HALD3
MCID: HYP438
MIFTS: 35

Hyperaldosteronism, Familial, Type Iii (HALD3)

Categories: Blood diseases, Cardiovascular diseases, Endocrine diseases, Genetic diseases, Nephrological diseases, Rare diseases

Aliases & Classifications for Hyperaldosteronism, Familial, Type Iii

MalaCards integrated aliases for Hyperaldosteronism, Familial, Type Iii:

Name: Hyperaldosteronism, Familial, Type Iii 57 13 39 70
Familial Hyperaldosteronism Type 3 20 58 29 6 70
Familial Hyperaldosteronism Type Iii 20 58 72
Fh Iii 57 20 72
Fh3 20 58 72
Fh-Iii 20 58
Hald3 57 72
Hyperaldosteronism, Familial, 3 72
Familial Hyperaldosteronism 3 72
Fh Type Iii 72

Characteristics:

Orphanet epidemiological data:

58
familial hyperaldosteronism type iii
Inheritance: Autosomal dominant; Prevalence: <1/1000000 (Worldwide); Age of onset: Adolescent,Childhood,Infancy;

OMIM®:

57 (Updated 05-Apr-2021)
Inheritance:
autosomal dominant

Miscellaneous:
onset of symptoms in first decade of life
patients with medication-resistant hypertension require bilateral adrenalectomy


HPO:

31
hyperaldosteronism, familial, type iii:
Inheritance autosomal dominant inheritance


Classifications:

Orphanet: 58  
Rare circulatory system diseases
Rare renal diseases
Rare endocrine diseases


Summaries for Hyperaldosteronism, Familial, Type Iii

GARD : 20 The following summary is from Orphanet, a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 251274 Definition Familial hyperaldosteronism type III (FH-III) is a rare heritable form of primary aldosteronism (PA) that is characterized by early-onset severe hypertension, non glucocorticoid-remediable hyperaldosteronism, overproduction of 18-oxocortisol and 18-hydroxycortisol, and profound hypokalemia. Epidemiology Seven families with FH-III have been reported to date. Clinical description Severe hypertension associated with profound hypokalemia generally manifests during early childhood. It can be accompanied with polydipsia, polyuria, nausea, vomiting and headaches. Marked bilateral adrenal hyperplasia has been described. In exceptional cases, a mild form of FH-III, resembling to FH type II (see this term) has been reported, with normal appearing adrenals and treatable with medical therapy. Etiology FH-III is due to heterozygous missense mutations of the KCNJ5 gene (11q24), encoding the G- protein -activated inward rectifier potassium channel GIRK-4. These mutations result in loss of channel selectivity, membrane depolarization of the zona glomerulosa cells of the adrenal cortex, opening of voltage-activated calcium channels, and activation of the calcium signaling pathway that trigger saldosterone biosynthesis. There is a genotype - phenotype correlation, with the mild phenotype observed in patients with the p.G151E and p.Y152C mutations. Diagnostic methods Blood and urinary tests show profound hypokalemia, an abnormal aldosterone/renin ratio with increased aldosterone levels not suppressible by dexamethasone, suppressed plasma renin activity, and elevated levels of the hybrid steroids 18-oxo- and 18-hydroxycortisol. Diagnosis is confirmed by genetic testing. Differential diagnosis The clinical presentation resembles that of the other familial forms of hyperaldosteronism (FH-I, FH-II) (see these terms). Genetic counseling Transmission is autosomal dominant. Management and treatment FH-III does not respond to glucocorticoid treatment. Severe cases require bilateral adrenalectomy to normalize blood pressure and hypokalemia, whereas mild cases are treated with medical therapy with aldosterone antagonists and/or other antihypertensive drugs if required. Prognosis In severe cases treated with bilateral adrenalectomy, life-long glucocorticoid and mineralocorticoid replacement therapy is required. In mild cases, prognosis is good with medical treatment.

MalaCards based summary : Hyperaldosteronism, Familial, Type Iii, also known as familial hyperaldosteronism type 3, is related to familial hyperaldosteronism and hyperaldosteronism, familial, type ii. An important gene associated with Hyperaldosteronism, Familial, Type Iii is KCNJ5 (Potassium Inwardly Rectifying Channel Subfamily J Member 5). Affiliated tissues include cortex, adrenal cortex and adrenal gland, and related phenotypes are hypertension and abnormal circulating renin

OMIM® : 57 This form of hyperaldosteronism is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or FH I; 103900), patients with FH III present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in FH III are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (Geller et al., 2008). (613677) (Updated 05-Apr-2021)

UniProtKB/Swiss-Prot : 72 Hyperaldosteronism, familial, 3: A form of hyperaldosteronism characterized by hypertension secondary to massive adrenal mineralocorticoid production. HALD3 patients present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18- hydroxycortisol. Hypertension and aldosteronism are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension.

