Clinical and genetic analysis of a case of Gitelman syndrome accompanied with Graves disease and adrenocortical adenoma: A case report.

RATIONALE: Gitelman syndrome (GS), also known as familial hypokalemia and hypomagnesemia, is a rare autosomal recessive inherited disease caused by primary renal desalinization caused by impaired reabsorption of sodium and chloride ions in the distal renal tubules. We report a case of clinical and genetic characteristics of GS accompanied with Graves disease and adrenocorticotrophic hormone (ACTH)-independent adrenocortical adenoma. PATIENT CONCERNS: The patient is a 45 year old female, was admitted to our hospital, due to a left adrenal gland occupying lesion as the chief complaint. DIAGNOSIS: The patient was finally diagnosed as GS with Graves disease and adrenocortical adenoma. INTERVENTIONS: Potassium magnesium aspartate (1788 mg/d, taken orally 3 times a day (supplement a few times a day, intake method, treatment duration). Contains 217.2 mg of potassium and 70.8 mg of magnesium, and potassium chloride (4.5 g/d, taken orally 3 times a day (supplement a few times a day, intake method, and treatment duration); Potassium 2356 mg), spironolactone (20 mg/d, taken orally once a day (supplement a few times a day, intake method, treatment duration). After 3 months of treatment, the patient's blood potassium fluctuated between 3.3-3.6 mmol/L, and blood magnesium fluctuated between 0.5-0.7 mmol/L, indicating a relief of fatigue symptoms. OUTCOMES: On the day 6 of hospitalization, the symptoms of dizziness, limb fatigue, fatigue and pain were completely relieved on patient. In the follow-up of the following year, no recurrence of the condition was found. LESSONS: The novel c.1444-10(IVS11)G > A variation may be a splicing mutation. The compound heterozygous mutations of the SLC12A3 gene may be the pathogenic cause of this GS pedigree.

Interpreting epigenetic causes of recurrent hypokalemia and seizures: Gitelman syndrome co-exist with pseudohypoparathyroidism type 1B.

We describe a unique case of 27-year-old male with Gitelman syndrome (GS) co-exist with pseudohypoparathyroidism type 1B (PHP1B). The patient presented with a 5-year history of seizures, tetany, and numbness of the extremities. Further examinations showed recurrent hypokalemia, inappropriate kaliuresis, hypocalcemia, hyperphosphatemia, and elevated PTH levels. A novel variant of autosomal recessive GS (p.Val287Met SLC12A3) and a novel 492.3Kb deletion containing the whole of STX16, were discovered by a whole-exome sequencing. Following the diagnosis, calcitriol, calcium, and potassium supplements were started. Hematuria calcium and phosphorus levels, as well as blood potassium levels, have recovered and remained within normal ranges after 3 years of follow-up. Our findings have important consequences for supporting the idea that heterozygosity for variants have effects on the patients' clinical performance with autosomal recessive inheritance disorders. Further study is need for the putative effects of the variant. Likewise, further investigation with regards to the gene-gene interaction relations between GS and other electrolyte imbalance disorders is warranted.

Potential low toxic alternative for Na-Cl cotransporter inhibition: A diuretic effect and mechanism study of Pyrrosia petiolosa.

BACKGROUND: Hydrochlorothiazide, a diuretic commonly used for the treatment of hypertension, is often associated with serious metabolic side effects. Pyrrosia petiolosa (Christ) Ching is a traditional Chinese medicine that possesses diuretic properties, without any obvious side effects. AIM: To evaluate the diuretic effect of P. petiolosa (Christ) Ching and to elucidate its underlying mechanism of action. METHODS: Extracts obtained from different polar components of P. petiolosa (Christ) Ching were analyzed for toxicity in a Kunming mouse model. The diuretic effects of the extracts were compared to that of hydrochlorothiazide in rats. In addition, compound isolation procedures, cell assays of Na-Cl cotransporter inhibition and rat diuretic test of monomeric compounds were conducted to identify the active ingredients in the extract. Subsequently, homology modeling and molecular docking were performed to explain the reason behind the diuretic activity observed. Finally, LC-MS analysis was used to elucidate the underlying mechanism of action of P. petiolosa (Christ) Ching. RESULTS: No toxicity was observed in mice administered P. petiolosa (Christ) Ching extracts. The ethyl acetate fraction showed the most significant diuretic effect. Similar results were obtained during the analysis for Na+ content in rat urine. Further separation of P. petiolosa (Christ) Ching components led to the isolation of methyl chlorogenate, 2',3'-dihydroxy propyl pentadecanoate, and ß-carotene. Results from cell assays showed that the Na-Cl cotransporter inhibitory activity of methyl chlorogenate was greater than that of hydrochlorothiazide. This result was again confirmed by the diuresis tests of monomeric compounds in rats. The molecular simulations explain the stronger interactions between the methyl chlorogenate and Na-Cl cotransporter. Of the compounds determined using LC-MS analysis, 185 were identified to be mostly organic acids. CONCLUSIONS: P. petiolosa possesses significant diuretic activities without any obvious toxicity, with least two possible mechanisms of action. Further study on this herb is warranted.

