Bartter's Syndrome Research Articles

A narrative review of monogenic disorders causing nephrolithiasis and chronic kidney disease.

The incidence and prevalence of genetic diseases associated with chronic kidney disease (CKD) have been increasing over the last decades. To identify the monogenic causes of kidney stone disorders linked to CKD, a comprehensive literature review was conducted to identify monogenic genes causing nephrolithiasis and CKD. Among 41 identifiable monogenic causes of nephrolithiasis the following diseases primary hyperoxaluria familial hypomagnesemia with hypercalciuria and nephrocalcinosis, cystinuria; Dent disease, adenine phosphoribosyltransferase deficiency, Lesch-Nyhan syndrome, and idiopathic Infantile hypercalciuria have been linked to CKD and may progress to end-stage kidney disease (ESKD). Autosomal dominant hypocalcemia and Bartter syndrome (BS) are also hereditary kidney diseases that can cause urolithiasis but are rarely associated with CKD. A few BS type III can be complicated with CKD. A substantial number of kidney stone patients with genetic disorders progress to CKD. Genetic diagnosis should be initiated in all children presenting with kidney stones.

Persistent renal dysfunction post-chemotherapy: a diagnostic conundrum in pediatric cancer survivorship – a case report

BackgroundLate-onset type II Bartter syndrome is an exceedingly rare condition, with only six documented cases presenting symptoms and signs beyond infancy. We report a unique case of late-onset type II Bartter syndrome with an atypical presentation and clinical course following chemotherapy treatment during childhood.Case presentationA 10-year-old boy, diagnosed with hepatoblastoma at age 2 and treated with cisplatin and epirubicin, presented with polyuria, polydipsia, failure to thrive, and electrolyte imbalances. He exhibited hypokalemia, metabolic alkalosis, and elevated urinary excretion of sodium, chloride, calcium, and magnesium. Whole exome sequencing and Sanger sequencing identified compound heterozygous variants in the KCNJ1 gene, confirming the diagnosis of type II Bartter syndrome. The patient’s clinical presentation was distinct from previously reported cases, with an absence of nephrocalcinosis, unusually small and hyperechoic kidneys, and a substantial decline in kidney function. Treatment included oral potassium supplementation, spironolactone, and angiotensin-converting enzyme inhibitors.ConclusionsThis case highlights the importance of considering late-onset Bartter syndrome in patients with a history of chemotherapy presenting with persistent electrolyte imbalances and ongoing renal dysfunction. The atypical features and rapid progression of chronic kidney disease in this patient may be attributed to the deleterious nature of the identified variants and the potential impact of previous chemotherapy on kidney susceptibility to damage. Careful monitoring and management of electrolyte imbalances and renal function are crucial in such cases.

Polymyxin-B induced bartter-like syndrome: an unusual adverse effect

Introduction and Importance: Bartter syndrome is a rare autosomal recessive disorder affecting renal tubular function, leading to electrolyte and volume homeostasis disturbances. It can also manifest as Bartter-like syndrome, a rare side effect of certain medications. Polymyxin-B, used to treat multidrug-resistant infections, is infrequently associated with BLS, making early recognition crucial to prevent severe electrolyte imbalances. Case Presentation: A 73-year-old female with coronary artery disease, COPD, hyperlipidemia, and other comorbidities presented with fever, respiratory distress, and hypoxia on mechanical ventilation. Initial labs showed leukocytosis, anemia, and normal potassium. Despite broad-spectrum antibiotics, sputum cultures revealed pandrug-resistant Acinetobacter baumannii, sensitive only to Polymyxin-B. After six days of Polymyxin-B, the patient developed fever, hypotension, hypokalemia, hypomagnesemia, and polyuria. Urine studies indicated increased potassium excretion. A diagnosis of Bartter like syndrome was made. Polymyxin-B was discontinued, and the patient’s electrolytes normalized, resolving the polyuria. She was discharged with daily potassium and magnesium supplements. Clinical Discussion: Bartter-like syndrome can result from Polymyxin-B-induced tubular dysfunction, characterized by hypokalemia and hypomagnesemia. Close electrolyte monitoring is essential for patients receiving this antibiotic, particularly in those with complex medical conditions. Early recognition allowed for timely discontinuation of Polymyxin-B, which rapidly reversed the electrolyte disturbances. Conclusion: This case underscores the importance of recognizing Polymyxin-B-induced Bartter-like syndrome. Clinicians should be vigilant for electrolyte disturbances in patients undergoing treatment with Polymyxin-B, ensuring timely interventions to mitigate adverse outcomes.

