9-fluorocortisone and Adrenal-Insufficiency

A male presented at age 2.2 years with a 6-week history of intermittent vomiting and hyperpigmentation. Investigations showed salt wasting with hyperkalaemia, a grossly impaired cortisol response to ACTH stimulation, elevated renin and ACTH. Family history revealed that two maternal uncles had died soon after birth. A third uncle failed to thrive during infancy but improved with a course of cortisone, then being untreated until further investigation revealed adrenal insufficiency. A fourth uncle died aged 10 days, with urinary salt loss and hypoplastic adrenal glands at postmortem. Molecular studies on the proband, his mother, maternal grandmother, and surviving uncle showed a novel C to G substitution at nucleotide position 794 (missense mutation T265R) in the DAX1 (NR0B1) gene. The proband has responded well to steroid replacement but has proved sensitive to 9alpha-fludrocortisone treatment, developing hypertension on a dose of 133 microg/m(2)/day. At 8.8 years he was noted to have testicular volumes of 4 ml, despite no other evidence of secondary sexual development and prepubertal gonadotrophin levels. Novel features of this family include a novel DAX1 mutation, marked variability in age of presentation, hypertension on 'standard' doses of 9alpha-fludrocortisone and mild testicular enlargement.

Topics: Adrenal Glands; Adrenal Insufficiency; Animals; Anti-Inflammatory Agents; Child, Preschool; Cortisone; DAX-1 Orphan Nuclear Receptor; DNA Mutational Analysis; DNA-Binding Proteins; Genetic Diseases, X-Linked; Humans; Hydrocortisone; Male; Mutation, Missense; Pedigree; Receptors, Retinoic Acid; Repressor Proteins; Testis

The regulatory function of glucocorticoids on thyroid hormone concentrations was studied in patients with adrenocortical insufficiency (ACI, n = 8) and in healthy subjects (n = 6). In patients with ACI withdrawal of glucocorticoid substitution for 84 h led to an increase in serum concentrations of total triiodothyronine (TT3) from 110 +/- 20 to 133 +/- 22 ng/dl and a decrease of serum reverse-T3 (rT3) from 23 +/- 6 to 18 +/- 6 ng/dl, whereas subsequent administration of dexamethasone (0.5 mg po q.i.d. for 3 days) induced a fall in TT3 (129 +/- 22 to 88 +/- 16 ng/dl) and a rise in rT3 (17 +/- 5 to 37 +/- 11 ng/dl) concentrations. Serum levels of total thyroxine (TT4) were unchanged by either withdrawal or re-administration of glucocorticoids. Basal plasma thyrotrophin (TSH) concentrations were unchanged by glucocorticoid withdrawal and fell from 2.2 +/- 1.5 to 1.1 +/- 0.8 mU/l during subsequent dexamethasone therapy. In healthy subjects a decrease of TT3 (89 +/- 8 to 69 +/- 8 ng/dl) and an increase in rT3 (19 +/- 5 to 32 +/- 8 ng/dl) concentrations were seen after stimulation of endogenous cortisol production by prolonged infusion of ACTH1-24 (0.5 mg, t = 8 h on 2 consecutive days), whereas concentrations of TT4 remained unchanged. During subsequent administration of dexamethasone serum level of both. TT3 and rT3 returned to basal levels. Thus, changes in thyroid hormone concentrations are induced by alterations of substitution therapy in patients with ACI. In healthy subjects the application of 2 mg dexamethasone/day following prolonged maximal stimulation of endogenous cortisol by iv ACTH may represent a state of relative glucocorticoid deficiency, thus explaining the observed hormonal changes, which are inverse to those generally induced in healthy man by endogenous or exogenous glucocorticoids.

Topics: Adrenal Insufficiency; Adrenocorticotropic Hormone; Adult; Cortisone; Dexamethasone; Female; Humans; Hydrocortisone; Male; Middle Aged; Thyroid Hormones; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse