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Monogenic forms of low-renin hypertension: clinical and molecular insights

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Abstract

Monogenic disorders of hypertension are a distinct group of diseases causing dysregulation of the renin–angiotensin–aldosterone system and are characterized by low plasma renin activity. These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). The final common pathway is plasma volume expansion and catecholamine/sympathetic excess that causes urinary potassium wasting; hypokalemia and early-onset refractory hypertension are characteristic. However, several single gene defects may show phenotypic heterogeneity, presenting with mild hypertension with normal electrolytes. Evaluation is based on careful attention to family history, physical examination, and measurement of blood levels of potassium, renin, and aldosterone. Genetic sequencing is essential for precise diagnosis and individualized therapy. Early recognition and specific management improves prognosis and prevents long-term sequelae of severe hypertension.

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References

  1. Padmanabhan S, Dominiczak AF (2021) Genomics of hypertension: the road to precision medicine. Nat Rev Cardiol 18:235–250

    Article  CAS  PubMed  Google Scholar 

  2. Rossi GM, Regolisti G, Peyronel F, Fiaccadori E (2020) Recent insights into sodium and potassium handling by the aldosterone-sensitive distal nephron: a review of the relevant physiology. J Nephrol 33:431–445

    Article  CAS  PubMed  Google Scholar 

  3. Simonetti GD, Mohaupt MG, Bianchetti MG (2012) Monogenic forms of hypertension. Eur J Pediatr 171:1433–1439

    Article  CAS  PubMed  Google Scholar 

  4. Vehaskari VM (2009) Heritable forms of hypertension. Pediatr Nephrol 24:1929–1937

    Article  PubMed  PubMed Central  Google Scholar 

  5. Fernandes-Rosa FL, Daniil G, Orozco IJ, Goppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, Schwarzmayr T, Strom TM, Jentsch TJ, Zennaro MC (2018) A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism. Nat Genet 50:355–361

    Article  CAS  PubMed  Google Scholar 

  6. Scholl UI, Stolting G, Schewe J, Thiel A, Tan H, Nelson-Williams C, Vichot AA, Jin SC, Loring E, Untiet V, Yoo T, Choi J, Xu S, Wu A, Kirchner M, Mertins P, Rump LC, Onder AM, Gamble C, McKenney D, Lash RW, Jones DP, Chune G, Gagliardi P, Choi M, Gordon R, Stowasser M, Fahlke C, Lifton RP (2018) CLCN2 chloride channel mutations in familial hyperaldosteronism type II. Nat Genet 50:349–354

  7. Pons Fernandez N, Moreno F, Morata J, Moriano A, Leon S, De Mingo C, Zuniga A, Calvo F (2019) Familial hyperaldosteronism type III a novel case and review of literature. Rev Endocr Metab Disord 20:27–36

    Article  CAS  PubMed  Google Scholar 

  8. Scholl UI, Stolting G, Nelson-Williams C, Vichot AA, Choi M, Loring E, Prasad ML, Goh G, Carling T, Juhlin CC, Quack I, Rump LC, Thiel A, Lande M, Frazier BG, Rasoulpour M, Bowlin DL, Sethna CB, Trachtman H, Fahlke C, Lifton RP (2015) Recurrent gain of function mutation in calcium channel CACNA1H causes early-onset hypertension with primary aldosteronism. Elife 4:e06315

    Article  PubMed  PubMed Central  Google Scholar 

  9. Daniil G, Fernandes-Rosa FL, Chemin J, Blesneac I, Beltrand J, Polak M, Jeunemaitre X, Boulkroun S, Amar L, Strom TM, Lory P, Zennaro MC (2016) CACNA1H mutations are associated with different forms of primary aldosteronism. EBioMedicine 13:225–236

  10. Wulczyn K, Perez-Reyes E, Nussbaum RL, Park M (2019) Primary aldosteronism associated with a germline variant in CACNA1H. BMJ Case Rep 12:e229031

    Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Stowasser M, Gunasekera TG, Gordon RD (2001) Familial varieties of primary aldosteronism. Clin Exp Pharmacol Physiol 28:1087–1090

    Article  CAS  PubMed  Google Scholar 

  13. Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, Lalouel JM (1992) A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature 355:262–265