Long-Term Indomethacin Treatment in a Chinese Child with Gitelman Syndrome: Case Report and Literature Review on its Efficacy and Tolerance.

BACKGROUND Gitelman syndrome (GS) is a rare inherited autosomal recessive salt-losing renal tubulopathy. Early-onset GS is difficult to differentiate from Bartter syndrome (BS). It has been reported in some cases that cyclooxygenase (COX) inhibitors, which pharmacologically reduce prostaglandin E2(PGE2) synthesis, are helpful for GS patients, especially in children, but the long-term therapeutic effect has not yet been revealed. CASE REPORT A 4-year-old boy was first brought to our hospital for the chief concern of short stature and growth retardation. Biochemical tests demonstrated severe hypokalemia, hyponatremia, and hypochloremic metabolic alkalosis. The patient's serum magnesium was normal. He was diagnosed with BS and treated with potassium supplementation and indomethacin and achieved stable serum potassium levels and slow catch-up growth. At 11.8 years of age, the patient showed hypomagnesemia and a genetic test confirmed that he had GS with compound heterozygous mutations in the SLC12A3 gene. At the age of 14.8 years, when indomethacin had been taken for nearly 10 years, the boy reported having chronic stomachache, while his renal function remained normal. After proton pump inhibitor and acid inhibitor therapy, the patient's symptoms were ameliorated, and he continued to take a low dose of indomethacin (37.5 mg/d divided tid) with good tolerance. CONCLUSIONS Early-onset GS in childhood can be initially misdiagnosed as BS, and gene detection can confirm the final diagnosis. COX inhibitors, such as indomethacin, might be tolerated by pediatric patients, and long-term therapy can improve the hypokalemia and growth retardation without significant adverse effects.

Gitelman syndrome combined with diabetes mellitus: A case report and literature review.

RATIONALE: Gitelman syndrome (GS) is an uncommon autosomal recessive tubulopathy resulting from a functional deletion mutation in the SLC12A3 gene. Its onset is typically insidious and challenging to discern, and it is characterized by hypokalemia, metabolic alkalosis, and reduced urinary calcium excretion. There is limited literature on the diagnosis and management of GS in individuals with concomitant diabetes. PATIENT CONCERNS: A 36-year-old male patient with a longstanding history of diabetes exhibited suboptimal glycemic control. Additionally, he presented with concurrent findings of hypokalemia, hypomagnesemia, hypocalciuria, and metabolic alkalosis. DIAGNOSIS: Building upon the patient's clinical manifestations and extensive laboratory evaluations, we conducted thorough genetic testing, leading to the identification of a compound heterozygous mutation within the SLC12A3 gene. This definitive finding confirmed the diagnosis of GS. INTERVENTIONS: We have formulated a detailed medication regimen for patients, encompassing personalized selection of hypoglycemic medications and targeted electrolyte supplementation. OUTCOMES: Following 1 week of comprehensive therapeutic intervention, the patient's serum potassium level effectively normalized to 3.79 mmol/L, blood glucose parameters stabilized, and there was significant alleviation of clinical symptoms. LESSONS: GS has a hidden onset and requires early diagnosis and intervention based on patient related symptoms and laboratory indicators in clinical practice, and personalized medication plans need to be provided according to the specific situation of the patient.

Novel heterozygous mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome: A care-compliant case report.