Cardiovascular and arrhythmic manifestations of Bartter's and Gitelman's syndromes: do not forget the heart. A narrative literature review.

Bartter's and Gitelman's syndromes (BS/GS) are genetically determined kidney tubulopathies leading to electrolyte and neurohormonal abnormalities. Although considered benign entities, major adverse cardiovascular events may complicate both syndromes, in form of ventricular arrhythmias leading to palpitations, syncope or sudden cardiac death, microvascular cardiac dysfunction and exercise-induced myocardial contractile deficit. The mechanisms leading to cardiovascular complications are not only driven by chronic electrolyte abnormalities, i.e. chronic hypokalemia and hypomagnesemia, but also by neurohormonal alterations that can impair vascular tone and myocardial contractility. In presence of triggering factors, BS/GS patients may experience a spectrum of cardiac arrhythmias necessitating prompt diagnosis and treatment. The aim of this review is to explore the pathophysiological mechanisms of BS and GS, highlighting those responsible for cardiovascular involvement, and to analyze the spectrum of associated cardiovascular complications. This highlights the importance of an integrated shared management of GS/BS patients between Nephrologist and Cardiologist.

ClC-Kb pore mutation disrupts glycosylation and triggers distal tubular remodeling.

Mutations in the CLCNKB gene (1p36), encoding a basolateral chloride channel, ClC-Kb, cause type 3 Bartter's syndrome. We identified a family with a mixed Bartter's / Gitelman's phenotype and early-onset kidney failure and employing a candidate gene approach, discovered a homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole exome sequencing. Compared to wild-type ClC-Kb, the Gly167Cys mutant conducted less current and impaired, complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, impairs complex glycosylation but that surface expression remains intact. Moreover, Asn364 was necessary for channel function and complex glycosylation. Morphologic evaluation of human kidney biopsies revealed typical basolateral localization of mutant Gly167Cys ClC-Kb in cortical distal tubular epithelia. However, we detected attenuated expression of distal sodium transport proteins, changes in abundance of distal tubule segments, and hypokalemia-associated intracellular condensates from the index patient compared to control nephrectomy specimens. The present data establish what we believe, are novel regulatory mechanisms of ClC-Kb activity and demonstrate nephron remodeling in man, caused by mutant ClC-Kb, with implications for renal electrolyte handling, blood pressure control, and kidney disease.