    Article  CAS  PubMed  Google Scholar 

  14. Chu MD, Ulick S (1982) Isolation and identification of 18-hydroxycortisol from the urine of patients with primary aldosteronism. J Biol Chem 257:2218–2224

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Fallo F, Pilon C, Williams TA, Sonino N, Morra Di Cella S, Veglio F, De Iasio R, Montanari P, Mulatero P (2004) Coexistence of different phenotypes in a family with glucocorticoid-remediable aldosteronism. J Hum Hypertens 18:47–51

    Article  CAS  PubMed  Google Scholar 

  17. Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG (1998) Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension 31:445–450

    Article  CAS  PubMed  Google Scholar 

  18. Litchfield WR, Coolidge C, Silva P, Lifton RP, Fallo F, Williams GH, Dluhy RG (1997) Impaired potassium-stimulated aldosterone production: a possible explanation for normokalemic glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 82:1507–1510

    CAS  PubMed  Google Scholar 

  19. McMahon GT, Dluhy RG (2004) Glucocorticoid-remediable aldosteronism. Arq Bras Endocrinol Metabol 48:682–686

    Article  PubMed  Google Scholar 

  20. Carvajal CA, Campino C, Martinez-Aguayo A, Tichauer JE, Bancalari R, Valdivia C, Trejo P, Aglony M, Baudrand R, Lagos CF, Mellado C, Garcia H, Fardella CE (2012) A new presentation of the chimeric CYP11B1/CYP11B2 gene with low prevalence of primary aldosteronism and atypical gene segregation pattern. Hypertension 59:85–91

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  22. Mosso L, Gomez-Sanchez CE, Foecking MF, Fardella C (2001) Serum 18-hydroxycortisol in primary aldosteronism, hypertension, and normotensives. Hypertension 38:688–691

    Article  CAS  PubMed  Google Scholar 

  23. McMahon GT, Dluhy RG (2004) Glucocorticoid-remediable aldosteronism. Cardiol Rev 12:44–48

    Article  PubMed  Google Scholar 

  24. Lenders JWM, Williams TA, Reincke M, Gomez-Sanchez CE (2018) Diagnosis of endocrine disease: 18-oxocortisol and 18-hydroxycortisol: is there clinical utility of these steroids? Eur J Endocrinol 178:R1–R9

    Article  CAS  PubMed  Google Scholar 

  25. Fardella CE, Pinto M, Mosso L, Gomez-Sanchez C, Jalil J, Montero J (2001) Genetic study of patients with dexamethasone-suppressible aldosteronism without the chimeric CYP11B1/CYP11B2 gene. J Clin Endocrinol Metab 86:4805–4807

    Article  CAS  PubMed  Google Scholar 

  26. Mulatero P, Veglio F, Pilon C, Rabbia F, Zocchi C, Limone P, Boscaro M, Sonino N, Fallo F (1998) Diagnosis of glucocorticoid-remediable aldosteronism in primary aldosteronism: aldosterone response to dexamethasone and long polymerase chain reaction for chimeric gene. J Clin Endocrinol Metab 83:2573–2575

    Article  CAS  PubMed  Google Scholar 

  27. Stowasser M, Gartside MG, Gordon RD (1997) A PCR-based method of screening individuals of all ages, from neonates to the elderly, for familial hyperaldosteronism type I. Aust NZ J Med 27:685–690

    Article  CAS  Google Scholar 

  28. Dluhy RG, Lifton RP (1999) Glucocorticoid-remediable aldosteronism. J Clin Endocrinol Metab 84:4341–4344

    Article  CAS  PubMed  Google Scholar 

  29. Halperin F, Dluhy RG (2011) Glucocorticoid-remediable aldosteronism. Endocrinol Metab Clin N Am 40:333–341 viii

    Article  CAS  Google Scholar 

  30. Yang T, He M, Hu C (2018) Regulation of aldosterone production by ion channels: from basal secretion to primary aldosteronism. Biochim Biophys Acta Mol Basis Dis 1864:871–881

