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Familial hyperaldosteronism type III a novel case and review of literature
Natividad Pons Fernandez1 . Francisca Moreno2 . Julia Morata 1 . Ana Moriano 1 . Sara Leon2 . Carmen De Mingo2 . Ángel Zuñiga2 · Fernando Calvo 1
C Springer Science+Business Media, LLC, part of Springer Nature 2018
Abstract
Less than 15% of hypertension cases in children are secondary to a primary hyperaldosteronism. This is idiopathic in 60% of the cases, secondary to a unilateral adenoma in 30% and 10% remaining by primary adrenal hyperplasia, familial hyperaldosteronism, ectopic aldosterone production or adrenocortical carcinoma.To date, four types of familial hyperaldosteronism (FH I to FH IV) have been reported. FH III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4. The mutations cause the channel to lose its selectivity for potassium, allowing large quantities of sodium to enter the cell. As a consequence, the membrane depolarizes, voltage-gated calcium channels open, calcium enters the cell, initiating the cascade that leads to aldosterone synthesis. Somatic mutations in KCNJ5 has also been described in aldosterone-producing adenomas. The most frequent presentation of FH III is with severe hyperaldosteronism symptoms and resistance to pharmacological therapy which leads to bilateral adrenalectomy. We will review current literature and describe a child with FH III due to a novel de novo deletion in KCNJ5 with wild phenotype as a sign of clinical variability of this disease.
Keywords Hypertension . Primary hyperaldosteronism · Mineralocorticoid receptor · KCNJ5 . Kir3.4
Abbreviations
FH Familial hyperaldosteronism
PA Primary aldosteronism
APA Aldosterone producing adenoma
BAH Bilateral adrenal hyperplasia
ACTH Adrenocorticotropic hormone
BP Blood pressure
SDS Standard deviation
1 Introduction
The etiology of hypertension in childhood varies depending on age. In infants, it is usually secondary to an underlying disease, but in adolescence, essential hypertension is more frequent, 90% of all cases. Aortic coarctation and renal pathology are the most
☒ Natividad Pons Fernández natividadpons@hotmail.com
1 Department of Pediatrics, Hospital Lluís Alcanyís de Xàtiva, Ctra. Xàtiva a Silla km 2, 46800 Xàtiva, Valencia, Spain
2 Hospital Universitario y Politécnico la Fe de Valencia, Valencia, Spain
common causes of secondary hypertension in childhood. However, primary aldosteronism (PA) is now recognized as the most common form of endocrine hypertension, responsible for around 10-15% of all cases. PA involves a heterogeneous group of disorders: 60% idiopathic, 30% secondary to aldoste- rone producing adenoma (APA) and 10% by bilateral adrenal hyperplasia (BAH), familial hyperaldosteronism (FH), ectopic aldosterone production or adrenocortical carcinoma [1]. The di- agnosis of PA and correct subtype differentiation, are of most importance, in light of the increased risk of cardio- and cerebro- vascular complications and the different treatment required.
Aldosterone is segregated in the zona glomerulosa of adrenal glands in response to hypovolemia (activation of renin- angiotensin system) and to hyperkaliemia (increase in serum potassium K+ concentration). Adrenocorticotropic hormone (ACTH) stimulates secretion in acute and transient way. Angiotensin II binds to its receptor on the zona glomerulosa cells, decreases potassium efflux, which depolarizes the cell, activates voltage-gated calcium channels and allows calcium entry. Calcium stimulates the activation of transcription factors that stimulate aldosterone synthesis, as well as cell proliferation (Fig. 1). Pathological secretion of aldosterone in the absence of normal physiological stimuli leads to PA, producing increased sodium reabsorption, potassium excretion and hypertension.
To date, four types of FH have been reported, referred to as FH-I to FH-IV, all with autosomal dominant inherence [2]. We
KCNJ5 Normal
CALCIUM Channel
KCNJ5 Mutated
ANG ii
AWWW
x
Conditional Depolarization
Constructive Depolarization
Ca2+ATPase Ca2+
K+
K+
[ Ca2+ ]
Na+
Na+ K+
CAMK
Na+ / K+ATPase
NURR/NGFIB/ATF1/CREBB
promoter
CYP11B2
Controlled cell cycle activation Physiologic aldosterone synthesis and release
Uncontrolled proliferation Excess aldosterone synthesis and release
will review current literature about them and finally describe a new case of FH III due to a novel germline mutation in KCNJ5 with wild phenotype as a sign of clinical variability of this disease.