RATIONALE: The diagnosis of Gentleman syndrome (GS) is usually delayed because the clinical symptoms are easily mistaken. PATIENT CONCERNS: A 19-year-old male patient was referred to endocrinology due to intermittent twitch of extremities for approximately 7 years. DIAGNOSES: The diagnosis of GS was made based on the laboratory and gene detection results. We identified 2 new variants in the SLC12A3 gene [c.857 A > C (exon7) and c.2089_2095del (exon17)] in his Asian family. INTERVENTIONS: The patient received the treatment of potassium chloride sustained release tablets, potassium magnesium aspartate and spironolactone. After given potassium supplement through enema, his serum potassium level was corrected to normal. OUTCOMES: The electrolyte imbalance including hypokalemia and hypomagnesemia were improved with a remission of the clinical manifestations. But the patient's condition still could not remain stable for his irregular oral potassium supplementation during the follow-up of nearly 3 months. LESSONS: Our finding broadens the variant spectrum of SLC12A3 and contributes to a more quickly genetic counseling. As a result, when a patient presents with persistent, unspecified, and inadequately treated hypokalemia, tests for GS should indeed be considered. For suspected cases of GS, genetic testing should always be considered in the diagnosis.

Identification of potential biomarkers and candidate therapeutic drugs for clear cell renal cell carcinoma by bioinformatic analysis and reverse network pharmacology.

This study aims to analyze the potential biomarkers using bioinformatics technology, explore the pathogenesis, and investigate potential Chinese herbal ingredients for the Clear cell renal cell carcinoma (ccRCC), which could provide theoretical basis for early diagnosis and effective treatment of ccRCC. The gene expression datasets GSE6344 and GSE53757 were obtained from the Gene Expression Omnibus database to screen differentially expressed genes (DEGs) involved in ccRCC carcinogenesis and disease progression. Enrichment analyses, protein-protein interaction networks construction, survival analysis and herbal medicines screening were performed with related software and online analysis platforms. Moreover, network pharmacology analysis has also been performed to screen potential target drugs of ccRCC and molecular docking analysis has been used to validate their effects. Total 274 common DEGs were extracted through above process, including 194 up-regulated genes and 80 down-regulated genes. The enrichment analysis revealed that DEGs were significantly focused on multiple amino acid metabolism and HIF signaling pathway. Ten hub genes, including FLT1, BDNF, LCP2, AGXT2, PLG, SLC13A3, SLC47A2, SLC22A8, SLC22A7, and SLC13A3, were screened. Survival analysis showed that FLT1, BDNF, AGXT2, PLG, SLC47A2, SLC22A8, and SLC12A3 were closely correlated with the overall survival of ccRCC, and AGXT2, SLC47A2, SLC22A8, and SLC22A7 were closely associated with DFS. The potential therapeutic herbs that have been screened were Danshen, Baiguo, Yinxing, Huangqin and Chuanshanlong. The active compounds which may be effective in ccRCC treatment were kaempferol, Scillaren A and (-)-epigallocatechin-3-gallate.

Spectrum of variants in a large Chinese Gitelman syndrome cohort.

Gitelman syndrome (GS) is caused by SLC12A3 biallelic variants. A previous study showed that large rearrangements (LRGs) of SLC12A3 accounted for the low sensitivity of genetic testing. However, a systematic screening for LRGs in Chinese GS patients is lacking. Massively parallel sequencing (MPS) and multiplex ligation-dependent probe amplification (MLPA) were performed to sequence the genomic DNA of patients with clinically diagnosed GS. Of 165 index cases, MPS identified 151 cases with two or more affected alleles and 14 cases with one variant allele. LRGs were detected by MLPA in 20 out of 27 cases, including 15 cases with suspected LRGs by MPS. Among these 20 cases with LRGs, the results of MPS and MLPA were identical in only 8 cases. Additional LRGs in 6 cases were detected by MLPA alone. In 6 cases, E4_E6del was identified by MPS, while E4_E5del and Intron6del were identified by MLPA. Among the 102 distinct variants, 30 are novel. LRGs were found in 20 cases (12.1%). LRGs were found in 12.1% of our Chinese GS patients cohort. We show that MPS and MLPA are two complementary techniques with the ability to improve the diagnostic yield of GS.

Case report: Gitelman syndrome with diabetes: Confirmed by both hydrochlorothiazide test and genetic testing.

