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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3214-3218
Copyright © 1998 by The Endocrine Society

Original Studies

Familial Hyperaldosteronism Type II: Description of a Large Kindred and Exclusion of the Aldosterone Synthase (CYP11B2) Gene1

David J. Torpy, Richard D. Gordon, Jing Ping Lin, Phillip R. Huggard, Susan E. Taymans, Michael Stowasser, George P. Chrousos and Constantine A. Stratakis

Unit on Genetics and Endocrinology (D.J.T., C.A.S., S.E.T.), Section on Pediatric Endocrinology (G.P.C.), Developmental Endocrinology Branch, National Institute of Child Health and Human Development; and the Section on Genetic Studies, Laboratory of Skin Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases (J.-P.L.), National Institutes of Health, Bethesda, Maryland 20892; and the Hypertension Unit, Greenslopes Hospital (R.D.G., M.S., P.R.H.), Greenslopes, Brisbane, Queensland 4120, Australia

Address all correspondence and requests for reprints to: Constantine A. Stratakis, M.D., D.Sc., Unit on Genetics and Endocrinology, Building 10, Room 10 N 262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail: stratakc{at}cc1.nichd.nih.gov


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Familial hyperaldosteronism type II (FH-II) is characterized by autosomal dominant inheritance and hypersecretion of aldosterone due to adrenocortical hyperplasia or an aldosterone-producing adenoma; unlike FH type I (FH-I), hyperaldosteronism in FH-II is not suppressible by dexamethasone. Of a total of 17 FH-II families with 44 affected members, we studied a large kindred with 7 affected members that was informative for linkage analysis. Family members were screened with the aldosterone/PRA ratio test; patients with aldosterone/PRA ratio greater than 25 underwent fludrocortisone/salt suppression testing for confirmation of autonomous aldosterone secretion. Postural testing, adrenal gland imaging, and adrenal venous sampling were also performed. Individuals affected by FH-II demonstrated lack of suppression of plasma A levels after 4 days of dexamethasone treatment (0.5 mg every 6 h). All patients had negative genetic testing for the defect associated with FH-I, the CYP11B1/CYP11B2 hybrid gene. Genetic linkage was then examined between FH-II and aldosterone synthase (the CYP11B2 gene) on chromosome 8q. A polyadenylase repeat within the 5'-region of the CYP11B2 gene and 9 other markers covering an approximately 80-centimorgan area on chromosome 8q21–8qtel were genotyped and analyzed for linkage. Two-point logarithm of odds scores were negative and ranged from -12.6 for the CYP11B2 polymorphic marker to -0.98 for the D8S527 marker at a recombination distance ({theta}) of 0. Multipoint logarithm of odds score analysis confirmed the exclusion of the chromosome 8q21–8qtel area as a region harboring the candidate gene for FH-II in this family. We conclude that FH-II shares autosomal dominant inheritance and hyperaldosteronism with FH-I, but, as demonstrated by the large kindred investigated in this report, it is clinically and genetically distinct. Linkage analysis demonstrated that the CYP11B2 gene is not responsible for FH-II in this family; furthermore, chromosome 8q21–8qtel most likely does not harbor the genetic defect in this kindred.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
PRIMARY hyperaldosteronism is a curable form of hypertension that is being recognized with increasing frequency due to the use of a sensitive screening method, the plasma aldosterone (A)/PRA (R) ratio (ARR) (1, 2, 3). At least two genetic disorders, both inherited in an autosomal dominant (AD) manner, are associated with primary bilateral adrenocortical hyperplasia leading to hyperaldosteronism (4).

Familial hyperaldosteronism type I (FH-I) or glucocorticoid-remediable hyperaldosteronism (GRA) is characterized by profound suppressibility of A secretion after the administration of exogenous glucocorticoids (5, 6). Patients with FH-I rarely develop adrenocortical adenomas (7); most of them have mild bilateral adrenocortical hyperplasia or even normal histology (4, 8). FH-I was recently shown to be caused by a hybrid gene formed by a cross-over of genetic material between the ACTH-responsive regulatory portion of the 11ß-hydroxylase (CYP11B1) gene and the coding sequence of the A synthase (AS; CYP11B2) gene (9).

Familial hyperaldosteronism type II (FH-II), on the other hand, is characterized by nondexamethasone (non-DEX)-suppressible hyperaldosteronism (4, 8, 10, 11, 12, 13). We have now identified 17 families with this condition in Brisbane, Australia. In 7 of these, the disease is clearly inherited in an AD manner (10, 11, 12, 13). Other familial cases of non-DEX-suppressible hyperaldosteronism have also been reported (14, 15, 16).

