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Familial hyperaldosteronism type III(HALD3)

MedGen UID:
824604
•Concept ID:
C3838758
•
Disease or Syndrome
Synonyms: Familial hyperaldosteronism type 3; FH III
SNOMED CT: Familial hyperaldosteronism type 3 (703234002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal dominant inheritance (Orphanet)
 
Gene (location): KCNJ5 (11q24.3)
 
Monarch Initiative: MONDO:0013359
OMIM®: 613677
Orphanet: ORPHA251274

Definition

Hyperaldosteronism type III (HALD3) is characterized by hypertension secondary to massive adrenal mineralocorticoid production. Like patients with glucocorticoid-remediable aldosteronism (GRA, or HALD1; 103900), patients with HALD3 present with childhood hypertension, elevated aldosteronism levels, and high levels of the hybrid steroids 18-oxocortisol and 18-hydroxycortisol. However, hypertension and aldosteronism in HALD3 are not reversed by administration of exogenous glucocorticoids and patients require adrenalectomy to control hypertension (Geller et al., 2008). [from OMIM]

Clinical features

From HPO
Hypercalciuria
MedGen UID:
43775
•Concept ID:
C0020438
•
Finding
Abnormally high level of calcium in the urine.
See: Feature record | Search on this feature
Polyuria
MedGen UID:
19404
•Concept ID:
C0032617
•
Sign or Symptom
An increased rate of urine production.
See: Feature record | Search on this feature
Hypertensive disorder
MedGen UID:
6969
•Concept ID:
C0020538
•
Disease or Syndrome
The presence of chronic increased pressure in the systemic arterial system.
See: Feature record | Search on this feature
Polydipsia
MedGen UID:
43214
•Concept ID:
C0085602
•
Sign or Symptom
Excessive thirst manifested by excessive fluid intake.
See: Feature record | Search on this feature
Hypokalemia
MedGen UID:
5712
•Concept ID:
C0020621
•
Finding
An abnormally decreased potassium concentration in the blood.
See: Feature record | Search on this feature
Metabolic acidosis
MedGen UID:
65117
•Concept ID:
C0220981
•
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
See: Feature record | Search on this feature
Hyperaldosteronism
MedGen UID:
6960
•Concept ID:
C0020428
•
Disease or Syndrome
Overproduction of the mineralocorticoid aldosterone by the adrenal cortex.
See: Feature record | Search on this feature
Adrenal hyperplasia
MedGen UID:
301220
•Concept ID:
C1621895
•
Disease or Syndrome
Enlargement of the adrenal gland.
See: Feature record | Search on this feature
Decreased circulating renin level
MedGen UID:
337182
•Concept ID:
C1845206
•
Finding
An decreased level of renin in the blood.
See: Feature record | Search on this feature
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Professional guidelines

PubMed

DIAGNOSIS OF ENDOCRINE DISEASE: 18-Oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids?
Lenders JWM, Williams TA, Reincke M, Gomez-Sanchez CE
Eur J Endocrinol 2018 Jan;178(1):R1-R9. Epub 2017 Sep 13 doi: 10.1530/EJE-17-0563. PMID: 28904009Free PMC Article
Somatic and inherited mutations in primary aldosteronism.
Fernandes-Rosa FL, Boulkroun S, Zennaro MC
J Mol Endocrinol 2017 Jul;59(1):R47-R63. Epub 2017 Apr 11 doi: 10.1530/JME-17-0035. PMID: 28400483
SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: Genetic diagnosis of primary aldosteronism.
Zennaro MC, Jeunemaitre X
Ann Endocrinol (Paris) 2016 Jul;77(3):214-9. Epub 2016 Jun 15 doi: 10.1016/j.ando.2016.02.006. PMID: 27315758