RATIONALE: Gitelman syndrome (GS) is an autosomal recessive tubulopathy caused by mutations of the SLC12A3 gene. It is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. Hypokalemia, hypomagnesemia, and increased renin-angiotensin-aldosterone system (RAAS) activity can cause glucose metabolism dysfunction. The diagnosis of GS includes clinical diagnosis, genetic diagnosis and functional diagnosis. The gene diagnosis is the golden criterion while as functional diagnosis is of great value in differential diagnosis. The hydrochlorothiazide (HCT) test is helpful to distinguish GS from batter syndrome, but few cases have been reported to have HCT testing. PATIENT CONCERNS: A 51-year-old Chinese woman presented to emergency department because of intermittent fatigue for more than 10 years. DIAGNOSES: Laboratory test results showed hypokalemia, hypomagnesemia, hypocalciuria and metabolic alkalosis. The HCT test showed no response. Using next-generation and Sanger sequencing, we identified 2 heterozygous missense variants (c.533C > T:p.S178L and c.2582G > A:p.R861H) in the SLC12A3 gene. In addition, the patient was diagnosed with type 2 diabetes mellitus 7 years ago. Based on these findings, the patient was diagnosed with GS with type 2 diabetic mellitus (T2DM). INTERVENTIONS: She was given potassium and magnesium supplements, and dapagliflozin was used to control her blood glucose. OUTCOMES: After treatments, her fatigue symptoms were reduced, blood potassium and magnesium levels were increased, and blood glucose levels were well controlled. LESSONS: When GS is considered in patients with unexplained hypokalemia, the HCT test can be used for differential diagnosis, and genetic testing can be continued to confirm the diagnosis when conditions are available. GS patients often have abnormal glucose metabolism, which is mainly caused by hypokalemia, hypomagnesemia, and secondary activation of RAAS. When a patient is diagnosed with GS and type 2 diabetes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) can be used to control the blood glucose level and assist in raising blood magnesium.

A case report of Gitelman syndrome in children.

RATIONALE: Giltelman syndrome (GS) is an autosomal recessive infectious disease, which is caused by the mutation of SLC12A3 gene encoding thiazide diuretic sensitive sodium chloride cotransporter located in the distal convoluted tubule of the kidney. PATIENT CONCERNS: A 7-year-old and 3-month-old male patient has poor appetite, slow growth in height and body weight since the age of 3, body weight: 16 kg (-3 standard deviation), height: 110 cm (-3 standard deviation), normal exercise ability and intelligence. One year ago, he was diagnosed with hypokalemia. After potassium supplement treatment, the blood potassium returned to normal. The patient developed abdominal pain, vomiting, limb weakness, and tetany 1 day before admission. DIAGNOSES: After admission examination, the patient was found to have hypokalemia (2.27-2.88 mmol/L), hypomagnesemia (0.47 mmol/L), hypophosphatemia (1.17 mmol/L), hypocalcemia (1.06 mmol/24 hours), and metabolic alkalosis (PH 7.60). The blood pressure is normal, and the concentration of aldosterone is 791.63 pg/mL. The adrenocorticotropic hormone and cortisol detected at 8 am are 4.95 pmol/L and 275.09 nmol/L, respectively. Twenty-four hours of urine potassium is 32.52 mmol. Gene sequencing results showed 2 pathogenic variants in the GS-related SLC12A3 gene, which are related to the phenotype of the subject. INTERVENTIONS: After admission, the patients were given potassium and magnesium supplements, as well as oral spironolactone. The symptoms of limb weakness and tetany were significantly relieved. After discharge, the patients continued to maintain treatment to keep the blood potassium at more than 3.0 mmol/L, and the blood magnesium at more than 0.6 mmol/L. OUTCOMES: Follow-up at 1 month after discharge, in the patient's self-description, he had no symptoms such as limb weakness and tetany, and his height was increased by 1 cm and the body weight increased by 1.5 kg. LESSONS: For patients with hypokalemia, hypomagnesemia, and metabolic alkalosis, the possibility of GS should be given priority. After the diagnosed by gene sequencing of SLC12A3 gene, potassium and magnesium supplementation could significantly improve symptoms.

