Diagnosis and Treatment of Monogenic Hypertension in Children
Monogenic Hypertension
Abstract views: 217
/ 
PDF downloads: 121
DOI:
https://doi.org/10.5281/zenodo.10654302Keywords:
Hypertension, monogenic inherited, pharmacogenetics, Liddle syndrome, Geller SyndromeAbstract
Hypertension (HT) is a common public health problem that develops due to primary and secondary causes. The prevalence of HT in children and adolescents is 3.6%. In childhood HT, complex and polygenic factors such as genetic, environmental, adaptive, neural, and hormonal mechanisms play a role. Among these factors, genetic factors are estimated to contribute to the development of HT by 30-60%; however, known genetic factors explain only 3% of the cases.
Monogenic inherited HT is associated with a mutation in a single gene, with or without the influence of mineralocorticoids, leading to increased sodium reabsorption and intravascular volume expansion. Typically, HT in these patients has an early onset, a family history of HT, is associated with electrolyte imbalance, and shows a clinical course refractory to treatment.
In treating monogenic inherited HT, understanding functional genetic mutations enables the utilization of highly effective pharmacogenetic pathways. This knowledge provides the opportunity to tailor treatments specifically to target the primary pathophysiological mechanism of the condition. Sodium-dependent, low renin levels, and monogenic inherited HT treatment are based on a low-sodium diet and block the pathological sodium reabsorption mechanism.
Diagnosis can be made through physical examination, blood pressure measurement, and measurement of renin, aldosterone, cortisol, and potassium levels. Monogenic inherited HTs are rare. Early diagnosis ensures blood pressure control early on, reducing the morbidity and mortality associated with HT. Genetic tests are necessary to confirm the diagnosis, make a differential diagnosis, and choose appropriate treatment.
Clinical manifestations of monogenic inherited HT in some patients extend beyond HT. Other systemic symptoms may accompany HT or manifest at certain stages of life. This article discusses monogenic inherited HT that manifests in the early stages of life, emphasizing the clinical aspects of HT.
References
Raina R, Krishnappa V, Das A, et al. Overview of Monogenic or Mendelian Forms of Hypertension. Front Pediatr. 2019;7:263. Published 2019 Jul 1. doi:10.3389/fped.2019.00263
Ahn SY, Gupta C. Genetic Programming of Hypertension. Front Pediatr. 2018;5:285. Published 2018 Jan 22. doi:10.3389/fped.2017.00285
Singh V, Van Why SK. Monogenic Etiology of Hypertension. Med Clin North Am. 2024;108(1):157-172. doi:10.1016/j.mcna.2023.06.005
Park SJ, Shin JI. Diagnosis and Treatment of Monogenic Hypertension in Children. Yonsei Med J. 2023;64(2):77-86. doi:10.3349/ymj.2022.0316
Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension. Cell. 2001;104(4):545-556. doi:10.1016/s0092-8674(01)00241-0
Lurbe E, Agabiti-Rosei E, Cruickshank JK, et al. 2016 European Society of Hypertension guidelines for the management of high blood pressure in children and adolescents. J Hypertens. 2016;34(10):1887-1920. doi:10.1097/HJH.0000000000001039
Precone V, Krasi G, Guerri G, et al. Monogenic hypertension. Acta Biomed. 2019;90(10-S):50-52. Published 2019 Sep 30. doi:10.23750/abm.v90i10-S.8759
Levanovich PE, Diaczok A, Rossi NF. Clinical and Molecular Perspectives of Monogenic Hypertension. Curr Hypertens Rev. 2020;16(2):91-107. doi:10.2174/1573402115666190409115330
Aggarwal A, Rodriguez-Buritica D. Monogenic Hypertension in Children: A Review With Emphasis on Genetics. Adv Chronic Kidney Dis. 2017;24(6):372-379. doi:10.1053/j.ackd.2017.09.006
Vehaskari VM. Heritable forms of hypertension. Pediatr Nephrol. 2009;24(10):1929-1937. doi:10.1007/s00467-007-0537-8
Garovic VD, Hilliard AA, Turner ST. Monogenic forms of low-renin hypertension. Nat Clin Pract Nephrol. 2006;2(11):624-630. doi:10.1038/ncpneph0309
Yau M, Haider S, Khattab A, et al. Clinical, genetic, and structural basis of apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase type 2 deficiency. Proc Natl Acad Sci U S A. 2017;114(52):E11248-E11256. doi:10.1073/pnas.1716621115
Choi KB. Hypertensive hypokalemic disorders. Electrolyte Blood Press. 2007;5(1):34-41. doi:10.5049/EBP.2007.5.1.34
Palermo M, Quinkler M, Stewart PM. Apparent mineralocorticoid excess syndrome: an overview. Arq Bras Endocrinol Metabol. 2004;48(5):687-696. doi:10.1590/s0004-27302004000500015