Related Diseases for Hyperaldosteronism, Familial, Type Iii

Diseases in the Familial Hyperaldosteronism family:

Hyperaldosteronism, Familial, Type I Hyperaldosteronism, Familial, Type Ii
Hyperaldosteronism, Familial, Type Iii Hyperaldosteronism, Familial, Type Iv
Rare Primary Hyperaldosteronism

Diseases related to Hyperaldosteronism, Familial, Type Iii via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 11)
# Related Disease Score Top Affiliating Genes
1 familial hyperaldosteronism 11.3
2 hyperaldosteronism, familial, type ii 11.2
3 hypercholesterolemia, familial, 3 11.0
4 hypokalemia 10.3
5 hyperaldosteronism, familial, type iv 10.2
6 long qt syndrome 10.1
7 adrenal adenoma 10.1
8 adenoma 10.1
9 diabetes insipidus 10.1
10 strabismus 10.0
11 mechanical strabismus 10.0

Graphical network of the top 20 diseases related to Hyperaldosteronism, Familial, Type Iii:



Diseases related to Hyperaldosteronism, Familial, Type Iii

Symptoms & Phenotypes for Hyperaldosteronism, Familial, Type Iii

Human phenotypes related to Hyperaldosteronism, Familial, Type Iii:

58 31 (show all 21)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 hypertension 58 31 obligate (100%) Obligate (100%) HP:0000822
2 abnormal circulating renin 58 31 obligate (100%) Obligate (100%) HP:0040084
3 hypokalemia 58 31 hallmark (90%) Very frequent (99-80%) HP:0002900
4 adrenal hyperplasia 58 31 hallmark (90%) Very frequent (99-80%) HP:0008221
5 glucocortocoid-insensitive primary hyperaldosteronism 58 31 hallmark (90%) Very frequent (99-80%) HP:0011740
6 muscle weakness 58 31 occasional (7.5%) Occasional (29-5%) HP:0001324
7 polydipsia 58 31 occasional (7.5%) Occasional (29-5%) HP:0001959
8 prolonged qt interval 58 31 occasional (7.5%) Occasional (29-5%) HP:0001657
9 left ventricular hypertrophy 58 31 occasional (7.5%) Occasional (29-5%) HP:0001712
10 hypercalciuria 58 31 occasional (7.5%) Occasional (29-5%) HP:0002150
11 epistaxis 58 31 occasional (7.5%) Occasional (29-5%) HP:0000421
12 intracranial hemorrhage 58 31 occasional (7.5%) Occasional (29-5%) HP:0002170
13 headache 58 31 occasional (7.5%) Occasional (29-5%) HP:0002315
14 tinnitus 58 31 occasional (7.5%) Occasional (29-5%) HP:0000360
15 nausea 58 31 occasional (7.5%) Occasional (29-5%) HP:0002018
16 metabolic alkalosis 58 31 occasional (7.5%) Occasional (29-5%) HP:0200114
17 metabolic acidosis 31 occasional (7.5%) HP:0001942
18 polyuria 31 occasional (7.5%) HP:0000103
19 hyperaldosteronism 31 HP:0000859
20 decreased circulating renin level 31 HP:0003351
21 dexamethasone-suppresible primary hyperaldosteronism 58 Excluded (0%)

Symptoms via clinical synopsis from OMIM®:

57 (Updated 05-Apr-2021)
Laboratory Abnormalities:
hypokalemia
hypercalciuria (in some patients)
decreased plasma renin activity
paradoxical increase or no change in serum aldosterone and blood pressure after dexamethasone administration

Metabolic Features:
metabolic acidosis (in some patients)
polydipsia (in some patients)

Endocrine Features:
adrenal hyperplasia, bilateral
elevated serum aldosterone
elevated 18-hydroxycortisol
elevated 18-oxocortisol

Genitourinary Kidneys:
hypercalciuria (in some patients)
adrenal hyperplasia, bilateral
elevated aldosterone secretion
hyperplasia of zona fasciculata of adrenal gland
hyperplasia of zona glomerulosa of adrenal gland
more
Cardiovascular Vascular:
hypertension, severe

Muscle Soft Tissue:
muscle weakness, hypokalemia-related

Clinical features from OMIM®:

613677 (Updated 05-Apr-2021)

Drugs & Therapeutics for Hyperaldosteronism, Familial, Type Iii

Search Clinical Trials , NIH Clinical Center for Hyperaldosteronism, Familial, Type Iii

