Familial hyperaldosteronism type IIISilvia Monticone

Familial hyperaldosteronism type III

Silvia Monticone

, Martina Tetti

, Jacopo Burrello

, Fabrizio Buffolo

, Raffaella De Giovanni

, Franco Veglio

, Tracy Ann Williams

, Paolo Mulatero

1

University of Torino, Department of Medical Sciences, Division of Internal Medicine and Hypertension Unit, Via Genova 3, 10126, Torino, Italy.

2

Division of Internal Medicine and Angiology, Department of Internal Medicine of Rimini, Giovanni Ceccarini Hospital, Riccione, Italy.

3

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, 80336 München, Germany

Word count: 3629

Brief title: Familial hyperaldosteronism type III

N° of figures and tables: 2 figures, 1 table

Funding: P.M. and S.M. are in receipt of a grant from the Italian Ministry of the Instruction, University and Research (ex-60% 2013 and 2014 P.M.; ex-60% 2014 and 2015 S.M).

Corresponding author:

Paolo Mulatero, MD, Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Via Genova 3, 10126, Torino, Italy.

e-mail: paolo.mulatero@libero.it

Phone: +390116336959 Fax: +390116336931

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Abstract

Primary aldosteronism is the most common form of endocrine hypertension. This disorder comprises both sporadic and familial forms. Four familial forms of primary aldosteronism (FH-I to FH-IV) have been described. FH-III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4 (also called GIRK4). These mutations alter the selectivity filter of the channel and lead to abnormal ion currents with loss of potassium selectivity, sodium influx and consequent increased intracellular calcium that causes excessive aldosterone biosynthesis. To date, eleven families have been reported, carrying six different mutations. Although the clinical features are variable, FH-III patients often display severe hyperaldosteronism with an early onset, associated with hypokalemia and diabetes insipidus-like symptoms. In most cases FH-III patients are resistant to pharmacological therapy and require bilateral adrenalectomy to control symptoms. In the present manuscript we review the genetics and pathological basis of FH-III, the diagnostic work-up, clinical features and therapeutic management. Finally, we will describe a new case of FH-III of an Italian patient carrying a Gly151Arg mutation.

Introduction

Primary aldosteronism (PA) is now recognized as the most common form of endocrine hypertension, responsible for around 10% of all cases of hypertension in referral centers (1). The diagnosis of PA and correct subtype differentiation are of outmost importance, in light of the increased risk of cardio- and cerebrovascular complications associated to aldosterone excess (2,3).

A wealth of studies has demonstrated the pivotal role of aldosterone excess in cardiac, vascular  and renal damage (4). PA is a heterogeneous group of disorders, involving both sporadic (aldosterone-producing adenoma and bilateral adrenal hyperplasia) and familial forms. To date, 4 types of familial hyperaldosteronism (FH) have been reported, referred to as FH-I to FH-IV (5,6).

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Until recently, our knowledge of the genetic and molecular basis of familial hyperaldosteronism was limited to FH-I, also known as glucocorticoid-remediable aldosteronism. FH-I is transmitted as an autosomal dominant disorder and is caused by an unequal crossing-over between the CYP11B1 and CYP11B2 genes, encoding for 11β-hydroxylase and aldosterone synthase, respectively (7). This genetic recombination results in the formation of a chimeric enzyme with aldosterone synthase activity and 11β-hydroxylase regulation, that can produce aldosterone under the control of ACTH (7,8). The biochemical hallmark of FH-I is the overproduction of the hybrid steroids 18- hydroxycortisol and 18-oxocortisol and clinically it can be cured with low doses of dexamethasone (9). FH-II is a non glucocorticoid remediable familial form of PA, first reported in 1991 (ref. 10).

FH-II is clinically and biochemically indistinguishable from sporadic PA and is diagnosed when at least two first-degree members of the same family are affected by PA. The causative molecular mechanism is likely to be heterogeneous and remains unclear although a linkage with 7p22 has been implicated in some families (11). The introduction of next-generation sequencing platforms, led to the identification of two novel forms of FH. FH-III was reported as a separate entity for the first time in 2008 and its genetic basis, represented by germline mutations in the KCNJ5 gene, was unravelled by Choi et al. in 2011 (ref. 12). FH-IV is inherited as an autosomal dominant trait with incomplete penetrance and is caused by mutations in the CACNA1H gene, encoding for the alpha subunit of a L-type voltage-gated calcium channel, Ca

3.2. Two patients have been reported with an additional genetic form of PA caused by germline de novo mutations in CACNA1D that is associated with neurological alterations (referred to as PASNA syndrome, Primary Aldosteronism with Seizures and Neurologic Abnormalities) (6,13). PASNA is not a familial form of PA because the severe neurological comorbidities do not allow the affected individuals to reproduce.

