Clinical, Biochemical and Molecular Genetic Data in Five Children with Gitelman’s Syndrome

Gitelman’s variant of Bartter’s syndrome, inherited hypokalemic alkalosis, is caused by mutation in the thiazide-sensitive NaCl co-transporter (NCCT). The main clinical symptoms are: muscular weakness, carpopedal spasm, constipation and short stature. The diagnosis was suspected in five children according to clinical criteria. All patients exhibited carpopedal spasm during febrile illness, three patients had short stature. Biochemical features were: metabolic alkalosis, hypokalemia, hypomagnesemia, low IGF-I levels, hyperkaliuria, hypernatriuria, hypocalciuria and normoprostaglandinuria. Three patients had elevated plasma renin activity and hyperaldosteronism. Mutational analysis of the NCCT gene confirmed the diagnosis in all five patients. Different forms of therapy, potassium and magnesium substitution, spironolactone and indomethacin failed to fully correct hypokalemia and hypomagnesemia, but markedly improved growth velocity and normalized IGF-I levels in the three patients with short stature. During therapy, clinical symptoms disappeared. We conclude that Gitelman’s syndrome is a disorder with a variable symptom profile, but can be suspected on clinical signs already in early childhood. The early diagnosis is essential in preventing complications.

Key words:

Gitelman’s Syndrome - Children - Carpopedal Spasm - Short Stature

References

• 1 Gitelman H J, Graham J B, Welt L G. A new familial disorder characterized by hypokalemia and hypomagnesemia.  Trans Assoc Am Physicians. 1966;  79 221-235
• 2 Simon D B, Nelson-Wiliams C, Johnson Bia M, Ellison D, Karet F E, Molina A M, Vaara I, Iwata F, Cushner H M, Koolen M, Gainza F J, Gitelman H J, Lifton R P. Gitelman’s variant of Bartter’s syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter.  Nature Genet. 1996;  12 24-30
• 3 Simon D B, Bindra R S, Mansfield T A, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales J M, Sanjad S A, Taylor C M, Pilz D, Brem A, Trachtman H, Griswold W, Richard G A, John E, Lifton R P. Mutations in the chloride channel gene, CLCNKB, cause Bartter’s syndrome type III.  Nature Genet. 1997;  17 171-178
• 4 Simon D B, Karet F E, Hamdan J M, Di Pietro A, Sanjad S A, Lifton R P. Bartter’s syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2.  Nature Genet. 1996;  13 183-189
• 5 Simon D B, Karet F E, Rodriguez-Soriano J, Hamdan J H, DiPietro A, Trachtman H, Sanjad S A, Lifton R P. Genetic heterogeneity of Bartter’s syndrome revealed by mutations in the K-channel, ROMK.  Nature Genet. 1996;  14 152-156
• 6 International Collaborative Study Group for Bartter-like S yndromes, consisting of: Group 1: Karolyi L, Konrad M, Köckerling A, Ziegler A, Zimmermann D K, Roth B, Wieg C, Grzeschik K H, Koch M C, Seyberth H W, Group 2: Vargas R, Forestier L, Jean G, Deschaux M, Rizzoni G F, Niaudet P, Antignac C, Group 3: Feldmann D, Lorridon F, Cougoureaux E, Laroze F, Alessandri J L, David L, Saunier P, Deschenes G, Group 4: Hildebrandt F, Vollmer M, Proesmans W, Brandis M, Group 5: van den Heuvel L PWJ, Lemmink H H, Nillesen W, Monnens L AH, Knoers N VAM, Group 6: Guay-Woodford L M, Wright C J, Madrigal G, Hebert S C. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity.  Hum Mol Gen. 1997;  6 17-26
• 7 Bettinelli A, Bianchetti M G, Girardin E, Caringella A, Ceccone M, Appiani A C, Pavanello L, Gastaldi R, Isimbaldi C, Lama G, Marchesoni C, Matteuci C, Patriarca P, Di Natale B, Setzu C, Vitucci P. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes.  J Pediatr. 1992;  120 38-43
• 8 Bourcier T, Blain P, Massin P, Grunfeld J P, Gaudric A. Sclerochoroidal calcifications associated with Gitelman syndrome.  Am J Ophthalm. 1999;  128 767-768
• 9 Gascon A, Cobeta-Garcia J C, Iglesias E. Hypomagnesemia and chondrocalcinosis in Gitelman syndrome.  Am J Med. 1999;  107 301-302
• 10 Schoof E, Marx M, Doerr H G. A boy presenting with familial short stature-diagnosis Gitelman syndrome.  J Pediatr Endocrinol Metab. 1999;  12 891-894
• 11 Prader A, Largo R H, Molinari L, Issler C. Physical growth of Swiss children from birth to 20 years of age. 1988 Helv Paed Acta 43 Suppl 52
• 12 Greulich W W, Pyle S I. Radiographic atlas of skeletal development of the hand and wrist.  Stanford, California:; Stanford University Press, 1959
• 13 Liaw L C, Banerjee K, Coulthard M G. Dose related growth response to indomethacin in Gitelman syndrome.  Arch Dis Child. 1999;  81 508-510
• 14 Flyvbjerg A, Dorup I, Everts M E, Orskov H. Evidence that potassium deficiency induces growth retardation through reduced circulating levels of growth hormone and insulin-like growth factor I.  Metabolism. 1991;  40 769-775
• 15 Boer L A, Zoppi G. Bartter’s syndrome with impairment of growth hormone secretion.  Lancet. 1992;  340 860
• 16 Ko C W, Koo J H. Recombinant human growth hormone and Gitelman’s syndrome.  Am J Kidney Dis. 1999;  33 (4) 778-781
• 17 Bettinelli A, Basilico E, Metta M G, Borella P, Jaeger P, Bianchetti M G. Magnesium supplementation in Gitelman syndrome.  Pediatr Nephrol. 1999;  13 311-314