Unusual phenotype in a family affected by glucocorticoid remediable aldosteronism

Abstract

Glucocorticoid remediable hyperaldosteronism (GRA), a monogenic form of inherited hypertension, is characterised by high plasma levels of aldosterone (regulated by ACTH) in the face of a suppressed plasma renin activity (PRA) and the production of two normally rare steroids, 18hydroxycortisol (18OHF) and 18oxocortisol (18oxoF). The GRA is caused by the presence of a chimeric gene originated from an unequal cross-over between CYP11B1 and CYP11B2 gene. In this work we described (clinically, biochemically and genetically) a large pedigree in which the presence of the chimeric gene is demonstrated in four generations of the family. Arterial blood pressures (BP), GRA screening (by long-PCR), creatinine, urinary kallicrein, 18OHF and 18oxoF, PRA, plasmatic aldosterone and cortisol measurements were detected. After demonstration of the presence of the chimeric gene by long-PCR and Southern blot we detected the site of the crossing-over between CYP11B1 and CYP11B2. Our results demonstrated a significant positive correlation between BP and age, BMI, 18OHF, 18oxoF and plasma aldosterone. Moreover urinary levels of 18OHF and 18oxoF were related with plasma aldosterone levels. No significant correlation was found between kallikrein levels and other variables. This family displays a mild phenotype with an average BP levels for the GRA+ patients of 131/86 mmHg and no subjects with hypokaliemia. Further no patients developed hypertension before the age of 18 and only 3 before the age of 36. Also the occurrence of stroke is very low and could be even not related to the GRA+ genotype. The site of the crossing-over between CYP11B1 and CYP11B2 was located at the end of the intron 3 just before the beginning of exon 4. We described a family originating from Sardinia that displays different characteristics from the published families with the same genetic disorder in fact this kindred shows a phenotype particularly benign with a high number of affected members normotensive or with mild hypertension and a very low frequency of stroke.