This review provides an overview of current knowledge on familial hyperaldosteronism type III.

The genetic basis, clinical phenotype and medical management are discussed and a new clinical case is described.

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Familial hyperaldosteronism type III Historical description

The first family affected by a form of non glucocorticoid-remediable familial hyperaldosteronism (that was named FH-III) was reported by Geller et al. in 2008 (ref. 14). This family was composed of three affected members, a father and his two daughters. Notably, the remarkable phenotype of the index case (the father) was previously reported by Therien el al. in 1958 (ref. 15). He presented at the age of 3 with hypertension, polyuria, polydipsia, nicturia, daily headache and myalgia. Blood pressure recordings at age of 5 years ranged between 160/200 mmHg for systolic blood pressure and 115/140 for diastolic blood pressure with one reading of 300/190 mmHg recorded. An electrocardiogram and a chest X-ray were performed and left ventricular hypertrophy was diagnosed. The remarkable biochemical findings were alkalosis (venous blood pH 7.47), severe hypokalaemia (2.1-3.0 mEq/L) and elevated 24h urinary aldosterone levels (67 µg/die, normal range 1-8 µg/die). Considering the clinical, hormonal and biochemical phenotype the boy was diagnosed with PA and underwent bilateral adrenalectomy at the age of 9 years. Histopathological examination revealed bilateral enlargement of the adrenal glands, with the right adrenal weighing 8.0 g and the left 9.0 g together with marked nodular hyperplasia of the zona fasciculata. After surgery, blood pressure, plasma potassium levels and diuresis normalized within two weeks (15).

Twenty-six years later, the two daughters of the index case came to medical attention because of early onset severe hypertension (14). They were aged 7 and 4 years and blood pressure reported values were 188/140 and 148/114 mmHg respectively. Biochemical and hormonal phenotype were characterized by low plasma potassium levels (<2 mEq/L for both sisters) and high aldosterone levels (up to 185 ng/dL) despite suppressed PRA. To rule out FH-I, the two girls were hospitalized and underwent a 3-weeks dexamethasone suppression test. Unexpectedly, not only blood pressure and plasma aldosterone levels failed to be normalized by dexamethasone, but showed a paradoxical progressive increase during glucocorticoid administration, while PRA remained suppressed. The

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two girls were then lost at follow up, but presented again 11 years later with severe hypertension and hypokalaemia resistant to multidrug therapy, including spironolactone and potassium supplementation (14). Plasma steroid profiling revealed suppressed ACTH levels and cortisol levels in normal range, marked elevations of desoxycorticosterone, 18-hydroxycorticosterone and minor elevations in corticosterone levels; urinary steroid excretion demonstrated normal free cortisone and cortisol and extremely elevated excretion of unconjugated 18-hydroxycortisol (6126 and 3432 µg/d) and 18-oxocortisol (250 and 200 µg/d). Due to the marked increase in hybrid steroids a second dexamethasone suppression test was performed, which failed again to normalize blood pressure and caused aldosterone level to double and cortisol excretion to paradoxically increase, indicating a complete deregulation of adrenal cortex function. The control of hypertension required, as for the father, bilateral adrenalectomy and after surgery blood pressure and potassium normalized within two weeks. The removed glands were markedly enlarged and at pathology presented complete loss of normal zonation, being composed mainly of lipid laden cells throughout the cortex without clearly discernible zona glomerulosa-like cells (16). A recent immunohistochemical and immunofluorescence study explored the cellular distribution of the main enzymes involved in human steroidogenesis, CYP17 (17alpha-hydroxylase), CYP11B1 and CYP11B2 in the adrenal glands removed from the two girls. The most relevant and unexpected finding was the co- expression of CYP11B2 and CYP11B1, CYP11B2 and CYP17 or even the expression of the three enzymes in some cells (contrary to its normal expression pattern), thereby explaining the high levels of hybrid steroids 18OH-cortisol and 18oxo-cortisol in these patients (16).