7331 A Rare Case Of Familial Hypoparathyroidism

Abstract Disclosure: N. Sekhon: None. K.Z. Win: None. Background: Autosomal dominant hypoparathyroidism disorders are very rare and mostly asymptomatic. We present an interesting case of autosomal hypoparathyroidism with a new variant of gene defect on genetic analysis. Case: A 66-year-old female was referred to the endocrinology clinic for familial hypoparathyroidism and calcium oxalate nephrolithiasis. She had onset of seizures at age 16. She was diagnosed with hypocalcemia and hypoparathyroidism at age 30 when she had her first episode of nephrolithiasis. She had recurrent nephrolithiasis and lithotripsies, ultimately developing chronic kidney impairment that was at stage 3b at the time of evaluation. Renal Ultrasound revealed bilateral nephrolithiasis, and nephrocalcinosis. There was a history of hypoparathyroidism in her father, paternal uncle, and son. Her medications included calcium carbonate-vitamin D3 600-400 mg-unit oral 2 tablets daily and calcitriol 0.5 mcg daily. The pertinent physical examination finding was a short stature with height 4’11” and calluses in fingers. Her recent serum chemistry showed calcium 8.8 mg/dL (reference range 8.3 - 10.6 mg/dL), PTH < 6.3 pg/mL (reference range 18.4 - 80.1 pg/ mL), and phosphorus 3.3 mg/dL (reference range 2.4 - 5.5 mg/dL). 24 hr urine calcium was 96 mg (reference range 50-300 mg/24h). She was treated with hydrochlorothiazide for nephrolithiasis but was discontinued due to hypokalemia. We performed genetic testing that resulted positive for CASR NM_001178065.1 with heterozygosity and damaging missense predictions inherited as autosomal dominant or recessive. Discussion: The calcium-sensing receptor (CaSR) has an important role in calcium homeostasis by regulating parathyroid hormone (PTH) secretion and urinary calcium excretion. Familial hypoparathyroidism disorders are divided into Autosomal dominant hypocalcemia (ADH) type 1 and Autosomal dominant hypocalcemia (ADH) type 2. ADH1 is caused by an activating mutation of calcium-sensing receptor (CASR). The estimated prevalence of ADH1 ranges from 1 per 70,000 to 3.9 per 100,000. It is characterized by mild to moderate hypocalcemia, hyperphosphatemia, hypercalciuria, and inappropriately low but detectable PTH levels. It can be associated with Bartter syndrome Type 5. ADH2 is due to mutations in the alpha subunit of the G protein G11 (Gα11). Our patient had classic symptoms of hypocalcemia including short stature, seizures, kidney stones and its sequelae. Her 24-hour urine analysis showed inappropriately normal urine calcium with low normal serum calcium, undetectable serum PTH, and normal phosphorus. Our patient’s genetic analysis revealed a heterozygous defect in gene CASR with DNA variants c.2564G>A with damaging missense predictions. There is no such variant reported or listed in the ClinVar database. To our knowledge, this is the first such case of an autosomal dominant hypoparathyroidism with this gene defect. Presentation: 6/1/2024

Association of Bartter Syndrome in a Filipino Patient with Overlap Syndrome

Association of Bartter Syndrome in a Filipino Patient with Overlap Syndrome

Гено-фенотипические особенности муковисцидоза у российских детей из Чеченской и Карачаево-Черкесской Республик

Background: Cystic fibrosis (CF) is an autosomal recessive disease that occurs with a frequency of 1:1,500 to 1:5,000 newborns, according to the World Health Organization. In the Russian Federation, the average incidence of the disease is 1:10,000 newborns. The medical and social significance of this disease is associated with the early disability of patients, the need for long-term treatment and constant follow-up, as well as the heterogeneity of phenotypic manifestations, which in turn requires early diagnosis using molecular genetic methods. The aim of the study: To study the clinical and molecular genetic characteristics of children with CF from the Chechen and Karachay-Cherkess Republics. Materials and methods: The study included 237 patients with a confirmed diagnosis of CF. Molecular genetic diagnostics was performed using the method of mass parallel sequencing using a hybridization target panel that includes the entire CFTR gene. Sequencing was performed on the MiSeq platform. All causal nucleotide variants were validated using Sanger sequencing. Results: The most common amino acid variants of the CFTR gene in patients with CF from the Chechen Republic are: p.Y515* (94 alleles/78.3%), p.E92K (18 alleles/15%). The presence of variants p.Y515* and p.E92K in the heterozygous state in the genotype is more often a favorable prognostic factor for the absence of pancreatic lesion. The main distinctive clinical feature of these patients is the onset of the disease with manifestations of pseudo-Bartter syndrome. The major amino acid variant of the CFTR gene in patients with CF from the Karachay-Cherkess Republic is: p.W1282* (28 alleles/70%). The number of patients with pseudo-Bartter syndrome was 54.5%. In 90% of cases, in patients who are homo- and heterozygous according to p.W1282*, a severe degree of pancreatic insufficiency was noted. Conclusion: Patients with cystic fibrosis from the Chechen and Karachay-Cherkess Republics are a difficult category of patients, despite neonatal screening, and cystic fibrosis therapy developed and implemented. This is partly due to the peculiarities of the phenotype and the unique distribution of alleles and genotypes of the CFTR gene. The high number of homozygous variants of the CFTR gene in patients from the Chechen and Karachay-Cherkess Republics is probably due to monoethnic marital assortativity.

