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Type 1 Aldosterone Synthase Deficiency Presenting in a Middle-Aged Man¹

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9063; and Division of Endocrinology, Fairview General Hospital and Cleveland Clinic Health System (H.C.T.), Cleveland, Ohio 44111

Address all correspondence and requests for reprints to: Perrin C. White, M.D., Department of Pediatrics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9063. E-mail: perrin.white{at}utsouthwestern.edu

	Abstract

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Aldosterone synthase deficiency due to mutations in the CYP11B2 gene usually presents in infancy with electrolyte abnormalities and failure to thrive, whereas affected adults are usually asymptomatic. We describe a patient who first came to medical attention in middle age when he developed hyperkalemia after preparation for a barium enema. Past medical history was notable for failure to thrive in infancy. He had elevated PRA with low serum and urinary levels of aldosterone and its metabolites and normal or slightly elevated levels of 18-hydroxycorticosterone. These findings suggested a diagnosis of type 1 aldosterone synthase deficiency. The patient had a homozygous duplication of six nucleotides at codon 143 in exon 3 of CYP11B2, leading to the insertion of two amino acid residues (Arg-Leu). When the corresponding mutant complementary DNA was expressed in cultured cells, the resulting enzyme was completely inactive, confirming the diagnosis. We conclude that aldosterone synthase deficiency represents an unusual cause of hyperreninemic hypoaldosteronism presenting in adult life, but it should be suspected if the past medical history is positive for failure to thrive in childhood or if the patient manifests no other recognized causes of hyperreninemic hypoaldosteronism.

	Introduction

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ADULTS WITH ISOLATED hypoaldosteronism typically differ from infants and children in both mode of presentation and underlying etiology. Hyporeninemic hypoaldosteronism in older patients ordinarily presents as asymptomatic hyperkalemia during the sixth to eighth decade of life and is usually caused by diabetes mellitus (1), although a variety of other disorders have been implicated, including systemic lupus erythematosus (2), Sjogren’s syndrome (3), multiple myeloma (4), and human immunodeficiency virus infection (5), as well as drugs such as nonsteroidal antiinflammatory agents (6). Hyperreninemic hypoaldosteronism may occur in critically ill adults (7), patients receiving heparin therapy (8), and, rarely, patients with tumors metastatic to the adrenal gland (9, 10).

In contrast, hyperreninemic hypoaldosteronism in young children is most often due to inherited defects of aldosterone biosynthesis. Whereas the most common of these is the salt-wasting form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, this disorder has an associated abnormality of cortisol biosynthesis as well as excessive secretion of adrenal androgens (11). Isolated aldosterone deficiency is rare. It usually results from mutations in aldosterone synthase (12, 13, 14, 15, 16, 17, 18, 19, 20), a mitochondrial cytochrome P450 enzyme encoded by the CYP11B2 gene on chromosome 8q24 (21, 22). Aldosterone synthase normally catalyzes the conversion of deoxycorticosterone to aldosterone, a process that requires three successive oxidative steps: 11-hydroxylation of deoxycorticosterone to corticosterone, 18-hydroxylation to 18-hydroxycorticosterone, and 18-oxidation (23). Although mutations in CYP11B2 account for most cases of isolated congenital aldosterone deficiency, such mutations could not be detected in two affected kindreds, raising the possibility that other genetic or environmental factors might account for some cases of this disorder (20, 24).

Two forms of aldosterone synthase deficiency are recognized. Patients with type 1 (corticosterone methyloxidase I) aldosterone synthase deficiency have low to normal levels of 18-hydroxycorticosterone and very low to undetectable levels of urinary tetrahydroaldosterone, whereas patients with the type 2 (corticosterone methyloxidase II) form have high levels of 18-hydroxycorticosterone and subnormal to occasionally normal levels of urinary tetrahydroaldosterone (25).

Infants with aldosterone synthase deficiency present with renal sodium wasting and consequent dehydration that may progress to shock and death if untreated. Infants and young children suffer from failure to thrive, but are often asymptomatic as adults; adults may have normal renin levels even with provocative stimuli such as iv furosemide (26). The reasons for the amelioration in disease severity with age are not well understood, but may involve maturation of the kidney with a decreased requirement for aldosterone to maintain sodium conservation as well as increases in dietary sodium intake.

