Familial hyperaldosteronism type III a novel case and review of literature

  • Natividad Pons FernándezEmail author
  • Francisca Moreno
  • Julia Morata
  • Ana Moriano
  • Sara León
  • Carmen De Mingo
  • Ángel Zuñiga
  • Fernando Calvo


Less than 15% of hypertension cases in children are secondary to a primary hyperaldosteronism. This is idiopathic in 60% of the cases, secondary to a unilateral adenoma in 30% and 10% remaining by primary adrenal hyperplasia, familial hyperaldosteronism, ectopic aldosterone production or adrenocortical carcinoma.To date, four types of familial hyperaldosteronism (FH I to FH IV) have been reported. FH III is caused by germline mutations in KCNJ5, encoding the potassium channel Kir3.4. The mutations cause the channel to lose its selectivity for potassium, allowing large quantities of sodium to enter the cell. As a consequence, the membrane depolarizes, voltage-gated calcium channels open, calcium enters the cell, initiating the cascade that leads to aldosterone synthesis. Somatic mutations in KCNJ5 has also been described in aldosterone-producing adenomas. The most frequent presentation of FH III is with severe hyperaldosteronism symptoms and resistance to pharmacological therapy which leads to bilateral adrenalectomy. We will review current literature and describe a child with FH III due to a novel de novo deletion in KCNJ5 with wild phenotype as a sign of clinical variability of this disease.


Hypertension Primary hyperaldosteronism Mineralocorticoid receptor KCNJ5 Kir3.4 



Familial hyperaldosteronism


Primary aldosteronism


Aldosterone producing adenoma


Bilateral adrenal hyperplasia


Adrenocorticotropic hormone


Blood pressure


Standard deviation


Authors Contribution

Dr. Pons conceptualized the review, drafted the initial manuscript, and approved the final manuscript as submitted. Drs Moreno, Morata, Moriano, León, de Mingo and Calvo carried out the initial analyses, reviewed and revised the manuscript, and approved the final manuscript as submitted. Dr. Zuñiga carried out the genetic test and approved the final manuscript.

Compliance with ethical standards

Financial disclosure

Dr. Pons and the remaining authors have no financial relationships relevant to this article to disclose.

Conflict of interest

Dr. Pons and the other authors have no conflicts of interest to disclose.