1.1 FH type I or glucocorticoid remediable aldosteronism
FH I was genetically characterized in 1992 by Lifton et al. [3]. It is transmitted as an autosomal dominant disorder. The en- zyme aldosterone synthase is encoded by the gene CYP11B2 located on chromosome 8q24.3-tel, close to the gene CYP11B1, which encodes the enzyme that catalyzes the final step of cortisol synthesis. FH I is caused by an unequal crossing-over between these genes. This genetic recombina- tion results in a chimeric enzyme with aldosterone synthase activity (coding region of CYP11B2) and 11ß-hydroxylase regulation (promoter region of CYP11B1). Normal subjects synthesize aldosterone in the zona glomerulosa, but not in the ACTH-sensitive zona fasciculata. The chimeric gene can pro- duce aldosterone in zona fasciculata under the control of ACTH [3]. As a result, these patients have markedly increased levels of 18-oxocortisol and 18-hydroxycortisol. And the hy- persecretion of aldosterone can be reversed with physiologic doses of glucocorticoid [4].
It is rare, in a study of 300 consecutive patients with PA only two patients were diagnosed with FH I (prevalence 0.66%) [5]. Clinically it should be suspected from the positive family history, onset of hypertension before 20 years and the
development of marked hypokalemia after thiazide diuretic administration. Plasma K+ is normal in a half of cases. For diagnosing, plasma aldosterone concentration is elevated and plasma renin activity is suppressed, but the aldosterone-renin ratio is typically not as high as in APA. Genetic testing to detect the chimeric gene is now preferred over dexamethasone suppression testing. As it is collected in the international Endocrine Society updated evidence-based guidelines for di- agnosis and treatment of PA (2016) [6]. Due to the cerebro- vascular complications observed, screening magnetic reso- nance angiography at puberty and every 5 years thereafter has been proposed.
Treatment with low doses of a glucocorticoid is the first- line therapy, administered at bedtime to suppress the early morning ACTH. The doses must be the lowest to normalize blood pressure (BP) and cardiac effects of PA avoiding Cushing syndrome even if only partial braking of aldosterone occurs. Second line therapy is mineralocorticoid receptor an- tagonist, which may be just as effective and avoids corticoid iatrogenic side effects.
1.2 FH type II
This type may be the most common form of FH. It was first reported in 1991 by Gordon et al. [7]. The vertical transmission suggests an autosomal dominant inheritance. The mutations that cause FH type II are unknown, but linkage analysis has mapped them to chromosome 7p22 in some families [8]. FH II is the familial occurrence of APA or BAH, or both, in the same
kindred. Biochemically it is indistinguishable from sporadic PA and is diagnosed when at least two first-degree relatives are affected by PA. Nowadays there is no genetic test for FH II. Therefore, screening of PA should be done in all first-degree relatives of patients with PA [6]. Diagnosis and treatment are similar to idiopathic PA (mineral corticoid receptor antagonist, potassium chloride and calcium antagonists).
1.3 FH type III
It was first described, in a single family, in 2008 by Geller et al. [9]. Its genetic basis, represented by germline mutations in the KCNJ5 gene, was discovered by Choi et al. in 2011 using a whole-exome sequencing approach [10]. KCNJ5 is located on chromosome 11q24 and encodes for a potassium channel, GIRK4, also known as Kir3.4. Under physiological conditions, adrenal zona glomerulosa cells display high rest- ing K+ conductance and GIRK4 contributes to the mainte- nance of the cell membrane in a hyperpolarized state. All the mutations described affect the selectivity filter of the channel which result in loss of ion selectivity, Na+ entry, cell mem- brane depolarization and increase intracellular Ca2+ concen- tration [11, 12]. The increased calcium concentration stimu- lates the transcription of CYP11B2 that increased aldosterone overproduction (Fig. 1) [13]. Since this initial report, eleven
families with early-onset PA have also been identified to have six different germline point mutations in the KCNJ5 gene (p.Glu145Gln, p.Gly151Arg, p.Gly151Glu, p.Tyr152Cys, p.Ile157Ser, p.Thr158Ala) (Fig. 2) [14].