At the first analysis, DNA sequencing of candidate genes did not uncover any causative mutations.

Thus, the genetic basis of FH-III remained unknown until the discovery of mutations driving aldosterone excess in the KCNJ5 gene as described below (12).

Genetics and pathophysiology.

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FH-III is caused by germline mutations in the KCNJ5 gene. Choi et al (12) identified a germline KCNJ5 mutation (Thr158Ala) using a whole exome sequencing approach in the FH-III family described by Geller et al. (14). The KCNJ5 gene is located on chromosome 11q24 and encodes for

an inward rectifying potassium channel, GIRK4, also known as Kir3.4, that exists both as a homotetramer and a hetero tetrameric complex with GIRK1 (encoded by the KCNJ3 gene) (17).

GIRK4 is expressed in heart (18), central and peripheral neurons (19). In the adrenal glands GIRK4 is expressed in APAs, fetal and adult normal adrenals (20), where it is localized to the zona glomerulosa and to the outer part of the zona fasciculata (12,20).

Under physiological conditions, adrenal zona glomerulosa cells display high resting K

conductance and GIRK4 contributes to the maintenance of the cell membrane in a hyperpolarized state. All the mutations alter highly conserved amino acids and affect the selectivity filter of the channel.

Electrophysiological studies showed that KCNJ5 mutations that cause FH-III result in loss of ion selectivity, Na

entry, cell membrane depolarization and increase intracellular Ca

concentration (21,22). The increased calcium concentration stimulates the transcription of CYP11B2 through its main transcriptional factor NR4A2 (ref. 20), which finally results in an increased aldosterone overproduction (21).

Following the original findings by Choi et al., a further 5 germline KCNJ5 mutations (Figure 1) and 10 FH-III families were reported (plus one in the present manuscript), as shown in Table 1. Of note, studies in vitro conducted on HAC15 adrenocortical cells, showed that the Tyr152Cys substitution resulted in a milder electrophysiological phenotype compared to other KCNJ5 mutations (23). The Gly151Glu mutation caused cell lethality. This lethality was due to a massive increase in Na

conductance with extremely high levels of intracellular Na

, causing osmotic shock and cell death.

This finding could at least partially explain the lack of adrenal hyperplasia and the mild clinical phenotype in the affected individual, as it will be further detailed. Nonetheless the surviving cells are able to produce large amount of aldosterone causing hypertension (24,25). In vitro studies on

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NCI-H295R adrenocortical cells showed that the mutated GIRK4 exhibited a different pharmacological profile compared to the wild-type channel. In particular, treatment with verapamil partially blocked the activity of both Gly151Arg and Thr158Ala GIRK4 (ref. 26), however this experimental data did not have a practical therapeutic implication in FH-III patients carrying these two mutations, which display hypertension resistant to multi-drug regimens.

Germline missense mutations that are further removed from the selectivity filter (Arg52His, Glu246Lys, and Gly247Arg) and a rare non-synonymous single nucleotide polymorphism rs7102584 causing the Glu282Gln substitution, have been proposed to play a role in the development of sporadic idiopathic hyperaldosteronism (27). Moreover, Sertedaki et al. described two novel heterozygous germline mutations in the KCNJ5 gene, Val259Met and Tyr348Asn in two hypertensive patients without PA, but who exhibited ACTH-dependent aldosterone hypersecretion, further expanding the clinical spectrum of phenotypes associated with KCNJ5 mutations (28).

Diagnosis, Prevalence and Phenotypes

According to the recently updated Endocrine Society Guideline, the diagnosis of FH-III should be considered in all patients with PA with onset at a very young age (29). The diagnosis of FH-III was based initially on the peculiar clinical phenotype of the family reported by Geller et al. (14).

However, it soon became evident that these special features were not a general feature of FH-III (30) and KCNJ5 sequencing of a peripheral blood sample is the only reliable way to diagnose the condition. Moreover, dexamethasone suppression testing has not been performed systematically in all affected subjects: therefore, the characteristic response of a patient with FH-III to this test remains to be determined.

FH-III is rare and the prevalence of the condition has not been investigated in large populations.

Mulatero et al. reported the presence of a KCNJ5 germline mutation in 2 PA-affected subjects from an Italian family in a cohort of 300 patients with PA and 12 families with non glucocorticoid remediable familial PA, corresponding to a 0.3% prevalence among PA patients and 8% among

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familial forms (25). Following the discovery of different KCNJ5 mutations causative for FH-III, a genotype-phenotype correlation became evident, with most of the affected families displaying a severe phenotype (30).

