Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid secretion. Mutations in the ACTH receptor (MC2R) account for approximately 25% of all FGD cases, but since these are usually missense mutations, a degree of receptor function is frequently retained. A recent report, however, suggested that disturbances in the renin–aldosterone axis were seen in some patients with potentially more severe MC2R mutations. Furthermore, MC2R knock out mice have overt aldosterone deficiency and hyperkalaemia despite preservation of a normal zona glomerulosa. We wished to determine whether a group of patients with severe nonsense mutations of the MC2R exhibited evidence of mineralocorticoid deficiency, thereby challenging the conventional diagnostic feature of FGD which might result in diagnostic misclassification.
Between 1993 and 2008, 164 patients with FGD were screened for mutations in the MC2R. Totally 42 patients (34 families) were found to have mutations in the MC2R. Of these, 6 patients (4 families) were found to have homozygous nonsense or frameshift mutations.
Mild disturbances in the renin–angiotensin–aldosterone axis were noted in four out of six patients, ranging from slightly elevated plasma renin levels to low aldosterone levels, although frank mineralocorticoid deficiency or electrolyte disturbance were not found. No patient required fludrocortisone replacement.