Isolated Addison’s is unlikely to be caused by mutations in MC2R, MRAP or StAR, three genes responsible for familial glucocorticoid deficiency

Renuka Dias, Li Chan, Louise Metherell, Simon Pearce and Adrian Clark

R Dias, Centre for Endocrinology, Queen Mary University of London, London, ec1m 6bq, United Kingdom
L Chan, Centre for Endocrinology, QMUL, London, United Kingdom
L Metherell, Centre for Endocrinology, QMUL, London, United Kingdom
S Pearce, Institute of Human Genetics, Centre for Life, Newcastle-upon-Tyne, United Kingdom
A Clark, Centre for Endocrinology, QMUL, London, United Kingdom

Correspondence: Renuka Dias, Email: r.dias@qmul.ac.uk

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 AD, with implications for treatment and genetic counselling. Currently mutations in 3 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

40 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 be underdiagnosed in the AD population. However, in ~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 maybe implicated in AD.

From http://www.eje.org/cgi/content/abstract/EJE-09-0720v1