The clinical phenotype of the subjects carrying the Thr158Ala (12,14,15) mutation has been described in a previous paragraph.

The Gly151Glu mutation (24,25,31) has been reported in seven patients from three different families (in one patient from a three generation kindred the genotype is not available, however he displayed the typical FH-III clinical phenotype with early onset PA). In one family from Torino, Italy, the hybrid steroid levels were slightly increased, but within the range observed for sporadic primary aldosteronism (25,32). Dexamethasone suppression testing demonstrated unchanged blood pressure and aldosterone levels, in contrast to the original FH-III family described by Geller et al (14). All but two of the affected members presented with severe hypertension and hypokalemia in early childhood. They were diagnosed with PA (high aldosterone levels and suppressed renin activity) but the disease progress was favourable. In all affected patients hypertension and hypokalemia were well controlled with pharmacological therapy with spironolactone and amiloride.

Only two patients underwent adrenalectomy (one had bilateral adrenalectomy and the other had 90% left adrenalectomy) because mineralocorticoid receptor antagonists were not available (24).

Furthermore, none of the patients showed hyperplasia at adrenal imaging.

The Gly151Arg mutation (24,33) was detected in six patients belonging to four different families (including the new case reported in the present manuscript). The affected patients had early onset PA (similar to patients with the Gly151Glu mutation), but the disease was progressive; the normalization of blood pressure, serum K

levels and the symptoms mimicking diabetes insipidus required bilateral adrenalectomy in three patients, one had total left adrenalectomy and partial right adrenalectomy and one patient was reported to have difficult to control hypertension but was lost at follow-up. Histological examination showed diffuse hyperplasia of the adrenal cortex in three out of

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four patients who had surgery. Interestingly, the patient reported by Adachi et al. (33), despite early onset and a severe phenotype, had blood pressure successfully controlled with spironolactone and adrenal imaging did not show adrenal enlargement (33). She displayed a modest increase in 18- hydroxycortisol (33), while for all the other patients carrying the Gly151Arg mutation hybrid steroids data were not available.

The Ile157Ser mutation (34) was reported in two patients from a single family. Both showed severe hypertension and hypokalemia in childhood with massive adrenal hyperplasia and bilateral adrenalectomy was required.

The Tyr152Cys mutation (23) was detected in a 62-year-old African-American woman.

Surprisingly, she was diagnosed with arterial hypertension at 48 years. Considering her resistant hypertension on four antihypertensive drugs, she underwent left adrenalectomy on the basis of adrenal CT scanning but serum aldosterone levels did not normalize. She displayed chronic kidney failure that progressed to end stage renal disease and she is currently on hemodialysis.

Glu145Gln mutation (22,35) was identified in 2 affected members from 2 families. The first case is a Caucasian girl showing severe hypertension, hypokalemia and hyperaldosteronism since the age of 2 years, who underwent bilateral adrenalectomy at the age of 19 years. The second case is a Chinese boy who presented with high blood pressure and low serum K

levels. He was diagnosed with PA and Cushing’s syndrome at the age of 23 years and underwent unilateral left adrenalectomy, he is now awaiting right adrenalectomy.

Description of a new case.

The index case is a Caucasian 55-year old man, who was referred to our Division with clinical suspicion of FH. He was born in 1961 to non-consanguineous parents from an uneventful pregnancy. Familial history revealed that the father suffered from hypertension and died from ischaemic stroke at the age of 50 years; the mother is normotensive. He had three younger brothers,

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one died from lung cancer, the others are in a good health. Biophysical development was characterized by mild retarded growth and low body weight, polyuria, polydipsia and enuresis since early childhood.

