeneity, and patients have presented as late as age 48 years [26]. Affected individuals have marked hypokalemia and profound hyperaldosteronism. In some cases, aldosterone hypersecretion is sufficiently severe that bilateral adrenalectomy is required.

●Prevalence – The estimated prevalence of germline KCNJ5 pathogenic variants is 0.3 percent in patients with primary aldosteronism and 8 percent among patients with FH [27,28].

Pathophysiology — FH type III was first described in a single family in 2008 [29]. Affected family members had refractory hypertension diagnosed in early childhood with adrenal glands that showed massive hyperplasia [29]. The causative germline pathogenic variant was identified in the potassium channel KCNJ5 [30]. This KCNJ5 variant affects the selectivity filter of the channel and causes increased sodium conductance and cell depolarization, triggering calcium entry into glomerulosa cells. Calcium entry is the stimulus for aldosterone production and cell proliferation.

Thus far, 12 kindreds carrying six different germline KCNJ5 pathogenic variants have been identified: p.Thr158Ala, p.Gly151Glu, p.Gly151Arg, p. Ile157Ser, p.Tyr152Cys, and p.Glu145Gln [27,30-33]. Other families with early-onset hyperaldosteronism also have been identified with germline point variants in the KCNJ5 gene [34,35]. For example, in families from Europe with FH in whom FH type I was excluded, a novel germline G151E variant was found in two individuals with primary aldosteronism and a remarkably milder clinical and biochemical phenotype [27]. In two of four families with early-onset primary aldosteronism, germline G151R variants were found in association with severe adrenal hyperplasia that required surgery. Two kindreds had G151E variants and mild primary aldosteronism [31]. Surprisingly, G151E produced much larger sodium conductance than G151R, resulting in rapid sodium-dependent cell lethality; thus, in vivo, this more severe variant may paradoxically lead to attenuated hyperaldosteronism and adrenal hyperplasia.

Diagnosis — Commercially available testing for germline KCNJ5 variants is now available. The laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)

The subtype evaluation in patients with FH type III is identical to that in patients with apparent sporadic primary aldosteronism (algorithm 3) [25]. Adrenal computed tomography (CT) may show massive or milder bilateral hyperplasia. If performed, adrenal venous sampling shows bilateral aldosterone hypersecretion. However, aldosterone secretion may be markedly asymmetric and thereby allow surgical debulking with unilateral adrenalectomy. (See "Diagnosis of primary aldosteronism", section on 'Subtype classification'.)

Management — The treatment of FH type III is usually identical to that of apparent sporadic primary aldosteronism (algorithm 2) [25]. However, in selected cases of refractory disease associated with massive bilateral adrenal hyperplasia, laparoscopic unilateral or bilateral adrenalectomy may need to be considered. (See "Treatment of primary aldosteronism".)

FAMILIAL HYPERALDOSTERONISM TYPE IV

Clinical presentation — Familial hyperaldosteronism (FH) type IV is a rare subtype of primary aldosteronism and should be suspected in children with primary aldosteronism. Findings on adrenal imaging are variable, and massive adrenal hyperplasia may be present. (See "Diagnosis of primary aldosteronism" and "Pathophysiology and clinical features of primary aldosteronism".)

Pathophysiology — In five unrelated families with early-onset primary aldosteronism, an exome-sequencing study identified germline pathogenic variants in CACNA1H, which encodes a T-type calcium channel [36]. A subsequent study identified four additional, unrelated patients with primary aldosteronism caused by germline pathogenic variants in CACNA1H, one of which had a multiplex developmental disorder [37].

Diagnosis — The laboratories that provide clinical genetic testing for germline CACNA1H pathogenic variants can be found in the Genetic Testing Registry. The subtype evaluation for FH type IV is that same as that for apparent sporadic primary aldosteronism (algorithm 3) [25]. Adrenal CT may show an apparent cortical adenoma, bilateral hyperplasia, or normal-appearing adrenal glands. If performed, adrenal venous sampling shows bilateral aldosterone hypersecretion. (See "Diagnosis of primary aldosteronism", section on 'Subtype classification'.)

Management — The treatment of FH type IV is identical to that of sporadic primary aldosteronism (algorithm 2) [25]. However, in selected cases of refractory disease associated with massive bilateral adrenal hyperplasia, laparoscopic bilateral adrenalectomy may need to be considered. (See "Treatment of primary aldosteronism".)

PRIMARY ALDOSTERONISM WITH SEIZURES AND NEUROLOGIC ABNORMALITIES — Primary aldosteronism with seizures and neurologic abnormalities (PASNA) is caused by de novo germline pathogenic variants in CACNA1D, which encodes an L-type calcium channel. Such variants have been reported in three children with primary aldosteronism, seizures, and neurologic abnormalities [38,39]. The severe neurologic abnormalities prevent reproduction, and thus, although due to a germline pathogenic variant, PASNA is not technically a familial form of primary aldosteronism. A missense CACNA1D germline pathogenic variant also was reported in a patient affected by autism and epilepsy, although this patient did not have primary aldosteronism [40].