Here we describe a patient with type 1 aldosterone synthase deficiency who was unusual in that he first came to medical attention as a middle-aged adult. He was homozygous for a previously undescribed mutation in CYP11B2, a duplication of six nucleotides at codon 143 in exon 3.

	Case History

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A 47-yr-old Caucasian male came to medical attention when, after institution of indapamide for hypertension and preparation for a barium enema with cathartics and enemas, he developed progressive weakness. He had a serum potassium of 8.9 mmol/L, blood urea nitrogen (BUN) of 6.8 mmol/L (41 mg/dL), and creatinine of 210 mol/L (2.4 mg/dL). After treatment of the hyperkalemia and dehydration, BUN and creatinine decreased to 4.2 mmol/L (25 mg/dL) and 130 µmol/L (1.5 mg/dL), respectively, and potassium to 4.5 mmol/L. A tentative diagnosis of aldosterone synthase deficiency was made (Table 1), and he was treated with fludrocortisone (Florinef, Apothecon, Princeton, NJ; 0.1 mg daily) for 3 yr. A definitive diagnosis of type 1 aldosterone synthase deficiency was made after discontinuing fludrocortisone for 5–10 weeks (Table 2). During the ensuing 11 yr the patient manifested progressive renal failure. Renal ultrasound performed in August 1993 showed the right kidney to be 8.7 cm in length and the left kidney to be 10.5 cm when creatinine was 170 µmol/L (1.9 mg/dL), without evidence of hydronephrosis or polycystic disease. No kidney biopsy was performed. His BUN and creatinine at 58 yr of age were, respectively, 12 mmol/L (70 mg/dL) and 850 µmol/L (9.6 mg/dL).

Family history was notable for the patient’s mother and father being third cousins. The patient had no children. There was no family history of chronic renal disease. Family history was otherwise noncontributory, except for a paternal uncle who was said to have failed to thrive in infancy, but subsequently developed normally. This uncle had normal tetrahydroaldosterone excretion as an adult (not shown), as did 26 other family members. Coincidentally, the patient’s wife was diagnosed with autoimmune primary adrenal insufficiency after the patient came to medical attention.

	Materials and Methods

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Serum and urinary steroids

Serum aldosterone levels and the initial 24-h urine aldosterone-18-glucuronide conjugate level were measured by double antibody RIA after extraction. Corticosterone was measured by RIA after multiple solvent extractions, 18-hydroxycorticosterone by RIA after paper chromatography, cortisol by direct RIA in dilute serum, deoxycorticosterone by RIA after high pressure liquid chromatography, 18-hydroxydeoxycorticosterone by RIA after extraction and paper chromatography, and PRA by RIA of angiotensin 1 generated at pH 5.5 at multiple time points (all at Endocrine Sciences, Inc., Calabasas Hills, CA). Basal steroid levels were obtained at 0915 h with the patient in the sitting position. Post-ACTH levels were obtained 1 h after the im injection of cosyntropin (0.25 mg). All other urinary steroids were measured by the late Stanley Ulick (Bronx V.A. Hospital, Bronx, NY) using mass fragmentography as previously described (25).

Molecular genetic studies

Approximately 80 ng genomic DNA (prepared from whole blood) were subjected to PCR in a 100-µL reaction volume using a GeneAmp PCR System 9600 (Perkin-Elmer Corp./Cetus, Norwalk, CT). The reactions contained either 1x Pre-Mix G (exons 1–5) or D (exons 6–9; Epicenter Technologies, Madison, WI), 25 pmol of each primer (Table 3), and 2.5 U AmpliTaq polymerase (Perkin-Elmer Corp./Cetus). Exons 1–5 and 6–9 were amplified using touchdown PCR (one cycle/1 C decline). Cycling conditions consisted of 30-s denaturation at 95 C, 30-s annealing (exons 1–5, 63 to 55 C; exons 6–9, 60 to 50 C), and 4-min extension at 72 C. This was followed by 35 cycles of PCR at the final annealing temperature (55 C for exons 1–5; 50 C for exons 6–9). A 2-min denaturation step (95 C) preceded cycling, and a 10-min primer extension step and a 4 C soak followed. A modified hot start procedure was performed by keeping the tubes on ice and placing them in the PCR machine only after the block temperature had risen above 90 C during the initial denaturation step.

