miR-155 and miR-103 are multifunctional miRNAs known to be involved in Angiotensin II (Ang II) signaling linked with hypertension and cardiovascular remodeling, although their role is controversial and not completely clarified. Gitelman syndrome (GS), rare genetic tubulopathy, represents a human model of an endogenous Ang II signaling antagonism and GS patients are in fact protected from Ang II-mediated cardiovascular remodeling. This study aimed to compare the expression of miR-155 and miR-103 in patients with GS vs. healthy controls. Sixteen patients with GS patients and 21 age- and sex-matched healthy controls were recruited from an active cohort at the Nephrology Unit of Padua University Hospital and among volunteers, respectively. The specific miRNA population was isolated from plasma, and miR-155 and miR-103 were then quantified using droplet PCR and Taqman miRNA Assays and compared using the Mann-Whitney U test. In GS patients, expression of miR-155 (528.7 vs 64.40 copies/sample, p=0.0015) and miR-103 (80.25 vs 23.94 copies/sample, p=0.0034), were significantly higher compared to the control group. This is the first study investigating circulating miRNAs in GS patients. The difference in expression levels of miR-155 and miR-103 in these patients compared to healthy subjects suggests that these miRNAs may be associated with mechanisms contributing to their well-established protection from Ang II-mediated cardiovascular remodeling.

Bartter syndrome (BS) type 3 typically presents in childhood and is caused by defects in NaCl transporters of the thick ascending limb of the loop of Henle. We report a 66‐year‐old woman with asymptomatic but severe hypokalemia (2.0 mmol/L), metabolic alkalosis, and hyperreninemic hyperaldosteronism. Initial clinic blood pressure was 157/88 mmHg, but repeated office and home measurements were ~120/70 mmHg, consistent with white‐coat hypertension. Imaging excluded renovascular disease. Sequential diuretic testing supported BS physiology: a thiazide loading test increased fractional excretion of chloride (FECl) from 0.46% to 3.88% (ΔFECl 3.4%), exceeding the 2.3% cutoff that argues against Gitelman syndrome; a furosemide test showed chloride reabsorption of 10.1%, indicating a profound loop‐segment defect, even lower than values commonly reported in BS3. Targeted next‐generation sequencing identified a homozygous CLCNKB stop‐gain variant (c.1830G >A; p.Trp610Ter), confirming BS type 3. High‐dose potassium chloride (9.9 g/day) failed to correct hypokalemia, whereas low‐dose enalapril plus spironolactone normalized serum potassium (4.0 mmol/L) without persistent hypotension. The urine calcium/creatinine ratio was borderline‐normal (0.65 mmol/mmol), rather than hypocalciuric. This case suggests that BS3 should remain in the differential diagnosis of refractory hypokalemia in older adults and highlights the diagnostic value of physiology‐guided diuretic testing combined with genetic analysis, as well as the potential efficacy of low‐dose ACE inhibitor plus mineralocorticoid receptor antagonist therapy when potassium supplementation alone is insufficient.

Mycobacterium shimoidei is a rare, nontuberculous mycobacterium that predominantly causes pulmonary disease mimicking pulmonary tuberculosis. Fewer than 50 cases have been reported worldwide, with only two cases previously published from Germany. Known risk factors include structural lung disease and immunosuppression. A 37-year-old female patient with anorexia nervosa (BMI 14.5kg/m2) and Gitelman syndrome, presented with general deterioration of condition and B symptoms. On admission, she displayed a high fever, hypotension and tachycardia. Chest imaging showed an inflamed large left upper lobe cavitary lesion and the patient was examined for Mycobacterium tuberculosis (tbc) pneumonia. Microscopy showed acid-fast bacilli but PCR was negative for tbc. The subsequent amplification of the gene for 16S RNA and its analysis by next generation sequencing (NGS) revealed M. shimoidei. Primarily based on literature research and later on antimicrobial susceptibility testing (AST), the patient was started on a combination therapy with Clarithromycin, Ethambutol and Rifabutin for a planned total of 12months. She could be discharged after defeverescence and further clinical improvement but was regularly followed up as an outpatient. After terminating therapy, the patient showed complete radiological regression of pneumonia and clinical remission. This case adds to the limited literature on Mycobacterium shimoidei pulmonary disease and supports its role as a clinically relevant cause of cavitary nontuberculous mycobacterial infection. Severe anorexia nervosa may represent a predisposing condition as it might be associated with structural lung diseases. The case further underscores the importance of next-generation sequencing for the identification of rare NTM species.

