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

Updated: Oct 19, 2018
  • Author: George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London); Chief Editor: Robert P Hoffman, MD  more...
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Answer

FH type I (FH-I), also referred to as glucocorticoid-remediable aldosteronism (GRA), may be detected in asymptomatic individuals during screening of the offspring of affected individuals, or patients may present in infancy with hypertension, weakness, and failure to thrive due to hypokalemia. FH-I is inherited in an autosomal dominant manner and has a low frequency of new mutations.

The first clinical description of GRA appeared in 1966, and the genetic mechanism was discovered in 1992. FH-I arises as a result of unequal crossing over of highly related CYP11B1 (the 11β-hydroxylase gene) and CYP11B2 (the aldosterone synthase gene) during meiosis, producing an anti-Lepore-type fusion product. [5, 6] This genetic rearrangement causes the expression of CYP11B2 to be placed under the control of the CYP11B1 promoter and the aldosterone synthesis to be abnormally regulated by ACTH rather than by the renin-angiotensin system.

The result is ACTH-dependent aldosterone production and production of 17-hydroxylated analogues of 18-hydroxycortisol under ACTH regulation from ectopic enzyme expression in the zona fasciculata. Bilateral hyperplasia of the zona fasciculata occurs, and high levels of novel 18-hydroxysteroids appear in the urine. Adenoma formation is rare, but patients do have a significant increase in incidence of cerebrovascular aneurysms, for which they require screening.


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