A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing’s Syndrome

Tong, Anli; Liu, Guanghua; Wang, Fen; Jiang, Jun; Zhou, Yan; Zhang, Dianxi; Zhang, Yinsheng; Cai, Jun

doi:10.1210/jc.2016-1504

Cited by 30 publications

(21 citation statements)

References 21 publications

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“…Yamada et al reported 2 female patients with APA co-secreting cortisol, without clinical signs of Cushing’s syndrome, which harbored mutations in KCNJ5 [4]. Tong et al described a patient with familial PA associated with overt Cushing’s syndrome, harboring a KNCJ5 germline mutations, who had a massive bilateral hyperplasia [48]. We could not confirm the presence of KCNJ5 mutations, as well as of mutations in other genes (i.e., ATP1A1 , ATP2B3 , CACNA1D ) involved in calcium signaling, in our series of cases.…”

Section: Discussionmentioning

confidence: 99%

Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

et al. 2017

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Purpose Aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion are reported in an increasing number of patients. Five aldosterone-producing adenomas from patients with primary aldosteronism and subclinical hypercortisolism were examined. The aims of our study were: (1) to analyze pathological features and immunohistochemical expression of CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) in these tumors; (2) to investigate somatic mutations involved in adrenal steroid hypersecretion and/or tumor growth. Methods Archival micro-dissected paraffin-embedded slides from tumor specimens were used for histological and molecular studies. Immunohistochemistry was performed using monoclonal anti-CYP11B1 and anti-CYP11B2 antibodies. Cellular composition was determined by examining for known features of zona fasciculata and zona glomerulosa, and immunoreactivity for CYP11B1 and CYP11B2 by McCarty H-score. Spot regions for mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, PRKACA, and CTNNB1 gene sequences were evaluated. Results Four APAs showed a predominant (≥50%) zona fasciculata-like cell pattern: one tumor had CYP11B1 H-score = 150, no detectable CYP11B2 expression, and harbored a PRKACA p.Leu206Arg mutation (that we have reported previously elsewhere), one had no CYP11B1 expression, CYP11B2 H-score = 40, and no mutations; the remaining two adenomas had high CYP11B1 H-score (160 and 240, respectively) and low CYP11B2 H-score (30 and 15, respectively), with the latter harboring a CTNNB1 p. Ser45Phe activating mutation. One of five aldosterone-producing adenomas had a predominant zona glomerulosa-like pattern, CYP11B1 H-score = 15, CYP11B2 H-score = 180, and no mutations. Conclusions The majority of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion were composed mainly of zona fasciculata-like cells, while CYP11B1 and CYP11B2 immunostaining demonstrated clear heterogeneity. In a subset of cases, different somatic mutations may be involved in hormone excess and tumor formation.

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Section: Discussionmentioning

confidence: 99%

Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

et al. 2017

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“…Similarly, the patient carrying the p.Tyr152Cys mutation displayed a less severe phenotype (31). Interestingly, a case of FH-III (due to the KCNJ5 p.Glu145Gln mutation) presenting with severe PA and tytpical Cushing's syndrome has recently been reported in a Chinese boy (32). In vitro electrophysiological studies showed that the p.Gly151Glu substitution was associated with a particularly severe impairment of the channel functioning, with massive Na + entry, osmotic shock and cell death.…”

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confidence: 99%

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Monticone

Buffolo

Tetti

et al. 2018

European Journal of Endocrinology

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2 AbstractAldosterone is the main mineralocorticoid hormone in humans and plays a key role in maintaining water and electrolyte homeostasis. Primary aldosteronism (PA), characterized by autonomous aldosterone overproduction by the adrenal glands, affects 6% of the general hypertensive population and can be either sporadic or familial. Aldosterone producing adenoma (APA) and bilateral adrenal hyperplasia (BAH) are the two most frequent subtypes of sporadic PA, and 4 forms of familial hyperaldosteronism (FH-I to FH-IV) have been identified. Over the last six years the introduction of next-generation sequencing has significantly improved our understanding of the molecular mechanisms responsible for autonomous aldosterone overproduction in both sporadic and familial PA. Somatic mutations in four genes (KCNJ5, ATP1A1, ATP2B3 and CACNA1D), differently implicated in intracellular ion homeostasis, have been identified in nearly 60% of the sporadic APAs. Germline mutations in KCNJ5 and CACNA1H cause FH-III and FH-IV, respectively, while germline mutations in CACNA1D cause the rare PASNA syndrome, featuring primary aldosteronism seizures and neurological abnormalities. Further studies are warranted to identify the molecular mechanisms underlying BAH and FH-II, the most common forms of sporadic and familial PA whose molecular basis has yet to be uncovered.