Lifton RP, Dluhy RG, Powers M, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355(6357):262-265. doi:10.1038/355262a0
Fisher A, Friel EC, Bernhardt R, et al. Effects of 18-hydroxylated steroids on corticosteroid production by human aldosterone synthase and 11beta-hydroxylase. J Clin Endocrinol Metab. 2001;86(9):4326-4329. doi:10.1210/jcem.86.9.7797
Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism. A systematic review of the literature. Endocrinol Metab Clin North Am. 2002;31(3):619-xi. doi:10.1016/s0889-8529(02)00013-0
Levanovich PE, Diaczok A, Rossi NF. Clinical and Molecular Perspectives of Monogenic Hypertension. Curr Hypertens Rev. 2020;16(2):91-107. doi:10.2174/1573402115666190409115330
Litchfield WR, Anderson BF, Weiss RJ, Lifton RP, Dluhy RG. Intracranial aneurysm and hemorrhagic stroke in glucocorticoid-remediable aldosteronism. Hypertension. 1998;31(1 Pt 2):445-450. doi:10.1161/01.hyp.31.1.445
Funder JW, Carey RM, Mantero F, 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):1889-1916. doi:10.1210/jc.2015-4061
Stowasser M, Gordon RD. Primary aldosteronism--careful investigation is essential and rewarding. Mol Cell Endocrinol. 2004;217(1-2):33-39. doi:10.1016/j.mce.2003.10.006
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(8):3117-3123. doi:10.1210/jc.2008-0594
Choi M, Scholl UI, Yue P, et al. K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science. 2011;331(6018):768-772. doi:10.1126/science.1198785
Korah HE, Scholl UI. An Update on Familial Hyperaldosteronism. Horm Metab Res. 2015;47(13):941-946. doi:10.1055/s-0035-1564166
Daniil G, Fernandes-Rosa FL, Chemin J, et al. CACNA1H Mutations Are Associated With Different Forms of Primary Aldosteronism. EBioMedicine. 2016;13:225-236. doi:10.1016/j.ebiom.2016.10.002
Fernandes-Rosa FL, Williams TA, Riester A, et al. Genetic spectrum and clinical correlates of somatic mutations in aldosterone-producing adenoma. Hypertension. 2014;64(2):354-361. doi:10.1161/HYPERTENSIONAHA.114.03419
Monticone S, Else T, Mulatero P, Williams TA, Rainey WE. Understanding primary aldosteronism: impact of next generation sequencing and expression profiling. Mol Cell Endocrinol. 2015;399:311-320. doi:10.1016/j.mce.2014.09.015
Shimkets RA, Warnock DG, Bositis CM, et al. Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell. 1994;79(3):407-414. doi:10.1016/0092-8674(94)90250-x
Hansson JH, Nelson-Williams C, Suzuki H, et al. Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome. Nat Genet. 1995;11(1):76-82. doi:10.1038/ng0995-76
Snyder PM, Price MP, McDonald FJ, et al. Mechanism by which Liddle’s syndrome mutations increase activity of a human epithelial Na+ channel. Cell. 1995;83(6):969-978. doi:10.1016/0092-8674(95)90212-0
Salih M, Gautschi I, van Bemmelen MX, et al. A Missense Mutation in the Extracellular Domain of αENaC Causes Liddle Syndrome. J Am Soc Nephrol. 2017;28(11):3291-3299. doi:10.1681/ASN.2016111163
Monnens L, Levtchenko E. Distinction between Liddle syndrome and apparent mineralocorticoid excess. Pediatr Nephrol. 2004;19(1):118-119. doi:10.1007/s00467-003-1311-1
Nesterov V, Krueger B, Bertog M, Dahlmann A, Palmisano R, Korbmacher C. In Liddle Syndrome, Epithelial Sodium Channel Is Hyperactive Mainly in the Early Part of the Aldosterone-Sensitive Distal Nephron. Hypertension. 2016;67(6):1256-1262. doi:10.1161/HYPERTENSIONAHA.115.07061
Furuhashi M, Kitamura K, Adachi M, et al. Liddle’s syndrome caused by a novel mutation in the proline-rich PY motif of the epithelial sodium channel beta-subunit. J Clin Endocrinol Metab. 2005;90(1):340-344. doi:10.1210/jc.2004-1027
Gordon RD. Syndrome of hypertension and hyperkalemia with normal glomerular filtration rate. Hypertension. 1986;8(2):93-102. doi:10.1161/01.hyp.8.2.93
Pathare G, Hoenderop JG, Bindels RJ, San-Cristobal P. A molecular update on pseudohypoaldosteronism type II. Am J Physiol Renal Physiol. 2013;305(11):F1513-F1520. doi:10.1152/ajprenal.00440.2013
Wilson FH, Disse-Nicodème S, Choate KA, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293(5532):1107-1112. doi:10.1126/science.1062844.
Boyden LM, Choi M, Choate KA, et al. Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities. Nature. 2012;482(7383):98-102. Published 2012 Jan 22. doi:10.1038/nature10814
Licht JH, Amundson D, Hsueh WA, Lombardo JV. Familiar hyperkalaemic acidosis. Q J Med. 1985;54(214):161-176.