At presentation, probands of families with FH-II were indistinguishable clinically and biochemically from those with the sporadic primary hyperaldosteronism in terms of age, sex, and frequency of hypokalemia or tumors. Other affected family members were identified by screening relatives with the ARR test, except in three cases where another family member had a well documented A-producing adenoma removed previously at another institution.

It has been suggested that FH-II is caused by mutations of the AS gene (CYP11B2) (16). AS catalyzes the last three steps of A biosynthesis in the zona glomerulosa. Inactivating mutations of the CYP11B2 gene lead to mineralocorticoid deficiency and hypotension in the corticosterone methyloxidase types I and II syndromes (17), whereas a hybrid CYP11B1/CYP11B2 gene causing increased (ACTH-driven) A biosynthesis results in DEX-responsive hypertension (FH-I) (6, 9). CYP11B2 has been considered a candidate gene in other forms of familial hypertension, mainly of the low renin type (18), and its molecular variants have been investigated in the hypertensive Dahl S rat (19).

In the present study, we report our clinical and genetic investigation of a family with FH-II, which is the largest of our series and has seven affected members. Genetic analysis showed that none of the patients in this family had the CYP11B1/CYP11B2 hybrid gene. CYP11B2 and its chromosomal region were also excluded by linkage analysis from harboring the gene defect in this kindred.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Patients and diagnostic testing

The studies were approved by the review boards of the participating institutions [Office for Human Subject’s Research, NIH (Bethesda, MD), and ethics committee of the University of Queensland (Brisbane, Australia)]. Written informed consent for DNA collection was obtained from all subjects. Clinical studies were performed by the Hypertension Unit of the University of Queensland Department of Medicine, Greenslopes Hospital (Brisbane, Australia). The pedigree of the family is indicated in Fig. 1Go (family FH.01). All patients were screened for hyperaldosteronism with a midmorning standing plasma ARR (1, 2), collected under random conditions with respect to salt intake. Drugs known to perturb A or R levels (such as spironolactone, diuretics, ß-blockers, angiotensin-converting enzyme antagonists, or dihydropyridine calcium antagonists) were suspended for sufficient time to allow their effects to wane before testing. ARR greater than 25 (A was measured in nanograms per dL and R in nanograms per mL/h) was verified at least once, and patients were then submitted to fludrocortisone/salt suppression testing (0.1 mg fludrocortisone every 6 h and 1200 mg oral sodium chloride three times daily for 4 days) to demonstrate that A secretion was autonomous and persisted despite suppression of angiotensin II secretion. Postural testing, adrenal computed tomography scanning, and adrenal venous sampling were performed to determine whether the autonomous A secretion involved one or both adrenal glands. The diagnostic algorithm used was described in detail previously (12). In patients identified as affected, plasma A was measured in blood collected at 1000 h after 2 h of upright posture basally and during 4 days of DEX (0.5 mg every 6 h). Individuals were screened for multiple endocrine neoplasia type 1 (MEN-1) by seeking a history of endocrine tumors, urolithiasis or lipomata and by measurements of plasma ionized calcium, PTH, serum PRL, and fasting gastrin levels.



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  		Figure 1. Kindred FH01, including seven members affected with primary hyperaldosteronism. Filled symbols indicate affected individuals. N, Unaffected; ?, uncertain affectation status. For description of affectation status parameters, see Table 1Go.

 
Genetic testing

Segregation analysis and assignment of affectation status. AD inheritance of FH-II was suggested by the pedigree presented in Fig. 1Go and other families analyzed by us (11, 13) and others (14, 15). Assignment of the affectation status for the purpose of genetic testing was defined as shown in Table 1Go and according to criteria established by our clinical studies (3, 4, 10–13).


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  		Table 1. Criteria for defining affectation status for linkage analysis in FH-II

 
DNA preparation and PCR analysis. Genomic DNA was prepared from 34 members of the family FH01 (Fig. 1Go), as previously described (20). All affected individuals were tested for the presence of the CYP11B1/CYP11B2 gene by a long PCR method that we recently developed to replace Southern blotting (21).

For linkage analysis, highly informative polymorphic microsatellite markers were amplified from genomic DNA using oligonucleotide primers by PCR. For each of the markers, the reverse primer was end labeled with [{gamma}-32P]deoxy (d)-ATP, using T4-polynucleotide kinase (New England Biolabs, Beverly, MA). Approximately 50 ng DNA were used in each reaction. The reaction was carried out in a 10-µL volume containing 1 µL DNA solution, 10 pmol unlabeled primer and dNTPs (1-µL total volume dilution of all dNTPs, each at a 10-µmol concentration), 0.1 pmol 32P-labeled primer in 1.5 mmol/L MgCl2 PCR buffer (1 µL 10 x PCR buffer), and 1 U Taq polymerase (Perkin-Elmer Roche, Branchburg, NJ). Thirty cycles were performed (94°C for 1 min, 57°C for 1 min, and 72°C for 30 s), followed by a final 7-min extension at 72°C. Aliquots of amplified DNA were mixed with an equal volume of loading buffer, denatured at 94°C for 5 min, and electrophoresed on a 6% polyacrylamide gel (Promega, Madison, WI). The dried gel was then exposed to Kodak X-Omat or Bio-Max autoradiography film for 16–24 h.