Gitelman syndrome (GS) is a rare inherited renal salt‐wasting tubulopathy characterized by hypokalemia, hypomagnesemia, and hypocalciuria. Its nonspecific presentation often overlaps with that of more common pediatric conditions, leading to delayed diagnosis, particularly in resource‐limited settings. We report an 11‐year‐old boy who presented with progressive weight loss, polyuria, polydipsia, and salt craving. His course was complicated by recurrent episodes of severe hypokalemia and hypomagnesemia, and he was initially evaluated for diabetes mellitus, other endocrine disorders, chronic infections such as tuberculosis, and malnutrition without a definitive diagnosis. During the index admission, he developed acute worsening of muscle weakness associated with severe hypokalemia and hypomagnesemia and biochemical findings consistent with renal salt wasting, supporting a diagnosis of GS in the absence of genetic testing. Management with correction of hypovolemia, electrolyte supplementation, liberal salt intake, and nutritional support led to marked clinical improvement and stabilization of biochemical abnormalities on follow‐up. This case highlights the importance of maintaining a high index of suspicion for GS in children presenting with polyuria, polydipsia, salt craving, and unexplained electrolyte disturbances, particularly in resource‐limited settings.

This study aimed to identify mutations in the SLC12A3 gene and investigate their role in the pathogenesis of Gitelman syndrome. Sanger sequencing of the SLC12A3 gene was performed using samples from a patient clinically suspected of having Gitelman syndrome, who was admitted to the Department of Endocrinology and Metabolism at Shanghai Fengxian District Central Hospital in August 2024. Upon identification of mutations, the relevant exons were sequenced in her first-degree relatives. Functional predictions of the protein were made using CADD, DANN, MetaSVM, Polyphen2, SIFT, and M-CAP software. A previously unreported missense variant, NM_000339:c.704C>A (p.Thr235Lys), located in exon 16 of SLC12A3, was identified in homozygosity in the proband and in heterozygosity in her daughter. This mutation was absent in all control individuals. Multiple prediction tools consistently indicated that the mutation likely disrupts gene/protein structure or function. The c.704C>A mutation in exon 16 of SLC12A3 is a novel pathogenic variant contributing to the development of Gitelman syndrome.

WCN26-4001 A Case of Gitelman Syndrome Complicated by Familial Chronic Intestinal Pseudo-Obstruction and Refractory Electrolyte Imbalance

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disorder caused by SLC12A3 gene variants. This study aimed to retrospectively analyze the clinical and genetic characteristics of pediatric GS patients and validate the function of a novel splicing variant. METHODS: Thirty genetically confirmed GS patients admitted to the Children’s Hospital of Nanjing Medical University between August 2017 and October 2025 were enrolled. We systematically reviewed clinical data, biochemical profiles, and SLC12A3 variants. We performed Minigene splicing analysis to verify the functional impact of the novel intronic variant c.1925 + 5G > T (NM_000339.3). RESULTS: All 30 patients presented with hypokalemia, and 90% (27/30) had hypomagnesemia. Fatigue (43.3%, 13/30) and short stature (36.7%, 11/30) were the most common clinical manifestations. A total of 37 SLC12A3 variants were identified, including 20 missense variants (54%), eight splicing variants (21.6%), six frameshift variants (16.2%), one synonymous variant, one deletion, and one duplication. We discovered four novel variants: c.2531T > G (NM_000339.3) (p.(Leu844Arg)), c.1925 + 5G > T(NM_000339.3), c.2960_2962dup(NM_000339.3) (p.(Ser987_Ser988insCys)), and p.(Phe535Cysfs*108). Minigene splicing assay confirmed that c.1925 + 5G > T induced complete skipping of exon 15, leading to in vitro validated truncated mRNA due to abnormal splicing of the SLC12A3 transcript. CONCLUSIONS: Pediatric GS presents with an insidious onset, and fatigue and short stature are the most common clinical manifestations in this single-center cohort. SLC12A3 variants are highly heterogeneous, with p.(Asp486Asn) and p.(Thr60Met) being frequent hotspots in the Chinese pediatric population. The novel splicing variant c.1925 + 5G > T contributes to GS pathogenesis by disrupting mRNA splicing. This study expands the SLC12A3 variant spectrum and provides clinical and experimental evidence for the early diagnosis and genetic counseling of pediatric GS.

