Table of Contents

HK J Paediatr (New Series)
Vol 18. No. 3, 2013

HK J Paediatr (New Series) 2013;18:174-177

Case Report

Gitelman's Syndrome: Asymptomatic Hypokalaemia in a Chinese Boy

ACC Fu, KP Lee, LCT Tong


Gitelman's syndrome is a rare heritable primary renal tubular disorder, characterised by hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. Most of them run a benign course. If present, symptoms include fatigue and muscle weakness. Rarely serious symptoms like cardiac arrest have been reported. Treatment is by magnesium supplement, potassium supplement or potassium-sparing diuretics. This report reviews incidental finding of Gitelman syndrome in an asymptomatic teenager and emphasizes clinical, laboratory and molecular features of the disease.

Keyword : Gitelman's syndrome; Hypokalaemia; Hypocalciuria; Hypomagnesaemia

Abstract in Chinese

Case Report

A 9-year-old Chinese boy presented to the casualty department of a local hospital in Hong Kong for 3-day history of fever with cough and sputum sound, which were progressive in severity. All along he enjoyed good past health and did not report any muscle weakness, cramps or tetany. His history was unremarkable for vomiting, diarrhoea and diuretic or laxative use. He did not have any family history of muscle weakness or electrolyte disturbance. His parents were non-consanguineous.

Physical examination on admission showed normal blood pressure. He was not in respiratory distress or toxic looking. There were crepitations over bilateral lung bases. His thyroid gland was not enlarged. He had neither neurological deficit nor muscle weakness.

He was treated with one course of Azithromycin for pneumonia. His fever subsided 2 days after admission and his respiratory symptoms gradually resolved.

Laboratory investigations on admission (Table 1) showed mildly elevated white blood cells and C-reactive protein. Marked hypokalaemia (down to 1.9 mmol/L) was the most striking biochemical abnormality. He was at first replaced by high doses of syrup potassium chloride. However, this could only transiently maintain his serum potassium level. He had rebound hypokalaemia one day after initial normalisation, till a second bolus of syrup potassium chloride was given. Nonetheless, he remained asymptomatic and his electrocardiogram tracing showed normal sinus rhythm without features of hypokalaemia (i.e. no flattening of T wave, inverted T wave, U wave, depression of ST segment, decreased QRS voltage or prolonged PR or QT interval) throughout the hospitalisation period.

Further investigations (Table 1) in exploring the cause of hypokalaemia were proceeded.1 His thyroid function was normal. His transtubular potassium gradient (TTKG), calculated by [urine/plasma potassium]/[urine/plasma osmolarity], when his urinary osmolality exceeded plasma osmolality, was 17.3. His urine potassium-creatinine (K-Cr) ratio was 19.6 mmol/mmol. Both of his TTKG and K-Cr ratio suggested renal loss of potassium. With metabolic alkalosis, hypomagnesaemia, normocalcaemia, hypocalciuria (spot and 24-hour urine collection) and elevated renin and aldosterone in this normotensive patient, the clinical diagnosis of Gitelman's syndrome was made. His genetic analysis revealed three heterozygous mutations of SLC12A3 gene (c.488C>T (p.THr163Met), c2612G>A (p.Arg871His) and c.3053G>A (p.Arg1018G1n)). The first two mutations have been described in Chinese patients with Gitelman's syndrome, while the latter mutation has been reported in at least one patient with Gitelman's syndrome.

He was treated with potassium sustained release tablets, three times per day. His serum potassium level was normalised one week after gradual titration of medication. Daily supplement with magnesium lactate was later added.

He remained asymptomatic and normokalaemic after 2 months of follow up.

