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'Treasure your exceptions': what we can learn from autosomal-dominant inherited forms of hypertension
F C Luft1, H Schuster, N Bilginturan
1Franz Volhard Clinic, Max Delbruck Centre for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin, Germany.
Insights
Rare monogenic hypertension forms, like glucocorticoid-remediable aldosteronism and Liddle's syndrome, offer insights into essential hypertension pathogenesis and treatment. Studying these rare conditions advances understanding of complex blood pressure regulation.
Area of Science:
- Endocrinology and Genetics
- Cardiovascular Medicine
- Nephrology
Background:
- Essential hypertension is a complex condition with multifactorial causes.
- Rare monogenic forms of hypertension provide valuable insights into its pathogenesis.
- Understanding these rare conditions can illuminate mechanisms of blood pressure regulation.
Purpose of the Study:
- To explore the relevance of rare monogenic hypertension forms to essential hypertension.
- To discuss their role in diagnosis, pathogenesis, and treatment strategies.
Main Methods:
- Review of identified monogenic hypertension forms with simple autosomal-dominant inheritance.
- Detailed elucidation of genetic defects and pathophysiology for glucocorticoid-remediable aldosteronism and Liddle's syndrome.
- Investigation of a third form of monogenic hypertension linked to brachydactyly.
Main Results:
- Glucocorticoid-remediable aldosteronism involves a chimeric gene affecting aldosterone synthase regulation.
- Liddle's syndrome results from mutations in the epithelial sodium channel, causing increased sodium reabsorption.
- A distinct autosomal-dominant hypertension with brachydactyly shows normal hormonal regulators and is not salt-sensitive, resembling essential hypertension.
Conclusions:
- Studying rare monogenic hypertension forms aids in understanding mineralocorticoid and salt-sensitive hypertension.
- These exceptional cases offer a unique window into the mechanisms underlying essential hypertension.
- Insights gained can inform diagnostic approaches and therapeutic interventions for common hypertension.
Objective:
To discuss the relevance of rare monogenic forms of hypertension to the diagnosis, pathogenesis and treatment of essential hypertension.
Study Selection:
Three monogenic forms of hypertension have been identified that are inherited as a simple autosomal-dominant trait. The genetic defects and the pathophysiology of two, namely glucocorticoid-remediable aldosteronism and Liddle's syndrome, have been elucidated in great detail. The third form of monogenic hypertension, which cosegregates with a second phenotype, brachydactyly, is being investigated.
Results:
Glucocorticoid-remediable aldosteronism is caused by the presence of a chimeric gene, which incorporates the regulatory region of the 11-beta-hydroxylase gene and the structural portion of the aldosterone synthase gene. The enzyme aldosterone synthase is not only expressed in the zona fasiculata but is also regulated by adrenocorticotrophic hormone in this condition. Liddle's syndrome is caused by mutations in the beta subunit of the epithelial sodium channel. The mutations result in inappropriate channel patency and increased distal sodium reabsorption. Both of these forms of inherited hypertension are low-renin forms of hypertension. Glucocorticoid-remediable aldosteronism resembles primary aldosteronism, whereas Liddle's syndrome resembles low-renin essential hypertension. An autosomal-dominant genetic form of hypertension has been described in northeastern Turkey. The hypertension cosegregates 100% with brachydactyly. This form resembles essential hypertension, because levels of renin, aldosterone, catecholamines and other regulators are normal. Furthermore, in contrast to glucocorticoid-remediable aldosteronism and Liddle's syndrome, the patients are not salt-sensitive.
Conclusions:
Mechanisms of mineralcorticoid hypertension, renally induced salt-sensitive hypertension, and possibly essential hypertension, may be elucidated by studying exceptional families.