Electrolyte Alteration in Bartter Syndrome: Case Report

Bartter syndrome is a clinical condition that presents with hyperaldosteronism, however, blood pressure is normal, this is associated with hypovolemia and high levels of PGE2. The clinical case of a pediatric patient who initially presents with significant electrolyte alterations with recurrently associated symptoms is presented. After several laboratory, imaging and genetic studies, she was diagnosed with Bartter Syndrome, for which she has been managed by several specialists. such as pediatric nephrology, genetics, and urology. The patient is currently under control and carries out her daily activities normally, under strict monitoring. It is the first clinical case of this characteristic reported in Ecuador, and contributes to those already registered worldwide, with the experience to contribute to a consensual management of this rare pathology.

Genetic background of neonatal hypokalemia.

Neonatal hypokalemia (defined as a serum potassium level <3.5 mEq/L) is the most common electrolyte disorder encountered in clinical practice. In addition to common secondary causes, primary genetic etiologies are also closely associated with hypokalemia. Currently, a systematic characterization of these genetic disorders is lacking, making early recognition challenging and clinical management uncertain. This review will aid clinicians by summarizing the genetic background of neonatal hypokalemia from two aspects: (1) increased excretion of K+, whereby genetic factors primarily lead to increased renal Na+ influx, decreased H+ efflux, or reduced Cl- influx, ultimately resulting in increased K+ efflux; and (2) decreased extracellular distribution of K+, whereby genetic factors result in abnormalities in transmembrane ion channels, reducing outward potassium currents or generating inward cation leak currents. We describe over ten genetic diseases associated with neonatal hypokalemia, which involve pathogenic variants in dozens of genes and affect multiple target organs, including the kidneys, intestines, and skeletal muscle. For example, in the renal tubules, pathogenic variants in the SLC12A1 gene encoding the Na+-K+-2Cl- cotransporter lead to renal K+ loss, causing Bartter syndrome type I; in intestinal epithelial cells, pathogenic variants in the SLC26A3 gene result in a defective Cl⁻-HCO₃⁻ exchanger, causing congenital chloride diarrhea; and in skeletal muscle, pathogenic variants in the CACNA1S gene impact membrane calcium ion channels resulting in hypokalemic periodic paralysis. Given the wide variety of organs and genetic alterations that can contribute to neonatal hypokalemia, we believe this review will provide valuable insights for clinical diagnosis and treatment.

SLC12A1 variant c.1684+1 G>A causes Bartter syndrome type 1 by promoting exon 13 skipping.

