Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A Chinese pedigree with glucocorticoid remediable aldosteronism

Hypertension Research volume 44, pages 1428–1433 (2021)Cite this article

Abstract

Glucocorticoid-remediable aldosteronism (GRA) is an autosomal-dominant inherited aldosteronism that is often accompanied by early-onset hypertension. GRA is caused by the unequal crossover of the 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. As a result of chimeric gene duplication, aldosterone is ectopically synthesized in the adrenal zona fasciculata under the control of adrenocorticotropic hormone (ACTH). Here, we describe a Chinese pedigree with three affected subjects. Both the uncle and nephew were hospitalized in our hospital due to early-onset hypertension (onset <20 years old) and were diagnosed with primary aldosteronism (PA). Their laboratory test results revealed hyperaldosteronism, hyporeninemia, a high plasma aldosterone to renin (ARR) ratio, and normal serum potassium (K+). Captopril failed to suppress aldosterone secretion. This family had a strong paternal history of hypertension. Thirteen members underwent gene testing, and three of them were found to be GRA positive. Through long-extension PCR (XL-PCR) and direct sequencing, we identified the CYP11B1/CYP11B2 chimeric gene, and with unequal crossover breakpoints located between intron 2 of CYP11B1 and exon 3 of CYP11B2 in the three patients. Low-dose dexamethasone was effective. This is the first family report of GRA in northern China. Moreover, a case of GRA combined with a CACNA1H gene mutation is reported for the first time. We found that dihydropyridine calcium channel blockers (CCBs) combined with aldosterone receptor antagonists exerted good therapeutic effects in controlling blood pressure in GRA patients for whom glucocorticoid therapy was not an option.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pizzolo F, Trabetti E, Guarini P, Mulatero P, Ciacciarelli A, Blengio GS, et al. Glucocorticoid remediable aldosteronism (GRA) screening in hypertensive patients from a primary care setting. J Hum Hypertens. 2005;19:325–327.

    Article  CAS  Google Scholar 

  2. Sutherland DJ, Ruse JL, Laidlaw JC. Hypertension, increased aldosterone secretion and low plasma renin activity relieved by dexamethasone. Can Med Assoc J. 1966;95:1109–1119.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 1998;31:445–450. 1 Pt 2

    Article  CAS  Google Scholar 

  4. Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, et al. Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase. Nat Genet. 1992;2:66–74.

    Article  CAS  Google Scholar 

  5. Jonsson JR, Klemm SA, Tunny TJ, Stowasser M, Gordon RD. A new genetic test for familial hyperaldosteronism type I aids in the detection of curable hypertension. Biochem Biophys Res Commun. 1995;207:565–571.

    Article  CAS  Google Scholar 

  6. MacConnachie AA, Kelly KF, McNamara A, Loughlin S, Gates LJ, Inglis GC, et al. Rapid diagnosis and identification of cross-over sites in patients with glucocorticoid remediable aldosteronism. J Clin Endocrinol Metab. 1998;83:4328–4331.

    Article  CAS  Google Scholar 

  7. Carvajal CA, Stehr CB, González PA, Riquelme EM, Montero T, Santos MJ, et al. A de novo unequal cross-over mutation between CYP11B1 and CYP11B2 genes causes familial hyperaldosteronism type I. J Endocrinol Investig. 2011;34:140–144.

    Article  CAS  Google Scholar 

  8. Myers S, Freeman C, Auton A, Donnelly P, McVean G. A common sequence motif associated with recombination hot spots and genome instability in humans. Nat Genet. 2008;40:1124–1129.

    Article  CAS  Google Scholar 

  9. Seidel E, Schewe J, Scholl UI. Genetic causes of primary aldosteronism. Exp Mol Med. 2019;51:1–12.

    Article  CAS  Google Scholar 

  10. Dluhy RG, Anderson B, Harlin B, Ingelfinger J, Lifton R. Glucocorticoid-remediable aldosteronism is associated with severe hypertension in early childhood. J Pediatr. 2001;138:715–720.

    Article  CAS  Google Scholar 

  11. Mulatero P, di Cella SM, Williams TA, Milan A, Mengozzi G, Chiandussi L, et al. Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation Italian pedigree. J Clin Endocrinol Metab. 2002;87:3187–3191.

    Article  CAS  Google Scholar 

  12. Dluhy RG, Lifton RP. Glucocorticoid-remediable aldosteronism (GRA): diagnosis, variability of phenotype and regulation of potassium homeostasis. Steroids. 1995;60:48–51.

    Article  CAS  Google Scholar 

  13. Jamieson A, Slutsker L, Inglis GC, Fraser R, White PC, Connell JM. Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric gene on phenotypic expression. Clin Sci. 1995;88:563–570.

    Article  CAS  Google Scholar 

  14. Rich GM, Ulick S, Cook S, Wang JZ, Lifton RP, Dluhy RG. Glucocorticoid-remediable aldosteronism in a large kindred: clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med. 1992;116:813–820.

    Article  CAS  Google Scholar 

  15. Mulatero P, Veglio F, Pilon C, Rabbia F, Zocchi C, Limone P, et al. Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab. 1998;83:2573–2575.

    Article  CAS  Google Scholar 

  16. McMahon GT, Dluhy RG. Glucocorticoid-remediable aldosteronism. Cardiol Rev. 2004;12:44–48.

    Article  Google Scholar 

  17. Litchfield WR, New MI, Coolidge C, Lifton RP, Dluhy RG. Evaluation of the dexamethasone suppression test for the diagnosis of glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 1997;82:3570–3573.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key R&D Program of China (Project ID.2018YFC1312703 from JC), CAMS Innovation Fund for Medical Sciences (2016-I2 M-1-006 from JC), National Natural Science Foundation of China (Project ID.81630014 and81825002 from JC, Project ID 81700374 from LJ), Beijing Outstanding Young Scientist Program (Project ID.BJJWZYJH01201910023029, from JC) and the Fundamental Research Funds for the Central Universities (Project ID.3332018055, from XL).

Author information

Authors and Affiliations

  1. Department of Hypertension, Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Xiaoning Liu, Huimin Zhang, Wenjun Ma, Lei Song, Xianliang Zhou & Jun Cai

  2. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China

    Ling Jin

Authors
  1. Xiaoning Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ling Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huimin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wenjun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xianliang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jun Cai.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, X., Jin, L., Zhang, H. et al. A Chinese pedigree with glucocorticoid remediable aldosteronism. Hypertens Res 44, 1428–1433 (2021). https://doi.org/10.1038/s41440-021-00685-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41440-021-00685-3

Keywords

Search

Advanced search

Quick links