The following markers were used for linkage analysis. An intragenic CYP11B2 polyadenine repeat [(A)n] located at the 5'-end of the gene was previously used for linkage analysis (22) and by our laboratory for radiation hybrid (RH) mapping of this gene (23). The primers for this marker have been reported (22, 23). We also performed linkage analysis with dinucleotide repeat [(CA)n] markers covering an approximately 80-centimorgan (cM)-long area on chromosome 8q21–8qtel. The chromosomal order of the markers and their relative cytogenetic positions were estimated from genome mapping information available on line (24) and by contig information both on line (http://www-genome.wi.mit.edu/cgi-bin/contig/phys_map, and other sources) and derived from other studies (25, 26, 27, 28, 29, 30, 31). The order, which we also confirmed by RH mapping (23), was [the estimated distance (in centimorgans) is given in parentheses] 8q centromere-D8S543 (2.5 cM)-D8S530 (1.8 cM)-D8S271 (1.1 cM)-D8S270 (12.7 cM)-D8S521 (9.4 cM)-D8S527 (16.8 cM)-D8S1128 (6.6 cM)-D8S256 (15.8 cM)-D8S1704-CYP11B2–8q telomere. The primers for these markers are available on line (given above and Ref. 32).

Linkage analysis. Two-point logarithm of odds (LOD) scores were calculated with LINKAGE (version 5.1) computer software using a dominant model of inheritance, 100% penetrance in both sexes and a gene frequency of 0.0001, as previously described (20, 33). Multipoint LOD scores using several markers close on the same chromosome, with allele frequencies determined from 20 unrelated chromosomes, was performed with the µLINK program (34), as previously described (20, 33).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Clinical studies and testing for GRA

Hypertension was present in five of the seven affected individuals. The two normotensive individuals were the youngest affected members of family FH01 (ages 14 and 17 yr, respectively); they were considered affected because of their high ARR and other features, as presented in Table 1Go.

ARR among the seven affected members of the family ranged between 38.1–262; unaffected individuals exhibited values less than 17.5 (Fig. 2Go). Midmorning standing plasma A levels among affected individuals were greater than 21.2 ng/dL (range, 21.2–71.4). Concomitant R levels were suppressed below 0.8 ng/mL·h. No affected member of the FH01 pedigree had spontaneous hypokalemia. One patient, a 46-yr-old female, had a plasma potassium level of 2.7 mmol/L while receiving treatment with a diuretic medication, methyclothiazide (5 mg daily). In the remaining six affected individuals, who were not receiving diuretics or potassium supplements, plasma potassium levels ranged between 3.6–4.0 mmol/L. Plasma A levels were not suppressed below 6 ng/dL by the fludrocortisone/salt suppression testing protocol; values ranged from 10.4–38.5 ng/dL.



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  		Figure 2. Plasma A (nanograms per dL)/R (nanograms per mL/h) ratios in patients and family members of kindred FH01. The upper normal limit of this ratio (25 ) is shown by a broken line. Affected status implies autonomous A secretion.

 
Upright plasma A levels by day 4 of DEX ranged from 7.3–21.5 ng/dL (basal levels, 16.1–38.6 ng/dL). There were no patients with A levels less than 5.0 ng/dL during DEX administration. By contrast, levels fell to less than 3.2 ng/dL in all 19 patients with GRA (with molecular confirmation of their diagnosis by Southern blot or long PCR testing) who were similarly studied (data not shown).

Computed tomography imaging of the adrenals, performed in six patients, revealed normal adrenal morphology in three, slight thickening of the left adrenal in two, and nodular hyperplasia of the left adrenal in one. Adrenal vein sampling was performed in the five hypertensive patients; comparison of the A/cortisol ratio in adrenal veins vs. those in peripheral plasma were consistent with bilateral hypersecretion of A (Table 2Go).


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  		Table 2. Plasma aldosterone and cortisol results from concomitant adrenal vein and peripheral vein sampling

 
No patient had signs or biochemical testing suggestive of MEN-1 or any other genetic disorder. Genetic testing by Southern blotting and by long PCR for GRA was negative (data not shown).

