Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism

Abstract

In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.

Prevalence and Characteristics of Familial Hyperaldosteronism

“…This is in agreement with a reported variability of FH-I/GRA between affected families 28,29 and even within the same family. 30 In this context, our reported low prevalence of hypertension and hypokalemia in the present study may have been exaggerated by the disproportion between patients from the family with the mild phenotype (nϭ21) and the family with the more severe phenotype (nϭ2). Our study also confirms that low renin is the most sensitive clinical parameter for detecting affected patients; although 18OHF and 18oxoF are also very sensitive parameters, they are not available in most centers.…”

“…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.…”

Genetics of primary hyperaldosteronism

“…Patients with FH-I come to clinical attention early in life (Table 1). However, some patients exhibit a mild clinical phenotype, and even normotensive patients have been reported (Fallo et al 2004). A high rate of cerebrovascular complications has been found in patients with GRA (Litchfield et al 1998).…”

“…FH-I has been found in 0.5-1% of the adult population with PA as opposed to children with PA, where FH-I is found in 1-3% of cases (Aglony et al 2011, Carvajal et al 2012. Among patients or within a family, FH-I is characterized by the presence of bilateral adrenal hyperplasia or a rare adrenal nodule exhibiting variable clinical and biochemical features (Fallo et al 2004, Aglony et al 2011. Patients with FH-I come to clinical attention early in life (Table 1).…”

Glucocorticoid remediable aldosteronism (GRA) screening in hypertensive patients from a primary care setting

“…1 Since 1992 the availability of genetic tests capable of detecting the hybrid gene has streamlined diagnosis and facilitated the screening, allowing the detection of family members with a variable phenotype, ranging from severe refractory hypertension to mild forms of hypertension or even normal blood pressure levels. [2][3][4] GRA is considered a relatively infrequent disease, accounting for about 0.5-1% of primary aldosteronism (PA). In recent years, however, with the wide diffusion of the aldosterone to renin ratio (ARR) as a screening test, the estimated prevalence of primary aldosteronism (PA) has risen from 1 to 10-30% of all forms of hypertension, allowing the detection of subjects clinically indistinguishable from patients with essential hypertension.…”