PASNA is exceedingly rare. It should be suspected in young children who present with neurologic manifestations and primary aldosteronism. The laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary aldosteronism".)

SUMMARY AND RECOMMENDATIONS

●When to suspect familial hyperaldosteronism (FH) – In individuals with a confirmed diagnosis of primary aldosteronism, FH should be suspected if one or more of the following is present (algorithm 1) (see 'When to suspect familial hyperaldosteronism' above):

•Age <20 years

•Family history of early-onset hypertension or known primary aldosteronism

•Personal or family history of stroke at age <40 years

•Massive adrenal hyperplasia

If present, certain clinical features can suggest specific forms of FH. (See 'Distinct features' above.)

●Diagnostic evaluation – In individuals with confirmed primary aldosteronism and any clinical characteristics suggesting FH, we proceed with genetic testing. Genetic testing is the preferred diagnostic strategy for all forms of FH, and laboratories that provide clinical genetic testing can be found in the Genetic Testing Registry. (See 'Diagnostic evaluation' above.)

●Glucocorticoid-remediable aldosteronism (GRA) – GRA or FH type I exhibits autosomal dominant inheritance and is a rare cause of primary aldosteronism.

•Clinical presentation – Individuals with GRA have elevated risk of vascular complications including hypertensive retinopathy, aortic dissection, and hemorrhagic stroke. Most individuals with GRA have normokalemia but may develop profound hypokalemia with thiazide diuretic use. Onset of hypertension usually occurs before age 20 years. (See 'Clinical presentation' above.)

•Pathophysiology – GRA is caused by a chimeric CYP11B1/CYP11B2 gene that results from fusion of the promoter region of the CYP11B1 gene and the coding sequences of CYP11B2. This chimeric gene causes corticotropin (ACTH)-dependent synthesis of aldosterone. (See 'Pathophysiology' above.)

•Management – We suggest treating GRA with glucocorticoid therapy (Grade 2C). The lowest effective dose of an intermediate-acting glucocorticoid (eg, prednisone, prednisolone) should be administered at bedtime. This will correct aldosterone hypersecretion by lowering ACTH and will usually normalize blood pressure. Mineralocorticoid receptor antagonists are a reasonable alternative. (See 'Management' above.)

●Familial hyperaldosteronism type II – FH type II is transmitted in autosomal dominant fashion.

•Clinical presentation – FH type II is the familial occurrence of aldosterone-producing adenoma or bilateral idiopathic hyperplasia, or both, in the same kindred. Biochemically and morphologically, FH type II is indistinguishable from sporadic primary aldosteronism. (See 'Clinical presentation' above.)

•Pathophysiology – Germline CLCN2 chloride channel pathogenic variants may be responsible for all or some of the individuals who have been classified at FH type II. (See 'Pathophysiology' above.)

•Management – Subtype evaluation and treatment of FH type II are the same as for sporadic primary aldosteronism (algorithm 2 and algorithm 3). (See 'Management' above.)

●Familial hyperaldosteronism type III – This rare subtype of primary aldosteronism should be suspected in children with hyperaldosteronism and in individuals with primary aldosteronism and massive adrenal hyperplasia. FH type III is caused by germline pathogenic variants in the potassium channel subunit KCNJ5. Treatment of FH type III is identical to that of sporadic primary aldosteronism (algorithm 2). However, in selected cases of refractory disease with massive bilateral adrenal hyperplasia, laparoscopic unilateral or bilateral adrenalectomy may need to be considered. (See 'Familial hyperaldosteronism type III' above.)

●Familial hyperaldosteronism type IV – FH type IV is also rare. Like FH type III, it should be suspected in children with primary aldosteronism and may present with massive adrenal hyperplasia. FH type IV is caused by germline variants in CACNA1H, which encodes a T-type calcium channel. Treatment of FH type IV is usually identical to that of sporadic primary aldosteronism (algorithm 2). However, in selected cases of refractory disease associated with massive bilateral adrenal hyperplasia, laparoscopic bilateral adrenalectomy may need to be considered. (See 'Familial hyperaldosteronism type IV' above.)

●Primary aldosteronism with seizures and neurologic abnormalities (PASNA) – PASNA is caused by de novo germline pathogenic variants in CACNA1D. The severe neurologic abnormalities prevent reproduction, and thus, PASNA is not technically a familial form of hyperaldosteronism. (See 'Primary aldosteronism with seizures and neurologic abnormalities' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to earlier versions of this topic review.