Genetic Tests for Hyperaldosteronism, Familial, Type Iii

Genetic tests related to Hyperaldosteronism, Familial, Type Iii:

# Genetic test Affiliating Genes
1 Familial Hyperaldosteronism Type 3 29

Anatomical Context for Hyperaldosteronism, Familial, Type Iii

MalaCards organs/tissues related to Hyperaldosteronism, Familial, Type Iii:

40
Cortex, Adrenal Cortex, Adrenal Gland

Publications for Hyperaldosteronism, Familial, Type Iii

Articles related to Hyperaldosteronism, Familial, Type Iii:

(show all 16)
# Title Authors PMID Year
1
Role for germline mutations and a rare coding single nucleotide polymorphism within the KCNJ5 potassium channel in a large cohort of sporadic cases of primary aldosteronism. 6 57
24420545 2014
2
A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. 57 6
24574546 2014
3
A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. 6 57
22628607 2012
4
Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. 57 6
22308486 2012
5
KCNJ5 mutations in European families with nonglucocorticoid remediable familial hyperaldosteronism. 6 57
22203740 2012
6
K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. 6 57
21311022 2011
7
Role of KCNJ5 in familial and sporadic primary aldosteronism. 57
23229280 2013
8
A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. 57
18505761 2008
9
Familial hyperaldosteronism, not suppressed by dexamethasone. 57
7119083 1982
10
Primary aldosteronism: clinical staff conference at the National Institutes of Health. 57
13521591 1958
11
DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? 61
28904009 2018
12
Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. 61
27793677 2017
13
An update on novel mechanisms of primary aldosteronism. 61
25424518 2015
14
Minireview: potassium channels and aldosterone dysregulation: is primary aldosteronism a potassium channelopathy? 61
24248457 2014
15
Genetics of mineralocorticoid excess: an update for clinicians. 61
23610123 2013
16
Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. 61
22315453 2012

Variations for Hyperaldosteronism, Familial, Type Iii

ClinVar genetic disease variations for Hyperaldosteronism, Familial, Type Iii:

