Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease resulting from adrenal unresponsiveness to ACTH. Patients present in early childhood with hyperpigmentation, hypoglycaemic episodes and seizures secondary to glucocorticoid deficiency. If left untreated this condition is fatal. Mineralocorticoid production is normal. Mutations in the ACTH receptor have been well described and account for approximately 25% of cases. We describe 3 additional novel mutations in the ACTH receptor. Patient 1 presented in the neonatal period with hyperpigmentation associated with very low cortisol and grossly elevated ACTH levels. Mutation analysis revealed compound heterozygous mutation S74I/H170L (serine 74 →isoleucine mutation on one allele and a histidine 170 →leucine mutation on the other). S74I homozygous mutations are well described and associated with Scottish ancestry. The S74I mutation effectively disables the receptor. The H170L mutation is novel, lying in the 2nd extracellular loop and hence may interfere with ligand binding. Patient 2 presented early in life with isolated glucocorticoid deficiency and carries a homozygous mutation resulting in a substitution of leucine →proline at position 55 in the region of the 1st intracellular loop. Patient 3 presented with hypoglycaemia and seizures, has a homozygous nonsense mutation resulting in a truncated protein at position 180 of the ACTH receptor (S180X). The protein lacks the 6th and 7th transmembrane domains, 3rd intracellular loop, 3rd extracellular loop and the C terminal tail. In keeping with this mutation, patient 3 has a severe phenotype requiring high replacement doses of hydrocortisone and despite this remains darkly pigmented with very high ACTH levels. There remains scope for further functional characterisation of ACTH receptor mutations which may enhance our knowledge of ACTH receptor action.
01 - 05 Apr 2006
European Society of Endocrinology