Frequency of Familial Hyperaldosteronism Type 1 in a Hypertensive Pediatric Population

Abstract

Abstract-Familial hyperaldosteronism type 1 is an autosomal dominant disorder attributed to a chimeric CYP11B1/ CYP11B2 gene (CG). Its prevalence and manifestation in the pediatric population has not been established. We aimed to investigate the prevalence of familial hyperaldosteronism type 1 in Chilean hypertensive children and to describe their clinical and biochemical characteristics. We studied 130 untreated hypertensive children (4 to 16 years old). Blood samples for measuring plasma potassium, serum aldosterone, plasma renin activity, aldosterone/renin ratio, and DNA were collected. The detection of CG was performed using long-extension PCR. We found 4 (3.08%) of 130 children with CG who belonged to 4 unrelated families. The 4 patients with CG had very high aldosterone/renin ratio (49 to 242). In addition, we found 4 children and 5 adults who were affected among 21 first-degree relatives. Of the 8 affected children, 6 presented severe hypertension, 1 presented prehypertension, and 1 presented normotension. High serum aldosterone levels (Ͼ17.7 ng/dL) were detected in 6 of 8 subjects (range: 18.6 to 48.4 ng/dL) and suppressed plasma renin activity (Յ0.5 ng/mL per hour) and high aldosterone/renin ratio (Ͼ10) in 8 of 8 children (range: 49 to 242). Hypokalemia was observed in only 1 of 8 children. We demonstrated that the prevalence of familial hyperaldosteronism type 1 in a pediatric hypertensive pediatric population was surprisingly high. We found a high variability in the clinical and biochemical characteristics of the affected patients, which suggests that familial hyperaldosteronism type 1 is a heterogeneous disease with a wide spectrum of presentations even within the same family group. (Hypertension. 2011; 57:1117-1121.) • Online Data Supplement Key Words: arterial hypertension Ⅲ aldosterone Ⅲ familial hyperaldosteronism Ⅲ glucocorticoid-remediable aldosteronism Ⅲ children F amilial hyperaldosteronism type I (FH-I; Online Mendelian Inheritance in Man, No. 103900), which is also known as glucocorticoid-remediable aldosteronism, is often characterized by severe hypertension, variable hyperaldosteronism, low plasma renin activity (PRA), normal or decreased serum potassium, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol, in adults. 1 FH-I occurs because of an unequal crossing over of the genes that encode the steroid 11ß-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B1) enzymes, which results in a chimeric CYP11B1/CYP11B2 gene (CG) with aldosterone synthase activity that is regulated by plasma adrenocorticotropic hormone levels instead of angiotensin II 2 ; this results in an ectopic expression of aldosterone synthase in the zone fasciculate. 3 FH-I is an autosomal dominant disorder, and different pedigrees exhibit different crossover patterns of the hybrid gene, which suggests that the mutations arose independently in each pedigree. 4 In the hypertensive adult population, this monogenic form of aldosteronism is thought to account for only 0.5% to 1.0% o...

Prevalence and Characteristics of Familial Hyperaldosteronism

“…We confirm the prevalence of FH-I/GRA to be relatively low; however, its diagnosis should be excluded in subjects with a higher risk of this form, such as patients with a family history of PA or of strokes at a young age or with an onset of hypertension at a young age 1 ; a recent study reported a relatively high prevalence (3.1%) of FH-I/GRA in hypertensive children in Chile, 26 and, thus, it seems reasonable to test for FH-I/GRA in all hypertensive children with low renin levels. 27 In our study we observed 2 FH-I/GRA families with different phenotypes, particularly mild in one (low prevalence of hypertension and cerebrovascular events, no hypokalemia, and relatively low aldosterone levels) and more severe in the other (all of the subjects were hypertensives, hypokalemic, and with high aldosterone levels and with relatives who died at young age for cardiovascular events).…”

“…Ninety-nine were excluded (65 because they were not informative and 34 because they refused or were unavailable); therefore, 199 families underwent the screening test for PA. The excluded PA patients did not display significant differences in terms of blood pressure levels (systolic blood pressure/diastolic blood pressureϭ155Ϯ26/97Ϯ12 mm Hg) or prevalence of hypokalemia and APA (24% and 29%, respectively), PRA (0.2 [0.1-0.3]), and aldosterone (30 [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]) compared with patients with FH-II, whereas similar potassium and hormonal levels but lower blood pressure levels were displayed compared with the group of sporadic PA included in the study. Therefore, the exclusion of these patients should not have affected the results of the present study.…”

Is Familial Hyperaldosteronism Underdiagnosed in Hypertensive Children?

“…The selection of children who should undergo long-PCR testing for FH-I/GRA could be performed by measuring PRA, aldosterone, and potassium levels to hypertensive children of unknown etiology. In accordance with the data of Aglony et al, 9 the long-PCR test should be performed in all patients with low PRA and normal/high aldosterone (and, thus, high ARR) and normal/ low potassium levels.…”

“…All of the FH-I/GRA patients identified in the study by Aglony et al 9 displayed good blood pressure response to glucocorticoid as expected: 10 of 13 patients had normalized blood pressure with cortisol or dexamethasone, and 3 of 13 required the addition of spironolactone.…”

“…10 The exact prevalence of different types of secondary hypertension in children is usually difficult to obtain, given that the lack of population-based studies and clinical studies from referral centers might be biased toward a specific cause. The study by Aglony et al 9 was also performed in a tertiary referral center for pediatric hypertension, and, therefore, the group of children under investigation might have been enriched by more severe forms of hypertension, resulting in an overestimation of the prevalence of FH-I/GRA. However, the results of this study are of significant importance; the authors performed a careful investigation aimed at the exclusion of other frequent causes of hypertension in children and measured the ARR in all of the other patients.…”