Gitelman syndrome (GS) is an autosomal recessive salt-losing tubulopathy caused by biallelic SLC12A3 variants. However, 10-30% of patients with an obvious clinical and biochemical GS phenotype carry only a single detectable variant on routine genetic testing. In such cases, identification of a heterozygous pathogenic variant does not confirm but strongly supports the clinical diagnosis, as the second allele likely remains undetected due to deep intronic mutations, copy number variations, or other non-canonical variants. We report a 5-year-old boy with classic GS features: recurrent hypokalemia and hypomagnesemia unmasked during intercurrent illnesses, metabolic alkalosis (pH 7.47, HCO₃⁻ 30.5 mmol/L), renal potassium wasting (fractional excretion of potassium 29.7%), hypocalciuria (urine calcium-to-creatinine ratio 0.07), and hyperreninemic hyperaldosteronism. Despite this robust phenotype, genetic testing identified only a single heterozygous pathogenic splice-site variant in SLC12A3 (c.1180+1G>T), inherited from the unaffected mother; additionally, a variant of uncertain significance in ATP6V0A4 (c.842G>A; p.Arg281His) was inherited from the healthy father. With potassium and magnesium supplementation, electrolyte balance normalized and catch-up growth was achieved over 5 years of follow-up. In patients with an unequivocal GS phenotype, a monoallelic finding supports rather than refutes the diagnosis and should prompt extended genetic analysis, including deep intronic sequencing and CNV assessment, to identify the missing second allele.

ABSTRACTGitelman syndrome (GS) is a rare autosomal recessive tubulopathy characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. A 27‐year‐old woman presented with a witnessed syncopal episode, progressive weakness, and nausea. She reported a 3‐year history of muscle cramps, paresthesias, salt craving, and nocturia, with only transient correction of hypokalemia despite supplementation. Examination showed orthostatic hypotension and proximal muscle weakness, and ECG revealed flattened T and prominent U waves. Laboratory tests demonstrated severe hypokalemia (2.7 mmol/L), metabolic alkalosis, hypomagnesemia, renal potassium wasting, hypocalciuria, elevated renin and aldosterone, and a negative diuretic screen, consistent with GS. Severe hypokalemia is arrhythmogenic; ECG changes and syncope in this patient prompted monitored cardiac care and urgent correction. She was treated with intravenous and oral potassium and magnesium plus amiloride, leading to symptomatic improvement but persistently low‐normal potassium levels (3.3–3.7 mmol/L). Genetic testing confirmed a pathogenic SLC12A3 variant. This case underscores the importance of considering GS in young adults with unexplained hypokalemia and the difficulty of achieving full biochemical correction despite optimal therapy.

This study aimed to characterize the imaging patterns of semicircular canal (SCC) aplasia on high-resolution computed tomography (CT) and magnetic resonance imaging (MRI) to identify associated cochleovestibular and internal auditory canal (IAC) abnormalities and to explore potential syndromic correlations. We retrospectively evaluated 12 patients (24 ears) diagnosed with SCC aplasia between January 2021 and January 2025. Imaging findings were reviewed for canal type, cochlear and vestibular abnormalities, vestibular aqueduct morphology, and IAC configuration. Syndromic associations and clinical outcomes were also assessed. Lateral SCC aplasia was most common (41.7%), followed by budding remnants (12.5%) and total aplasia (12.5%). Total aplasia consistently coexisted with vestibular hypoplasia (P = 0.020) and was frequently accompanied by narrowing of the IAC (P = 0.04). Cochlear hypoplasia was found in one patient with bilateral total aplasia. Sensorineural hearing loss was present in 75% of patients, and caloric testing revealed subclinical vestibular dysfunction in two clinically asymptomatic adults. Syndromic associations included two cases of DiGeorge syndrome and a newly identified coexistence with Gitelman syndrome. SCC aplasia encompasses a spectrum of rare anomalies, most commonly affecting the lateral canal and closely related to vestibular dysplasia. Recognition of IAC narrowing is important, as it can complicate cochlear implantation. The identification of Gitelman syndrome as a new association expands the spectrum of systemic diseases associated with SCC abnormalities. Comprehensive imaging with both CT and MRI is essential not only for diagnosis but also for surgical planning and syndromic screening. Systematic assessment of the IAC and vestibular structures on CT and MRI is essential in patients with congenital hearing loss. Recognizing IAC narrowing and vestibular dysplasia aids in preoperative cochlear implant planning and supports targeted syndromic or genetic evaluation.

CRISPR/Cas9-based SLC12A3 gene knock in: a model for cellular feature analysis in Gitelman syndrome.