Mutations were introduced into the normal sequence of CYP11B2 complementary DNA (cDNA) by a PCR using oligonucleotides containing the desired change. In brief, CYP11B2 cDNA was amplified from pCMV4-CYP11B2 plasmid (23) with Taq polymerase in two overlapping fragments, each using one oligonucleotide corresponding to either the 5'- or 3'-end of the cDNA-coding sequence and one containing the desired mutant sequence. The second PCR step used the overlapping PCR products as template and primers corresponding to the 5'- and 3'-ends of the entire coding region of CYP11B2 plus NheI (5'-end) and EcoRI (3'-end) sites. In addition, the 5'-primer was designed with a Kozak sequence to optimize translation efficiency. The second step PCR product containing the two-amino acid insertion was digested with NheI and EcoRI and ligated into the mammalian expression vector, pCDNA3.1+zeo (Invitrogen, San Diego, CA), which had been similarly digested. The complete sequence of each recombinant was checked to ensure that it had the predicted two-amino acid insertion but no other changes. Plasmid DNA for transfection was prepared using a QIAGEN Midiprep Kit.

Transient transfection assay for enzyme activity

Plasmid DNA was transfected into human embryonic kidney 293 cells using the FUGENE 6 transfection reagent (Roche, Indianapolis, IN) according to the manufacturer’s protocol. The day before the transfection, approximately 3 x 10⁵ cells were plated in six-well plates. The cells were exposed to a mixture containing 6 µL transfection reagent, 0.5 µg pCMV4-hADX encoding human adrenodoxin (original clone provided by Walter Miller), and 1.0 µg pCDNA3.1+, pCDNA3.1+B2, or pCDNA3.1+mutant B2 in 1.5 mL culture medium. The cells were washed 24 h later and incubated with fresh medium for an additional 24 h to permit cell recovery and expression of the transfected genes.

To assay the enzymatic activity of the transfected cells, the medium was replaced with 1 mL serum-free medium with 0.1% BSA containing 0.5 µmol/L [¹⁴C]deoxycorticosterone (0.01 µCi; NEN Life Science Products, Boston, MA). Medium was removed 24 h later, supplemented with 10 nmol unlabeled steroid, and extracted with 2.5 mL methylene chloride. The organic phase was dried down under nitrogen gas, separated on TLC plates, and analyzed as previously described (23). Experiments were run in quadruplicate.

	Results

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Clinical data

The patient had a low serum aldosterone level under basal conditions that responded poorly to cosyntropin, whereas PRA was markedly elevated, and levels of aldosterone precursors were normal or mildly increased (Table 1). The initial 24-h urinary aldosterone-18-glucuronide level was less than 1 µg/1840 mg creatinine with concomitant sodium of 368 mmol/L. When tested off therapy several years later (Table 2), urinary tetrahydroaldosterone was undetectable on two separate occasions, and excretion of 18-hydroxy-11-dehydrotetrahydrocorticosterone, the major urinary metabolite of 18-hydroxycorticosterone, was reduced. All of these data are consistent with type I aldosterone synthase deficiency. Excretion of cortisol and cortisone metabolites was high; this is unusual for adult patients with aldosterone synthase deficiency (25).

Molecular genetic characterization

The patient had a homozygous duplication of six nucleotides (CGA TTG) at codon 143 in exon 3 of CYP11B2, leading to the insertion of two amino acid residues (Arg-Leu). The patient’s mother was heterozygous for the same mutation.

To prove that this mutation caused the patient’s disease, it was recreated in CYP11B2 cDNA and expressed in cultured human embryonic kidney 293 cells. Cells transiently transfected with normal CYP11B2 cDNA converted [¹⁴C]deoxycorticosterone to corticosterone and lesser amounts of 18-hydroxycorticosterone and aldosterone, but cells transfected with the mutant cDNA were enzymatically inactive with this substrate (Fig. 1).

