title: Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism.
abstract: In glucocorticoid-remediable aldosteronism (GRA), there is a large interfamily variation of phenotype. We report three subjects with GRA in a single family (parents, two brothers and two sisters), of whom only one (proband) displayed classical features of the mineralocorticoid excess. The proband was a man found to be hypertensive and hypokalaemic at the age of 24 years. Plasma renin activity was suppressed and plasma aldosterone was repeatedly elevated. Blood pressure and aldosterone levels normalized within 5 days of dexamethasone therapy. The presence of a chimaeric CYP11B1/CYP11B2 gene was demonstrated by long-PCR and Southern blotting (crossover site at the end of intron 3) in the proband, in the younger sister (sibling 1) and in the father. In these patients, sequencing of the chimaeric portion of CYP11B1 did not reveal any mutation, while sequencing of the chimaeric portion of CYP11B2 showed a V386A polymorphism in exon 7, known to cause only a minimal impairment of enzymatic activity. Sibling 1 was normotensive, normokalaemic and had normal PRA and aldosterone. The father had normal blood pressure and potassium, low-normal PRA and normal aldosterone. All three subjects had elevated levels of urinary 18-hydroxycortisol and 18-oxocortisol. Baseline 11-deoxycorticosterone (DOC), corticosterone (B) and aldosterone were high in the proband and normal in the father and sibling 1; 11-deoxycortisol (S) and cortisol (F) were normal. ACTH induced a normal increase of B, DOC, S and F, and an excessive aldosterone increase in all three patients. Abnormalities in the chimaeric portions of CYB11B1 or CYP11B2 genes did not account for the phenotypic disparity of the different members in a single GRA family. Altered regulation of the chimaeric gene may be responsible for differences in its activity.
authors.affiliation: Department of Medical and Surgical Sciences, University of Padova, Italy. francesco.fallo@unipd.it
authors.forename: F
authors.initials: F
authors.lastname: Fallo
authors.forename: C
authors.initials: C
authors.lastname: Pilon
authors.forename: T A
authors.initials: TA
authors.lastname: Williams
authors.forename: N
authors.initials: N
authors.lastname: Sonino
authors.forename: S
authors.initials: S
authors.lastname: Morra Di Cella
authors.forename: F
authors.initials: F
authors.lastname: Veglio
authors.forename: R
authors.initials: R
authors.lastname: De Iasio
authors.forename: P
authors.initials: P
authors.lastname: Montanari
authors.forename: P
authors.initials: P
authors.lastname: Mulatero
mesh_terms: D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood / Q000652:urine; D003350:Cortodoxone / Q000652:urine; D019405:Cytochrome P-450 CYP11B2 / Q000235:genetics; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D005938:Glucocorticoids / Q000627:therapeutic use*; D006801:Humans; D006854:Hydrocortisone / Q000031:analogs & derivatives* / Q000652:urine; D006929:Hyperaldosteronism / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D012083:Renin / Q000097:blood / Q000652:urine; D013252:Steroid 11-beta-Hydroxylase / Q000235:genetics
chemical_list: D005938:Glucocorticoids; D000450:Aldosterone; D003907:Dexamethasone; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase; D012083:Renin; C033689:18-hydroxycortisol; D003350:Cortodoxone; D006854:Hydrocortisone