FH III is very rare and inherited as autosomal dominant. This should be suspected in children with PA and in patients with severe BAH and genetic test should be done. Adrenal computed tomography may show massive or milder BAH. Adrenal venous sampling would show aldosterone hyperse- cretion. Treatment should be identical to patients with appar- ent sporadic PA.
1.4 FH type IV
FH IV is inherited as an autosomal dominant trait with incom- plete penetrance and caused by mutations in the CACNA1H gene. Germline mutations in this gene were identified by an exome-sequencing study in five unrelated families with early- onset PA [15]. CACNA1H located in chromosome 16p13, encodes a T-type voltage-gated calcium channel (Cav3.2) expressed in adrenal glomerulosa. Mutations in CACNA1H (more frequent p.Met1549Val substitution) showed drastically impaired channel inactivation and activation at more hyperpolarized potentials, producing increased intracellular Ca2+, the signal for aldosterone production (Fig. 3) [16].
T158A
I157S
Y152C
E145Q
G151E
G151R
R52H
E246K
G247R
E282Q
NH2
V259M
☐ Pore-forming/selectivity filter
Y348N
☐ Germline mutation causing FH-III
☒ Germline mutation associated with sporadic
idiopathic PA
☐ Germline mutation causing ACTH-dependent aldosterone hypersecretion
COOH
KCNJ5 Normal
CALCIUM Channel mutated
KCNJ5 Normal
CALCIUM Channel
ANG
ANG
x
Conditional Depolarization
Calcium entry
X
Conditional Depolarization
Depolarization Calcium entry
Ca2+ATPase
Ca2+ATPase
K+
[ Ca2+ ]
[ Ca2+ ]
Ca2+
CAMK
Ca2+
CAMK
Na+
NURR/NGFIB/ATF1/CREBB
Na+
H+
NURRNGFIB/ATF1/CREBB
K+
K+
Na+ / K+ATPase
Na+ / K+ ATPase
promoter
CYP11B2
promoter
CYP11B2
Uncontrolled proliferation Excess aldosterone
Uncontrolled proliferation Excess aldosterone
Clinically it’s similar to sporadic PA in children <10 years. Adrenal computed tomography shows an apparent APA, BAH, or can be normal. Adrenal venous sampling would show bilateral aldosterone hypersecretion. Treatment should be identical to sporadic PA but if refractory disease associated with massive BAH, bilateral laparoscopic adrenalectomy may be considered.
Two patients have been reported with PA, seizures and neurodevelopmental and neuromuscular abnormalities caused by germline de novo mutations in CACNA1D, L-type
voltage-gated calcium channel (Cav1.3) gene (Fig. 3). It’s re- ferred to as PASNA syndrome (PA, Seizures and Neurologic Abnormalities) and is not a familial form of PA because the severe neurological comorbidities do not allow the affected individuals to reproduce [15, 17].
KCNJ5, CACNA1D and another two genes: ATP1A1 (cod- ing for the &1 subunit of Na+/K+-ATPase) and ATP2B3 (coding for the plasma membrane Ca2+-ATPase, type 3) are now known as aldosterone-driver genes implicated in APA (Fig. 3).
To summary FH I to IV characteristics see Table 1.
| FH-I | FH-II | FH-III | FH-IV | |
|---|---|---|---|---|
| OMIN | #103900 | #605635 | #613677 | #617027 |
| GEN | CYP11B1/CYP11B2 | ?? | KCNJ5 | CACNA1H |
| Inheritance | Autosomal dominant | Autosomal dominant | Autosomal dominant | Autosomal dominant |
| Adrenal | BAH or APA | BAH or APA | BAH | Hyperplasia |
| HF % | 1% | 3-5% | 0,3% | 5 families |
| Age debut | Child/adulthood | Childhood | Childhood | |
| HT severity | Normal tension to resistant | Normal tension to resistant | Grade II to resistant | Normal tension to resistant |
| 18-oxocortisol/ 18-hydroxycortisol | Elevated | Not elevated | Mildly to extremely elevated | Normal |
| Aldosterone response to dexamethasone | Complete suppression | Partial reduction or no change | No change | Suppression (1 patient) |
| Treatment | Dexamethasone Hydrocortisone | Mineral corticoid antagonist Adrenalectomy | T1: Adrenalectomy T2: mineral corticoid blocker | Calcium channel antagonist |
BAH bilateral adrenal hyperplasia, APA aldosterone producing adenoma
2 New case of FH III
We present the case of an 11-year-old boy, born to nonconsanguineous parents, remitted for study of hyperten- sion detected in health exam. The patient was asymptomatic, weight 28.7 kg (SDS -1.56), height 145 cm (SDS -0.7), BMI 13.65 (SDS-1.74), heart rate 88 bpm, respiratory rate 20 bpm and BP 177/110 mmHg (>99th height-corrected percentile for age) corroborated in different measurements and days. Chest auscultation showed an ejection murmur I / VI on left sternal border. Electrocardiogram showed signs of left ventricle marked hypertrophy with alteration of repolarization. The car- diac ultrasound confirmed left ventricle concentric symmetric hypertrophy and ruled out another congenital heart disease. The diagnosis of stage 2 hypertension (160-179/100-109) was confirmed by ambulatory BP monitoring.
In the analytical study, hypokalemia and marked metabolic alkalosis was noted. K+ 2.4 mEq/L, Na+148 mEq/L and ele- vated potassium excretion fraction. Thyroid hormones, basal cortisol and ACTH were in normal range. Plasma aldosterone concentration higher than 1400 pg/ml (normal range: 50- 300 pg/ml) and plasma renin activity less than 0.13 ng/ml/h (normal range: 1-4 ng/ml/h) and aldosterone-renin ratio > 30 led to suspicion of primary hyperaldosteronism. Aldosterone remained elevated (>470 pg/ml) after dexamethasone sup- pression test (4 ugr/day for 2 days). The abdominal ultrasound was normal and magnetic resonance showed normal adrenals but dubious vascular malformation in the left kidney; incon- clusive study. The determination of 18-oxocortisol and 18- hydroxycortisol, elevated in hyperplasia and not in idiopathic forms, is not routinely performed in Spanish laboratories. Genetic study of the CYP11B1/CYP11B2 was performed and did not show the chimeric gene. Screening test in hyper- tensive fist-degree relatives was carried out with normal re- sults. So that made least likely FH II.
Given the diagnosis of idiopathic primary hyperaldosteronism, treatment with spironolactone (1- 3 mg/kg/day, maximum 100 mg/day), potassium chloride and calcium-channel blocker (nifedipine 0.6 mg/kg/day) was initiated. In the first days, electrolyte values were normalized and soon he achieved improvement in the sys- tolic BP but not in the values of diastolic BP despite optimizing doses of spironolactone. The magnetic reso- nance of control showed a pseudo nodular thickening of left adrenal compatible with incipient adenoma or hyper- plasia. Our patient was referred to pediatric endocrinology reference service. There, a genetic study of KCN5J, ATP1A1, ATP2B3, CACNA1D was requested, given the existing doubt about whether it was an incipient adenoma and somatic mutations in these genes were previously identified in APA [17].
Given the result of unilateral thickening, the absence of control of the diastolic BP and the desire of the patient for
definitive surgical treatment, adrenal scintigraphy (Iodo131- Colesterol 1 mCi) was performed. Treatment was replaced with nicardipine and bisoprolol given their hormonal neutral- ity. Images of the adrenal area were made on the 2nd day with suppression with Dexamethasone (4 mg/day) and 4th day (without suppression) and after thyroid blockade with Lugol. On the 2nd day a slight tracer accumulation was observed at the adrenal areas, while on the 4th day bilateral uptake without significant asymmetries discarded APA.
The genetic analysis by ultra-sequencing techniques (NGS) identified a novel germline heterozygous deletion in KCNJ5: c.445_447delACC. This causes a loss in threonine amino acid at position 149 (p. Thr149del). This variant is not described in genetic dates bases. Prediction in silico with Mutation Taster suggests that it is a pathogenic change; not described in ExACnor 1000G and not detected in the parents, indicating a de novo pathologic mutation.
After 4 years of tracing the patient has completed his pu- bertal development and has improved his physical condition: Weight 54.5 kg (SDS -0.5), height 168 cm (SDS 0.02), BMI 19.3 (SDS-0.57). Electrocardiogram and ultrasound findings show left ventricular hypertrophy improvement. BP is in 90th height-corrected percentile for age, so we are adjusting doses of medical treatment.