    Article  CAS  PubMed  Google Scholar 

  31. Choi M, Scholl UI, Yue P, Bjorklund P, Zhao B, Nelson-Williams C, Ji W, Cho Y, Patel A, Men CJ, Lolis E, Wisgerhof MV, Geller DS, Mane S, Hellman P, Westin G, Akerstrom G, Wang W, Carling T, Lifton RP (2011) K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331:768–772

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Scholl UI, Goh G, Stolting G, de Oliveira RC, Choi M, Overton JD, Fonseca AL, Korah R, Starker LF, Kunstman JW, Prasad ML, Hartung EA, Mauras N, Benson MR, Brady T, Shapiro JR, Loring E, Nelson-Williams C, Libutti SK, Mane S, Hellman P, Westin G, Akerstrom G, Bjorklund P, Carling T, Fahlke C, Hidalgo P, Lifton RP (2013) Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Nat Genet 45:1050–1054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Scholl UI (2019) CLCN2 clicks with aldosterone-producing adenomas, too! Eur J Endocrinol 181:C21–C22

    Article  CAS  PubMed  Google Scholar 

  34. Nanba K, Blinder AR, Rege J, Hattangady NG, Else T, Liu CJ, Tomlins SA, Vats P, Kumar-Sinha C, Giordano TJ, Rainey WE (2020) Somatic CACNA1H mutation as a cause of aldosterone-producing adenoma. Hypertension 75:645–649

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Reimer EN, Walenda G, Seidel E, Scholl UI (2016) CACNA1H(M1549V) mutant calcium channel causes autonomous aldosterone production in HAC15 cells and is inhibited by mibefradil. Endocrinology 157:3016–3022

    Article  CAS  PubMed  Google Scholar 

  37. Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC (1995) Human hypertension caused by mutations in the kidney isozyme of 11 beta-hydroxysteroid dehydrogenase. Nat Genet 10:394–399

    Article  CAS  PubMed  Google Scholar 

  38. Yau M, Haider S, Khattab A, Ling C, Mathew M, Zaidi S, Bloch M, Patel M, Ewert S, Abdullah W, Toygar A, Mudryi V, Al Badi M, Alzubdi M, Wilson RC, Al Azkawi HS, Ozdemir HN, Abu-Amer W, Hertecant J, Razzaghy-Azar M, Funder JW, Al Senani A, Sun L, Kim SM, Yuen T, Zaidi M, New MI (2017) Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11beta-hydroxysteroid dehydrogenase type 2 deficiency. Proc Natl Acad Sci U S A 114:E11248–E11256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nimkarn S (2011) Apparent mineralocorticoid excess - update. Adv Exp Med Biol 707:47–48

    Article  CAS  PubMed  Google Scholar 

  40. Funder JW (2017) Apparent mineralocorticoid excess. J Steroid Biochem Mol Biol 165:151–153

    Article  CAS  PubMed  Google Scholar 

  41. Fan P, Lu YT, Yang KQ, Zhang D, Liu XY, Tian T, Luo F, Wang LP, Ma WJ, Liu YX, Zhang HM, Song L, Cai J, Lou Y, Zhou XL (2020) Apparent mineralocorticoid excess caused by novel compound heterozygous mutations in HSD11B2 and characterized by early-onset hypertension and hypokalemia. Endocrine 70:607–615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wilson RC, Krozowski ZS, Li K, Obeyesekere VR, Razzaghy-Azar M, Harbison MD, Wei JQ, Shackleton CH, Funder JW, New MI (1995) A mutation in the HSD11B2 gene in a family with apparent mineralocorticoid excess. J Clin Endocrinol Metab 80:2263–2266

    CAS  PubMed  Google Scholar 

  43. Morineau G, Sulmont V, Salomon R, Fiquet-Kempf B, Jeunemaitre X, Nicod J, Ferrari P (2006) Apparent mineralocorticoid excess: report of six new cases and extensive personal experience. J Am Soc Nephrol 17:3176–3184

    Article  CAS  PubMed  Google Scholar 

  44. Rogers SL, Hughes BA, Jones CA, Freedman L, Smart K, Taylor N, Stewart PM, Shackleton CH, Krone NP, Blissett J, Tomlinson JW (2014) Diminished 11beta-hydroxysteroid dehydrogenase type 2 activity is associated with decreased weight and weight gain across the first year of life. J Clin Endocrinol Metab 99:E821–E831

