GS is a salt-losing tubulopathy with the clinical features of hypokalemic alkalosis, hypomagnesaemia and hypocalciuria. Chronic low potassium leads to symptoms of weakness, fatigue, thirst and the abnormal heart palpitation. Severe case can cause rhabdomyolysis, ventricular arrhythmias, or sudden cardiac arrest . GS is associated with dysfunction of NCCT encoded by SLC12A3 gene in the renal distal convoluted tubule (DCT). The decreased reabsorption of Na+ and Cl− leads to compensatory excessive exchange through Na+/K+ and Na+/H+ pump, and results in excessive K+ and H+ excretion and hypokalemic alkalosis. In a small minority of GS patients, mutations in the CLCNKB gene encoding the chloride channel ClC-Kb have been identified .
To our knowledge, this is the first time to report the novel c.1077 C > G (p.Asn359Lys) and c.1666 C > T (p.Pro556Ser) mutations of SLC12A3 and its relation with phenotypes. The phenotypes are more severe in patients with more than one mutated alleles, with lower serum potassium level, and more difficult to be corrected with potassium supplement [6, 11].
BS (especially type III) is the most important renal salt-wasting disease which should be considered as the differential diagnosis of GS. BS is also characterized by hypokalemia, metabolic alkalosis, polyuria, increased renin activity and aldosterone level, but without hypertension or edema. It exhibits the increased urinary calcium excretion, but rarely leads to nephrocalcinosis. BS is caused by mutations of NKCC2 (Na+-K+-2Cl− cotransporter) in the thick ascending limb (TAL) of Henle loop (Type 1 BS) , ROMK (outwardly rectifying potassium channel) (Type 2 BS), or CLCNKB (chloride channel) (Type 3 BS) which is a regulator of NKCC2. A minority of GS patients has been shown to have mutations of CLCNKB gene . Type 4 BS is induced by mutations of both the kidney-specific chloride channel ClC-Ka and ClC-Kb, leading to dysfunction of Cl− reabsorption. Activating mutations of calcium-sensing receptor (CaSR) suppresses the NKCC2 and ROMK expression to induce type 5 GS . The site of defect in BS is at the TAL of the Henle loop, whereas in GS is at the renal DCT . GS used to be thought as a mild type of BS. However, the pathogenesis and clinical characteristics are different. BS typically presents in infancy or early childhood, with more severe clinical manifestations and complications, such as severe electrolyte derangements, short stature, polyuria, and hypercalciuria induced nephrocalcinosis . GS usually shows hypomagnesaemia with increased urinary manganese excretion (FEMg > 4%), but lower urinary calcium excretion (uCa/uCr < 0.2) . Diuretic loading test using furosemide and hydrochlorothiazide is helpful to differ GS from BS .
Usually, hypocalciuria in GS is related to the increased calcium reabsorption in the proximal tubule and distal renal unit, which is caused by NCCT dysfunction . In this case, the proband exhibited hypokalemia, hypomagnesaemia, metabolic alkalosis, but with hypercalcuria, similar to the features of BS, which makes it confused for differential diagnosis. It is contradicted with the features of hypocalcuria in classic GS. Chronic renal potassium loss can cause renal tubular epithelial cell injury or vacuolar deformation, to reduce the reabsorption of calcium . In addition, loss-of-function of NCCT up-regulates the expression of intestinal calcium transporter, and increases calcium uptake in gut tract . Hypercalcemia inhibits PTH release by negative feedback. In reverse, the suppressed PTH level reduces the calcium reabsorption by the renal tubule, and increases urinary calcium excretion. This patient also has diabetes mellitus. Hyperglycemia causes osmotic diuresis to increase urinary calcium excretion. Increased urinary calcium excretion and chronic hypomagnesaemia are the causes of renal calcification. The relationship between mutated gene sites and urinary calcium levels has not been reported. It is unclear whether hypercalcuria is associated with three mutations of SLC12A3.
It is reported that GS patient have a tendency of glucose intolerance and impaired insulin secretion . Potassium plays an important role in the regulation of insulin release. Reduced extracellular potassium ion concentration could suppress the insulin secretion and release via ATP sensitive potassium channel on beta cells. Long-term low potassium and magnesium level is one of the factors of diabetes development. In addition, hyperaldosteronism was also reported to promote insulin resistance .
Studies have shown that GS can be combined with autoimmune diseases,such as Graves' disease, Hashimoto's thyroiditis, IgA nephropathy, Sjogren's syndrome, or latent autoimmune diabetes in adults (LADA) [22, 23].
The therapeutic strategy of GS focuses on the correction of electrolyte disturbance, especially potassium and magnesium replacement. The level of serum magnesium may affect the severity and effect of potassium supplement [6, 24]. Other options include the inhibitors for the secondary elevated renin-aldosterone system (RAAS), such as non-selective or selective aldosterone antagonist antisterone or eplerenone, or NaCl transporter blockers such as aminophenidine . Non-steroidal anti-inflammatory drugs (NASID) such as indomethacin can suppress renin secretion by inhibiting renal prostaglandin E2 (PGE2) synthesis, and ameliorate the up-regulation of aldosterone level induced by potassium supplement. It also could increase potassium level without worsening sodium and volume depletion in GS patients . However, the gastrointestinal side effect and interstitial renal damage make the application to be limited.