Recent clinical studies

Etiology

Genetics of primary aldosteronism.
Vaidya A, Hamrahian AH, Auchus RJ
Endocr Pract 2015 Apr;21(4):400-5. Epub 2015 Feb 9 doi: 10.4158/EP14512.RA. PMID: 25667376Free PMC Article
a Novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III.
Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, Sterner C, Warth R, Mulatero P, Rainey WE
J Clin Endocrinol Metab 2013 Nov;98(11):E1861-5. Epub 2013 Sep 13 doi: 10.1210/jc.2013-2428. PMID: 24037882Free PMC Article
Genetics of adrenocortical disease: an update.
Bar-Lev A, Annes JP
Curr Opin Endocrinol Diabetes Obes 2012 Jun;19(3):159-67. doi: 10.1097/MED.0b013e328352f013. PMID: 22476103

Diagnosis

Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia.
Maria AG, Suzuki M, Berthon A, Kamilaris C, Demidowich A, Lack J, Zilbermint M, Hannah-Shmouni F, Faucz FR, Stratakis CA
Am J Hypertens 2020 Feb 22;33(2):124-130. doi: 10.1093/ajh/hpz172. PMID: 31637427Free PMC Article
Familial hyperaldosteronism type III.
Monticone S, Tetti M, Burrello J, Buffolo F, De Giovanni R, Veglio F, Williams TA, Mulatero P
J Hum Hypertens 2017 Dec;31(12):776-781. Epub 2017 Apr 27 doi: 10.1038/jhh.2017.34. PMID: 28447626
A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing's Syndrome.
Tong A, Liu G, Wang F, Jiang J, Yan Z, Zhang D, Zhang Y, Cai J
J Clin Endocrinol Metab 2016 Nov;101(11):4290-4297. Epub 2016 Jul 12 doi: 10.1210/jc.2016-1504. PMID: 27403928Free PMC Article
Genetics of primary aldosteronism.
Vaidya A, Hamrahian AH, Auchus RJ
Endocr Pract 2015 Apr;21(4):400-5. Epub 2015 Feb 9 doi: 10.4158/EP14512.RA. PMID: 25667376Free PMC Article
A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue.
Monticone S, Bandulik S, Stindl J, Zilbermint M, Dedov I, Mulatero P, Allgaeuer M, Lee CC, Stratakis CA, Williams TA, Tiulpakov A
J Clin Endocrinol Metab 2015 Jan;100(1):E114-8. doi: 10.1210/jc.2014-3636. PMID: 25322277Free PMC Article

Therapy

Cushing Syndrome in a Pediatric Patient With a KCNJ5 Variant and Successful Treatment With Low-dose Ketoconazole.
Tatsi C, Maria AG, Malloy C, Lin L, London E, Settas N, Flippo C, Keil M, Hannah-Shmouni F, Hoffman DA, Stratakis CA
J Clin Endocrinol Metab 2021 May 13;106(6):1606-1616. doi: 10.1210/clinem/dgab118. PMID: 33630995Free PMC Article
Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature.
Adachi M, Muroya K, Asakura Y, Sugiyama K, Homma K, Hasegawa T
Horm Res Paediatr 2014;82(2):138-42. Epub 2014 May 10 doi: 10.1159/000358197. PMID: 24819081

Prognosis

Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia.
Maria AG, Suzuki M, Berthon A, Kamilaris C, Demidowich A, Lack J, Zilbermint M, Hannah-Shmouni F, Faucz FR, Stratakis CA
Am J Hypertens 2020 Feb 22;33(2):124-130. doi: 10.1093/ajh/hpz172. PMID: 31637427Free PMC Article
Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature.
Adachi M, Muroya K, Asakura Y, Sugiyama K, Homma K, Hasegawa T
Horm Res Paediatr 2014;82(2):138-42. Epub 2014 May 10 doi: 10.1159/000358197. PMID: 24819081

Clinical prediction guides

A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing's Syndrome.
Tong A, Liu G, Wang F, Jiang J, Yan Z, Zhang D, Zhang Y, Cai J
J Clin Endocrinol Metab 2016 Nov;101(11):4290-4297. Epub 2016 Jul 12 doi: 10.1210/jc.2016-1504. PMID: 27403928Free PMC Article

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