3 Discussion
PA clinic is due to hypertension and hypokalemia (muscle weakness, cramping, headaches, palpitations, polyuria). As some patients can present hypertension without hypokalemia, it is important to maintain a high level of suspicion. Our pa- tient conversely was asymptomatic at the diagnosis.
Using the Endocrine Society guidelines, PA must be suspected in patients with BP above 150/100 mmHg on each of three measurements obtained on different days, with hyper- tension (BP >140/90) resistant to three conventional antihy- pertensive drugs (including a diuretic), or controlled BP (<140/90) on four or more antihypertensive drugs, hyperten- sion and spontaneous or diuretic-induced hypokalemia, hy- pertension and adrenal incidentaloma, hypertension and sleep apnea, early onset hypertension in family history or cerebro- vascular accident at a young age (< 40 years) and all hyper- tensive first-degree relatives of patients with PA. They recom- mend diagnosis in three steps: screening, confirmation and subtype classification [6, 18].
Screening must be done with aldosterone-renin ratio. The literature of the last 20 years demonstrated that aldosterone- renin ratio is the parameter with the highest sensitivity (68- 94%) for screening compared to other biological variables: Serum potassium, plasma aldosterone concentration or uri- nary aldosterone. The drawback was that it was nor perfectly standardized: values vary with assay technique, assay kit and
units used to express results, intra- and inter-patient variation coefficients vary, and environmental factors influence results. All these factors are discussed in guidelines consensus [6, 18, 19]. The most commonly adopted cutoff values are 30 for plasma aldosterone concentration and plasma renin activity in conventional units and 750 when plasma aldosterone con- centration is expressed in SI units [18]. In our case, at diagno- sis, aldosterone-renin ratio was 1078 in conventional units, and remained elevated after treatment. These values can be used in children too, because they are out of normal range for children, such as were published by Martinez-Aguayo in 2010 [20]. Patients with a positive aldosterone-renin ratio un- dergo one or more confirmatory tests to definitively confirm or exclude the diagnosis. However, as in our patient with spontaneous hypokalemia, PRC below detection levels (0.13 ng/ml/h) plus plasma aldosterone concentration > 20 ng/dl (140 ng/dl), there may be no need for further confir- matory testing [6]. Previously consensus of French endocri- nology society, French hypertension society and Francophone Endocrine Surgery Association (2013-2015), this exception is also collected [21, 22].
Currently there are no gold standard confirmatory tests [6, 22]:
- Salt loading test. Give oral salt tablets 6 g/day for 3 days. Measure 24 h urine aldosterone and sodium. Confirmation: 24 h urine aldosterone level is >12 µg/ 24 h with concomitant 24 h urine sodium excretion >200 mmol/d.
- Intravenous saline infusion. Infuse 2 L of normal saline over 4 h (8:00-12:00 h). Measure plasma aldosterone con- centration post infusion, supine position. Confirmation: plasma aldosterone concentration > 10 ng/dL.
- Fludrocortisone suppression test. Conditions: Dietary sodium 110 mEq/d. Administration of fludrocortisone 0.1 mg/6 h 4 days. Measure of seated plasma aldosterone concentration at 5 d. Confirmation: plasma aldosterone concentration > 5 ng/dL or urine aldosterone >12 µg/24 h. - Captopril test. Administration of oral captopril 25- 50 mg. Measure plasma aldosterone concentration 120 min after seated or standing. Confirmation: plasma aldosterone concentration > 15 ng/dl o aldosterone-renin ratio > 50.
For subtype classification adrenal computed tomogra- phy is the initial study to exclude adrenocortical carcinoma or APA subsidiary of surgery (magnetic resonance when CT is contraindicated) [6, 19, 23]. Unilateral adenomas appear as small hypodense nodules <2 cm in diameter. In contrast, adrenal carcinomas are heterogeneous and usually >4 cm. BAH can appear as bilateral nodules. However, sometimes, the adrenal computed tomography scan can be read as normal or inconclusive.
An additional instrument in the diagnosis of APA versus BAH is the measurement of hybrid steroids in 24-h urine, 18- oxocortisol and 18-hydroxycortisol, which are produced in large amount in APA compared with BAH [4, 23]. It has been proposed 18-oxocortisol cut-off value of 4.7 ng/dl for discrim- ination of APA from BAH. But in our case this analysis pre- cise external laboratories and were not done [24].