    Article  CAS  PubMed  Google Scholar 

  45. Palermo M, Quinkler M, Stewart PM (2004) Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol 48:687–696

    Article  PubMed  Google Scholar 

  46. Moudgil A, Rodich G, Jordan SC, Kamil ES (2000) Nephrocalcinosis and renal cysts associated with apparent mineralocorticoid excess syndrome. Pediatr Nephrol 15:60–62

    Article  CAS  PubMed  Google Scholar 

  47. Yadav M, Sinha A, Hari P, Bagga A (2021) Impaired distal tubular acidification, renal cysts and nephrocalcinosis in monogenic hypertension. Indian J Pediatr 88:579–581

    Article  PubMed  Google Scholar 

  48. Bockenhauer D, van't Hoff W, Dattani M, Lehnhardt A, Subtirelu M, Hildebrandt F, Bichet DG (2010) Secondary nephrogenic diabetes insipidus as a complication of inherited renal diseases. Nephron Physiol 116:p23–p29

    Article  CAS  PubMed  Google Scholar 

  49. Palermo M, Delitala G, Mantero F, Stewart PM, Shackleton CH (2001) Congenital deficiency of 11beta-hydroxysteroid dehydrogenase (apparent mineralocorticoid excess syndrome): diagnostic value of urinary free cortisol and cortisone. J Endocrinol Investig 24:17–23

    Article  CAS  Google Scholar 

  50. Zhou C, Ye F, Wu H, Ye H, Chen Q (2017) Recent advances in the study of 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2) inhibitors. Environ Toxicol Pharmacol 52:47–53

    Article  CAS  PubMed  Google Scholar 

  51. Hinz L, Pacaud D, Kline G (2018) Congenital adrenal hyperplasia causing hypertension: an illustrative review. J Hum Hypertens 32:150–157

    Article  CAS  PubMed  Google Scholar 

  52. Miura K, Yasuda K, Yanase T, Yamakita N, Sasano H, Nawata H, Inoue M, Fukaya T, Shizuta Y (1996) Mutation of cytochrome P-45017 alpha gene (CYP17) in a Japanese patient previously reported as having glucocorticoid-responsive hyperaldosteronism: with a review of Japanese patients with mutations of CYP17. J Clin Endocrinol Metab 81:3797–3801

    CAS  PubMed  Google Scholar 

  53. Melcescu E, Phillips J, Moll G, Subauste JS, Koch CA (2012) 11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension. Horm Metab Res 44:867–878

    Article  CAS  PubMed  Google Scholar 

  54. Breil T, Yakovenko V, Inta I, Choukair D, Klose D, Mittnacht J, Schulze E, Alrajab A, Grulich-Henn J, Bettendorf M (2019) Typical characteristics of children with congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency: a single-Centre experience and review of the literature. J Pediatr Endocrinol Metab 32:259–267

    Article  CAS  PubMed  Google Scholar 

  55. Zhang M, Sun S, Liu Y, Zhang H, Jiao Y, Wang W, Li X (2015) New, recurrent, and prevalent mutations: clinical and molecular characterization of 26 Chinese patients with 17alpha-hydroxylase/17,20-lyase deficiency. J Steroid Biochem Mol Biol 150:11–16

    Article  CAS  PubMed  Google Scholar 

  56. Costa-Santos M, Kater CE, Auchus RJ, Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group (2004) Two prevalent CYP17 mutations and genotype-phenotype correlations in 24 Brazilian patients with 17-hydroxylase deficiency. J Clin Endocrinol Metab 89:49–60

    Article  CAS  PubMed  Google Scholar 

  57. Martin RM, Lin CJ, Costa EM, de Oliveira ML, Carrilho A, Villar H, Longui CA, Mendonca BB (2003) P450c17 deficiency in Brazilian patients: biochemical diagnosis through progesterone levels confirmed by CYP17 genotyping. J Clin Endocrinol Metab 88:5739–5746