  1. 1.
    Thomas RM, Ruel E, Shantavasinkul PC, Corsino L. Endocrine hypertension: an overview on the current etiopathogenesis and management options. World J Hypertens. 2015;5:14–27.CrossRefGoogle Scholar
  2. 2.
    Young WF, Sterns RH. Familial hyperaldosteronism. 2018 in Accessed 21 Aug 2018
  3. 3.
    Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355:262–5.CrossRefGoogle Scholar
  4. 4.
    Mulatero P, di Cella SM, Monticone S, Schiavone D, Manzo M, Mengozzi G, et al. 18-hydroxycorticosterone, 18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes. J Clin Endocrinol Metab. 2012;97:881–9.CrossRefGoogle Scholar
  5. 5.
    Mulatero P, Tizzani D, Viola A, Bertello C, Monticone S, Mengozzi G, et al. Prevalence and characteristics of familial hyperaldosteronism: the PATOGEN study (primary Aldosteronism in TOrino-GENetic forms). Hypertension. 2011;58:797–803.CrossRefGoogle Scholar
  6. 6.
    Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, et al. The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(5):1889–916.
  7. 7.
    Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Finn WL, Krek AL. Clinical and pathological diversity of primary aldosteronism, including a new familial variety. Clin Exp Pharmacol Physiol. 1991;18:283–6.CrossRefGoogle Scholar
  8. 8.
    Sukor N, Mulatero P, Gordon RD, So A, Duffy D, Bertello C, et al. Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families. J Hypertens. 2008;26:1577–82.CrossRefGoogle Scholar
  9. 9.
    Geller DS, Zhang J, Wisgerhof MV, Shackleton C, Kashgarian M, Lifton RP. A novel form of human mendelian hypertension featuring nonglucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab. 2008;93:3117–23.CrossRefGoogle Scholar
  10. 10.
    Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331:768–72.CrossRefGoogle Scholar
  11. 11.
    Monticone S, Hattangady NG, Penton D, Isales CM, Edwards MA, Williams TA, et al. A novel Y152C KCNJ5 mutation responsible for familial hyperaldosteronism type III. J Clin Endocrinol Metab. 2013;98:E1861–5.CrossRefGoogle Scholar
  12. 12.
    Monticone S, Bandulik S, Stindl J, Zilbermint M, Dedov I, Mulatero P, et al. A case of severe hyperaldosteronism caused by a de novo mutation affecting a critical salt bridge Kir3.4 residue. J Clin Endocrinol Metab. 2015;100:E114–8.CrossRefGoogle Scholar
  13. 13.
    Galati SJ, Hopkins SM, Cheesman KC, Zhuk RA, Levine AC. Primary aldosteronism: emerging trends. Trends Endocrinol Metab. 2013;24:421–30.CrossRefGoogle Scholar
  14. 14.
    Monticone S, Tetti M, Burrello J, Buffolo F, de Giovanni R, Veglio F, et al. Familial hyperaldosteronism type III. J Hum Hypertens. 2017;31:776–81.CrossRefGoogle Scholar
  15. 15.
    Scholl UI, Stolting G, Nelson-Williams C, et al. Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife. 2015;4:e06315.CrossRefGoogle Scholar
  16. 16.
    Monticone S, Buffolo F, Tetti M, Veglio F, Pasini B, Mulatero P. Genetics in endocrinology: the expanding genetic horizon of primary aldosteronism. Eur J Endocrinol. 2018;178:R101–11.CrossRefGoogle Scholar
  17. 17.
    Fernandes-Rosa FL, Williams TA, Riester A, Steichen O, Beuschlein F, Boulkroun S, et al. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension. 2014;64:354–61.CrossRefGoogle Scholar
  18. 18.
    Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:3266–81.CrossRefGoogle Scholar
  19. 19.
    Douillard C, Houillier P, Nussberger J, Girerd X. SFE/SFHTA/AFCE consensus on primary Aldosteronism, part 2: first diagnostic steps. Ann Endocrinol (Paris). 2016;77:192–201.CrossRefGoogle Scholar
  20. 20.
    Martinez-Aguayo A, Aglony M, Campino C, Garcia H, Bancalari R, Bolte L, et al. Aldosterone, plasma renin activity, and aldosterone/renin ratio in a normotensive healthy pediatric population. Hypertension. 2010;56:391–6.CrossRefGoogle Scholar
  21. 21.
    Amar L, Baguet JP, Bardet S, Chaffanjon P, Chamontin B, Douillard C, et al. SFE/SFHTA/AFCE primary aldosteronism consensus: introduction and handbook. Ann Endocrinol (Paris). 2016;77:179–86.CrossRefGoogle Scholar
  22. 22.
    Reznik Y, Amar L, Tabarin A. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 3: confirmatory testing. Ann Endocrinol (Paris). 2016;77:202–7.CrossRefGoogle Scholar
  23. 23.
    Satoh F, Morimoto R, Ono Y, Iwakura Y, Omata K, Kudo M, et al. Measurement of peripheral plasma 18-oxocortisol can discriminate unilateral adenoma from bilateral diseases in patients with primary aldosteronism. Hypertension. 2015;65:1096–102.CrossRefGoogle Scholar
  24. 24.
    Crudo V, Monticone S, Burrello J, Buffolo F, Tetti M, Veglio F, et al. Hyperaldosteronism: how to discriminate among different disease forms? High Blood Press Cardiovasc Prev. 2016;23:203–8.CrossRefGoogle Scholar
