Glucocorticoid-remediable aldosteronism (GRA) is a rare cause of hypertension and hypokalaemia mediated by hyperaldosteronism. An association with cerebral aneurysms has also been described. GRA is due to a mutation of the GRA gene and it is transmitted as autosomal dominant trait. Cascade genetic screening of first-degree relatives of an index case is a strategy to identify individuals affected. However, the penetrance and expressivity of the GRA gene are not known. Our aim was to describe a case highlighting a profound discrepancy between genotype and phenotype.Design and method:
Case report with description of family pedigree, molecular genetic tests for GRA, clinical and biochemical phenotype.Results:
A 33-year old woman was referred to our unit for the assessment of possible GRA and related-cerebral aneurysms. Pedigree: mother and one of her 3 siblings had a diagnosis of GRA supported by positive genetic tests. Both affected relatives had been prescribed corticosteroid therapy and had cerebral aneurysms coiled. In our patient PCR analysis was positive for the 3.9 fragment indicating the chimeric gene characteristic of GRA. However, she was consistently normotensive in the clinic and had a mean blood pressure of 135/85 on 24-hour monitoring. Blood tests showed normal serum potassium at 3.9 mmol/L and normal aldosterone/renin ratio after prolonged sitting at 767 (pmol/L over pmol/mL/hour). Magnetic resonance imaging did not identify cerebral aneurysms.Conclusions:
Our case demonstrates that the expressivity and penetrance of the GRA gene can be variable and that the presence of GRA gene mutation does not necessarily predict the clinical phenotype of hyperaldosteronism. This finding has crucial implications in terms of strategy for cascade family screening as well as for the implications of a positive genetic test for the individuals tested.