High-salt diet accelerates bone loss accompanied by activation of ion channels related to kidney and bone tissue in ovariectomized rats.

Excessive salt intake can induce a variety of diseases, such as hypertension, cardiovascular disease, kidney disease and so on，it is also one of the factors promoting bone resorption. The mechanism of osteoporosis-induced exacerbations of high salt diet is not well-defined. In this study, we used ovariectomized 6-month-old Sprague Dawley rats to construct a high bone turnover model, and then administrated with high sodium chloride diet (2.0% w/w NaCl, 8.0% w/w NaCl) for 12 weeks to observe the effect of high salt diet on bone metabolism. The results showed that high salt diet could lead to the destruction of bone microstructure, promote the excretion of urinary calcium and phosphorus and accelerate the bone turnover, as well as cause the pathologic structural abnormalities in renal tubular. At the same time, it was accompanied by the up-regulated expression of the epithelial sodium channel (ENaCα), voltage-gated chloride channels (ClC)- 3 and the down-regulated expression of Na-Cl cotransporter (NCC), sodium calcium exchanger (NCX1) in femoral tissue and renal tubules. These findings confirm that high salt diet can destroy the microstructure of bone by increasing bone resorption and affect some ion channels of bone tissue and renal tubule in ovariectomized rats.

Potassium and the kidney: a reciprocal relationship with clinical relevance.

By controlling urinary potassium excretion, the kidneys play a key role in maintaining whole-body potassium homeostasis. Conversely, low urinary potassium excretion (as a proxy for insufficient dietary intake) is increasingly recognized as a risk factor for the progression of kidney disease. Thus, there is a reciprocal relationship between potassium and the kidney: the kidney regulates potassium balance but potassium also affects kidney function. This review explores this relationship by discussing new insights into kidney potassium handling derived from recently characterized tubulopathies and studies on sexual dimorphism. These insights reveal a central but non-exclusive role for the distal convoluted tubule in sensing potassium and subsequently modifying the activity of the sodium-chloride cotransporter. This is another example of reciprocity: activation of the sodium-chloride cotransporter not only reduces distal sodium delivery and therefore potassium secretion but also increases salt sensitivity. This mechanism helps explain the well-known relationship between dietary potassium and blood pressure. Remarkably, in children, blood pressure is related to dietary potassium but not sodium intake. To explore how potassium deficiency can cause kidney injury, we review the mechanisms of hypokalemic nephropathy and discuss if these mechanisms may explain the association between low dietary potassium intake and adverse kidney outcomes. We discuss if potassium should be repleted in patients with kidney disease and what role dietary potassium plays in the risk of hyperkalemia. Supported by data and physiology, we reach the conclusion that we should view potassium not only as a potentially dangerous cation but also as a companion in the battle against kidney disease.

Novel SLC12A3 mutation in Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive disease characterised by the presence of hypokalaemic metabolic alkalosis with hypomagnesaemia and hypocalciuria. The prevalence of this disease is 1-10/40 000. GS is usually associated with mild and non-specific symptoms and many patients are only diagnosed in adulthood. The disease is caused by mutations in the SLC12A3 gene. We present the case of a 49-year-old man referred to a nephrology appointment due to persistent hypokalaemia and hypomagnesaemia. Complementary evaluation revealed hypokalaemia, hypomagnesaemia, metabolic alkalosis, hyperreninaemia, increased chloride and sodium urinary excretion, and reduced urinary calcium excretion. Renal function, remainder serum and urinary ionogram, and renal ultrasound were normal. A diagnosis of GS was established and confirmed with genetic testing which revealed a novel mutation in SLC12A3 (c.1072del, p.(Ala358Profs*12)). This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS.

Long-term Clinical Course after Living Kidney Donation by a Patient with Gitelman Syndrome Harboring a Compound Heterozygous Mutation of the SLC12A3 Gene.

The eligibility for kidney donation and long-term post-donation renal prognosis of patients with Gitelman syndrome (GS) are unknown. We herein report a 44-year-old woman with GS who donated her kidney for transplant. A gene sequence analysis revealed compound heterozygous mutations of T180K and L858H in the SLC12A3 gene. Since transplantation, the renal function and serum potassium and magnesium levels of the donor and recipient have remained stable for seven years with careful monitoring and supplementation. Patients with asymptomatic GS who have no complications can be considered eligible to donate their kidney for transplant with proper monitoring after transplantation.

