Abstract
Congenital adrenal hyperplasia (CAH) in its severe salt-wasting form is a challenge for pediatric endocrinologists in order to maintain water and sodium homeostasis, particularly in the neonatal period. The pathophysiology of this impaired sodium balance is still poorly investigated as well as its therapeutic management. This chapter will summarize mechanisms of sodium and water reabsorption, particularly the aldosterone-mineralocorticoid receptor signaling pathway, its expression and regulation in neonates, and the impact of a complete 21-hydroxylase deficiency.
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Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JMC, Ross RJ, United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95:5110–21. https://doi.org/10.1210/jc.2010-0917.
Bassett MH, White PC, Rainey WE. The regulation of aldosterone synthase expression. Mol Cell Endocrinol. 2004;217:67–74. https://doi.org/10.1016/j.mce.2003.10.011.
Berger S, Bleich M, Schmid W, Cole TJ, Peters J, Watanabe H, Kriz W, Warth R, Greger R, Schütz G. Mineralocorticoid receptor knockout mice: pathophysiology of Na+ metabolism. Proc Natl Acad Sci U S A. 1998;95:9424–9. https://doi.org/10.1073/pnas.95.16.9424.
Bonfig W, Roehl F, Riedl S, Brämswig J, Richter-Unruh A, Fricke-Otto S, Hübner A, Bettendorf M, Schönau E, Dörr H, Holl RW, Mohnike K. Sodium chloride supplementation is not routinely performed in the majority of German and Austrian infants with classic salt-wasting congenital adrenal hyperplasia and has no effect on linear growth and hydrocortisone or fludrocortisone dose. Horm Res Paediatr. 2018;89:7–12. https://doi.org/10.1159/000481775.
Bongiovanni AM, Root AW. The adrenogenital syndrome. N Engl J Med. 1963;268:1283–9. https://doi.org/10.1056/NEJM196306062682308.
Bornstein SR, Tajima T, Eisenhofer G, Haidan A, Aguilera G. Adrenomedullary function is severely impaired in 21-hydroxylase-deficient mice. FASEB J. 1999;13:1185–94. https://doi.org/10.1096/fasebj.13.10.1185.
Bourchier D. Plasma aldosterone levels in the 1st week of life in infants of less than 30 weeks gestation. Eur J Pediatr. 2005;164:141–5. https://doi.org/10.1007/s00431-004-1572-0.
Chang SS, Grunder S, Hanukoglu A, Rösler A, Mathew PM, Hanukoglu I, Schild L, Lu Y, Shimkets RA, Nelson-Williams C, Rossier BC, Lifton RP. Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1. Nat Genet. 1996;12:248–53. https://doi.org/10.1038/ng0396-248.
Charmandari E, Hindmarsh PC, Johnston A, Brook CG. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab. 2001;86:2701–8. https://doi.org/10.1210/jcem.86.6.7522.
Cherradi N, Brandenburger Y, Capponi AM. Mitochondrial regulation of mineralocorticoid biosynthesis by calcium and the StAR protein. Eur J Endocrinol. 1998;139:249–56. https://doi.org/10.1530/eje.0.1390249.
Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, Arlt W, Auchus RJ, Falhammar H, Flück CE, Guasti L, Huebner A, Kortmann BBM, Krone N, Merke DP, Miller WL, Nordenström A, Reisch N, Sandberg DE, Stikkelbroeck NMML, Touraine P, Utari A, Wudy SA, White PC. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev. 2022;43:91–159. https://doi.org/10.1210/endrev/bnab016.
Coulm B, Coste J, Tardy V, Ecosse E, Roussey M, Morel Y, Carel J-C, DHCSF Study Group. Efficiency of neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency in children born in mainland France between 1996 and 2003. Arch Pediatr Adolesc Med. 2012;166:113–20. https://doi.org/10.1001/archpediatrics.2011.774.
Coulter CL, Jaffe RB. Functional maturation of the primate fetal adrenal in vivo: 3. Specific zonal localization and developmental regulation of CYP21A2 (P450c21) and CYP11B1/CYP11B2 (P450c11/aldosterone synthase) lead to integrated concept of zonal and temporal steroid biosynthesis. Endocrinology. 1998;139:5144–50. https://doi.org/10.1210/endo.139.12.6333.
Devuyst O. Salt wasting and blood pressure. Nat Genet. 2008;40:495–6. https://doi.org/10.1038/ng0508-495.
Dupont B, Oberfield SE, Smithwick EM, Lee TD, Levine LS. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet. 1977;2:1309–12. https://doi.org/10.1016/s0140-6736(77)90362-2.