Bartter syndrome type 1, an autosomal recessive genetic disorder, is caused by pathogenic loss-of-function variants in the SLC12A1 gene. It is characterized by metabolic alkalosis and prenatal-onset polyuria leading to polyhydramnios. We identified pathogenic gene in a 12-day-old newborn boy with Bartter syndrome type 1 using whole-exome sequencing. Sanger sequencing validated the identified variants. A minigene assay was performed to investigate the effect of a novel splice site variant on pre-mRNA splicing. We found a compound heterozygous variants in the SLC12A1 gene, consisting of a known pathogenic missense mutation (NM_000338: c.769 G>A; p.Gly257Ser) and a novel splice site variant (c.1684+1 G>A). In silico predictions and an in vitro minigene splicing assay demonstrated that the splicing variant c.1684+1 G>A abolished a consensus splice donor site of SLC12A1 intron 13, resulting in complete exon 13 skipping, translational frameshift, and premature termination codon, ultimately leading to loss of SLC12A1 function. Using a cell-based in vitro assay, we revealed the aberrant effect of the pathogenic splicing variant SLC12A1 c.1684+1 G>A on pre-mRNA splicing. Our findings expand the gene mutation spectrum of Bartter syndrome type 1, providing a basis for genetic diagnosis and the development of genetic medicines.

Paradoxes in magnesium transport in type 1 Bartter's syndrome and Gitelman's syndrome: a modeling analysis.

Type 1 Bartter's syndrome and Gitelman's syndrome are characterized by mutations in two key renal Na+ transporters, Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC). Since these two transporters play an important role in regulating magnesium (Mg2+) and calcium (Ca2+) transport in the kidney, significant alterations in the transport of these two electrolytes are observed in type 1 Bartter's syndrome and Gitelman's syndrome. In this study, we used our sex-specific computational models of renal electrolyte transport in rats to understand the complex compensatory mechanisms, in terms of alterations in tubular dimensions and ion transporter activities, that lead to Mg2+ and Ca2+ preservation or wasting in these two genetic disorders. Given the sexual dimorphism in renal transporter patterns, we also assessed how the magnitude of these alterations may differ between males and females. Model simulations showed that in type 1 Bartter's syndrome, nephron adaptations prevent salt wasting and favor Mg2+ preservation but not Ca2+, whereas in Gitelman's syndrome, those adaptations favor Ca2+ preservation over Mg2+. In addition, our models predicted that the compensatory alterations in tubular dimensions and ion transporter activities are stronger in females than in males.NEW & NOTEWORTHY Although changes in Ca2+ excretion in type 1 Bartter's syndrome and Gitelman's syndrome are well understood, Mg2+ excretion displays an interesting paradox. This computational modeling study provides insights into how renal adaptations in these two disorders impact Ca2+ and Mg2+ transport along different nephron segments. Model simulations showed that nephron adaptations favor Mg2+ preservation over Ca2+ in Bartter's syndrome and Ca2+ preservation over Mg2+ in Gitelman's syndrome and are stronger in females than in males.

Cyclic Adenosine Monophosphate Signaling in Chronic Kidney Disease: Molecular Targets and Therapeutic Potentials.

Chronic kidney disease (CKD) is characterized by a steady decline in kidney function and affects roughly 10% of the world's population. This review focuses on the critical function of cyclic adenosine monophosphate (cAMP) signaling in CKD, specifically how it influences both protective and pathogenic processes in the kidney. cAMP, a critical secondary messenger, controls a variety of cellular functions, including transcription, metabolism, mitochondrial homeostasis, cell proliferation, and apoptosis. Its compartmentalization inside cellular microdomains ensures accurate signaling. In kidney physiology, cAMP is required for hormone-regulated activities, particularly in the collecting duct, where it promotes water reabsorption through vasopressin signaling. Several illnesses, including Fabry disease, renal cell carcinoma, nephrogenic diabetes insipidus, Bartter syndrome, Liddle syndrome, diabetic nephropathy, autosomal dominant polycystic kidney disease, and renal tubular acidosis, have been linked to dysfunction in the cAMP system. Both cAMP analogs and phosphodiesterase inhibitors have the potential to improve kidney function and reduce kidney damage. Future research should focus on developing targeted PDE inhibitors for the treatment of CKD.

Untangling the Uncertain Role of Overactivation of the Renin-Angiotensin-Aldosterone System with the Aging Process Based on Sodium Wasting Human Models.