Background: Patients with acute coronary syndrome (ACS) complicated by heart failure with reduced ejection fraction (HFrEF) are at increased risk for malignant ventricular arrhythmias due to ischemia-related electrical instability and impaired repolarization reserve (Al-Khatib et al., 2018, Wellens et al., 2014). Loop diuretics are frequently required for the management of congestion; however, furosemide-induced renal potassium and magnesium wasting may produce an acquired electrolyte phenotype resembling Bartter or Gitelman syndromes (Seyberth and Schlingmann, 2011, Colussi et al., 1992). In the proarrhythmic milieu of ACS and HFrEF, this disturbance can precipitate QT prolongation and torsades de pointes (TdP) (Al-Khatib et al., 2018, Wellens et al., 2014, Roden, 2004). Case Summary: We report three patients with ACS and HFrEF who developed severe hypokalemia and hypomagnesemia during furosemide therapy, resulting in marked QT prolongation and TdP. All patients were successfully treated with prompt rhythm stabilization, intravenous magnesium, aggressive potassium repletion, withdrawal or modification of precipitating factors, and heart-rate augmentation when required (Al-Khatib et al., 2018, Roden, 2004, Tzivoni et al., 1988). No patient experienced arrhythmia recurrence after correction of electrolyte abnormalities. Conclusion: In patients with ACS and HFrEF, the occurrence of TdP should prompt immediate evaluation for diuretic-induced electrolyte depletion representing a reversible acquired pseudo–Bartter/Gitelman syndrome. Early recognition and targeted correction are lifesaving and may prevent unnecessary long-term device therapy (Al-Khatib et al., 2018, Wellens et al., 2014, Roden, 2004).

ABSTRACTWe present a case study of a 34‐year‐old man with morbid obesity and a suspected Bartter–Gitelman spectrum tubulopathy (without genetic confirmation), weighing 135 kg, and with a BMI of 42.5 kg/m2, who was referred to the metabolic and bariatric surgery department due to morbid obesity to address abnormal electrolyte levels. The clinical presentation suggested renal tubular salt wasting. Post‐sleeve gastrectomy, the patient had sustained and prolonged normalization in his electrolytes without the use of any medications. This provides evidence of a possible relationship between metabolic surgery and renal tubular function. This case supports recognizing a suspected tubulopathy in candidates for metabolic surgery.

Gitelman syndrome (GS) is a rare, autosomal recessive salt-losing tubulopathy caused by mutations in the SLC12A3 gene. It involves dysfunction of the sodium-chloride cotransporter positioned on the apical membranes of the distal convoluted tubule cells, causing sodium shortage and mimicking the use of thiazide diuretics. Hyperaldosteronism secondary to sodium depletion and hypovolemia causes hypokalaemia and metabolic alkalosis. This is associated with inhibition of the Transient Receptor Potential Cation Channel, Subfamily M, Member 6 -TRPM6 channel, which leads to urinary magnesium leakage and hypomagnesemia, subsequently stopping PTH secretion and resulting in hypocalcemia and hypocalciuria. Gitelman syndrome frequently presents later in life, as the symptoms are usually not very threatening. However, early identification, diagnosis, and urgent intervention are essential to improve patient prognosis and quality of life. Importantly, both hypomagnesemia and hypokalaemia can impair insulin secretion and sensitivity. Furthermore, hyperaldosteronism caused by the secondary activation of the R-A-A system can also lead to these disorders. Glucose metabolism problems have been shown to prevail amongst GS patients and manifest more frequently in comparison to the general population. When it comes to the treatment used to reduce hyperglycemia in GS-related T2DM, we consider which of the available drugs are the best for those patients. The article analyses the association of Gitelman syndrome with diabetes mellitus based on the available medical literature-as there are no clinical trials or meta-analyses available for this group, it is presented as a narrative review.

Akshaya Kamalashree Ganesh, M.B.B.S., Venkata Siva Karthik Budumuri, M.B.B.S., Kavya Veeramreddy, M.B.B.S., Aneesh Basheer, M.D., Janardhanan Subramonia Kumar, M.D., F.R.C.P.. J Rheum Dis -0001;0:. https://doi.org/10.4078/jrd.2025.0120

IntroductionGitelman syndrome (GS) presents with a broad range of clinical manifestations. Although uncommon, seizures secondary to severe metabolic alkalosis or hypomagnesemia have been documented. A concurrent diagnosis of epilepsy in patients with GS is even rarer.Case presentationWe report the case of a 12-year-old boy whose chief complaint was recurrent convulsions. Initial laboratory evaluation revealed normal serum magnesium levels, which subsequently decreased during follow-up. Persistent hypokalemia, hyperaldosteronism, and hypomagnesemia in subsequent disease course, as well as mutations of the SLC12A3 gene, confirmed the diagnosis of GS. Based on long-term monitoring of seizure episodes, electroencephalogram findings, and the electrolyte levels during an epileptic seizure, a diagnosis of epilepsy was established. His seizures were well controlled with levetiracetam.ConclusionWe report a case of GS presenting with convulsions as the chief complaint. The etiology of epilepsy in this case remains unclear and may represent either a causal association or a coincidental comorbidity with GS. The mechanism of the atypical dynamics of serum magnesium levels in this patient—normal levels initially followed by a subsequent decrease—warrants further investigation.

