Monogenic Forms of Low-Renin Hypertension

Vesna D Garovic; Anthony A Hilliard; Stephen T Turner

Nat Clin Pract Nephrol. 2006;2(11):624-630.

Gordon's Syndrome

Recently identified mutations of WNK1 and WNK4 (members of a family of serine-threonine kinases) have been shown to cause the rare familial autosomal dominant disease, Gordon's syndrome (also known as pseudohypoaldosteronism type II).^[22] Wild-type WNK1 and WNK4 inhibit the thiazide-sensitive Na-Cl co-transporter in the distal tubule. Mutations of these proteins are associated with gain of function (Figure 3D_a) and increased co-transporter activity, excessive chloride and sodium reabsorption, and volume expansion.^[23] This syndrome is characterized by short stature, intellectual impairment, dental abnormalities, muscle weakness, severe hypertension by the third decade of life, low fractional excretion of sodium, normal renal function, hyperchloremic metabolic acidosis, and low renin and aldosterone levels. Hyperkalemia, another hallmark of this syndrome, might be a function of diminished sodium delivery to the cortical collecting tubule (sodium reabsorption provides the driving force for potassium excretion, which is mediated by the renal outer medullary potassium channel ROMK). Alternatively, the same mutations in WNK4 that result in a gain of function of the Na-Cl co-transporter, might inhibit ROMK activity (Figure 3D_b), resulting in hyperkalemia, as suggested by recent genetic studies.^[24] Treatment consists of either a low-salt diet or thiazide diuretics, aimed at decreasing chloride intake and blocking Na-Cl co-transporter activity, respectively.

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Table 1. Characteristics of and Treatments for Monogenic Forms of Low-renin Hypertension
Disorder	Age of onset	Pattern of inheritance	Aldosterone level	Serum potassium level	Genetic test (reference)	Treatment^h
^{FH-I (GRA)}a	^{Second or third decade}	^{Autosomal dominant}	^High	^{Decreased in 50% of cases; marked decrease with thiazides}	^Commercial	^{Glucocorticoids}
^FH-IIa	^Middle	^{Autosomal dominant}	^High	^{Low to normal}	^{Research (11)}	^{Spironolactone, eplerenone}
^{DOC oversecretion due to CAH}b,^c	^Childhood	^{Autosomal recessive}	^Low	^{Low to normal}	^{Research (25)}	^{Glucocorticoids}
^{Activating MCR mutation exacerbated by pregnancy}d	^{Second or third decade}	^Unknown	^Low	^{Low to normal}	^{Research (14,15)}	^{Delivery of fetus}
^AMEb,e	^Childhood	^{Autosomal recessive}	^Low	^{Low to normal}	^Commercial	^{Spironolactone, dexamethasone}
^{Liddle syndrome}f	^{Third decade}	^{Autosomal dominant}	^Low	^{Low to normal}	^Commercial	^{Amiloride, triamterene}
^{Gordon's syndrome}g	^{Second or third decade}	^{Autosomal dominant}	^Low	^High	^{Research (22)}	^{Thiazide diuretic, low-sodium diet}

^aDue to hyperaldosteronism.
^bDue to production of non-aldosterone mineralocorticoids.
^cAcquired forms due to DOC-producing tumors.
^dDue to increased activity of MCRs.
^eAcquired forms due to either licorice ingestion or ectopic ACTH secretion.
^fDue to increased activity of sodium channels.
^gDue to increased activity of Na-Cl co-transporter in the distal tubule.
^hSpecific for underlying mechanisms (other forms of treatment, including different antihypertensive medications = might be needed to adequately control blood pressure).
Abbreviations: ACTH = adrenocorticotropic hormone; AME = apparent mineralocorticoid excess; CAH = congenital adrenal hyperplasia; DOC = deoxycorticosterone; FH-I = familial hyperaldosteronism type I; FH-II = familial hyperaldosteronism type II; GRA = glucocorticoid-remediable aldosteronism; MCR = mineralocorticoid receptor.

Table 1. Characteristics of and Treatments for Monogenic Forms of Low-renin Hypertension
Disorder	Age of onset	Pattern of inheritance	Aldosterone level	Serum potassium level	Genetic test (reference)	Treatment^h
^{FH-I (GRA)}a	^{Second or third decade}	^{Autosomal dominant}	^High	^{Decreased in 50% of cases; marked decrease with thiazides}	^Commercial	^{Glucocorticoids}
^FH-IIa	^Middle	^{Autosomal dominant}	^High	^{Low to normal}	^{Research (11)}	^{Spironolactone, eplerenone}
^{DOC oversecretion due to CAH}b,^c	^Childhood	^{Autosomal recessive}	^Low	^{Low to normal}	^{Research (25)}	^{Glucocorticoids}
^{Activating MCR mutation exacerbated by pregnancy}d	^{Second or third decade}	^Unknown	^Low	^{Low to normal}	^{Research (14,15)}	^{Delivery of fetus}
^AMEb,e	^Childhood	^{Autosomal recessive}	^Low	^{Low to normal}	^Commercial	^{Spironolactone, dexamethasone}
^{Liddle syndrome}f	^{Third decade}	^{Autosomal dominant}	^Low	^{Low to normal}	^Commercial	^{Amiloride, triamterene}
^{Gordon's syndrome}g	^{Second or third decade}	^{Autosomal dominant}	^Low	^High	^{Research (22)}	^{Thiazide diuretic, low-sodium diet}

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Monogenic Forms of Low-Renin Hypertension

Gordon's Syndrome

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