6 (show top 50) (show all 80)
# Gene Name Type Significance ClinVarId dbSNP ID Position
1 KCNJ5 NM_000890.5(KCNJ5):c.452G>A (p.Gly151Glu) SNV Pathogenic 135679 rs587777437 GRCh37: 11:128781620-128781620
GRCh38: 11:128911725-128911725
2 KCNJ5 NM_000890.5(KCNJ5):c.470T>G (p.Ile157Ser) SNV Pathogenic 135680 rs587777438 GRCh37: 11:128781638-128781638
GRCh38: 11:128911743-128911743
3 KCNJ5 NM_000890.5(KCNJ5):c.736G>A (p.Glu246Lys) SNV Pathogenic 135681 rs587777439 GRCh37: 11:128781904-128781904
GRCh38: 11:128912009-128912009
4 KCNJ5 NM_000890.5(KCNJ5):c.472A>G (p.Thr158Ala) SNV Pathogenic 30125 rs387906778 GRCh37: 11:128781640-128781640
GRCh38: 11:128911745-128911745
5 KCNJ5 NM_000890.5(KCNJ5):c.451G>A (p.Gly151Arg) SNV Pathogenic 91915 rs386352319 GRCh37: 11:128781619-128781619
GRCh38: 11:128911724-128911724
6 KCNJ5 NM_000890.5(KCNJ5):c.*650C>T SNV Uncertain significance 877306 GRCh37: 11:128787276-128787276
GRCh38: 11:128917381-128917381
7 KCNJ5 NM_000890.5(KCNJ5):c.-213G>A SNV Uncertain significance 879673 GRCh37: 11:128761414-128761414
GRCh38: 11:128891519-128891519
8 KCNJ5 NM_000890.5(KCNJ5):c.-145C>T SNV Uncertain significance 880037 GRCh37: 11:128761482-128761482
GRCh38: 11:128891587-128891587
9 KCNJ5 NM_000890.5(KCNJ5):c.-35G>C SNV Uncertain significance 880038 GRCh37: 11:128761592-128761592
GRCh38: 11:128891697-128891697
10 KCNJ5 NM_000890.5(KCNJ5):c.435G>A (p.Glu145=) SNV Uncertain significance 880039 GRCh37: 11:128781603-128781603
GRCh38: 11:128911708-128911708
11 KCNJ5 NM_000890.5(KCNJ5):c.*191C>T SNV Uncertain significance 880106 GRCh37: 11:128786817-128786817
GRCh38: 11:128916922-128916922
12 KCNJ5 NM_000890.5(KCNJ5):c.*284G>A SNV Uncertain significance 880107 GRCh37: 11:128786910-128786910
GRCh38: 11:128917015-128917015
13 KCNJ5 NM_000890.5(KCNJ5):c.-9A>C SNV Uncertain significance 931771 GRCh37: 11:128781160-128781160
GRCh38: 11:128911265-128911265
14 KCNJ5 NM_000890.5(KCNJ5):c.430A>G (p.Ile144Val) SNV Uncertain significance 303628 rs369703183 GRCh37: 11:128781598-128781598
GRCh38: 11:128911703-128911703
15 KCNJ5 NM_000890.5(KCNJ5):c.*200C>A SNV Uncertain significance 303638 rs756204980 GRCh37: 11:128786826-128786826
GRCh38: 11:128916931-128916931
16 KCNJ5 NM_000890.5(KCNJ5):c.*978T>G SNV Uncertain significance 303658 rs886048017 GRCh37: 11:128787604-128787604
GRCh38: 11:128917709-128917709
17 KCNJ5 NM_000890.5(KCNJ5):c.-63G>C SNV Uncertain significance 303626 rs557063967 GRCh37: 11:128761564-128761564
GRCh38: 11:128891669-128891669
18 KCNJ5 NM_000890.5(KCNJ5):c.455A>G (p.Tyr152Cys) SNV Uncertain significance 877245 GRCh37: 11:128781623-128781623
GRCh38: 11:128911728-128911728
19 KCNJ5 NM_000890.5(KCNJ5):c.476A>G (p.Glu159Gly) SNV Uncertain significance 877246 GRCh37: 11:128781644-128781644
GRCh38: 11:128911749-128911749
20 KCNJ5 NM_000890.5(KCNJ5):c.-307C>G SNV Uncertain significance 878218 GRCh37: 11:128761320-128761320
GRCh38: 11:128891425-128891425
21 KCNJ5 NM_000890.5(KCNJ5):c.-305C>G SNV Uncertain significance 878219 GRCh37: 11:128761322-128761322
GRCh38: 11:128891427-128891427
22 KCNJ5 NM_000890.5(KCNJ5):c.-303C>G SNV Uncertain significance 878220 GRCh37: 11:128761324-128761324
GRCh38: 11:128891429-128891429
23 KCNJ5 NM_000890.5(KCNJ5):c.-301C>G SNV Uncertain significance 878221 GRCh37: 11:128761326-128761326
GRCh38: 11:128891431-128891431
24 KCNJ5 NM_000890.5(KCNJ5):c.-299C>G SNV Uncertain significance 878222 GRCh37: 11:128761328-128761328
GRCh38: 11:128891433-128891433
25 KCNJ5 NM_000890.5(KCNJ5):c.-297C>G SNV Uncertain significance 878223 GRCh37: 11:128761330-128761330
GRCh38: 11:128891435-128891435
26 KCNJ5 NM_000890.5(KCNJ5):c.956G>A (p.Arg319Gln) SNV Uncertain significance 878287 GRCh37: 11:128786322-128786322
GRCh38: 11:128916427-128916427
27 KCNJ5 NM_000890.5(KCNJ5):c.*1090C>T SNV Uncertain significance 878929 GRCh37: 11:128787716-128787716
GRCh38: 11:128917821-128917821
28 KCNJ5 NM_000890.5(KCNJ5):c.-291C>G SNV Uncertain significance 879671 GRCh37: 11:128761336-128761336
