Isolated Addison's disease is unlikely to be caused by mutations in MC2R, MRAP or STAR, three genes responsible for familial glucocorticoid deficiency.
BACKGROUND
Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease caused by ACTH resistance and leads to isolated glucocorticoid deficiency. Although FGD patients typically have normal mineralocorticoid secretion, subtle alterations in the renin-angiotensin-aldosterone axis have been reported in a subset of patients at presentation. Anecdotally, some patients with FGD have been initially diagnosed as having Addison's disease (AD), with implications for treatment and genetic counselling. Currently, mutations in three genes: the ACTH receptor (MC2R); the melanocortin 2 receptor accessory protein (MRAP); and the steroidogenic acute regulatory protein (STAR) are known to give rise to FGD types 1-3. We investigated a cohort of autoantibody-negative AD patients for mutations in these genes.


METHODS
Forty patients with known AD without evidence of autoimmune disease were screened for mutations in MC2R, MRAP and STAR. In addition, patients were genotyped for the MC2R promoter polymorphism previously associated with reduced responsiveness to ACTH.


RESULTS
No mutations in MC2R, MRAP or STAR were identified in any patient. The frequencies of the MC2R promoter polymorphism were similar to those reported in healthy controls.


CONCLUSIONS
FGD does not appear to be underdiagnosed in the AD population. However, in approximately 50% of patients with FGD, no genetic cause has yet been identified and it is possible that the other, as yet unidentified, genes giving rise to FGD may be implicated in AD.
Dias
R P
RP
Barts and the London School of Medicine and Dentistry, Centre for Endocrinology, John Vane Science Centre, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
Chan
L F
LF
Metherell
L A
LA
Pearce
S H S
SH
Clark
A J L
AJ
D000224:Addison Disease / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics*; D055815:Young Adult; D000098682:Steroidogenic Acute Regulatory Protein
D005938:Glucocorticoids; C458099:MRAP protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; D044103:Receptor, Melanocortin, Type 2; D000098682:Steroidogenic Acute Regulatory Protein