Falhammar H, Frisén L, Norrby C, Hirschberg AL, Almqvist C, Nordenskjöld A, Nordenström A. Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2014;99:E2715–21. https://doi.org/10.1210/jc.2014-2957.
Garrahy A, Thompson CJ. Hyponatremia and glucocorticoid deficiency. Front Horm Res. 2019;52:80–92. https://doi.org/10.1159/000493239.
Globerman H, Rösler A, Theodor R, New MI, White PC. An inherited defect in aldosterone biosynthesis caused by a mutation in or near the gene for steroid 11-hydroxylase. N Engl J Med. 1988;319:1193–7. https://doi.org/10.1056/NEJM198811033191804.
Graves LE, Torpy DJ, Coates PT, Alexander IE, Bornstein SR, Clarke B. Future directions for adrenal insufficiency: cellular transplantation and genetic therapies. J Clin Endocrinol Metab. 2023;108:1273–89. https://doi.org/10.1210/clinem/dgac751.
Hasler U, Mordasini D, Bianchi M, Vandewalle A, Féraille E, Martin P-Y. Dual influence of aldosterone on AQP2 expression in cultured renal collecting duct principal cells. J Biol Chem. 2003;278:21639–48. https://doi.org/10.1074/jbc.M212388200.
Helve O, Pitkänen OM, Andersson S, O’Brodovich H, Kirjavainen T, Otulakowski G. Low expression of human epithelial sodium channel in airway epithelium of preterm infants with respiratory distress. Pediatrics. 2004;113:1267–72. https://doi.org/10.1542/peds.113.5.1267.
Hummler E, Barker P, Gatzy J, Beermann F, Verdumo C, Schmidt A, Boucher R, Rossier BC. Early death due to defective neonatal lung liquid clearance in alpha-ENaC-deficient mice. Nat Genet. 1996;12:325–8. https://doi.org/10.1038/ng0396-325.
Jiang X, Tang F, Feng Y, Li B, Jia X, Tang C, Liu S, Huang Y. The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling. J Pediatr Endocrinol Metab. 2019;32:1253–8. https://doi.org/10.1515/jpem-2019-0140.
Kerem E, Bistritzer T, Hanukoglu A, Hofmann T, Zhou Z, Bennett W, MacLaughlin E, Barker P, Nash M, Quittell L, Boucher R, Knowles MR. Pulmonary epithelial sodium-channel dysfunction and excess airway liquid in pseudohypoaldosteronism. N Engl J Med. 1999;341:156–62. https://doi.org/10.1056/NEJM199907153410304.
Koo WW, Gupta JM. Breast milk sodium. Arch Dis Child. 1982;57:500–2. https://doi.org/10.1136/adc.57.7.500.
Kulle A, Krone N, Holterhus PM, Schuler G, Greaves RF, Juul A, de Rijke YB, Hartmann MF, Saba A, Hiort O, Wudy SA, EU COST Action. Steroid hormone analysis in diagnosis and treatment of DSD: position paper of EU COST Action BM 1303 “DSDnet.”. Eur J Endocrinol. 2017;176:P1–9. https://doi.org/10.1530/EJE-16-0953.
Lee G, Makhanova N, Caron K, Lopez MLS, Gomez RA, Smithies O, Kim H-S. Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice. Endocrinology. 2005;146:2650–6. https://doi.org/10.1210/en.2004-1102.
Lefebvre H, Duparc C, Naccache A, Lopez A-G, Castanet M, Louiset E. Paracrine regulation of aldosterone secretion in physiological and pathophysiological conditions. Vitam Horm. 2019;109:303–39. https://doi.org/10.1016/bs.vh.2018.10.001.
Lindower JB. Water balance in the fetus and neonate. Semin Fetal Neonatal Med. 2017;22:71–5. https://doi.org/10.1016/j.siny.2017.01.002.
MacKenzie SM, van Kralingen JC, Davies E. Regulation of aldosterone secretion. Vitam Horm. 2019;109:241–63. https://doi.org/10.1016/bs.vh.2018.07.001.
Martinerie L, Pussard E, Foix-L’Hélias L, Petit F, Cosson C, Boileau P, Lombès M. Physiological partial aldosterone resistance in human newborns. Pediatr Res. 2009a;66:323–8. https://doi.org/10.1203/PDR.0b013e3181b1bbec.
Martinerie L, Viengchareun S, Delezoide A-L, Jaubert F, Sinico M, Prevot S, Boileau P, Meduri G, Lombès M. Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates. Endocrinology. 2009b;150:4414–24. https://doi.org/10.1210/en.2008-1498.