Potassium Effects on NCC Are Attenuated during Inhibition of Cullin E3-Ubiquitin Ligases.

The thiazide-sensitive sodium chloride cotransporter (NCC) plays a vital role in maintaining sodium (Na+) and potassium (K+) homeostasis. NCC activity is modulated by with-no-lysine kinases 1 and 4 (WNK1 and WNK4), the abundance of which is controlled by the RING-type E3 ligase Cullin 3 (Cul3) and its substrate adapter Kelch-like protein 3. Dietary K+ intake has an inverse correlation with NCC activity, but the mechanism underlying this phenomenon remains to be fully elucidated. Here, we investigated the involvement of other members of the cullin family in mediating K+ effects on NCC phosphorylation (active form) and abundance. In kidneys from mice fed diets varying in K+ content, there were negative correlations between NCC (phosphorylated and total) and active (neddylated) forms of cullins (Cul1, 3, 4, and 5). High dietary K+ effects on phosphorylated NCC were attenuated in Cul3 mutant mice (CUL3-Het/Δ9). Short-term (30 min) and long-term (24 h) alterations in the extracellular K+ concentration did not affect cullin neddylation levels in ex vivo renal tubules. In the short term, the ability of high extracellular K+ to decrease NCC phosphorylation was preserved in the presence of MLN4924 (pan-cullin inhibitor), but the response to low extracellular K+ was absent. In the long term, MLN4924 attenuated the effects of high extracellular K+ on NCC phosphorylation, and responses to low extracellular K+ were absent. Our data suggest that in addition to Cul3, other cullins are involved in mediating the effects of K+ on NCC phosphorylation and abundance.

Identification of compound mutations of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome exhibiting Bartter syndrome-liked phenotypes.

BACKGROUND: Gitelman syndrome is a rare salt-losing renal tubular disorder associated with mutation of SLC12A3 gene, which encodes the Na-Cl co-transporter (NCCT). Gitelman syndrome is characterized by hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and renin-angiotensin-aldosterone system (RAAS) activation. Different SLC12A3 variants may lead to phenotypic variability and severity. METHODS: In this study, we reported the clinical features and genetic analysis of a Chinese pedigree diagnosed with Gitelman syndrome. RESULTS: The proband exhibited hypokalaemia, hypomagnesemia, metabolic alkalosis, but hypercalciuria and kidney stone formation. The increased urinary calcium excretion made it confused to Bartter syndrome. The persistent renal potassium wasting resulted in renal tubular lesions, and might affect urinary calcium reabsorption and excretion. Genetic analysis revealed mutations of SLC12A3 gene with c.433C > T (p.Arg145Cys), c.1077C > G (p.Asn359Lys), and c.1666C > T (p.Pro556Ser). Potential alterations of structure and function of NCCT protein due to those genetic variations of SLC12A3 are predicted. Interestingly, one sibling of the proband carried the same mutant sites and exhibited similar clinical features with milder phenotypes of hypokalemia and hypomagnesemia, but hypocalciuria rather than hypercalciuria. Family members with at least one wild type copy of SLC12A3 had normal biochemistry. With administration of spironolactone, potassium chloride and magnesium supplement, the serum potassium and magnesium were maintained within normal ranges. CONCLUSIONS: In this study, we identified compound mutations of SLC12A3 associated with varieties of clinical features. Further efforts are needed to investigate the diversity in clinical manifestations of Gitelman syndrome and its correlation with specific SLC12A3 mutations.

Outcome of twin pregnancy in a patient with Gitelman syndrome: a case report and literature review.

Gitelman syndrome (GS) is a rare autosomal-recessive disease characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria. The impact of GS to pregnant and fetus is not wellknown, with few reports until now and no report about twin pregnancy and GS. We report the successful outcome of monochorionic twin pregnancy in a patient with GS. Oral or intravenously potassium chloride and magnesium citrate were prescribed. The course of the pregnancy was uneventful and the patient remained asymptomatic despite persistent hypokalemia. At 36+4 weeks of gestation, two female babies were delivered, weighing 2,380 and 2,210 g respectively. SLC12A3 gene analysis in mother and two babies revealed heterozygous mutations at 988 ATA codon in exon 26, which convert isoleucine to threonine (I988T). The mother and the twins are all in good health condition during three years follow-up. Close fetal serial surveillance, frequent electrolyte evaluation and adequately supplement with potassium and magnesium should be required to prevent obstetrical and fetal complications in a patient with GS. Management by multidisciplinary team is critical to optimizing outcomes for mother and fetus.