Table 1 Laboratory investigations
Parameters Value Reference range (unit)
 Haemoglobin 10.3 11.5-15.5 (g/dL)
 White blood cells 16.2 4.5-13.5 x 109 (/L)
 Neutrophils 10.5 1.8-8.0 x 109 (/L)
 Platelet 595 150-400 x 109 (/L)
 Sodium 133 137-144 (mmol/L)
 Potassium 1.9 3.5-5.0 (mmol/L)
 Urea 4.0 3.1-7.8 (mmol/L)
 Creatinine 57 34-65 (mmol/L)
 C-reactive protein 99.8 <9.9 (mg/L)
 Calcium (adjusted) 2.16 2.15-2.55 (mmol/L)
 Phosphate 1.11 0.72-1.39 (mmol/L)
 Magnesium 0.55 0.66-1.07 (mmol/L)
 Chloride 106 98-107 (mmol/L)
 Glucose, random 6.0 ≤7.8 (mmol/L)
 Blood gas, venous pH 7.53 7.35-7.45
 Base excess +3 -2 to +3 (mmol/L)
 Osmolarity 270 275-295 (mOsm/kg)
 Renin 10.8 1.31-3.95
 Aldosterone 990 111-862
 TSH 2.0 0.28-4.3 (mIU/L)
Spot urine    
 Potassium 55.6 N/A (mmol/L)
 Calcium <0.5 N/A (mmol/L)
 Creatinine 2.84 N/A (mmol/L)
 Osmolarity 331 50-1400 (mOsm/kg)
 pH 7.1 4.5-8.0
 K-Cr ratio 19.6 N/A (mmol/mmol)
 TTKG 17.3 N/A
24-hour urine collection    
 Calcium <0.4 2.0-7.4 (mmol/day)
 Creatinine 5.66 9.00-21.00 (mmol/day)
 24-hour urine Ca/Cr <0.07 <0.2 (mmol/mmol)
N/A: not applicable; TSH: thyroid stimulating hormone; K-Cr: potassium-creatinine; TTKG: transtubular potassium gradient; Ca/Cr: calcium/creatinine


Table 2 Summary of genetic and clinical features of different subtypes of Bartter's and Gitelman's syndrome
  Gene locus Gene Gene product Renal defect Clinical features
Bartter's syndrome
Type I 15q15-21 SLC12A1 NKCC2 TAL Polyhydramnios, prematurity, polyuria, nephrocalcinosis
Type II 11q24-25 KCNJ1 ROMK TAL Polyhydramnios, prematurity, polyuria, nephrocalcinosis, transient hyperkalaemic acidosis
Type III 1p36 CLCNKB CLC-Kb TAL No nephrocalcinosis
Type IV 1p31 BSND Barttin TAL Sensorineural deafness, no nephrocalcinosis
Type V 3q13.3-q21 CASR CASR TAL Hypocalcaemia, suppressed PTH
Gitelman's syndrome
  16q13 SLC12A3 NCCT Distal tubule Hypocalciuria, hypomagnesaemia
TAL: Thick ascending limb of the loop of Henle; KCNJ1: K channel subfamily J member 1; NKCC2: furosemide-sensitive Na-K-Cl cotransporter; ROMK: renal outer-medullary K channel; CLCNKB: chloride channel Kb; BSND: Bartter's syndrome sensorineural deaf


Gitelman's syndrome, also known as familial hypokalaemia-hypomagnesaemia, is a rare primary salt-losing renal tubular disorder first reported by Gitelman et al in 1966.2 It is inherited as autosomal recessive traits. The prevalence is estimated approximately at 1 in 40000 inhabitants. No gender difference is observed.

The clinical manifestations are caused by loss-of-function mutations in the solute carrier family, member 3 (SLC12A3) gene, which encodes thiazide sensitive NaCl co-transporter (NCCT) in the distal convoluted tubules.3,4 To date, there have been more than 180 different NCCT mutations reported in the literature, but negative genetic screening may be encountered. Detection of large genomic rearrangement explains the negative genetic finding. Normally homozygous and combined heterozygous mutations are expected in Gitelman's syndrome as it is inherited in autosomal recessive trait. However, in a large cohort study of 448 patients in whom Gitelman's syndrome was suspected, by direct sequencing analysis, two affected alleles were only identified in 315 patients (70%). One affected allele was identified in 81 patients (18%). By identifying genomic rearrangement by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF), mutation detection rate has been improved to 91%.5

The inactivated NCCT can explain most, but not all, features of Gitelman's syndrome. Reduced sodium reabsorption leads to increased delivery of sodium to collecting ducts and secondary volume depletion. The intravascular volume contraction stimulates sodium reabsorption in the collecting duct via upregulation of renin-angiotension-aldosterone system, maintaining sodium homeostasis at the expense of increased potassium and hydrogen ion secretion. This results in hypokalaemia and metabolic alkalosis.

NCCT inactivation also contributes to reduced chloride absorption hence raised renal tubular calcium reabsorption, which is a discernible parameter from Bartter's syndrome (which often conversely has hypercalciuria). In addition to decreased urinary calcium excretion, majority of Gitelman's syndrome also has mild degree of hypomagnesaemia, which is not a constant finding in Bartter's syndrome.