Martinerie L, Munier M, Le Menuet D, Meduri G, Viengchareun S, Lombès M. The mineralocorticoid signaling pathway throughout development: expression, regulation and pathophysiological implications. Biochimie. 2013;95:148–57. https://doi.org/10.1016/j.biochi.2012.09.030.
Martinerie L, Pussard E, Yousef N, Cosson C, Lema I, Husseini K, Mur S, Lombès M, Boileau P. Aldosterone-signaling defect exacerbates sodium wasting in very preterm neonates: the Premaldo study. J Clin Endocrinol Metab. 2015;100:4074–81. https://doi.org/10.1210/jc.2015-2272.
Mesiano S, Jaffe RB. Developmental and functional biology of the primate fetal adrenal cortex. Endocr Rev. 1997;18:378–403. https://doi.org/10.1210/edrv.18.3.0304.
Miao H, Yu Z, Lu L, Zhu H, Auchus RJ, Liu J, Jiang J, Pan H, Gong F, Chen S, Lu Z. Analysis of novel heterozygous mutations in the CYP11B2 gene causing congenital aldosterone synthase deficiency and literature review. Steroids. 2019;150:108448. https://doi.org/10.1016/j.steroids.2019.108448.
Naccache A, Louiset E, Duparc C, Laquerrière A, Patrier S, Renouf S, Gomez-Sanchez CE, Mukai K, Lefebvre H, Castanet M. Temporal and spatial distribution of mast cells and steroidogenic enzymes in the human fetal adrenal. Mol Cell Endocrinol. 2016;434:69–80. https://doi.org/10.1016/j.mce.2016.06.015.
Narasaka T, Suzuki T, Moriya T, Sasano H. Temporal and spatial distribution of corticosteroidogenic enzymes immunoreactivity in developing human adrenal. Mol Cell Endocrinol. 2001;174:111–20. https://doi.org/10.1016/s0303-7207(00)00445-7.
New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 2013;110:2611–6. https://doi.org/10.1073/pnas.1300057110.
Ng SM, Stepien KM, Krishan A. Glucocorticoid replacement regimens for treating congenital adrenal hyperplasia. Cochrane Database Syst Rev. 2020;3:CD012517. https://doi.org/10.1002/14651858.CD012517.pub2.
Paizoni L, Auer MK, Schmidt H, Hübner A, Bidlingmaier M, Reisch N. Effect of androgen excess and glucocorticoid exposure on metabolic risk profiles in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2020;197:105540. https://doi.org/10.1016/j.jsbmb.2019.105540.
Palmer LG, Schnermann J. Integrated control of Na transport along the nephron. Clin J Am Soc Nephrol. 2015;10:676–87. https://doi.org/10.2215/CJN.12391213.
Pang SY, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon IC, Dobbins RH, Kling S, Fujieda K, Suwa S. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 1988;81:866–74.
Pascoe L, Curnow KM, Slutsker L, Rösler A, White PC. Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency. Proc Natl Acad Sci U S A. 1992;89:4996–5000. https://doi.org/10.1073/pnas.89.11.4996.
Prete A, Auchus RJ, Ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol. 2021;186:R1–R14. https://doi.org/10.1530/EJE-21-0794.
Pussard E, Travers S, Bouvattier C, Xue Q-Y, Cosson C, Viengchareun S, Martinerie L, Lombès M. Urinary steroidomic profiles by LC-MS/MS to monitor classic 21-hydroxylase deficiency. J Steroid Biochem Mol Biol. 2020;198:105553. https://doi.org/10.1016/j.jsbmb.2019.105553.
Robertson S, Diver LA, Alvarez-Madrazo S, Livie C, Ejaz A, Fraser R, Connell JM, MacKenzie SM, Davies E. Regulation of corticosteroidogenic genes by MicroRNAs. Int J Endocrinol. 2017;2017:2021903. https://doi.org/10.1155/2017/2021903.
Romagni P, Rossi F, Guerrini L, Quirini C, Santiemma V. Aldosterone induces contraction of the resistance arteries in man. Atherosclerosis. 2003;166:345–9. https://doi.org/10.1016/s0021-9150(02)00363-5.
Sartorato P, Khaldi Y, Lapeyraque A-L, Armanini D, Kuhnle U, Salomon R, Caprio M, Viengchareun S, Lombès M, Zennaro M-C. Inactivating mutations of the mineralocorticoid receptor in Type I pseudohypoaldosteronism. Mol Cell Endocrinol. 2004;217:119–25. https://doi.org/10.1016/j.mce.2003.10.017.
Sasano H, White PC, New MI, Sasano N. Immunohistochemical localization of cytochrome P-450C21 in human adrenal cortex and its relation to endocrine function. Hum Pathol. 1988;19:181–5. https://doi.org/10.1016/s0046-8177(88)80346-0.