When surgical treatment is feasible and desired by the pa- tient, an experience radiologist should use selective catheteriza- tion of the adrenal veins to make the distinction between uni- lateral and bilateral disease [6, 19]. Blood samples are taken from both adrenal veins and compared to the inferior vena cava. Aldosterone and cortisol concentrations are measured. Samples are reliable if cortisol ratio adrenal vein about cortisol in cava is >1.1 or> 5 after ACTH administration. To account for dilution, the aldosterone concentration is then corrected using cortisol so that an aldosterone/cortisol ratio is obtained. The ratios of aldo- sterone to cortisol from each side are then compared. The cut off for distinguishing a unilateral source of aldosterone is a lateralization ratio (aldosterone /cortisol of dominant adrenal vein to that of no dominant) of >4. A ratio of <3 is suggestive of BAH [1, 6, 19, 21]. For lateralization index between 3 and 4 other clinical parameters should be considered for final decision [24-26]. But there are some exceptions to recommend adrenal venous sampling: age < 40 years with PA and a clear unilateral APA and normal contralateral adrenal on computed tomogra- phy, unacceptable high risks of surgery, suspected carcinoma and proven FH I and FH III.
In our patient, diastolic BP was not completely controlled, magnetic resonance images were inconclusive and the patient had shown his desire for surgery. Iodo131-Colesterol 1 mCi scintigraphy showed normal adrenals. But scintigraphy sensi- tivity depends on the size of the adenoma and is poor in ade- nomas smaller than 1.5 cm in diameter. Last protocols sug- gest, with low evidence, not using functional imaging for eti- ology diagnosis of PA [25]. Therefore, we thought a therapeu- tic option would be unilateral adrenalectomy after selection by adrenal venous sampling and the patient was referred to a reference hospital. But, given the subsequent result of genetic test, this option has been currently dismissed [27].
The guidelines suggest, with moderate evidence, genetic testing for FH I in patients with confirmed PA <20 years of age and in those who have a family history of PA or strokes at a young age (< 40 years). For this reason, we studied CYP11B1-CYP11B2 genes in our patient [6, 19, 27, 28]. In hypertensive children with seizures or complex neurologic syndrome sequencing of CDCNA1D mutations are recom- mend [28]. In young patients <20 years with PA, it is also advised, testing for germline mutations in KCNJ5 causing FH III, as we did in our case. Sequencing of KCNJ5 gene is the best method [28]. As referred previously clinical severity of FH III varies significantly, ranging from early to late man- ifestations, mild to severe hypertension and different
responsiveness to medical therapy. Severe phenotype is asso- ciated with GIRK4 p.Gly151Arg, p.Thr158Ala, p.Ile157Ser and p.Tyr152Cys mutations, and a milder phenotype is asso- ciated with p.Gly151Glu. A summary of these characteristics can be found in Table 2.
Adachi et al. described in 2014 a patient with p.Gly151Arg mutation, predictive of a severe phenotype, who responded to medical therapy [29] and another similar case had been pub- lish by Monticone et al. in 2017 [14]. That’s why authors suggest other genetic or epigenetic factors might influence the clinical presentations in FH III patients.
Combined aldosterone and cortisol over secretion associat- ed with massive BAH was described in a Chinese patient carrying the germline KCNJ5 mutation p. Glu145Gln by Tong et al. recently. The authors suggest that hypersecretion of cortisol might be ascribed to overly large size of the hyper- plastic adrenal because CYP11B1 expression was relatively low in his adrenal. Like aldosterone, synthesis and secretion of cortisol in the mutant adrenal may be mediated by voltage- gated Ca2+ channels [30].
Another study by Gomez-Sanchez et al. in 2017 has reported that adrenals from patients carrying the germline KCNJ5 muta- tion p.Thr158Ala (referred at Table 2) were markedly enlarged with loss of zonation. These adrenals show a mixture of cells expressing aldosterone synthase and/or 11ß-hydroxylase, with and without 17x-hydroxylase, and some expressing all three enzymes. GIRK4 was abundantly expressed in almost all cells, suggesting that the mutation not only altered the potassium filter selectivity of the channel, but also a signal that designated spec- ificity for CYP11B2-expressing cells, or the presence of a sec- ond mutation in this family that abolishes selectivity of steroido- genesis on the basis of adrenal zonation [31].
