Abstract:Primary aldosteronism, a common cause of severe hypertension1, features constitutive production of the adrenal steroid aldosterone. We analyzed a multiplex family with familial hyperaldosteronism type II (FH-II)2 and 80 additional probands with unsolved early-onset primary aldosteronism. Eight probands had novel heterozygous variants in CLCN2, including two de novo mutations and four independent occurrences of the identical p.Arg172Gln mutation; all relatives with early-onset primary aldosteronism carried the … Show more
“…In a recent report of a family with FH type II and 80 additional probands with unsolved early onset PA, the authors found germline CLCN2 chloride channel mutations in eight of the probands [103]. All relatives with early onset PA carried the CLCN2 variant found in the proband.…”
Section: Fh Type I: Cyp11b1/cyp11b2 Germline Chimeric Genementioning
Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone‐specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. Confirmatory testing is indicated in most patients with positive case detection testing results. The next step is to determine whether patients with confirmed PA have a disease that can be cured with surgery or whether it should be treated medically; this step is guided by computed tomography scan of the adrenal glands and adrenal venous sampling. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low‐sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high–normal serum potassium concentration without the aid of oral potassium supplements.
“…In a recent report of a family with FH type II and 80 additional probands with unsolved early onset PA, the authors found germline CLCN2 chloride channel mutations in eight of the probands [103]. All relatives with early onset PA carried the CLCN2 variant found in the proband.…”
Section: Fh Type I: Cyp11b1/cyp11b2 Germline Chimeric Genementioning
Primary aldosteronism (PA), the most common form of secondary hypertension, can be either surgically cured or treated with targeted pharmacotherapy. PA is frequently undiagnosed and untreated, leading to aldosterone‐specific cardiovascular morbidity and nephrotoxicity. Thus, clinicians should perform case detection testing for PA at least once in all patients with hypertension. Confirmatory testing is indicated in most patients with positive case detection testing results. The next step is to determine whether patients with confirmed PA have a disease that can be cured with surgery or whether it should be treated medically; this step is guided by computed tomography scan of the adrenal glands and adrenal venous sampling. With appropriate surgical expertise, laparoscopic unilateral adrenalectomy is safe, efficient and curative in patients with unilateral adrenal disease. In patients who have bilateral aldosterone hypersecretion, the optimal management is a low‐sodium diet and lifelong treatment with a mineralocorticoid receptor antagonist administered at a dosage to maintain a high–normal serum potassium concentration without the aid of oral potassium supplements.
“…Criteria for the diagnosis of FH II are at least two first-degree members of the same family have confirmed PA and FH-I and familial hyperaldosteronism type-III (FH-III) have been excluded 76 . Six different mutations have been identified in CLCN2, encoding for a chloride channel, at conserved regions of the channel (p.M22K, p.G24D, p.Y26N, p.R172Q, p.delK362 and p.S865R) 77,78 . Mutation leads to open the channel and abolish the voltage dependency of the channel.…”
Aldosterone producing tumors (APA, also known as Conn tumors) are adrenal tumors that overproduce aldosterone, a hormone that regulates the sodium levels in blood and contributes to blood pressure (BP) regulation. Excessive production of aldosterone causes hypertension and approximately 5-15% of hypertensive patients have hyperaldosteronism, known as primary aldosteronism (PA). Major causes of PA are bilateral adrenal hyperplasia (BAH) or aldosterone producing adenoma (APA) and about 30% of PA patients have APAs. In most cases, the disease is unilateral, in rare case bilateral. Patients with APA are often detected when they have elevated blood pressure (BP>160/100mmHg) or when BP cannot be controlled with drugs. Surgery dramatically normalizes or lowers BP in patients with APA.
“…FH‐II is a not glucocorticoid remediable form of PA, traditionally considered as clinically and biochemically indistinguishable from a sporadic form . The genetic basis of some of the families affected by FH‐II has been very recently identified in germline mutations in the CLCN2 gene, encoding for the chloride channel ClC‐2, which is expressed in adrenal zona glomerulosa . The reported mutations facilitate the channel opening at the zona‐glomerulosa resting potential, resulting in cell membrane depolarization and up‐regulation of CYP11B2 expression .…”
Section: Primary Aldosteronismmentioning
confidence: 99%
“…53,54 The reported mutations facilitate the channel opening at the zona-glomerulosa resting potential, resulting in cell membrane depolarization and up-regulation of CYP11B2 expression. 53,54 The mode of transmission is autosomal dominant with incomplete penetrance. 54 Further studies are warranted to establish the impact (in term of prevalence) of CLCN2 mutations in FH.…”
Section: Familial Primary Aldosteronismmentioning
confidence: 99%
“…53,54 The mode of transmission is autosomal dominant with incomplete penetrance. 54 Further studies are warranted to establish the impact (in term of prevalence) of CLCN2 mutations in FH.…”
Renin-angiotensin-aldosterone system (RAAS) plays a crucial role in maintaining water and electrolytes homoeostasis, and its deregulation contributes to the development of arterial hypertension. Since the historical description of the "classical" RAAS, a dramatic increase in our understanding of the molecular mechanisms underlying the development of both essential and secondary hypertension has occurred. Approximatively 25% of the patients affected by arterial hypertension display low-renin levels, a definition that is largely arbitrary and depends on the investigated population and the specific characteristics of the assay. Most often, low-renin levels are expression of a physiological response to sodium-volume overload, but also a significant number of secondary hereditary or acquired conditions falls within this category. In a context of suppressed renin status, the concomitant examination of plasma aldosterone levels (which can be inappropriately elevated, within the normal range or suppressed) and plasma potassium are essential to formulate a differential diagnosis. To distinguish between the different forms of low-renin hypertension is of fundamental importance to address the patient to the proper clinical management, as each subtype requires a specific and targeted therapy. The present review will discuss the differential diagnosis of the most common medical conditions manifesting with a clinical phenotype of low-renin hypertension, enlightening the novelties in genetics of the familial forms.
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