What is the pathophysiology of familial hyperaldosteronism type III (FH-III)?

Updated: Sep 08, 2020
  • Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Robert P Hoffman, MD  more...
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FH-III is a rare autosomal dominant form of PA characterized by early-onset hypertension, nonglucocorticoid-remediable hyperaldosteronism, and hypokalemia. Germline heterozygous missense mutations of the KCNJ5 gene, encoding Kir3.4, a member of the inwardly rectifying K+ channel family, have been identified as a cause of FH-III. Thus far, 4 mutations (G151R, G151E, T158A, and I157S) have been reported in 6 families. [11, 12, 13]

The clinical phenotype of patients harboring the above mutations ranges from severe PA and hypertension refractory to medical treatment that requires bilateral adrenalectomy, to mild or moderate hypertension responsive to medical therapy. In some patients, adrenal hyperplasia has been described.

Various studies from different centers report a prevalence of somatic KCNJ5 mutations in sporadic APAs ranging from 30-65%. [11, 14, 15, 16] There are 2 recurrent mutations, G151R and L168R, reported by all studies, whereas there is one report of a 3-nucleotide deletion, the delI157. [17]

The affected residues of both the germline and the somatic mutations are in or near the selectivity filter of the Kir3.4 potassium channel and are highly conserved among different species. Electrophysiologic studies demonstrate that these mutations result in loss of channel selectivity, with increased Na+ conductance leading to membrane depolarization. In zona glomerulosa cells, membrane depolarization leads to opening of voltage activated Ca2+ channels, with activation of the calcium-signalling pathway, the major mediator of aldosterone production.

APAs with KCNJ5 mutations are more prevalent in females than males and in younger patients. They are also associated with higher preoperative aldosterone levels. They are not related with the tumor size, but they are related with higher aldosterone levels and lower K+ concentrations.

Transcriptome and real-time polymerase chain reaction (PCR) analyses demonstrate that APAs with KCNJ5 mutations exhibit increased expression of the CYP11B2 gene and its transcriptional regulator NR4A2, thus increasing aldosterone production. It has also been found that APAs with and without KCNJ5 mutations display slightly different gene expression patterns. [16] Another study reports KCNJ5 mRNA levels higher in the APAs with KCNJ5 mutations and significantly higher in APA than cortisol-producing adenomas and pheochromocytomas. [15]

Somatic mutations in ATP1A1 (gene that encodes the alpha-1 [catalytic] subunit of the Na+/K+ ATPase, a member of the P-type ATPase family), ATP2B3 (gene that encodes the plasma membrane calcium transporting ATPase 3 [PMAC3], another member of the P-type ATPase family), or CACNA1D (gene that encodes Cav1.3, the alpha subunit of an L-type voltage-gated calcium channel) are present in approximately 6%, 1% and 8% of all cases of an aldosterone-producing adenoma, respectively. More recently, de novo germline mutations in CACNA1D were reported in 2 children with a previously undescribed syndrome that featured PA and neuromuscular abnormalities. [18]

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