Gitelman syndrome is an autosomal recessive salt-wasting tubulopathy affecting the distal convoluted tubule, characterised by hypokalaemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, and secondary hyperreninemic hyperaldosteronism, mimicking the effects of chronic thiazide diuretic use. Although hypocalcaemia is uncommon, it can occur due to hypomagnesaemiainduced suppression of parathyroid hormone (PTH) secretion, leading to functional hypoparathyroidism. Symptomatic hypocalcaemia and tetany are extremely rare presentations of Gitelman syndrome.We report a 30-year-old man who presented with transient loss of consciousness and muscle cramps. He had experienced similar episodes over the preceding year, accompanied by perioral numbness and salt cravings. He had previously been diagnosed with primary hypoparathyroidism based on persistently low serum parathyroid hormone (PTH) levels despite calcium supplementation. Examination revealed carpopedal spasms and a positive Chvostek sign.Laboratory investigations revealed hypokalaemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, and elevated renin and aldosterone levels, consistent with Gitelman syndrome and hypocalcaemia. Treatment with intravenous calcium, magnesium, and potassium resulted in symptom resolution. Due to persistent hypokalaemia, spironolactone was added. Genetic testing confirmed mutations in SLC12A3 consistent with Gitelman syndrome.This case highlights the importance of evaluating serum magnesium in patients with unexplained or treatment-refractory hypocalcaemia. Magnesium deficiency can mimic hypoparathyroidism by suppressing PTH secretion and impairing the end-organ responsiveness to PTH. The combination of hypokalaemia, hypomagnesaemia, and hypocalciuria is characteristic of Gitelman syndrome and should prompt further evaluation, including genetic.

Normocalcemic tetany is a clinical condition characterized by neuromuscular hyperexcitability in the absence of overt hypocalcemia, resulting from disturbances in ionized calcium, magnesium, potassium, or acid–base balance. Although tetany is most commonly associated with hypocalcemia, cases with normal total calcium levels pose diagnostic challenges and are frequently underrecognized. This review consolidates current knowledge regarding the etiology, clinical manifestations, diagnostic evaluation, and management of normocalcemic tetany. The etiology includes hereditary renal tubulopathies such as Gitelman and Bartter syndromes, hyperventilation-related alkalosis, magnesium deficiency, and rare autoimmune disorders involving antibodies against the voltage-gated potassium channel complex (CASPR2). Clinical presentations range from overt tetanic seizures with characteristic carpopedal spasms to latent tetany detectable via Chvostek and Trousseau signs or ischemia-induced EMG abnormalities. Case reports highlight unusual scenarios, including tetany triggered by vomiting, postoperative parathyroidectomy, and hereditary neuromuscular hypersensitivity, emphasizing that serum total calcium may remain normal while ionized calcium or other electrolytes fluctuate. Management strategies focus on prompt recognition, correction of underlying electrolyte disturbances—particularly calcium, magnesium, and potassium—and supportive care. Early administration of intravenous calcium, alongside addressing precipitating factors, is critical for rapid symptom relief. Latent or recurrent tetany in the context of normal electrolytes warrants consideration of genetic, neurologic, or autoimmune etiologies, and may require specialized testing including EMG, antibody panels, or genetic analysis. Increased awareness among clinicians, timely evaluation of ionized calcium and other electrolytes, and early intervention are essential to prevent severe complications, including life-threatening muscle spasms, rhabdomyolysis, and cardiovascular instability. This review underscores the need for further population-based studies to define the prevalence, at-risk groups, and optimal management of normocalcemic tetany.

Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disorder characterised by hypokalaemia, hypomagnesaemia, metabolic alkalosis, and hypocalciuria. It typically manifests during adolescence or adulthood, while paediatric presentations are uncommon and often misdiagnosed. We report the case of an eight-year-old girl presenting with recurrent episodes of severe hypokalaemia and muscle cramps triggered by acute gastroenteritis. Genetic testing identified two heterozygous pathogenic variants in the solute carrier family 12 member 3 SLC12A3) gene, confirming GS.

The osteoarticular features of Gitelman Syndrome: Chondrocalcinosis and more.