Clinical Analysis Of 36 Patients With Gitelman Syndrome And 1 Patient With SLC12A3/KCNJ1 Double Heterozygous Mutation

Background and objectGitelman Syndrome(GS)is an autosomal recessive renal tubular disease caused by the inactivation of the NCCT encoded by the mutation in the SLC12A3 gene.NCCT is a hydrochlorothiazide diuretic sensitive sodium chloride co-transporter,mainly expressed in the distal convoluted tubules of the kidney,responsible for the reabsorption of 5?10%of sodium ions filtered through the glomerular[1].The main manifestations of this disease are hypokalemia alkalosis,normal or partial hypotension,low urinary calcium and partial patients can appear hypomagnesemia.The disease is relatively rare while the genetic mutation and phenotypic heterogeneity of this disease are multifarious,so it's prone to be misdiagnosed and missed diagnosed in clinical practice.This study analyzed and summed up the clinical features of 36 cases with GS in order to enhance the cognition of this disease.Bartter's Syndrome(BS)is another hereditary tubular disease with phenotype similar to GS.This study also analyzed and summarized the clinical data of a patient with heterozygous mutations in both GS and BS pathogenic genes,whose phenotype was more similar to that of mild BS patients to explore the possible causes of the phenotype in this patient.MethodsClinical data of 36 patients with GS and one with SLC12A3/KCNJ1 double heterozygous mutation who were admitted to the Endocrinology Department of the First Affiliated Hospital of Zhengzhou University from January 2008 to January 2019 was collected,and the clinical characteristics,results of gene detection and the therapeutic schedules were analyzed retrospectively.Results(1)Among the patients with GS,22.2%(8/36 cases)had normal blood magnesium.Blood pressure was high in 11.1%(4/36 cases).(2)52.6%(10/19 cases)of the patients had hypoparathyroid function,and there was a significant positive correlation between blood magnesium and PTH(P<0.05).(3)Hyperglycemia was found in 61.1%(11/18 cases).19.4%(7/36 cases)of the patients had hyperuricemia.Thyroid abnormalities were presented in 30%(9/30)of the patients.(4)A total of 16 different mutations were detected in 36 GS patients,including 11 missense mutations,l deletion mutation,2 splicing mutations,1 insertion deletion mutation,1 transcoding mutation.Frequent mutations were p.T60M(2/9)and p.D486N(3/9).Four were newly discovered:c.2890C>T,p.Arg964Trp;c.257dupT,p.A8TGfs*2;c.2633+1-2633+2insT,Splicing;c.2549-18G>A,Splicing.(5)Special cases of gene test:One patient showed clinical symptoms and the laboratory examination in accordance with the performance of GS,but none of significant mutation sites was found in all exons of SLC12A3.One patient was found GS and BS pathogenic gene heterozygous mutations whose phenotype was closer to BS.(6)Phenotypic analysis:?Serum magnesium was an important factor affecting phenotype:Serum chloride and serum sodium in the group of normal blood magnesium were higher than those in low magnesium group(P<0.05).?Influence of genotype on phenotype:urinary calcium in the group with frequent mutation was higher than that in the group with non-frequent mutation.(7)The treatment of GS patients was mainly supplemented with Potassium chloride and Potassium Magnesium aspartate,at the same time,Spironolactone and/or non steroidal anti inflammatory drugs,such as Indomethacin and Ibuprofen were given orally.Conclusions(1)Hypomagnesemia might be the cause of decreased parathyroid function in some GS patients.(2)Even if there were hypertension or normal blood magnesium,the possibility of GS couldn't be ruled out.(3)GS phenotypes such as hypokalemia,metabolic alkalosis,hypomanesemia,and hypocalcinuria were not necessarily caused by exon mutations in the SLC12A3 gene.(4)The patient with SLC12A3/KCNJ1 double heterozygous mutation could present BS phenotypes such as hypokalemia,metabolic alkalosis,normal blood magnesium,normal urinary calcium,and kidney stones.