    Article  CAS  PubMed  Google Scholar 

  58. Khattab A, Haider S, Kumar A, Dhawan S, Alam D, Romero R, Burns J, Li D, Estatico J, Rahi S, Fatima S, Alzahrani A, Hafez M, Musa N, Razzghy Azar M, Khaloul N, Gribaa M, Saad A, Charfeddine IB, Bilharinho de Mendonca B, Belgorosky A, Dumic K, Dumic M, Aisenberg J, Kandemir N, Alikasifoglu A, Ozon A, Gonc N, Cheng T, Kuhnle-Krahl U, Cappa M, Holterhus PM, Nour MA, Pacaud D, Holtzman A, Li S, Zaidi M, Yuen T, New MI (2017) Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency. Proc Natl Acad Sci U S A 114:E1933–E1940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kardelen AD, Toksoy G, Bas F, Yavas Abali Z, Gencay G, Poyrazoglu S, Bundak R, Altunoglu U, Avci S, Najafli A, Uyguner O, Karaman B, Basaran S, Darendeliler F (2018) Clinical and genetic findings and follow-up characteristics of six patients with 17-hydroxylase deficiency including two novel mutations. J Clin Res Pediatr Endocrinol 10:206–215

    Article  PubMed  PubMed Central  Google Scholar 

  60. Vitellius G, Lombes M (2020) Genetics in endocrinology: glucocorticoid resistance syndrome. Eur J Endocrinol 182:R15–R27

    Article  CAS  PubMed  Google Scholar 

  61. Mendonca BB, Leite MV, de Castro M, Kino T, Elias LL, Bachega TA, Arnhold IJ, Chrousos GP, Latronico AC (2002) Female pseudohermaphroditism caused by a novel homozygous missense mutation of the GR gene. J Clin Endocrinol Metab 87:1805–1809

    Article  CAS  PubMed  Google Scholar 

  62. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, Meinke G, Tsai FT, Sigler PB, Lifton RP (2000) Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science 289:119–123

    Article  CAS  PubMed  Google Scholar 

  63. Zennaro MC, Fernandes-Rosa F (2017) 30 years of the mineralocorticoid receptor: mineralocorticoid receptor mutations. J Endocrinol 234:T93–T106

    Article  CAS  PubMed  Google Scholar 

  64. Knight KK, Olson DR, Zhou R, Snyder PM (2006) Liddle’s syndrome mutations increase Na+ transport through dual effects on epithelial Na+ channel surface expression and proteolytic cleavage. Proc Natl Acad Sci U S A 103:2805–2808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Tetti M, Monticone S, Burrello J, Matarazzo P, Veglio F, Pasini B, Jeunemaitre X, Mulatero P (2018) Liddle syndrome: review of the literature and description of a new case. Int J Mol Sci 19:812

    Article  PubMed Central  CAS  Google Scholar 

  66. Bogdanovic R, Kuburovic V, Stajic N, Mughal SS, Hilger A, Ninic S, Prijic S, Ludwig M (2012) Liddle syndrome in a Serbian family and literature review of underlying mutations. Eur J Pediatr 171:471–478

    Article  PubMed  Google Scholar 

  67. Frindt G, Bertog M, Korbmacher C, Palmer LG (2020) Ubiquitination of renal ENaC subunits in vivo. Am J Physiol Renal Physiol 318:F1113–F1121

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Salih M, Gautschi I, van Bemmelen MX, Di Benedetto M, Brooks AS, Lugtenberg D, Schild L, Hoorn EJ (2017) A missense mutation in the extracellular domain of alpha ENaC causes Liddle syndrome. J Am Soc Nephrol 28:3291–3299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yang KQ, Lu CX, Fan P, Zhang Y, Meng X, Dong XQ, Luo F, Liu YX, Zhang HM, Wu HY, Cai J, Zhang X, Zhou XL (2018) Genetic screening of SCNN1B and SCNN1G genes in early-onset hypertensive patients helps to identify Liddle syndrome. Clin Exp Hypertens 40:107–111

    Article  CAS  PubMed  Google Scholar 

  70. Fan P, Pan XC, Zhang D, Yang KQ, Zhang Y, Tian T, Luo F, Ma WJ, Liu YX, Wang LP, Zhang HM, Song L, Cai J, Zhou XL (2020) Pediatric Liddle syndrome caused by a novel SCNN1G variant in a Chinese family and characterized by early-onset hypertension. Am J Hypertens 33:670–675

