Human ACTH hypersensitivity syndrome associated with abnormalities of the ACTH receptor gene.
OBJECTIVE
Activating mutations of the ACTH receptor have not been previously described. We investigated a 69-year-old woman with normal blood cortisol but undetectable blood ACTH concentrations. The aim of this study was to evaluate her hypothalamo-pituitary-adrenal axis by measuring circadian variation in blood ACTH and cortisol, and by performing CRH and ACTH stimulation and dexamethasone suppression tests. We also examined biological activity of her circulating blood ACTH using bovine adrenocortical cell suspensions and ACTH receptor gene structure by Northern blotting analysis.


RESULTS
Random plasma cortisol concentrations ranged from 182 to 328 nmol/l, while ACTH concentrations were always undetectable. After an intravenous bolus injection of human CRH 100 micrograms, plasma ACTH rose slightly, while plasma cortisol increased appropriately. ACTH stimulation tests revealed that a small amount of ACTH (5 ng/kg b.w.) had the maximal cortisol stimulatory activity, and even smaller amounts of ACTH (0.5 and 0.05 ng/kg b.w.) produced significant increases in cortisol levels. ACTH bioassay of the patient's plasma demonstrated weak biological activity in the HPLC fractions which corresponded to the band of synthetic human ACTH 1-39. The ACTH receptor coding region was amplified by polymerase chain reaction using the leucocyte genomic DNA. There were two base mutations; cysteine 21-->arginine and serine 247-->glycine in the sequences coding for the first extramembranous N-terminal domain and the third extramembranous loop of the ACTH receptor.


CONCLUSIONS
This patient with normal blood cortisol but undetectable ACTH levels showed increased adrenocortical sensitivity to ACTH and two point mutations in the ACTH receptor gene. This study, therefore, reports a previously undescribed syndrome--ACTH hypersensitivity syndrome--and provides insights into the molecular mechanism of ACTH receptor action.
Hiroi
N
N
First Department of Internal Medicine, Toho University School of Medicine, Tokyo, Japan.
Yakushiji
F
F
Shimojo
M
M
Watanabe
S
S
Sugano
S
S
Yamaguchi
N
N
Miyachi
Y
Y
D000304:Adrenal Cortex Function Tests; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000368:Aged; D000450:Aldosterone / Q000097:blood; D015415:Biomarkers / Q000097:blood; D003346:Corticotropin-Releasing Hormone; D003366:Cosyntropin; D003687:Dehydroepiandrosterone / Q000097:blood; D005260:Female; D005928:Glossitis / Q000097:blood* / Q000235:genetics; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018043:Receptors, Corticotropin / Q000235:genetics* / Q000378:metabolism; D012016:Reference Values; D017422:Sequence Analysis, DNA; D013281:Stomatitis, Aphthous / Q000097:blood* / Q000235:genetics; D013577:Syndrome
D015415:Biomarkers; D018043:Receptors, Corticotropin; D003366:Cosyntropin; D003687:Dehydroepiandrosterone; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D006854:Hydrocortisone