Abstract
Inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive co-transporter causes Gitelman syndrome. The main features of this syndrome include normal or low blood pressure, hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and hyperreninemia. These patients are at low risk for preterm birth and do not present with symptoms before school age. As a consequence, the condition is usually diagnosed in late childhood or in adult life. We report on four patients, two pairs of prematurely born twins, in whom hypokalemia was demonstrated early in life. In these children, a tendency towards hypokalemia was first noted during the third week of life. Overt hypokalemia subsequently appeared associated with normal blood pressure, hypochloremia, hyperreninemia, and an inappropriately high fractional excretion of potassium and chloride. Molecular biology studies failed to detect mutations in the SLC12A1, KCNJ1, and CLCNKB genes responsible for the Bartter syndromes type I, II and III, respectively. Compound heterozygous mutations in the SLC12A3 gene were detected in both pairs of twins: a frameshift mutation in exon 10 (c.1196_1202dup7bp), leading to the truncated protein p.Ser402X, and a missense mutation in exon 11, p.Ser475Cys (c.1424C>G) in the first pair; two missense mutations, p.Thr392Ile (c.1175C>T) in exon 9 and p.Ser615Leu in exon 15 (c.1844C>T), in the second pair. In conclusion, the diagnosis of Gitelman syndrome deserves consideration in infants with unexplained hypokalemia.
References
Gitelman HJ, Graham JB, Welt LG (1966) A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 79:221–235
Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, Vaara I, Iwata F, Cushner HM, Koolen M, Gainza FJ, Gitleman HJ, Lifton RP (1996) Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 12:24–30
Mastroianni N, Bettinelli A, Bianchetti M, Colussi G, De Fusco M, Sereni F, Ballabio A, Casari G (1996) Novel molecular variants of the Na-Cl cotransporter gene are responsible for Gitelman syndrome. Am J Hum Genet 59:1019–2106
Knoers NV (2009) Inherited forms of renal hypomagnesemia: an update. Pediatr Nephrol 24:697–705
Bettinelli A, Borsa N, Bellantuono R, Syrèn ML, Calabrese R, Edefonti A, Komninos J, Santostefano M, Beccaria L, Pela I, Bianchetti MG, Tedeschi S (2007) Patients with biallelic mutations in the chloride channel gene CLCNKB: long-term management and outcome. Am J Kidney Dis 49:91–98
Puricelli E, Bettinelli A, Borsa N, Sironi F, Mattiello C, Tammaro F, Tedeschi S, Bianchetti MG, Italian Collaborative Group for Bartter Syndrome (2010) Long-term follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant. doi:10.1093/ndt/gfq119
Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB, Yale Gitelman’s and Bartter’s Syndrome Collaborative Study Group (2001) Gitelman’s syndrome revisited: an evaluation of symptoms and health-related quality of life. Kidney Int 59:710–717
Colussi G, Bettinelli A, Tedeschi S, De Ferrari ME, Syrén ML, Borsa N, Mattiello C, Casari G, Bianchetti MG (2007) A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin J Am Soc Nephrol 2:454–460
Cortesi C, Bettinelli A, Emma F, Fischbach M, Bertolani P, Bianchetti MG (2005) Severe syncope and sudden death in children with inborn salt-losing hypokalaemic tubulopathies. Nephrol Dial Transplant 20:1981–1983
Gurkan S, Estilo GK, Wei Y, Satlin LM (2007) Potassium transport in the maturing kidney. Pediatr Nephrol 22:915–925
Martinerie L, Viengchareun S, Delezoide AL, Jaubert F, Sinico M, Prevot S, Boileau P, Meduri G, Lombès M (2009) Low renal mineralocorticoid receptor expression at birth contributes to partial aldosterone resistance in neonates. Endocrinology 150:4414–4424
Van Acker KJ, Scharpe SL, Deprettere AJ, Neels HM (1979) Renin-angiotensin-aldosterone system in the healthy infant and child. Kidney Int 16:196–203
Zietse R, Zoutendijk R, Hoorn EJ (2009) Fluid, electrolyte and acid-base disorders associated with antibiotic therapy. Nat Rev Nephrol 5:193–202
Alazami M, Lin SH, Cheng CJ, Davids MR, Halperin ML (2006) Unusual causes of hypokalaemia and paralysis. QJM 99:181–192
Konrad M, Vollmer M, Lemmink HH, van den Heuvel LP, Jeck N, Vargas-Poussou R, Lakings A, Ruf R, Deschênes G, Antignac C, Guay-Woodford L, Knoers NV, Seyberth HW, Feldmann D, Hildebrandt F (2000) Mutations in the chloride channel gene CLCNKB as a cause of classic Bartter syndrome. J Am Soc Nephrol 11:1449–1459
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Tammaro, F., Bettinelli, A., Cattarelli, D. et al. Early appearance of hypokalemia in Gitelman syndrome. Pediatr Nephrol 25, 2179–2182 (2010). https://doi.org/10.1007/s00467-010-1575-1
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DOI: https://doi.org/10.1007/s00467-010-1575-1