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The clinical significance of aldosterone synthase deficiency: report of a novel mutation in the CYP11B2 gene
© Hui et al.; licensee BioMed Central Ltd. 2014
Received: 27 January 2014
Accepted: 31 March 2014
Published: 3 April 2014
Aldosterone 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.
We 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.
Although 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.
Aldosterone is the main mineralocorticoid hormone in humans that regulates sodium excretion and intravascular volume. It acts via distal renal tubules and cortical collecting ducts by increasing sodium reabsorption from and potassium excretion into the urine. It is synthesized by aldosterone synthase (CYP11B2), an enzyme encoded by CYP11B2, expression of which is almost entirely confined to the adrenal cortex and exclusively in the zona glomerulosa layer. Aldosterone synthase is a cytochrome P450 enzyme that catalyses the final 3 steps of aldosterone biosynthesis: first by the hydroxylation of deoxycorticosterone (DOC) at position 11β to form corticosterone (B), then the hydroxylation at position 18 to form 18-hydroxycorticosterone (18OHB), and lastly the oxidation at position 18 to aldosterone . Isolated deficiencies of aldosterone biosynthesis are caused by inactivating mutations in the CYP11B2 gene [2, 3]. Aldosterone deficiency leads to excessive sodium excretion and potassium retention, resulting in hyponatraemia, hyperkalaemia, and metabolic acidosis. Cases of aldosterone synthase deficiency (ASD) have been identified in Iranian Jews, Europeans and North Americans . In Asians, it has been reported in Thai, Japanese and Indian individuals [5, 6]. To our knowledge, there has been no report of Chinese cases with confirmed genetic analysis. Here, we describe a case of aldosterone synthase deficiency in a Chinese man and results of CYP11B2 analysis in the patient and his family.
Plasma steroid profile of the patient
Post-ACTH stimulation (nmol/L)
0.19 (0.01 – 0.55)
7.06 (0.56 – 1.46)
12.1 (0.83 – 5.5)
44.4 (0.14 – 14.23)
151.8 (34.0 - 208.4)
5.28 (0.58 – 6.1)
0.57 (0.09 – 0.57)
2.36 (0.27 – 1.35)
1.94 (0.095 – 3.15)
2.96 (0.52 – 2.55)
3.09 (0.24 – 4.93)
15.2 (1.88 – 10.96)
14.5 (1.36 - 9.44)
274.3 (59.9 - 480)
721.5 (317.3 – 979.3)
59.9 (34.8 – 79.7)
We describe a Chinese man who presented with severe salt-wasting in infancy and hyperreninaemic hypoaldosteronism, and in whom genetic analysis confirmed aldosterone synthase deficiency. He remained clinically well in adulthood with normal electrolytes and blood pressure whilst on fludrocortisone.
Inadequate aldosterone production results in decreased renal sodium reabsorption and potassium excretion in ASD. Clinical severity varies, with the most severe forms presenting in infancy. Affected infants usually develop vomiting, dehydration, hypovolaemia, and failure to thrive at a few days to weeks following delivery . However, salt-losing crisis in isolated ASD is usually indistinguishable clinically from other forms of defective steroid biosynthesis, such as 21-hydroxylase deficiency in congenital adrenal hyperplasia. Therefore, life-threatening salt-wasting in affected infants is usually treated initially with both hydrocortisone and fludrocortisone pending steroid hormone analysis . Phenotypically, infants with ASD have normal external genitalia . Hydrocortisone can be withdrawn once characteristic steroid profile or genetic mutations of CYP11B2 gene are confirmed. A typical biochemical profile of this disorder includes hyponatraemia, hyperkalaemia, raised plasma renin activity, undetectable or low aldosterone level, and normal or elevated cortisol levels.
Aldosterone synthase deficiency has been classified based on biochemical phenotypes: in type 1 ASD, the enzymatic CYP11B2 activity is completely abolished. Affected individuals have low to normal levels of 18OHB, and undetectable to low levels of plasma aldosterone or its urinary metabolite, tetrahydroaldosterone . In type 2 deficiency, the mutations in the CYP11B2 gene only decrease 18-hydroxylase and 18-oxidase activities, but not 11β-hydroxylase activity. It differs from type 1 in that 18-OHB levels are markedly elevated, whilst plasma aldosterone levels and urinary tetrahydroaldosterone are low . However, it is now recognised that these biochemical phenotypes have clinical, hormonal and genotypic overlapping features  and that type 1 and type 2 ASD would be better considered a continuous spectrum of the same disease .
As clinical severity gradually improves with age, affected adults are usually asymptomatic despite no mineralocorticoid therapy [5, 12]. However, termination of mineralocorticoid may lead to postural hypotension and hyperkalaemia when triggered by stress due to dehydration or reduced salt intake in some affected adults . Generalised weakness with marked hyperkalaemia and dehydration has been reported as the first presentation in a middle-aged man after concurrent institution of indapamide for hypertension and bowel preparation for barium enema. Interestingly, further questioning revealed a past history of vomiting and failure to thrive in early infancy that resolved without any mineralocorticoid replacement . Therefore, detailed childhood history would be a helpful clue in suspected ASD case presenting in adulthood. Possible mechanisms for reduced clinical severity of ASD with advancing age include increasing sensitivity to mineralocorticoid action and sodium intake with age. It has been shown that mineralocorticoid receptor expression in human kidneys begins with low levels in late gestation and rises progressively after birth . Another potential mechanism is age-dependent impaired 11β-hydroxysteroid dehydrogenase type 2 activity, leading to greater cortisol availability for the mineralocorticoid receptor with age .
Neonatal screening for CAH using 17-hydroxyprogesterone measurement would fail to detect ASD, as infants with ASD usually have normal  or slightly elevated basal and stimulated 17-hydroxyprogesterone . The diagnosis of ASD may therefore be missed until the patient presents with salt-wasting crisis. Therefore, comprehensive hormonal investigation followed by genetic confirmation for suspected adults and their respective partners would be useful to assess the genetic implication in their offspring and to minimize the potential life-threatening risk.
Multiple sequence alignment of a segment of the CYP11B2 gene
Homozygous p.Lys175del (previously described as homozygous deletion of codon 173 before the use of the latest HGVS nomenclature) has been reported in a girl presenting with salt-wasting during infancy . CYP11B2 is polymorphic at this position, encoding arginine or lysine. Amino acid residue 173 is positioned in α-helix D, and the secondary structure of aldosterone synthase was presumed to be altered by the single amino acid deletion. Indeed, using fission yeast system, Tin et al. demonstrated that the deletion mutation at codon 173 displayed markedly reduced 11-β-hydroxylation activity (16.3%), and no 18-hydroxylation and 18-oxidation activities .
Aldosterone synthase deficiency is a rare cause of hyperreninaemic hypoaldosteronism and its genetic and molecular basis is more heterogeneous than previously described. It should be suspected in infants without virilisation presenting with salt-wasting or in adults presenting with stress-induced hyperkalaemia and a history of failure to thrive in childhood. Our case illustrates the clinical significance to recognize this condition as it has a good long-term prognosis when adequate fludrocortisone replacement is instituted.
Written informed consent was obtained by the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
We thank the patient and his family for their support.
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