Our patient shows a novel germline heterozygous deletion in KCNJ5: c.445_447delACC. This causes a loss in threonine amino acid at position 149 (p. Thr149del) which has not been described before. This deletion affects an amino acid Thr149 with higher conservation among orthologs and paralogs, very closed to previously described in FH III and that would there- fore affect the selectivity filter of the Kir3.4 channel pore. Prediction in silico with Mutation Taster suggests that it is a pathogenic change. In the same codon, has been described a somatic variant with an in frame 3 bp insertion of a T149 in a
patient with drug resistant hypertension caused by an APA.
That would indicate the important role of this residue, close to, but just outside of, the Kir3.4 selectivity filter. In vitro, mod- ifications of Thr 149 residue have demonstrated cause mem- brane depolarization, raise intracellular Ca2+ and increase al- dosterone production [32-34]. All this will support a patho- logical potential of the KCNJ5 mutation identified in this case. Somatic mutations in KCN5J, ATP1A1, ATP2B3, CACNA1D have been detected in removed adenoma tissue of APA. These results were published by Fernandes-Rosa et al. in 2014 in a large European cohort (474 patients with APA from
| Thr158Ala | Gly151Glu | Gly151Arg | Ile157Ser | Tyr152Cys | Glu145Gln | Thr149del | |
|---|---|---|---|---|---|---|---|
| Family | 1 | 3 | 4 | 1 | 1 | 2 | 1 |
| (patients) | (3) | (8) | (6) | (2) | (1) | (2) | (1) |
| Sex (M: F) | 1:2 | 4:4 | 1:5 | 0:2 | 0:1 | 1:1 | 1:0 |
| Age at diagnosis | 4-7 | 1-18 | 1-7 | 2-7 | 48 | 2 | 11 |
| Clinic manifestations | Polyuria, polydipsia, nicturia, myalgia, LVH | Polyuria, polydipsia, LVH, nephron-calcinosis | Polyuria, polydipsia, alkalosis, muscular weakness | None | End stage renal disease | Polyuria, polydipsia. Concomitant cortisol hypersecretion | LVH, alkalosis, muscular weakness |
| SBP/ | 160-200/ | 130-160/ | 120-210/ | 150-170/ | 250/ | 115-140/ | 170/ |
| DBP | 114-148 | 80-120 | 70-140 | 100 | 130 | 60-90 | 110 |
| Min serum K+ | 1.8-3.0 | 1.8-3.5 | 1.4-3.2 | 2.7 | 2.1 | 2.0-2.3 | 2.4 |
| (mEq/L) | |||||||
| PAC (ng/dl) | 137-185 | 113-187 | 23-109.6 | 118 | 24 | >180 | 140 |
| CT/RM adrenals | Enlarged, nodular hyperplasia | Normal | Normal/ enlarged | Enlarged (diffuse hyperplasia) | Nodular hyperplasia | Diffuse hyperplasia /normal | normal |
| Only Medical Treatment | 6 Medical | 1 medical 4 bilateral | Bilateral | Unilateral | Medical | ||
| Adrenalectomy | Bilateral | 2 Uni/bilateral | Uni/Bilateral |
reference centers) [17]. Somatic mutations were found in more than 50% of APAs (38% in KCNJ5, 9.3% in CACDNA1D, 5.3% in ATP1A1 and 1.7% in ATP2B3). A similar prevalence was reported in the American population by Scholl et al. in 2015 [35]. There was no association between the mutation and preop- erative plasma aldosterone concentration or plasma renin activity, aldosterone-renin ratio or the number of medications taken be- fore surgery. Other regulatory mechanisms may be necessary to APA development [36, 37].
Regarding treatment we employed mineralocorticoid re- ceptor antagonist, spironolactone, at standard doses (first line) and a calcium channel blocker, nifedipine (second line) [6]. Spironolactone at 1-3 mg/kg/day could control hypertension and hypokalemia, avoiding doses >150 mg/ day relapse with the appearance of gynecomastia and other libido, menstrual or gastrointestinal disorders (It is also an androgen and progesterone receptor antagonist). The re- sponse to treatment is also considered as a confirmation of the diagnosis. Eplerenone, given its selectivity and de- spite its cost, can be an alternative of spironolactone. Calcium antagonists had been used since this ion is in- volved in peripheral vascular resistance and as a second messenger in the action of aldosterone secretors, but there is not enough evidence of its synergistic effect with spironolactone. Aldosterone exerts its actions on hyperten- sion by up-regulation of distal tubular sodium epithelial channel, so antagonists of this sodium channel can also be used (amiloride). It should be preferred to long-course potassium supplementation [38]. If BP remains above nor- mal other antihypertensives can be associated in third line: angiotensin-converting enzyme inhibitors, angiotensin re- ceptors blockers [6, 38].