GRCh38: 11:128891441-128891441
29 KCNJ5 NM_000890.5(KCNJ5):c.-272A>G SNV Uncertain significance 303623 rs886048007 GRCh37: 11:128761355-128761355
GRCh38: 11:128891460-128891460
30 KCNJ5 NM_000890.5(KCNJ5):c.-253G>T SNV Uncertain significance 303625 rs886048009 GRCh37: 11:128761374-128761374
GRCh38: 11:128891479-128891479
31 KCNJ5 NM_000890.5(KCNJ5):c.*103G>C SNV Uncertain significance 303636 rs886048012 GRCh37: 11:128786729-128786729
GRCh38: 11:128916834-128916834
32 KCNJ5 NM_000890.5(KCNJ5):c.-293C>G SNV Uncertain significance 303610 rs376640553 GRCh37: 11:128761334-128761334
GRCh38: 11:128891439-128891439
33 KCNJ5 NM_000890.5(KCNJ5):c.*1151C>T SNV Uncertain significance 303662 rs886048019 GRCh37: 11:128787777-128787777
GRCh38: 11:128917882-128917882
34 KCNJ5 NM_000890.5(KCNJ5):c.-287G>C SNV Uncertain significance 303619 rs868130049 GRCh37: 11:128761340-128761340
GRCh38: 11:128891445-128891445
35 KCNJ5 NM_000890.5(KCNJ5):c.*936C>G SNV Uncertain significance 303653 rs77525858 GRCh37: 11:128787562-128787562
GRCh38: 11:128917667-128917667
36 KCNJ5 NM_000890.5(KCNJ5):c.*747A>G SNV Uncertain significance 303646 rs886048015 GRCh37: 11:128787373-128787373
GRCh38: 11:128917478-128917478
37 KCNJ5 NM_000890.5(KCNJ5):c.*960G>C SNV Uncertain significance 303655 rs186315097 GRCh37: 11:128787586-128787586
GRCh38: 11:128917691-128917691
38 KCNJ5 NM_000890.5(KCNJ5):c.-295C>G SNV Uncertain significance 303601 rs372328307 GRCh37: 11:128761332-128761332
GRCh38: 11:128891437-128891437
39 KCNJ5 NM_000890.5(KCNJ5):c.*667C>T SNV Uncertain significance 303645 rs886048014 GRCh37: 11:128787293-128787293
GRCh38: 11:128917398-128917398
40 KCNJ5 NM_000890.5(KCNJ5):c.*228G>T SNV Uncertain significance 303639 rs886048013 GRCh37: 11:128786854-128786854
GRCh38: 11:128916959-128916959
41 KCNJ5 NM_000890.5(KCNJ5):c.*1024A>G SNV Uncertain significance 303659 rs886048018 GRCh37: 11:128787650-128787650
GRCh38: 11:128917755-128917755
42 KCNJ5 NM_000890.5(KCNJ5):c.-289G>C SNV Uncertain significance 303618 rs60658163 GRCh37: 11:128761338-128761338
GRCh38: 11:128891443-128891443
43 KCNJ5 NM_000890.5(KCNJ5):c.968T>C (p.Met323Thr) SNV Uncertain significance 303632 rs886048011 GRCh37: 11:128786334-128786334
GRCh38: 11:128916439-128916439
44 KCNJ5 NM_000890.5(KCNJ5):c.-285G>C SNV Uncertain significance 303621 rs886048006 GRCh37: 11:128761342-128761342
GRCh38: 11:128891447-128891447
45 KCNJ5 NM_000890.5(KCNJ5):c.800G>A (p.Arg267His) SNV Uncertain significance 303631 rs886048010 GRCh37: 11:128781968-128781968
GRCh38: 11:128912073-128912073
46 KCNJ5 NM_000890.5(KCNJ5):c.*449A>T SNV Likely benign 303642 rs115414355 GRCh37: 11:128787075-128787075
GRCh38: 11:128917180-128917180
47 KCNJ5 NM_000890.5(KCNJ5):c.1159G>C (p.Gly387Arg) SNV Likely benign 8856 rs199830292 GRCh37: 11:128786525-128786525
GRCh38: 11:128916630-128916630
48 KCNJ5 NM_000890.5(KCNJ5):c.*795G>A SNV Benign 877307 GRCh37: 11:128787421-128787421
GRCh38: 11:128917526-128917526
49 KCNJ5 NM_000890.5(KCNJ5):c.171T>C (p.Ser57=) SNV Benign 137990 rs6590357 GRCh37: 11:128781339-128781339
GRCh38: 11:128911444-128911444
50 KCNJ5 NM_000890.5(KCNJ5):c.*1216C>T SNV Benign 303664 rs566376081 GRCh37: 11:128787842-128787842
GRCh38: 11:128917947-128917947

UniProtKB/Swiss-Prot genetic disease variations for Hyperaldosteronism, Familial, Type Iii:

72
# Symbol AA change Variation ID SNP ID
1 KCNJ5 p.Gly151Arg VAR_065930 rs386352319
2 KCNJ5 p.Thr158Ala VAR_065931 rs387906778
3 KCNJ5 p.Gly151Glu VAR_067090 rs587777437
4 KCNJ5 p.Tyr152Cys VAR_077577
5 KCNJ5 p.Ile157Ser VAR_077578 rs587777438

Expression for Hyperaldosteronism, Familial, Type Iii

Search GEO for disease gene expression data for Hyperaldosteronism, Familial, Type Iii.

Pathways for Hyperaldosteronism, Familial, Type Iii

GO Terms for Hyperaldosteronism, Familial, Type Iii

Sources for Hyperaldosteronism, Familial, Type Iii

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