Gitelman syndrome (GS) is an autosomal recessive disease caused by inactivation of mutations in the SLC12A3 gene. It is characterized by hypopotassic metabolic alkalosis, hypomagnesemia, and hypouricemia . Approximate 140 different mutations in SLC12A3 has been associated to the pathogenesis of GS, including insertion mutations, splicing mutations, and missense mutations . GS can manifest as a variety of clinical symptoms. Mild symptoms include fatigue, nocturia, muscle weakness, while patients with severe symptoms can show hand-foot convulsions, paralysis, rhabdomyolysis, epilepsy, or fatal arrhythmia. Long-term complications can lead to calcification and choroidal calcification [7, 8]. Consumption of potassium and magnesium will prolong the duration of action potentials in cardiac muscle cells , which will subsequently lead to prolongation of QT interval in about 50% of children and increase the risk of arrhythmia . This shows that the clinical manifestations of children with GS are mostly non-specific symptoms. Therefore, children diagnosed with GS have a large misdiagnosis rate and missed diagnosis rate .
In the diagnosis of GS, it is necessary to distinguish it from Bartter syndrome (BS). In particular, type III Bartter syndrome caused by a mutation in the CLCNKB gene is similar to GS in clinical and laboratory tests, both of which have hypokalemia, renal potassium loss, hypochlorite metabolic alkalosis, RAAS activation, and normal blood pressure. However, other types of BS usually have an earlier age of onset and severe clinical symptoms. Relatively, GS is mild and has a late age of onset. Therefore, the main points of identification are the age of onset, the presence of hypocalcemia, hypomagnesemia, and whether they have combined delayed development. Although a few children with severe hypokalemia and hypomagnesemia may have growth retardation, the the growth and development of patients with GS are generally not affected.
The diagnosis of GS depends on clinical symptoms and laboratory tests. According to the consensus and guidance on Gitelman syndrome published in 2016 and the "Consensus of Experts in Diagnosis and Treatment of Gitelman Syndrome" published in 2017, the biallelic mutation of the SLC12A3 gene was used as diagnostic criteria [7,10]. This patient had hypokalemic metabolic alkalosis, hypomagnesemia, hypochloremia, hypocalciuria, RAAS activation, normal blood pressure, calcium/creatinine ratio <0.2, and no abnormalities in urinary ultrasound, consistent with GS clinical manifestations. Combined with genetic diagnosis, we found two heterozygous mutations in SLC12A3 gene, which further validates the diagnosis of Gitelman syndrome. The main pathogenic gene in GS is SLC12A3, which encodes a thiazide-sensitive Na+-Cl-cotransporter (NCC) located on the apical membrane of the first part of the renal tubules . Genetic screening of this patient revealed genetic mutations at two loci: c.248G> A (nucleotide 248 of the coding region was mutated from guanine to adenine), resulting in an amino acid change of p.R83Q (amino acid number 83 by The arginine mutation is glutamine), which was a missense mutation; the other mutationwas c.2875_2876del, which was a frameshift mutation and resulted in the amino acid change to p.R959Sfs * 11. The above mutations are preliminarily determined to be pathogenic mutations according to the ACMG guidelines, which have been recorded in the HGMD (The Human Gene Mutation Database) database. At the same time, the parents of the children were genetically sequenced. It was found that the parents carry different site mutations of the SLC12A3 gene, and the proband was a heterozygous mutation.
Although no effective cures for GS are currently availble, most patients have a good prognosis. In some cases, delayed growth and development may be caused by severe hypokalemia and hypomagnesemia. The main purpose of current treatments is to correct electrolyte disorders, reduce clinical symptoms. Individualized lifelong oral potassium and magnesium supplements are the main treatment for patients with GS. When persistent symptomatic hypokalemia occurs, potassium supplementation can be used together with potassium diuretics, renin angiotensin system blockers, or non-steroidal anti-inflammatory drugs [12,13,14]. In this case, the child had hypokalemia and hypomagnesemia that were difficult to correct by oral potassium and magnesium supplementation. Therefore, according to the guidelines, potassium diuretics and renin angiotensin system blockers were administrated at the same time. At the time of discharge, the blood potassium was 3.90 mmol/L and the blood magnesium was 0.72 mmol/L.
To sum up, this case report systematically analyzes the clinical and laboratory examination characteristics of children with GS.In addition, gene sequencingconfirms GS caused by SLC12A3 complex heterozygous mutations. Combined with previous domestic and foreign reports on GS, we believe that current case report of patient’s clinical characteristics, diagnosis and treatment ideas will improve clinicians the understanding of children's GS, thereby reducing the rate of misdiagnosis and missed diagnosis.