View larger version (46K): [in this window] [in a new window]   Figure 1. Mutation causing type 1 aldosterone synthase deficiency. Top, The CYP11B1 gene is diagramed; the gene is approximately 8 kb long. Numbered boxes represent exons, and the position of the mutation is denoted by an arrow. The normal and mutant nucleotide and amino acid sequences in this region are presented, starting with codon 142. An insertion of six nucleotides is underlined. Bottom, Results of a representative transfection experiment. Cells were transfected with normal (N) or mutant (M) CYP11B2 cDNA constructs or with a control (C) adrenodoxin construct (see Materials and Methods). After incubating cells with [14C]deoxycorticosterone, the medium was subjected to TLC, and plates were autoradiographed. Positions of reactants and products are marked; note that mutant and control lanes are indistinguishable.

	Discussion

Top Abstract Introduction Case History Materials and Methods Results Discussion References

Considering that our patient’s mutation in CYP11B2 destroys enzymatic activity when expressed in cultured cells, several aspects of his steroid profile deserve comment. The elevated serum levels of corticosterone presumably reflect increased CYP11B1 activity. Although most circulating 18-hydroxycorticosterone is normally synthesized by CYP11B2 (in which case it might be expected to be very low if CYP11B2 is inactive), the CYP11B1 isozyme may retain some 18- hydroxylase activity that assumes greater prominence when CYP11B1 activity is high and CYP11B2 is inactive (27). The combination of urinary aldosterone being undetectable by mass fragmentography (25) and low, but detectable, serum aldosterone levels by RIA (28) has been previously reported in a patient homozygous for a frameshift mutation in CYP11B2 (13). It may reflect a low degree of cross-reactivity in the RIA.

Mutations have been identified in four kindreds with type 1 aldosterone synthase deficiency. A five-nucleotide deletion in exon 1 was found in three patients from a single Amish family (13); R384P (14) and a nonsense mutation, E255X (20), were found in separate German patients, and two homozygous sequence changes, E198D and V386A, were found in a single French kindred (17). The first three mutations destroy enzymatic activity. Combined with the data from the present study, this might suggest that type 1 and 2 aldosterone synthase deficiency are allelic variants, with type 1 deficiency associated with mutations that destroy activity. However, mutations destroying enzymatic activity have also been detected in patients with type 2 deficiency (15, 19), and conversely, patients with type 1 deficiency may carry a mutant enzyme that retains a small amount of activity (17). Thus, a molecular explanation for the existence of the two forms of aldosterone synthase deficiency remains to be elucidated (27).

Presentation in an adult

The patient reported here had severe failure to thrive as a young child, but was asymptomatic for most of his adult life. This is typical for patients with aldosterone synthase deficiency who survive childhood (26, 28). In contrast, decompensation in middle age has not, to our knowledge, been reported previously.

There are several possible explanations for the unusual features of this case. Most patients with aldosterone synthase deficiency who have been studied in adult life have the type 2 form of the disease, which is often associated with less severe impairment of enzymatic activity and with recovery of normal aldosterone synthesis in adults; patients with type 1 deficiency may be more vulnerable to stressors such as dehydration. Our patient received an unusual stress in the form of cathartics and enemas as preparation for a barium enema; this may have caused excessive loss of electrolytes through the colon. Finally, this patient developed renal failure for unknown reasons, presumably unrelated to aldosterone synthase deficiency, which may have exacerbated the electrolyte abnormalities.

We conclude that aldosterone synthase deficiency represents an unusual cause of hyperreninemic hypoaldosteronism presenting in adult life, but it should be suspected if the past medical history is positive for signs of hypoaldosteronism, such as failure to thrive in childhood, or if the patient manifests no other recognized causes of hyperreninemic hypoaldosteronism.

	Acknowledgments

 
We are grateful to the late Stanley Ulick and to Jennifer Wang for performing urinary steroid assays.

	Footnotes

 
¹ This work was supported by NIH Grant R37-DK-37867.

Received September 29, 2000.

Revised November 13, 2000.

Accepted November 15, 2000.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kayes-Wandover, K. M. Articles by White, P. C. Search for Related Content PubMed PubMed Citation Articles by Kayes-Wandover, K. M. Articles by White, P. C. Pubmed/NCBI databases Gene GEO Profiles HomoloGene OMIM Protein UniGene Compound via MeSH Substance via MeSH