He was diagnosed with PA at the age of 7 years, on the basis of arterial hypertension, severe hypokalemia and elevated urinary aldosterone levels despite low plasma renin levels (clinical and hormonal data at diagnosis are not available). Treatment with spironolactone and K

supplementation was started, however, on the basis of persistent resistant hypertension, he underwent left adrenalectomy at the same age. Between the ages of 7 and 15 years he had several hospital admissions because of uncontrolled hypertension and hypokalemia. In particular, at the age of 10 years he presented with severe hypertension (165/120 mmHg) and tetany secondary to severe hypokalemia (plasma K

1.4 mEq/L). At the age of 15 years he was again admitted to hospital because of uncontrolled hypertension (210/140 mmHg) and headache. Blood and urine testing revealed a suppressed plasma renin activity (0.82 mg/mL/h) with elevated urinary aldosterone levels (> 100 µg/24h) and hypokalemia (1.8 mEq/L), mild chronic kidney failure (serum creatinine 1.8 mg/dL) with a proteinuria of 150 mg/dL and 24h urinary K

of 100 mEq. Moreover, he had signs of left ventricular hypertrophy with altered repolarization at electrocardiogram and fundus oculi examination revealed hypertensive retinopathy stage III. To further investigate the chronic kidney failure he underwent pyelography and renal vein catheterization (to dose PRA in each renal vein and exclude a concomitant renal artery stenosis). During renal vein catheterization right adrenal venography was attempted, but the adrenal vein was not cannulated.

Successively, in 1977 at the age of 16, he underwent partial right adrenalectomy. The partially removed right adrenal weighted 20 g and presented nodular hyperplasia of the zona fasciculata. At discharge, he showed a blood pressure of 130/80-90 mmHg, serum K+ of 3.9-4.8 mEq/L and urinary aldosterone of 9.5 µg/24h under treatment with clonidine and hydralazine three times/day.

Kidney failure progressively worsened and the patient is now on hemodialysis since 2001. A recent

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cardiological evaluation (02/2016) revealed a diagnosis of aortic root dilatation (44 mm) with moderate aortic insufficiency and bicuspid aortic valve with normal left ventricular function and wall thickness. Adrenal CT scanning (06/2016) showed multinodular hyperplasia of the residual right adrenal gland (with two nodules measuring 16 mm and one nodule measuring 10 mm). Blood pressure was 120/80 mmHg under treatment with bisoprolol, enalapril and canrenone.

DNA sequencing from peripheral blood showed that the patient carries the KCNJ5 p.Gly151Arg mutation (Figure 2), the presence of the chimaeric CYP11B1/CYP11B2 gene was excluded by long PCR (8).

Conclusions

FH-III is a rare and clinical heterogeneous form of genetic hyperaldosteronism caused by germline mutations affecting the selectivity filter of the K

channel GIRK4 (encoded by the KCNJ5 gene). In the majority of the patients, the disorder presents with early onset PA, polyuria, polydipsia, hypokalemia and severe resistant hypertension requiring bilateral adrenalectomy to control blood pressure. However, a mild presentation characterized by hypertension and hypokalemia well controlled by medical therapy has also been reported. Until recently, the different clinical phenotypes in FH-III patients were attributed to the degree of the electrophysiological effects induced by the germline mutations responsible of the disease, with a clear-cut genotype phenotype correlation. Nevertheless, a FH-III patient, carrying the Gly151Arg mutation, predictive of a severe phenotype, displayed a good response to spironolactone therapy, indicating that other genetic or epigenetic factors might influence the different clinical presentations observed in FH-III patients.

Herein, we report a new FH-III case, due to a Gly151Arg mutation, presenting in infancy with symptoms of diabetes insipidus and requiring adrenalectomy on one side and partial adrenalectomy on the other side, further expanding our knowledge of this rare condition. In conclusion, additional

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studies are warranted to further elucidate the prevalence and the clinical spectrum of FH-III, including the molecular mechanisms responsible, in some patients, for massive adrenal hyperplasia and overproduction of hybrid steroids.

Search strategy

We performed a literature search of articles published in English using PubMed Database. The key words used were “familial hyperaldosteronism” and “KCNJ5”. We took in consideration those articles that concerned the aim of this review.

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34. Charmandari E, Sertedaki A, Kino T, Merakou C, Hoffman DA, Hatch MM, et al. A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. J Clin Endocrinol Metab 2012; 97: E1532-9.

35. Tong A, Liu G, Wang F, Jiang J, Yan Z, Zhang D, et al. A novel phenotype of familial hyperaldosteronism type III: Concurrence of aldosteronism and Cushing’s syndrome. J Clin Endocrinol Metab 2016;101: 4290-4297.

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Figure 1. Overview of KCNJ5 gene germline mutations.

Figure 2. Sequencing of peripheral blood DNA showing the KCNJ5 c.451G>C substitution resulting in the p.Gly151Arg mutation.

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