Type 2 diabetes mellitus caused by Gitelman syndrome-related hypokalemia: A case report.

INTRODUCTION: Gitelman syndrome (GS) is an autosomal-recessive disease caused by SLC12A3 gene mutations. It is characterized by hypokalemic metabolic alkalosis in combination with hypomagnesemia and hypocalciuria. Recently, patients with GS are found at an increased risk for developing type 2 diabetes mellitus (T2DM). However, diagnosis of hyperglycemia in GS patients has not been thoroughly investigated, and family studies on SLC12A3 mutations and glucose metabolism are rare. Whether treatment including potassium and magnesium supplements, and spironolactone can ameliorate impaired glucose tolerance in GS patients, also needs to be investigated. PATIENT CONCERNS: We examined a 55-year-old Chinese male with intermittent fatigue and persistent hypokalemia for 17 years. DIAGNOSES: Based on the results of the clinical data, including electrolytes, oral glucose tolerance test (OGTT), and genetic analysis of the SLC12A3 gene, GS and T2DM were newly diagnosed in the patient. Two mutations of the SLC12A3 gene were found in the patient, one was a missense mutation p.N359K in exon 8, and the other was a novel insert mutation p.I262delinsIIGVVSV in exon 6. SLC12A3 genetic analysis and OGTT of 9 other family members within 3 generations were also performed. Older brother, youngest sister, and son of the patient carried the p.N359K mutation in exon 8. The older brother and the youngest sister were diagnosed with T2DM and impaired glucose tolerance by OGTT, respectively. INTERVENTIONS: The patient was prescribed potassium and magnesium (potassium magnesium aspartate, potassium chloride) oral supplements and spironolactone. The patient was also suggested to maintain a high potassium diet. Acarbose was used to maintain the blood glucose levels. OUTCOMES: The electrolyte imbalance including hypokalemia and hypomagnesemia, and hyperglycemia were improved with a remission of the clinical manifestations. CONCLUSION: GS is one of the causes for manifestation of hypokalemia. SLC12A3 genetic analysis plays an important role in diagnosis of GS. Chinese male GS patients characterized with heterozygous SLC12A3 mutation should be careful toward occurrence of T2DM. Moreover, the patients with only 1 SLC12A3 mutant allele should pay regular attention to blood potassium and glucose levels. GS treatment with potassium and magnesium supplements, and spironolactone can improve impaired glucose metabolism.

Clinical and laboratory features of female Gitelman syndrome and the pregnancy outcomes in a Chinese cohort.

AIM: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients. METHODS: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed. RESULTS: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe. CONCLUSION: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester.

Gitelman syndrome associated with chondrocalcinosis and severe neuropathy: a novel heterozygous mutation in SLC12A3 gene.

Gitelman syndrome (GS) is an inherited salt-wasting tubulopathy characterized by hypocalciuria, hypokalemia, hypomagnesemia and metabolic alkalosis, due to inactivating mutations in the SLC12A3 gene. Symptoms may be systemic, neurological, cardiovascular, ophthalmological or musculoskeletal. We describe a 70 year-old patient affected by recurrent arthralgias, hypoesthesia and hyposthenia in all 4 limbs and severe hypokalemia, complicated by atrial flutter. Moreover, our patient reported eating large amounts of licorice, and was treated with medium-high dosages of furosemide, thus making diagnosis very challenging. Genetic analysis demonstrated a novel heterozygous mutation in the SLC12A3 gene; therefore, we diagnosed GS and started potassium and magnesium replacement. GS combined with chondrocalcinosis and neurological involvement is quite common, but this is the first case of an EMG-proven severe neuropathy associated with GS. Herein, we underline the close correlation between hypomagnesemia, chondrocalcinosis and neurological involvement. Moreover, we report a new heterozygous mutation in exon 23 (2738G>A), supporting evidence of a large genetic heterogeneity in this late-onset congenital tubulopathy.