Schröder MAM, Claahsen-van der Grinten HL. Novel treatments for congenital adrenal hyperplasia. Rev Endocr Metab Disord. 2022;23:631–45. https://doi.org/10.1007/s11154-022-09717-w.
Seccia TM, Caroccia B, Gomez-Sanchez EP, Gomez-Sanchez CE, Rossi GP. The biology of normal zona glomerulosa and aldosterone-producing adenoma: pathological implications. Endocr Rev. 2018;39:1029–56. https://doi.org/10.1210/er.2018-00060.
Speiser PW, Agdere L, Ueshiba H, White PC, New MI. Aldosterone synthesis in salt-wasting congenital adrenal hyperplasia with complete absence of adrenal 21-hydroxylase. N Engl J Med. 1991;324:145–9. https://doi.org/10.1056/NEJM199101173240302.
Speiser PW, Arlt W, Auchus RJ, Baskin LS, Conway GS, Merke DP, Meyer-Bahlburg HFL, Miller WL, Murad MH, Oberfield SE, White PC. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2018;103:4043–88. https://doi.org/10.1210/jc.2018-01865.
Suarez-Rivera M, Bonilla-Felix M. Fluid and electrolyte disorders in the newborn: sodium and potassium. Curr Pediatr Rev. 2014;10:115–22. https://doi.org/10.2174/157339631002140513102053.
Tamhane S, Rodriguez-Gutierrez R, Iqbal AM, Prokop LJ, Bancos I, Speiser PW, Murad MH. Cardiovascular and metabolic outcomes in congenital adrenal hyperplasia: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2018;103:4097–103. https://doi.org/10.1210/jc.2018-01862.
Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJC, Adams J. Current status of newborn screening worldwide: 2015. Semin Perinatol. 2015;39:171–87. https://doi.org/10.1053/j.semperi.2015.03.002.
Travers S, Martinerie L, Boileau P, Lombès M, Pussard E. Alterations of adrenal steroidomic profiles in preterm infants at birth. Arch Dis Child Fetal Neonatal Ed. 2018;103:F143–51. https://doi.org/10.1136/archdischild-2016-312457.
Travers S, Bouvattier C, Fagart J, Martinerie L, Viengchareun S, Pussard E, Lombès M. Interaction between accumulated 21-deoxysteroids and mineralocorticoid signaling in 21-hydroxylase deficiency. Am J Physiol Endocrinol Metab. 2020;318:E102–10. https://doi.org/10.1152/ajpendo.00368.2019.
Tusié-Luna MT, White PC. Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms. Proc Natl Acad Sci U S A. 1995;92:10796–800. https://doi.org/10.1073/pnas.92.23.10796.
Underwood MA, Gilbert WM, Sherman MP. Amniotic fluid: not just fetal urine anymore. J Perinatol. 2005;25:341–8. https://doi.org/10.1038/sj.jp.7211290.
Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombès M. The mineralocorticoid receptor: insights into its molecular and (patho)physiological biology. Nucl Recept Signal. 2007;5:e012. https://doi.org/10.1621/nrs.05012.
Viengchareun S, Pussard E, Castanet M, Sachs LM, Vu TA, Boileau P, Lombès M, Martinerie L. The invention of aldosterone, how the past resurfaces in pediatric endocrinology. Mol Cell Endocrinol. 2021;535:111375. https://doi.org/10.1016/j.mce.2021.111375.
White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med. 1994;331:250–8. https://doi.org/10.1056/NEJM199407283310408.
White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245–91. https://doi.org/10.1210/edrv.21.3.0398.
White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A. 1986;83:5111–5. https://doi.org/10.1073/pnas.83.14.5111.
Wils J, Duparc C, Cailleux A-F, Lopez A-G, Guiheneuf C, Boutelet I, Boyer H-G, Dubessy C, Cherifi S, Cauliez B, Gobet F, Defortescu G, Ménard J-F, Louiset E, Lefebvre H. The neuropeptide substance P regulates aldosterone secretion in human adrenals. Nat Commun. 2020;11:2673. https://doi.org/10.1038/s41467-020-16470-8.
Zoetis T, Hurtt ME. Species comparison of anatomical and functional renal development. Birth Defect Res B. 2003;68:111–20. https://doi.org/10.1002/bdrb.10013.
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Martinerie, L. (2023). Electrolyte Disturbance in Congenital Adrenal Hyperplasia Due to 21-OH Deficiency. In: Caprio, M., Fernandes-Rosa, F.L. (eds) Hydro Saline Metabolism. Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-030-44628-4_9-1
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