The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene

Abstract

BackgroundAldosterone synthase (CYP11B2) deficiency is a rare autosomal recessive disorder, usually presenting with severe salt-wasting in infancy or stress-induced hyperkalaemia and postural hypotension in adulthood. Neonatal screening for congenital adrenal hyperplasia, another cause of salt wasting, using 17-hydroxyprogesterone measurement would fail to detect aldosterone synthase deficiency, a diagnosis which may be missed until the patient presents with salt-wasting crisis. Due to this potential life-threatening risk, comprehensive hormonal investigation followed by genetic confirmation for suspected patients would facilitate clinical management of the patient and assessment of the genetic implication in their offspring.Case presentationWe describe a 33-year old Chinese man who presented in infancy with life-threatening hyponatraemia and failure to thrive, but remained asymptomatic on fludrocortisone since. Chromosomal analysis confirmed a normal male karyotype of 46, XY. Plasma steroid profile showed high plasma renin activity, low aldosterone level, and elevated 18-hydroxycorticosterone, compatible with type 2 aldosterone synthase deficiency. The patient was heterozygous for a novel CYP11B2 mutation: c.977C > A (p.Thr326Lys) in exon 3. He also carried a heterozygous mutation c.523_525delAAG (p.Lys175del) in exon 6, a known pathogenic mutation causing aldosterone synthase deficiency. Sequencing of CYP11B2 in his parents demonstrated that the mother was heterozygous for c.977C > A, and the father was heterozygous for c.523_525delAAG.ConclusionAlthough a rare cause of hyperreninaemic hypoaldosteronism, aldosterone synthase deficiency should be suspected and the diagnosis sought in patients who present with life-threatening salt-wasting in infancy, as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted. To our knowledge, this is the first Chinese patient in which the molecular basis of aldosterone synthase deficiency has been identified.

Multiplexed steroid profiling of gluco- and mineralocorticoids pathways using a liquid chromatography tandem mass spectrometry method

“…It also allows differential diagnosis among almost all subtypes of steroid-related disorders, e.g. detection of heterozygous CYP21A2 mutation carriers [31] and other forms of CAH: 11-hydroxylase deficiency (CYP11B1), 17-hydroxylase deficiency/17-20 lyase, 3β-hydroxysteroid dehydrogenase or aldosterone synthase (CYP11B2) deficiencies [1,[32][33][34]. Although 11-deoxycorticosterone, 18OHDOC, 18OHB and corticosterone have a less significant mineralocorticoid activity than aldosterone, they have demonstrated usefulness in identification of different forms of CAH resulting from enzyme deficiencies [33][34][35][36] and in characterizing subtypes of primary hyperaldosteronism [37].…”

Corticosterone Methyl Oxidase Deficiency Type 1 with Normokalemia in an Infant

“…Cases of aldosterone synthase deficiency have been reported in various ethnic groups, including Europeans, North Americans, and Asians (9,10,11,12). One previous case of aldosterone synthase deficiency in a patient of Turkish origin was reported from Japan (4).…”

Congenital hyperreninemic hypoaldosteronism due to aldosterone synthase deficiency type I in a Portuguese patient – Case report and review of literature

“…The aldosterone synthesis is dependent on aldosterone synthase (AS), an enzyme encoded by the CYP11B2 gene, one of the cytochrome P450 enzymes (P450c11Aldo). AS, previously named corticosterone methyloxidase is expressed in the adrenal cortex and is responsible for catalysing the final three steps of the aldosterone biosynthesis: from 11-desoxycorticosterone (DOC) to corticosterone, then to 18-hidroxicorticosterone (18-OHB) and finally to aldosterone (1,2).…”