Editorial Commentary Is Familial Hyperaldosteronism Underdiagnosed in Hypertensive Children?

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension in adults, accounting for 5% to 15% of hypertensive patients, depending on the severity of blood pressure levels.1,2 Patients with PA undergo a higher rate of cardiovascular complications compared with essential hypertensives, and, thus, the screening of hypertensive subgroups of patients with higher prevalence of PA is recommended.2 Three genetic forms of PA have been described so far: familial hyperaldosteronism type I (FH-I), also know as glucocorticoid-remediable aldosteronism (GRA); familial hyperaldosteronism type II (FH-II); and familial hyperaldosteronism type III (FH-III; Table). FH-I/GRA-affected patients display hypertension, elevated adrenocorticotropic hormone–dependent aldosterone secretion, renin suppression, and high levels of the 18OH-cortisol and 18oxo-cortisol.3 FH-I/GRA is attributed to an unequal recombination between CYP11B1 (11-hydroxylase) and CYP11B2 (aldosterone synthase), generating a chimeric CYP11B gene containing CYP11B1 sequences (including the promoter) at its 5 end and CYP11B2 sequences at its 3 end. Because CYP11B1 expression is regulated by adrenocorticotropic hormone, the hybrid gene encodes a chimeric enzyme with aldosterone synthase activity and adrenocorticotropic hormone–dependent expression throughout the adrenal cortex.3 Most affected individuals develop severe hypertension in early life, but different degrees of severity and even normotension have also been described.4 Diagnosis of FH-I/ GRA is commonly made by long-PCR,4 and genetic testing for FH-I/GRA in adults is recommended for patients with onset of PA before 20 years of age and in those with a family history of PA or stroke at a young age ( 40 years).2 FH-II is a nonglucocorticoid-remediable form of PA, indistinguishable from sporadic PA. The molecular basis of FH-II is still unknown, although several analyses have shown a linkage with chromosomal region 7p22.5 Intriguingly, a linkage analysis performed in a large hypertensive population demonstrated aldosterone/plasma renin activity (PRA) ratio (ARR) to be in linkage with 7p21-22.6 However, the genetic background of this form seems to be heterogeneous, because not all of the families showed linkage with this chromosomal region. The diagnosis of FH-II requires PA to be confirmed in 2 family members and exclusion of FH-I/GRA and is suggested in hypertensive family members of PA patients.2 FH-III is a new familial form of PA characterized by a particularly severe hyperaldosteronism that is resistant to aggressive pharmacotherapy and therefore requires bilateral adrenalectomy; the underlying genetic cause has been shown recently to be attributed to mutations in the gene encoding the potassium channel KCNJ57 (Kir 3.4, potassium inwardly rectifying channel, subfamily 1, member 5): the mutation occurs near the selectivity filter for potassium resulting in increased sodium conductance and cell depolarization, which, in adrenal glomerulosa cells, produces calcium entry and, thus, increased aldosterone production and cell proliferation.7 Intriguingly, somatic mutations in the same gene have also been shown in aldosterone-producing adenomas from PA patients with severe hypertension and hypokalemia.7 FH-I/GRA is considered a very rare disease, accounting for 1% of PA patients; FH-II is considered more frequent, with a prevalence of 3%, whereas FH-III has only been shown so far in a single family. However, until now, the prevalence of familial hyperaldosteronism in hypertensive children was unknown. Along with the epidemic increase in childhood obesity, the prevalence of pediatric hypertension is increasing in Western society, presently accounting for 3% to 5% of all children and 7% to 15% being prehypertensives.8 In children, secondary hypertension is more frequent in younger patients and in those with higher blood pressure levels. The most frequent secondary causes are kidney diseases, whereas endocrine causes account for 10% of all cases.8 In this issue of Hypertension, Aglony et al9 report a high prevalence of FH-I among hypertensive children in Chile. They studied a selected group of hypertensives aged 4 to 16 years, after exclusion of obesity, renal diseases, diabetes mellitus, hypercortisolism, and hypercalcemia. In this subgroup of patients they found an increased ARR in 3.9% and FH-I/GRA in 3.1% of children. The study of the relatives resulted in the identification of 13 other affected subjects (8 children and 5 adults). Of the 8 children with FH-I/GRA, 6 were hypertensives, 1 experienced an ischemic stroke at the age of 4 years, 1 was prehypertensive, and 1 was normotensive. Only 1 child was hypokalemic, in agreement with previous reports on the low prevalence of hypokalemia in FH-I/GRA patients,2,4 6 of 8 displayed high aldosterone levels for age, and all displayed low PRA and high ARR. Normality levels of these hormones in children were derived The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Division of Internal Medicine and Hypertension Unit, Department of Medicine and Experimental Oncology, University of Torino, Torino, Italy. Correspondence to Paolo Mulatero, Medicina Interna 4 e Centro Ipertensione, AOU S. Giovanni Battista, Via Genova 3, 10126 Torino, Italy. E-mail [email protected] (Hypertension. 2011;57:1053-1055.) © 2011 American Heart Association, Inc.