  25. 25.
    Bardet S, Chamontin B, Douillard C, Pagny JY, Hernigou A, Joffre F, et al. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 4: subtype diagnosis. Ann Endocrinol (Paris). 2016;77:208–13.CrossRefGoogle Scholar
  26. 26.
    Rossi GP, Auchus RJ, Brown M, Lenders JWM, Naruse M, Plouin PF, et al. An expert consensus statement on use of adrenal vein sampling for the subtyping of primary aldosteronism. Hypertension. 2014;63:151–60.CrossRefGoogle Scholar
  27. 27.
    Pérez AJ, Casal M, Courel MA, Andrade MA. Hiperaldosteronismo primario: aspectos diagnósticos y terapéuticos. Hipertension y Riesgo Vascular. 2002;19:70–9.Google Scholar
  28. 28.
    Zennaro MC, Jeunemaitre X. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 5: genetic diagnosis of primary aldosteronism. Ann Endocrinol (Paris). 2016;77:214–9.CrossRefGoogle Scholar
  29. 29.
    Adachi M, Muroya K, Asakura Y, Sugiyama K, Homma K, Hasegawa T. Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature. Horm Res Paediatr. 2014;82:138–42.CrossRefGoogle Scholar
  30. 30.
    Tong A, Liu G, Wang F, Jiang J, Yan Z, Zhang D, et al. A novel phenotype of familial hyperaldosteronism type III: concurrence of Aldosteronism and Cushing's syndrome. J Clin Endocrinol Metab. 2016;101:4290–7.CrossRefGoogle Scholar
  31. 31.
    Gomez-Sanchez CE, Qi X, Gomez-Sanchez EP, Sasano H, Bohlen MO, Wisgerhof M. Disordered zonal and cellular CYP11B2 enzyme expression in familial hyperaldosteronism type 3. Mol Cell Endocrinol. 2017;439:74–80.CrossRefGoogle Scholar
  32. 32.
    Nanba K, Omata K, Tomlins SA, Giordano TJ, Hammer GD, Rainey WE, et al. Double adrenocortical adenomas harboring independent KCNJ5 and PRKACA somatic mutations. Eur J Endocrinol. 2016;175:K1–6.CrossRefGoogle Scholar
  33. 33.
    Kuppusamy M, Caroccia B, Stindl J, Bandulik S, Lenzini L, Gioco F, et al. A novel KCNJ5-insT149 somatic mutation close to, but outside, the selectivity filter causes resistant hypertension by loss of selectivity for potassium. J Clin Endocrinol Metab. 2014;99:E1765–73.CrossRefGoogle Scholar
  34. 34.
    Zheng FF, Zhu LM, Nie AF, Li XY, Lin JR, Zhang K, et al. Clinical characteristics of somatic mutations in Chinese patients with aldosterone-producing adenoma. Hypertension. 2015;65:622–8.CrossRefGoogle Scholar
  35. 35.
    Scholl UI, Healy JM, Thiel A, Fonseca AL, Brown TC, Kunstman JW, et al. Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype. Clin Endocrinol. 2015;83:779–89.CrossRefGoogle Scholar
  36. 36.
    Nakamura Y, Yamazaki Y, Tezuka Y, Satoh F, Sasano H. Expression of CYP11B2 in aldosterone-producing adrenocortical adenoma: regulatory mechanisms and clinical significance. Tohoku J Exp Med. 2016;240:183–90.CrossRefGoogle Scholar
  37. 37.
    Fernandes-Rosa FL, Boulkroun S, Zennaro MC. Somatic and inherited mutations in primary aldosteronism. J Mol Endocrinol. 2017;59:R47–63.CrossRefGoogle Scholar
  38. 38.
    Pechere-Bertschi A, Herpin D, Lefebvre H. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 7: medical treatment of primary aldosteronism. Ann Endocrinol (Paris). 2016;77:226–34.CrossRefGoogle Scholar
  39. 39.
    Steichen O, Amar L, Chaffanjon P, Kraimps JL, Menegaux F, Zinzindohoue F. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 6: adrenal surgery. Ann Endocrinol (Paris). 2016;77:220–5.CrossRefGoogle Scholar
  40. 40.
    He BJ, Anderson ME. Aldosterone and cardiovascular disease: the heart of the matter. Trends Endocrinol Metab. 2013;24:21–30.CrossRefGoogle Scholar
  41. 41.
    Baguet JP, Steichen O, Mounier-Vehier C, Gosse P. SFE/SFHTA/AFCE consensus on primary aldosteronism, part 1: epidemiology of PA, who should be screened for sporadic PA? Ann Endocrinol (Paris). 2016;77:187–91.CrossRefGoogle Scholar
  42. 42.
    Tamargo J, Solini A, Ruilope LM. Comparison of agents that affect aldosterone action. Semin Nephrol. 2014;34:285–306.CrossRefGoogle Scholar
  43. 43.
    Zennaro MC, Caprio M, Feve B. Mineralocorticoid receptors in the metabolic syndrome. Trends Endocrinol Metab. 2009;20:444–51.CrossRefGoogle Scholar
  44. 44.
    Parviz Y, Iqbal J, Pitt B, Adlam D, Al-Mohammad A, Zannad F. Emerging cardiovascular indications of mineralocorticoid receptor antagonists. Trends Endocrinol Metab. 2015;26:201–11.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Natividad Pons Fernández
    • 1
    Email author
  • Francisca Moreno
    • 2
  • Julia Morata
    • 1
  • Ana Moriano
    • 1
  • Sara León
    • 2
  • Carmen De Mingo
    • 2
  • Ángel Zuñiga
    • 2
  • Fernando Calvo
    • 1
  1. 1.Department of PediatricsHospital Lluís Alcanyís de XàtivaXàtivaSpain
  2. 2.Hospital Universitario y Politécnico la Fe de ValenciaValenciaSpain

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