Linkage analysis

The polyadenylase marker within the 5'-region of the CYP11B2 gene (22) did not segregate with the FH-II phenotype. A LOD score of -12.57 at a recombination distance ({theta}) of 0 was obtained for this marker, excluding this gene from harboring the defect for FH-II in this family (Table 3Go). Nine other polymorphic markers were genotyped in the 8q21–8qtel region; they all produced negative LOD scores, excluding (by multipoint linkage analysis) this region from containing the gene responsible for FH-II in the FH01 kindred (Table 3Go and Fig. 3Go). These results did not change by altering the penetrance of the disease to 80% or 90% (data not shown).


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  		Table 3. Pairwise Lod scores for chromosome 8q markers and FH-II (markers in chromosomal order 8qcen-tel)

 


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  		Figure 3. Multipoint linkage analysis of markers on the long arm of chromosome 8, excluding this region, which contains the CYP11B2 gene. The distances refer to genetic distance. However, the actual physical distance is likely to be greater, as the physical distance between D8S270 and D8S271 has been determined to be 8 megabases (48 ).

 
The exclusion of the entire chromosome 8q telomeric region was performed because of the original mapping of the CYP11B1/CYP11B2 locus to 8q21–22 (17, 35, 36). However, we recently showed that CYP11B2 maps to the telomere of chromosome 8q (23), in close proximity to marker D8S1704, which was also genotyped in this study. Meiotic mapping results confirmed our physical and RH mapping data (data not shown) for final placement of the human CYP11B2 gene in the chromosome 8q24.3-tel region.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Although normokalemic primary hyperaldosteronism has long been recognized (37), persistent use of plasma potassium as a screening tool may have underestimated the contribution of hyperaldosteronism to hypertension in the general population (38). Recently, use of ARR as a screening test has increased the detection of hyperaldosteronism among hypertensive individuals (3, 4, 10, 38, 39). Use of this screening test in families with one member affected by hyperaldosteronism has led us to detect 14 families (37 affected patients) with autonomous A secretion (11, 13), including family FH01 presented in this report. In 3 additional families (7 affected patients), relatives had already been diagnosed with primary hyperaldosteronism and had been treated successfully elsewhere when our patients presented. In the family studied in this report, it is noteworthy that ARR identified 2 members who had autonomous A secretion but did not have hypertension. These subjects were the 2 youngest members of the family with elevated ARR, indicating the potential usefulness of this test in carrier detection for FH-II.

FH-II should be clinically distinguished from FH-I or GRA. FH-I was first described in the 1960s as a form of DEX-suppressible hyperaldosteronism occasionally associated with bilateral adrenocortical hyperplasia (5, 6). It was not known to be associated with adrenocortical adenomas until recently (7), and tumors are probably rare in FH-I. On the other hand, FH-II appears to be associated with bilateral adrenocortical disease and frequently with adenomas (4, 8, 10, 11, 12, 13, 15). In addition, hyperaldosteronism in patients with FH-II is not DEX suppressible. Despite these differences, when the gene defect in FH-I was identified (9) and found to be invariably present in patients with GRA, it was thought that FH-II could be due to an activating mutation of the CYP11B2 gene (40).

Genetic analysis of the FH01 family in this report confirms the genetic differences between the two disorders. Our results indicate that FH-II in this large kindred is not caused by mutations in the CYP11B2 gene or any other gene in its proximity on the long arm of chromosome 8, establishing FH-II as a disorder genetically distinct from FH-I.

It is well established that FH-I is inherited in an autosomal dominant fashion, because affected members can be clearly identified by genetic testing. In FH-II, for which a genetic test is not yet available, the mode of inheritance remains speculative. However, in the family presented in this report and in six other families vertical transmission of the disorder strongly suggests dominant inheritance.

Because of the association of MEN-1 with bilateral adrenocortical tumors (41), the MEN-1 locus on human chromosome 11q13 was investigated in tumors excised from patients with FH-II and other A-producing adenomas (42). Five of 11 informative tumors showed loss of heterozygosity around the MEN-1 locus. The study was expanded, and 10 of 64 paired tumor-blood DNA samples indicated loss of heterozygosity of the same region (43). However, recent linkage analysis of the FH01 family excluded the MEN-1 locus from harboring the gene defect for FH-II (data not shown). We have now initiated a genome-wide screen for the identification of the gene defect for this disorder. In this process, we recently excluded another potential candidate, the angiotensin II receptor type I gene (44), which had been investigated by others in A-producing adrenocortical adenomas (45).

The delineation of FH-II as a genetically separate disorder from FH-I suggests that yet another genetic defect may be a cause of heritable hypertension in humans. An understanding of the molecular basis of FH-II may lead to better understanding of the pathogenesis of low renin hypertension, a disorder that accounts for 20% of "essential hypertension" (46) and in which dysregulation of A secretion has been suggested (47).


   Footnotes
 
1 This work was supported by the National Heart Foundation of Australia (Grant-in-Aid G97B4788). Back

Received March 24, 1998.

Revised May 14, 1998.

Accepted May 20, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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