Schambelan M, Sebastian A, Rector FC Jr. Mineralocorticoid-resistant renal hyperkalemia without salt wasting (type II pseudohypoaldosteronism): role of increased renal chloride reabsorption. Kidney Int. 1981;19(5):716-727. doi:10.1038/ki.1981.72
Portrat S, Mulatero P, Curnow KM, Chaussain JL, Morel Y, Pascoe L. Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11beta-hydroxylase) and CYP11B2(aldosterone synthase) cause steroid 11beta-hydroxylase deficiency and congenital adrenal hyperplasia. J Clin Endocrinol Metab. 2001;86(7):3197-3201. doi:10.1210/jcem.86.7.7671
Sahakitrungruang T. Clinical and molecular review of atypical congenital adrenal hyperplasia. Ann Pediatr Endocrinol Metab. 2015;20(1):1-7. doi:10.6065/apem.2015.20.1.1
Yang N, Ray DW, Matthews LC. Current concepts in glucocorticoid resistance. Steroids. 2012;77(11):1041-1049. doi:10.1016/j.steroids.2012.05.007
Vitellius G, Fagart J, Delemer B, et al. Three Novel Heterozygous Point Mutations of NR3C1 Causing Glucocorticoid Resistance. Hum Mutat. 2016;37(8):794-803. doi:10.1002/humu.23008
van Rossum EF, Lamberts SW. Glucocorticoid resistance syndrome: A diagnostic and therapeutic approach. Best Pract Res Clin Endocrinol Metab. 2006;20(4):611-626. doi:10.1016/j.beem.2006.09.005
Geller DS, Farhi A, Pinkerton N, et al. Activating mineralocorticoid receptor mutation in hypertension exacerbated by pregnancy. Science. 2000;289(5476):119-123. doi:10.1126/science.289.5476.119
Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol. 1998;10(3):384-391. doi:10.1016/s0955-0674(98)80015-x
Baker ME. Adrenal and sex steroid receptor evolution: environmental implications. J Mol Endocrinol. 2001;26(2):119-125. doi:10.1677/jme.0.0260119
Hellal-Levy C, Couette B, Fagart J, Souque A, Gomez-Sanchez C, Rafestin-Oblin M. Specific hydroxylations determine selective corticosteroid recognition by human glucocorticoid and mineralocorticoid receptors. FEBS Lett. 1999;464(1-2):9-13. doi:10.1016/s0014-5793(99)01667-1
Naraghi R, Schuster H, Toka HR, et al. Neurovascular compression at the ventrolateral medulla in autosomal dominant hypertension and brachydactyly. Stroke. 1997;28(9):1749-1754. doi:10.1161/01.str.28.9.1749
Schuster H, Toka O, Toka HR, et al. A cross-over medication trial for patients with autosomal-dominant hypertension with brachydactyly. Kidney Int. 1998;53(1):167-172. doi:10.1046/j.1523-1755.1998.00732.x
Wakabayashi S, Tsutsumimoto T, Kawasaki S, Kinoshita T, Horiuchi H, Takaoka K. Involvement of phosphodiesterase isozymes in osteoblastic differentiation. J Bone Miner Res. 2002;17(2):249-256. doi:10.1359/jbmr.2002.17.2.249
Maass PG, Aydin A, Luft FC, et al. PDE3A mutations cause autosomal dominant hypertension with brachydactyly. Nat Genet. 2015;47(6):647-653. doi:10.1038/ng.3302
Maurice DH, Palmer D, Tilley DG, et al. Cyclic nucleotide phosphodiesterase activity, expression, and targeting in cells of the cardiovascular system. Mol Pharmacol. 2003;64(3):533-546. doi:10.1124/mol.64.3.533
Toka O, Maass PG, Aydin A, et al. Childhood hypertension in autosomal-dominant hypertension with brachydactyly. Hypertension. 2010;56(5):988-994. doi:10.1161/HYPERTENSIONAHA.110.156620
Toka O, Tank J, Schächterle C, et al. Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly. Hypertension. 2015;66(4):800-808. doi:10.1161/HYPERTENSIONAHA.115.06000
Neumann HP, Wiestler OD. Clustering of features of von Hippel-Lindau syndrome: evidence for a complex genetic locus. Lancet. 1991;337(8749):1052-1054. doi:10.1016/0140-6736(91)91705-y
Ishizaka Y, Itoh F, Tahira T, et al. Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene. 1989;4(12):1519-1521.
Welander J, Larsson C, Bäckdahl M, et al. Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas. Hum Mol Genet. 2012;21(26):5406-5416. doi:10.1093/hmg/dds402
Kaplan NM, Victor RG. Kaplan’s Clinical Hypertension. Philadelphia, PA: Lippincott Williams and Wilkins (2009).
Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2023 Apr 13;108(5):e200]. J Clin Endocrinol Metab. 2014;99(6):1915-1942. doi:10.1210/jc.2014-1498
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Faysal Gök, Mehmet Emin Demir
This work is licensed under a Creative Commons Attribution 4.0 International License.
The journal is licensed under a 