Every individual at some point encounters the progressive biological process of aging, which is considered one of the major risk factors for common diseases. The main drivers of aging are oxidative stress, senescence, and reactive oxygen species (ROS). The renin-angiotensin-aldosterone system (RAAS) includes several systematic processes for the regulation of blood pressure, which is caused by an imbalance of electrolytes. During activation of the RAAS, binding of angiotensin II (ANG II) to angiotensin II type 1 receptor (AGTR1) activates intracellular nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to generate superoxide anions and promote uncoupling of endothelial nitric oxide (NO) synthase, which in turn decreases NO availability and increases ROS production. Promoting oxidative stress and DNA damage mediated by ANG II is tightly regulated. Individuals with sodium deficiency-associated diseases such as Gitelman syndrome (GS) and Bartter syndrome (BS) show downregulation of inflammation-related processes and have reduced oxidative stress and ROS. Additionally, the histone deacetylase sirtuin-1 (SIRT1) has a significant impact on the aging process, with reduced activity with age. However, GS/BS patients generally sustain higher levels of sirtuin-1 (SIRT1) activity than age-matched healthy individuals. SIRT1 expression in GS/BS patients tends to be higher than in healthy age-matched individuals; therefore, it can be assumed that there will be a trend towards healthy aging in these patients. In this review, we highlight the importance of the hallmarks of aging, inflammation, and the RAAS system in GS/BS patients and how this might impact healthy aging. We further propose future research directions for studying the etiology of GS/BS at the molecular level using patient-derived renal stem cells and induced pluripotent stem cells.

A Case Report About One Patient with Citrullinemia Type I with Classic Bartter Syndrome Simultaneously

Introduction and Case Presentation: This report describes a 9-year-old child diagnosed simultaneously with two rare metabolic and nephrogenic disorders. The diagnosis followed non-specific symptoms that began in early infancy and were further investigated through laboratory results. Conclusions: Each of these disorders requires independent treatment and care. Therefore, it was essential for the patient to receive training on recognizing warning signs.

An Unusual Presentation of Failure to Thrive in a Toddler: Bartter Syndrome

An Unusual Presentation of Failure to Thrive in a Toddler: Bartter Syndrome

Regulation of ClC-K/barttin by endocytosis influences distal convoluted tubule hyperplasia.

ClC-K/barttin channels are involved in the transepithelial transport of chloride in the kidney and inner ear. Their physiological role is crucial in humans because mutations in CLCNKB or BSND, encoding ClC-Kb and barttin, cause Bartter's syndrome types III and IV, respectively. In vitro experiments have shown that an amino acid change in a proline-tyrosine motif in the C-terminus of barttin stimulates ClC-K currents. The molecular mechanism of this enhancement and whether this potentiation has any in vivo relevance remains unknown. We performed electrophysiological and biochemical experiments in Xenopus oocytes and kidney cells co-expressing ClC-K and barttin constructs. We demonstrated that barttin possesses a YxxØ motif and, when mutated, increases ClC-K plasma membrane stability, resulting in larger currents. To address the impact of mutating this motif in kidney physiology, we generated a knock-in mouse. Comparing wild-type (WT) and knock-in mice under a standard diet, we could not observe any difference in ClC-K and barttin protein levels or localization, either in urinary or plasma parameters. However, under a high-sodium low-potassium diet, known to induce hyperplasia of distal convoluted tubules, knock-in mice exhibit reduced hyperplasia compared to WT mice. In summary, our in vitro and in vivo studies demonstrate that the previously identified PY motif is indeed an endocytic YxxØ motif in which mutations cause a gain of function of the channel. KEY POINTS: It is revealed by mutagenesis and functional experiments that a previously identified proline-tyrosine motif regulating ClC-K plasma membrane levels is indeed an endocytic YxxØ motif. Biochemical characterization of mutants in the YxxØ motif in Xenopus oocytes and human embryonic kidney cells indicates that mutants showed increased plasma membrane levels as a result of an increased stability, resulting in higher function of ClC-K channels. Mutation of this motif does not affect barttin protein expression and subcellular localization in vivo. Knock-in mice with a mutation in this motif, under conditions of a high-sodium low-potassium diet, exhibit less hyperplasia in the distal convoluted tubule than wild-type animals, indicating a gain of function of the channel in vivo.