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Monnens L, Levtchenko E (2004) Distinction between Liddle syndrome and apparent mineralocorticoid excess. Pediatr Nephrol 19:118–119

    Article  CAS  PubMed  Google Scholar 

  72. Warnock DG (2001) Liddle syndrome: genetics and mechanisms of Na+ channel defects. Am J Med Sci 322:302–307

    Article  CAS  PubMed  Google Scholar 

  73. O'Shaughnessy KM (2015) Gordon syndrome: a continuing story. Pediatr Nephrol 30:1903–1908

    Article  PubMed  Google Scholar 

  74. Mabillard H, Sayer JA (2019) The molecular genetics of Gordon syndrome. Genes (Basel) 10:986

    Article  CAS  Google Scholar 

  75. Wilson FH, Disse-Nicodeme S, Choate KA, Ishikawa K, Nelson-Williams C, Desitter I, Gunel M, Milford DV, Lipkin GW, Achard JM, Feely MP, Dussol B, Berland Y, Unwin RJ, Mayan H, Simon DB, Farfel Z, Jeunemaitre X, Lifton RP (2001) Human hypertension caused by mutations in WNK kinases. Science 293:1107–1112

    Article  CAS  PubMed  Google Scholar 

  76. Boyden LM, Choi M, Choate KA, Nelson-Williams CJ, Farhi A, Toka HR, Tikhonova IR, Bjornson R, Mane SM, Colussi G, Lebel M, Gordon RD, Semmekrot BA, Poujol A, Valimaki MJ, De Ferrari ME, Sanjad SA, Gutkin M, Karet FE, Tucci JR, Stockigt JR, Keppler-Noreuil KM, Porter CC, Anand SK, Whiteford ML, Davis ID, Dewar SB, Bettinelli A, Fadrowski JJ, Belsha CW, Hunley TE, Nelson RD, Trachtman H, Cole TR, Pinsk M, Bockenhauer D, Shenoy M, Vaidyanathan P, Foreman JW, Rasoulpour M, Thameem F, Al-Shahrouri HZ, Radhakrishnan J, Gharavi AG, Goilav B, Lifton RP (2012) Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature 482:98–102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Louis-Dit-Picard H, Barc J, Trujillano D, Miserey-Lenkei S, Bouatia-Naji N, Pylypenko O, Beaurain G, Bonnefond A, Sand O, Simian C, Vidal-Petiot E, Soukaseum C, Mandet C, Broux F, Chabre O, Delahousse M, Esnault V, Fiquet B, Houillier P, Bagnis CI, Koenig J, Konrad M, Landais P, Mourani C, Niaudet P, Probst V, Thauvin C, Unwin RJ, Soroka SD, Ehret G, Ossowski S, Caulfield M, International Consortium for Blood P, Bruneval P, Estivill X, Froguel P, Hadchouel J, Schott JJ, Jeunemaitre X (2012) KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron. Nat Genet 44(456–460):S451–S453

  78. Park JS, Park E, Hyun HS, Ahn YH, Kang HG, Ha IS, Cheong HI (2017) Three cases of Gordon syndrome with dominant KLHL3 mutations. J Pediatr Endocrinol Metab 30:361–364

    Article  CAS  PubMed  Google Scholar 

  79. Sakoh T, Sekine A, Mori T, Mizuno H, Kawada M, Hiramatsu R, Hasegawa E, Hayami N, Yamanouchi M, Suwabe T, Sawa N, Ubara Y, Fujimaru T, Sohara E, Shinichi U, Hoshino J, Takaichi K (2019) A familial case of pseudohypoaldosteronism type II (PHA2) with a novel mutation (D564N) in the acidic motif in WNK4. Mol Genet Genomic Med 7:e705

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, de Ferranti SD, Dionne JM, Falkner B, Flinn SK, Gidding SS, Goodwin C, Leu MG, Powers ME, Rea C, Samuels J, Simasek M, Thaker VV, Urbina EM, Subcommittee on screening and management of high blood pressure in children (2017) Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics 140:e20171904

  81. Lurbe E, Agabiti-Rosei E, Cruickshank JK, Dominiczak A, Erdine S, Hirth A, Invitti C, Litwin M, Mancia G, Pall D, Rascher W, Redon J, Schaefer F, Seeman T, Sinha M, Stabouli S, Webb NJ, Wuhl E, Zanchetti A (2016) 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens 34:1887–1920