The calcium channel blocker verapamil inhibits the p.Leu168Arg mutant channel, suggesting a potential thera- peutic use of this drug. Another possible treatment are some macrolides which inhibit mutant GIRK4, but not the wild-type channel. But animal studies are needed before developing clinical trials in humans [16].
Surgical treatment with unilateral laparoscopic adrenalec- tomy is indicated for unilateral PA or BAH with refractory disease. If a patient is unable or unwilling to undergo surgery, medical treatment is indicated [6, 38]. After surgery antihy- pertensive treatment has to be continued life-long in more than a half of cases [39].
Currently, our patient is asymptomatic but should continue to periodic follow-up given the risk of cardiac remodeling, coronary endothelial damage and cardiac arrhythmias. Hypertrophic cardiomyopathy is due to both the hypertension itself and the presence of mineralocorticoid receptor in the cardiomyocytes and the aldosterone biosynthesis itself in car- diac tissue. Different studies show that PA increases left ven- tricle tele-diastolic volume and wall thickness as compared to otherwise similar patients with essential hypertension (odds
ratio of about 2). On the other hand, diastolic BP is also dif- ficult to control due to aldosterone release of pro inflammatory markers (cyclooxygenase-2, monocyte chemoattractant pro- tein 1, connective tissue growth factor, metalloproteases and NADPH oxidases). These markers produce vascular endothe- lial damage [13, 40]. Either adrenalectomy or medical therapy can reverse the cardiovascular morbidity caused by aldoste- rone excess [41]. Moreover, hyperkalemia secondary to treat- ment can lead to cardiac arrhythmias [42]. Screening of organ damage is indicated in PA patients [6, 38, 41]. An increased prevalence of chronic kidney disease, metabolic syndrome, type 2 diabetes mellitus and obstructive sleep apnea was found in these patients. Direct (aldosterone excess) and indirect (hy- pokalemia, oxidative stress) mechanisms have been suggested to explain this effect [43]. Treatment with mineralocorticoid receptor antagonists have been demonstrated efficacy in hy- pertension, cardiac failure, pulmonary hypertension, renal failure and stroke [41, 44]. But the secondary effects have made necessary the development of third and fourth genera- tion antagonists. On the other hand, the biosynthesis of aldo- sterone itself is not modified with this treatment. That is why the inhibitors of aldosterone synthesis (such as LCI699) are the future of the treatment to anticipate endothelial damage and cardiac remodeling [42]. But more studies may be done before authorizing its use in children.
4 Conclusions
Advances in genetic and functional studies have allowed to characterize sporadic and familial PA in last years. Four types of FH have been currently characterized and somatic muta- tions, altering intracellular ion homeostasis, with subsequent aldosterone overproduction are found in more than 50% of APA. However, the molecular mechanisms of the most fre- quent type FH II, remain unknown and the clinical variability observed FH III patients made necessary further investigation. Probably other genetic or epigenetic factors might influence the clinical presentations.
We reported a novel mutation in KCNJ5 gene responsible for a mild PA in a Spanish child who had responded to standard medical treatment but will need future medical monitoring. To date, with this case, seven different germline mutations in KCNJ5 have been described as a cause of FH III and more will be described in the future as diagnostic techniques improve. However similar advances in treatment would be desirable.
Authors Contribution Dr. Pons conceptualized the review, drafted the initial manuscript, and approved the final manuscript as submitted. Drs Moreno, Morata, Moriano, León, de Mingo and Calvo carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Zuñiga carried out the genetic test and approved the final manuscript.
Compliance with ethical standards
Financial disclosure Dr. Pons and the remaining authors have no finan- cial relationships relevant to this article to disclose.
Conflict of interest Dr. Pons and the other authors have no conflicts of interest to disclose.
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