1.
Aldosterone signaling defect in young infants: single-center report and review.
Wijaya, M, Ma, H, Zhang, J, Du, M, Li, Y, Chen, Q, Guo, S
BMC endocrine disorders. 2021;(1):149
Abstract
BACKGROUND Aldosterone (Ald) is a crucial factor in maintaining electrolyte and water homeostasis. Defect in either its synthesis or function causes salt wasting (SW) manifestation. This disease group is rare, while most reported cases are sporadic. This study aimed to obtain an overview of the etiology and clinical picture of patients with the above condition and report our rare cases. METHODS A combination of retrospective review and case studies was conducted at the Pediatric Endocrine unit of The First Affiliated Hospital Sun Yat Sen University from September 1989 to June 2020. RESULTS A total of 187 patients with SW were enrolled, of which 90.4% (n = 169) were diagnosed with congenital adrenal hyperplasia (CAH). SW type 21-hydroxylase deficiency accounted for 98.8% (n = 167) of CAH diagnosis, while 1.2% (n = 2) was of lipoid CAH. Non-CAH comprised 9.6% (n = 18) of the total patients whose etiologies included SF-1 gene mutation (n = 1), X-linked adrenal hypoplasia congenita (n = 9), aldosterone synthase deficiency (ASD, n = 4), and pseudo-hypoaldosteronism type 1 (PHA1, n = 1). Etiologies were not identified in three patients. All of patients with ASD and PHA1 exhibited SW syndrome in their early neonatal period. DNA sequencing showed mutations of CYP11B2 for P1-P4 and NR3C2 for P5. P1 and P2 were sibling brothers affected by compound heterozygous mutations of c.1121G > A (p.R374Q) and c.1486delC p.(L496fs); likewise, P4 was identified with compound heterozygous mutations of c.1200 + 1G > A and c.240-1 G > T; meanwhile P3 demonstrated c.1303G > A p.(G435S) homozygous mutation in CYP11B2 gene. Lastly, P5 showed c.1768 C > T p.(R590*) heterozygous mutation in the NR3C2 gene. CONCLUSION Etiology of infant with aldosterone defect was mostly congenital. Renal and adrenal imaging are recommended to exclude renal causes. If clinical picture is suggestive, normal plasma Ald in early infancy cannot rule out aldosterone insufficiency.
2.
PRKACA Somatic Mutations Are Rare Findings in Aldosterone-Producing Adenomas.
Rhayem, Y, Perez-Rivas, LG, Dietz, A, Bathon, K, Gebhard, C, Riester, A, Mauracher, B, Gomez-Sanchez, C, Eisenhofer, G, Schwarzmayr, T, et al
The Journal of clinical endocrinology and metabolism. 2016;(8):3010-7
Abstract
CONTEXT Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. OBJECTIVE The objective of the study was to investigate PRKACA somatic variants identified in APA cases. DESIGN Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. SETTING AND PATIENTS APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. RESULTS PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. CONCLUSIONS We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.
3.
Aldosterone-induced fibrosis in the kidney: questions and controversies.
Brem, AS, Morris, DJ, Gong, R
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2011;(3):471-9
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Abstract
Over the years, aldosterone has been a favorite topic of renal physiologists given its role in the maintenance of body fluids. Investigators only recently are coming to appreciate a second proinflammatory and profibrotic role for this hormone. Mineralocorticoids such as aldosterone trigger a profibrotic process that in many respects mimics the early phase of wound healing. Depending on the type of cell involved, aldosterone may activate the profibrotic process through classic mineralocorticoid receptors, nonclassic membrane-associated mineralocorticoid receptors, and/or glucocorticoid receptors. In the kidney, the actions of aldosterone can be attenuated by 11-dehydro metabolites of endogenous glucocorticoids generated by isoforms of the enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD-1 and 11β-HSD-2). Thus, the renal 11β-HSD isoforms may have 2 functions: to block the improper activation of mineralocorticoid receptors by binding endogenous glucocorticoids and to synthesize agents that limit the actions of aldosterone. Although sodium in the diet has been implicated in aggravating aldosterone-induced renal fibrotic processes, preliminary findings are consistent with the view that aldosterone alone can initiate matrix production in renal tissue even in the absence of active sodium transport. Thus, there is a growing body of laboratory and clinical evidence supporting the use of inhibitors of aldosterone action in patients with both glomerular and tubular diseases.