    Article  CAS  PubMed  Google Scholar 

  82. Gupta-Malhotra M, Banker A, Shete S, Hashmi SS, Tyson JE, Barratt MS, Hecht JT, Milewicz DM, Boerwinkle E (2015) Essential hypertension vs. secondary hypertension among children. Am J Hypertens 28:73–80

    Article  PubMed  Google Scholar 

  83. Gomes RS, Quirino IG, Pereira RM, Vitor BM, Leite AF, Oliveira EA, Simoes e Silva AC (2011) Primary versus secondary hypertension in children followed up at an outpatient tertiary unit. Pediatr Nephrol 26:441–447

  84. Aglony M, Martinez-Aguayo A, Carvajal CA, Campino C, Garcia H, Bancalari R, Bolte L, Avalos C, Loureiro C, Trejo P, Brinkmann K, Giadrosich V, Mericq V, Rocha A, Avila A, Perez V, Inostroza A, Fardella CE (2011) Frequency of familial hyperaldosteronism type 1 in a hypertensive pediatric population: clinical and biochemical presentation. Hypertension 57:1117–1121

    Article  CAS  PubMed  Google Scholar 

  85. Wang LP, Yang KQ, Jiang XJ, Wu HY, Zhang HM, Zou YB, Song L, Bian J, Hui RT, Liu YX, Zhou XL (2015) Prevalence of Liddle syndrome among young hypertension patients of undetermined cause in a Chinese population. J Clin Hypertens (Greenwich) 17:902–907

    Article  CAS  Google Scholar 

  86. Bao M, Li P, Li Q, Chen H, Zhong Y, Li S, Jin L, Wang W, Chen Z, Zhong J, Geng B, Fan Y, Yang X, Cai J (2020) Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting. J Med Genet 57:571–580

    Article  CAS  PubMed  Google Scholar 

  87. Funder JW, Carey RM, Mantero F, Murad MH, Reincke M, Shibata H, Stowasser M, Young WF Jr (2016) The management of primary aldosteronism: case detection, diagnosis, and treatment: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 101:1889–1916

    Article  CAS  PubMed  Google Scholar 

  88. Barigou M, Ah-Kang F, Orloff E, Amar J, Chamontin B, Bouhanick B (2015) Effect of postural changes on aldosterone to plasma renin ratio in patients with suspected secondary hypertension. Ann Cardiol Angeiol (Paris) 64:169–174

    Article  CAS  Google Scholar 

  89. Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM, Kong AP (2005) The use of aldosterone-renin ratio as a diagnostic test for primary hyperaldosteronism and its test characteristics under different conditions of blood sampling. J Clin Endocrinol Metab 90:72–78

    Article  CAS  PubMed  Google Scholar 

  90. Stowasser M, Ahmed AH, Pimenta E, Taylor PJ, Gordon RD (2012) Factors affecting the aldosterone/renin ratio. Horm Metab Res 44:170–176

    Article  CAS  PubMed  Google Scholar 

  91. Martinez-Aguayo A, Aglony M, Campino C, Garcia H, Bancalari R, Bolte L, Avalos C, Loureiro C, Carvajal CA, Avila A, Perez V, Inostroza A, Fardella CE (2010) Aldosterone, plasma renin activity, and aldosterone/renin ratio in a normotensive healthy pediatric population. Hypertension 56:391–396

    Article  CAS  PubMed  Google Scholar 

  92. Precone V, Krasi G, Guerri G, Stuppia L, Romeo F, Perrone M, Marinelli C, Zulian A, Dallavilla T, Bertelli M (2019) Monogenic hypertension. Acta Biomed 90:50–52

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, 110029, India

    Priyanka Khandelwal

  2. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Jaap Deinum

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  1. Priyanka Khandelwal
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  2. Jaap Deinum
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Correspondence to Priyanka Khandelwal.

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Khandelwal, P., Deinum, J. Monogenic forms of low-renin hypertension: clinical and molecular insights. Pediatr Nephrol 37, 1495–1509 (2022). https://doi.org/10.1007/s00467-021-05246-x

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