The Investigation of the Effect of Electrolyte Disorder on Sweat Test in Newborns with Positive Cystic Fibrosis Screening

Background and objectives: The aim of this study is to investigate the effect of the electrolyte and acid-base status present at the time of admission to the hospital on the sweat test (ST) of the patients who were found to have a positive newborn screening test (NST) for Cystic Fibrosis (CF). Methods: The patients who referred to pediatric pulmonology clinic for ST with positive NST for CF and diagnosed as CF were analyzed retrospectively. From the medical records acid-base status measured simultaneously with the ST and with serum sodium, potassium, and chloride levels were included in the study. Results: The study completed with 37 patients who met the inclusion criteria. At the time of ST, the mean sodium, potassium and chlorine values were 134.83±4.25 (122.0-141.0), 4.94±0.95 (2.9-7.6) and 97.72±12.40 (64.0-116.0) mEq/L, respectively. Patients whose electrolytes were measured at the time of diagnosis, 27.0% (n=10) had hyponatremia, 8.1% (n=3) had hypokalemia, and 4.8% (n=1) had hypochloremia. There was a significant difference between serum chloride and bicarbonate levels according to the negative, borderline, positive ST groups (p=0,036). In addition, no significance detected between the sweat test values of patients with Pseudo-Bartter Syndrome (PBS) (38.7%) and without. Conclusion: The chloride level during ST is lower in patients with borderline and negative ST results. The mean potassium and chloride values of the patients with PBS are lower while the mean bicarbonate value is higher. This may cause false negative results in ST. So, it is important to check the serum electrolyte levels before the ST is performed in the newborn screening positive baby.

Management of potassium-wasting syndrome in the antepartum, intrapartum and postpartum period.

Potassium-wasting syndromes, including Gitelman or Bartter syndrome, require close medical and biochemical review during pregnancy to reduce potentially severe complications, morbidity and mortality. We report a case of severe potassium-wasting syndrome managed successfully in pregnancy with extremely high oral potassium intake.

X-linked transient antenatal Bartter syndrome related to MAGED2 gene: Enriching the phenotypic description and pathophysiologic investigation

PurposeTransient Bartter syndrome related to pathogenic variants of MAGED2 is the most recently described antenatal Bartter syndrome. Despite its transient nature, it is the most severe form of Bartter syndrome in the perinatal period. Our aim was to describe 14 new cases and to try to explain the incomplete penetrance in women. MethodsWe report on 14 new cases, including 3 females, and review the 40 cases described to date. We tested the hypothesis that MAGED2 is transcriptionally regulated by differential methylation of its CpG-rich promotor by pyrosequencing of DNA samples extracted from fetal and adult leukocytes and kidney samples. ResultsAnalysis of the data from 54 symptomatic patients showed spontaneous resolution of symptoms in 27% of cases, persistent complications in 41% of cases, and fatality in 32% of cases. Clinical anomalies were reported in 76% of patients, mostly renal anomalies (52%), cardiovascular anomalies (29%), and dysmorphic features (13%). A developmental delay was reported in 24% of patients. Variants were found in all regions of the gene. Methylation analysis of the MAGED2 CpG-rich promotor showed a correlation with gender, independent of age, tissue or presence of symptoms, excluding a role for this mechanism in the incomplete penetrance in women. ConclusionThis work enriches the phenotypic and genetic description of this recently described disease and deepens our understanding of the pathophysiological role and regulation of MAGED2. Finally, by describing the wide range of outcomes in patients, this work opens the discussion on genetic counseling offered to families.