Analysis Of Clinical Phenotypes And Genotypes Of Three Patients With Gitelman Syndrome And Comparison Of Literature Cases

Research ObjectiveBy analyzing the clinical characteristics and genotype results of three patients with Gitelman Syndrome（GS）,the gene mutation types and differences in blood potassium and magnesium of GS patients in Chinese databases（China National Knowledge Network and Wanfang database）were compared and analyzed.To explore the phenotypic heterogeneity of GS and the relationship between clinical phenotype and genotype,in order to improve the clinical understanding of GS and reduce missed diagnosis and misdiagnosis.Research methodsClinical data of patients clinically diagnosed with GS admitted to the First Affiliated Hospital of Guangzhou Medical University from 2012 to 2022 were collected.High-throughput sequencing technology was used to conduct gene sequencing of patients,and GS patients with clear genetic diagnosis（n=3）were screened out,and their initial symptoms,clinical manifestations,signs,concomitants,biochemical characteristics and genetic characteristics were analyzed.Using"Gitelman"as the title,the cases（N=233）identified by genetic diagnosis as GS in CNKI.com and Wanfang database from 2012 to 2022 were retrieved for analysis,and the differences in gender,age and gene mutation types of the three patients with GS in this study were compared.The blood potassium and blood magnesium of patients with different gene mutations were compared and analyzed.ResultsIn this study,the general information of three patients with GS（C₁,C₂,C₃）was as follows:（1）C₁:female,onset age was 15 years,course of disease was 4 months,BMI was 22.37kg/m²,blood pressure was normal,and no obvious clinical symptoms.（2）C₂:Female,onset age was 59 years,course of disease was 2 years,BMI was20.31kg/m²,blood pressure was normal,the main clinical manifestations were limb weakness;（3）C₃:Male,onset age was 25 years,course of disease was 14 years,had been diagnosed as Bartter Syndrome（BS）for a long time,BMI was 21.06kg/m²,blood pressure was normal,clinical symptoms were mainly manifested as weakness of limbs,dry mouth,polydipsia,polyuria,palpitation,chest tightness.In terms of laboratory examination,hypokalemia was associated with renal hyperkalemia（3/3）,increased activity of the renin-angiotensin-aldosterone system（3/3）,metabolic alkalosis（2/3）,hypomagnesium（2/3）,hypocalcium（1/3）,and renal loss of chlorine（2/3）in the three patients.C₂combined with abnormal glucose metabolism;C₃combined with abnormal glucose metabolism and a small amount of albuminuria,the urinary protein quantification was 0.85g/24h.In terms of imaging examination,no obvious arrhythmia was observed in the electrocardiogram of the three patients,and the QT interval was normal.C₂thyroid color ultrasound indicated bilateral thyroid nodules.C₃color ultrasound of urinary system indicated multiple small cysts and small stones in both kidneys.In terms of genetic testing,SLC12A3 gene mutations were detected in all three patients,among which C₁and C₂were SLC12A3 gene complex heterozygous mutations,and C₃was SLC12A3 gene single heterozygous mutations.There were five related gene mutation sites in the three patients,including four missense mutations（p.T60M、p.G460A、p.R83W、p.R871H）and one intron mutation（c.602-16G>A）.C₁carries a complex heterozygous mutation of p.T60M and p.G460A,among which p.T60M is one of the most common pathogenic mutation sites in Chinese,and p.G460A mutation is a novel pathogenic allele in SLC12A3 gene reported by our team for the first time.In terms of treatment,the symptoms of the three patients were relieved after oral and intravenous potassium supplementation,combined with potassium magnesium aspartate,spironolactone,fosinopril and other treatment regiments.When C₁and C₂were discharged,the blood potassium level increased to the normal level.Spironolactone was stopped due to the side effect of male breast development in C₃,and the use of spironolactone was resumed after Raloxifene hydrochloride tablets were used to antagonize estrogen.The blood potassium level at discharge was2.30mmol/L.And other comorbid diseases should be treated accordingly.The search results showed that a total of 233 GS patients with complete clinical data were eligible for inclusion in the analysis from 2012 to 2022.Among them,the age of onset ranged from 2 years old to 75 years old.46 patients with GS were younger than 18 years old,and the mean blood potassium and magnesium levels were2.57mmol/L,0.59mmol/L,and 54 patients with normal magnesium levels.There were154 complex heterozygous mutations,28 homozygous mutations,20multiheterozygous mutations,and 31 single heterozygous mutations.Further analysis showed that male and low magnesium GS patients had lower blood potassium level（P<0.05）,and adult and female GS patients had lower blood magnesium level（P<0.05）,and there was no statistical significance in blood potassium and blood magnesium levels among different gene mutation types（P>0.05）.Conclusion1.The clinical manifestations of GS are lack of specificity,and hypomagnesemia does not seem to be a specific manifestation of this disease;2.A variety of metabolic abnormalities and target organ damage may exist in patients with GS syndrome at the time of diagnosis,which requires attention,timely screening and treatment;3.Three patients in this study had five different SLC12A3 gene mutations,among which p.G460A mutation was reported for the first time.The discovery of the mutation site of this pathogenic gene enriched the gene mutation database of GS;4.The degree of potassium and magnesium electrolyte disturbance may have a certain correlation with gender,but not with the mutant genotype.