However, the exact mechanism of hypocalciuria and hypomagnesaemia in Gitelman's syndrome is still not fully understood.

Clinical symptoms of Gitelman's syndrome include fatigue, cramps, muscle weakness, carpopedal spasms, salt craving and rarely serious symptoms such as paralysis and cardiac arrest. Growth retardation may also be seen in Gitelman's syndrome but not as frequent as in Bartter's syndrome. Ten percent of patients have prolongation of QT interval. Most symptomatic patients present during periods of fever or when extra magnesium is lost during vomiting or diarrhoea. However, many of the patients with Gitelman's syndrome remain asymptomatic during neonatal, infancy and preschool years.4 Often hypokalaemia is only detected during routine blood taking for other reasons, as in our patient. Even so, one cohort study of 50 adult patients with Gitelman's syndrome showed a lower quality of life score compared with controls in terms of musculoskeletal, renal, paresthesia and palpitation.6

Antenatal/neonatal Bartter's syndrome, classical Bartter's syndrome and Gitelman's syndrome are three phenotypes of Bartter-like diseases that have now been recognised. Until its genetic background has been unraveled since 1996, previously Gitelman's syndrome is mistaken as a "milder form" of Bartter's syndrome, the site of defect in the latter is now recognised in the thick ascending limb of loop of Henle. Defective chloride transport leads to loss of sodium and calcium, activation of renin-aldosterone system and loss of potassium. Bartter's syndrome has been classified into 5 types.

Patients with Bartter's syndrome usually present early in childhood and the failure to thrive is more severe and with a greater degree of growth retardation. Gitelman's syndrome is associated with no or much milder failure to thrive and growth retardation. Nonetheless, they share similar physiologic derangements including hypokalaemic, hypochloremic metabolic alkalosis (except type II Bartter's syndrome which initially presents with transient hyperkalaemic metabolic acidosis), high renin and aldosterone with increased urinary excretion of Na+, Cl- and K+.7 Table 2 summarises the clinical presentations, biochemical parameters and genetic mutations of Gitelman's and Bartter's syndrome.7,8

The diagnosis of Gitelman's syndrome in this patient was made from laboratory investigation findings including hypokalaemia, hypomagnesaemia, metabolic alkalosis and hypocalciuria. Molecular analysis further confirmed the diagnosis.

Treatment of Gitelman's syndrome is mainly symptomatic by supplementation of potassium chloride and magnesium chloride. Observation of chondrocalcinosis with persistent magnesium deficiency favours supplementation of magnesium. However, normalisation of serum magnesium is difficult since high dose of magnesium causes diarrhoea. Sometimes aldosterone antagonists are required to correct and maintain serum potassium level. Patients are encouraged to maintain a high-salt diet. The long-term prognosis of Gitelman's syndrome, in terms of growth and life expectancy, is favourable.


This case demonstrated a classical case of Gitelman's syndrome. He had fulfilled most of the diagnostic criteria for Gitelman's syndrome including normotensive hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. His age group with normal physical examination further confirms the diagnosis. Electrolyte disturbance was resolved with potassium and magnesium supplementation. Hypocalciuria and hypomagnesaemia are two parameters that distinguish it from Bartter's syndrome. In addition, diagnosis of Gitelman's syndrome is feasible by genetic analysis.


1. Lin SH, Lin YF, Chen DT, Chu P, Hsu CW, Halperin ML. Laboratory tests to determine the cause of hypokalemia and paralysis. Arch Intern Med 2004;164:1561-6.

2. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966;79:221-35.

3. Meij I, Knoers N. Gitelman syndrome. Orphanet encyclopedia, May 2003.

4. Knoers NV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008;3:22.

5. Vargas-Poussou R, Dahan K, Kahila D, Venisse A, Riveira-Munoz E, Debaix H, et al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol 2011;22:693-703.

6. Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB; Yale Gitelman's and Bartter's Syndrome Collaborative Study Group. Gitelman's syndrome revisited: An evaluation of symptoms and health-related quality of life. Kidney Int 2001;59:710-7.

7. Chiu MC, Yap HK, eds. Practical Paediatric Nephrology. An Update of Current Practices. Hong Kong: Medcom Limited 2005;201-4.

8. Fremont OT, Chan JC. Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr 2012;8:25-30.


This web site is sponsored by Johnson & Johnson (HK) Ltd.
©2024 Hong Kong Journal of Paediatrics. All rights reserved. Developed and maintained by Medcom Ltd.