Generalised glucocorticoid resistance diagnosed by chance
E Owen1, L Lloyd2, A Wayte3 & A Wilton1
Generalised resistance to glucocorticoid is a rare familial or sporadic disease with partial target tissue insensitivity to glucocorticoids. Compensatory activation of the hypothalamopituitaryadrenal axis occurs with raised andrenocorticotrophic (ACTH) hormone levels and increased synthesis of adrenal steroids. The phenotype varies from asymptomatic to excess glucocorticoid, mineralocorticoid and androgenic effects.
A 20-year-old female was found on screening tests by her general practitioner to have a 0900 h cortisol level of 1636 nmol/l. She was not cushingoid. The explanation appeared to be treatment with a combined oral contraceptive pill. Despite stopping treatment for 6 weeks a repeat 0900 h cortisol remained elevated at 1003 nmol/l. We further investigated the patient, her 18 year old sister (who was receiving laser treatment for hirsutism) and parents:-
Sister 1 (sister 2) weight 55.2 kg (64.2 kg), BMI 23.5 (24.5), hirsutism score 5 (11), both normotensive and normokalaemic. Of 0900 h ACTH 89.1 ng/l (48), cortisol 915 nmol/l (780). Urinary free cortisol 630 nmol/24 h (460). ACTH/cortisol profile. Of 0900 h 43.1 (24.2), 811 (1165). 1100 h 21.8 (7.2), 412 (594). Of 1400 h 31 (17), 436 (708) and 1600 h 19.9 (22.2), 393 (711) ng/l/nmol/l. One microgram dexamethasone suppression test, ACTH 15.5 ng/l (11.7), cortisol 272 nmol/l (321). Testosterone 2.4 nmol/l (2.7), androstenedione 16.3 nmol/l (22.5 nmol/l), 17 hydroxyprogesterone 2.6 nmol/l (6.2) and DHEAS 5.5 umol/l (9.5). Investigations on parents all normal. These sisters fulfill the diagnostic criteria for generalised glucocorticoid resistance with elevated plasma ACTH/cortisol levels, increased 24 h urinary free cortisol excretion, normal circadian pattern of cortisol and ACTH secretion with resistance to dexamethasone suppression. The only phenotypic abnormality was hirsutism in sister two which was absent in sister 1 despite the presumed same genotype. It is inferred that the mode of inheritance is autosomal recessive as both parents are unaffected.