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“…Different studies have identified germline KCNJ5 mutations in FH-III families with a phenotypic variability, ranging from spironolactone-responsive hyperaldosteronism to massive adrenal hyperplasia with drug-resistant hypertension (Choi et al 2011, Charmandari et al 2012, Mussa et al 2012, Scholl et al 2012, Monticone et al 2013, Adachi et al 2014, Tong et al 2016. This variability was attributed to the type of KCNJ5 mutation, with a severe phenotype associated with GIRK4 p.Gly151Arg, p.Thr158Ala, p.Ile157Ser and p.Tyr152Cys mutations, and a milder phenotype associated with KCNJ5 p.Gly151Glu mutations.…”

Section: Familial Hyperaldosteronism Type III and Germline Kcnj5 Mutamentioning

confidence: 99%

“…Combined aldosterone and cortisol oversecretion associated with massive bilateral adrenal hyperplasia was described in a patient carrying a germline KCNJ5 mutation (p.Glu145Gln) (Tong et al 2016). In primary cell culture of the resected hyperplastic adrenal, calcium channel blockers inhibited the secretion of both aldosterone and cortisol and the mRNA expression of steroidogenic enzymes.…”

Section: Familial Hyperaldosteronism Type III and Germline Kcnj5 Mutamentioning

confidence: 99%

“…In primary cell culture of the resected hyperplastic adrenal, calcium channel blockers inhibited the secretion of both aldosterone and cortisol and the mRNA expression of steroidogenic enzymes. The authors suggest that the hypersecretion of cortisol might be ascribed to overly large size of the hyperplastic adrenal (with low CYP11B1 expression) and, like aldosterone secretion, may be mediated by voltagegated Ca 2+ channels (Tong et al 2016). A second study reported that adrenals from patients carrying a germline KCNJ5 mutation (p. p.Thr158Ala) were markedly enlarged with loss of zonation and cells expressing aldosterone synthase and/or 11β-hydroxylase, with and without 17α-hydroxylase, and some expressing all three enzymes .…”

Section: Familial Hyperaldosteronism Type III and Germline Kcnj5 Mutamentioning

confidence: 99%

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Somatic and inherited mutations in primary aldosteronism

Fernandes-Rosa

Boulkroun

Zennaro

2017

Journal of Molecular Endocrinology

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Primary aldosteronism (PA), the most common form of secondary hypertension, is caused in the majority of cases by unilateral aldosterone-producing adenoma (APA) or bilateral adrenal hyperplasia. Over the past few years, somatic mutations in KCNJ5, CACNA1D, ATP1A1 and ATP2B3 have been proven to be associated with APA development, representing more than 50% of sporadic APA. The identification of these mutations has allowed the development of a model for APA involving modification on the intracellular ionic equilibrium and regulation of cell membrane potential, leading to autonomous aldosterone overproduction. Furthermore, somatic CTNNB1 mutations have also been identified in APA, but the link between these mutations and APA development remains unknown. The sequence of events responsible for APA formation is not completely understood, in particular, whether a single hit or a double hit is responsible for both aldosterone overproduction and cell proliferation. Germline mutations identified in patients with early-onset PA have expanded the classification of familial forms (FH) of PA. The description of germline KCNJ5 and CACNA1H mutations has identified FH-III and FH-IV based on genetic findings; germline CACNA1D mutations have been identified in patients with very early-onset PA and severe neurological abnormalities. This review summarizes current knowledge on the genetic basis of PA, the association of driver gene mutations and clinical findings and in the contribution to patient care, plus the current understanding on the mechanisms of APA development.

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A Novel Phenotype of Familial Hyperaldosteronism Type III: Concurrence of Aldosteronism and Cushing’s Syndrome

Cited by 30 publications

References 21 publications

Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

Histopathological and genetic characterization of aldosterone-producing adenomas with concurrent subclinical cortisol hypersecretion: a case series

GENETICS IN ENDOCRINOLOGY: The expanding genetic horizon of primary aldosteronism

Somatic and inherited mutations in primary aldosteronism

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