Autosomal Recessive Tubular Disorder Research Articles

#3572 CLINICAL AND GENETIC CHARACTERISTICS OF CHILDREN WITH BARTTER SYNDROME: A SINGLE CENTER LONG-TERM EXPERIENCE

Abstract Background and Aims Bartter syndrome is an autosomal recessive renal tubular disorder. Clinical diagnosis can be challenging due to rarity and phenotypic overlap. Little information is available on a long term follow-up in Bartter syndrome. Our aim was to describe clinical -genetic correlations as well as our experience from the long term follow up of these patients. Method Clinical and genetic characteristics of patients with Bartter syndrome at diagnosis and long term follow up are reported in 19 children. Genetic testing (whole exome sequencing, WES) was done in 14/19 patients. The study period was 17 years (January 1, 2006 to December 31, 2022). Results 16 Caucasian and 3 of gipsy origin (13 boys, 68%) were included. The median age at diagnosis was 0,52 yrs. Median follow up time was 9.8yrs (IQR 6.86-13.8). WES revealed 6 mutations in KCNJ1 genes, 5 in SLC12A1 and 3 in CLCNKB genes. 4 new mutations were identified (3 in KCNJ1 genes and 1 in SLC12A1. 18/19 children were born pre-term (including 2/3 patients with CLCNKB). Nephrocalcinosis was present in 18/19 patients (included the 3 patients with CLCKNB mutations). 4/6 patients with KCNJ1 mutations presented initially with hyperkalemia. Medical treatment in the last follow up included supplementation with potassium in 18, non -steroidal anti-inflammatory agents in 15 and gastroprotective drugs in 13, ramipril in 2. 2/19 received recombinant growth hormone. At last follow up body weight and height were within normal ranges in 16/19 (84%) patients. Hyperparathyroidism (median time of PTH 151.5 pg/ml) have 6/11 (56%) of patients with Bartter I (ΚCNJ1mutation) and Bartter II (SLC12A1 mutation) and only 1/3 with Bartter III (CLCNKB mutation). 2/19 patients have proteinuria. Chronic kidney disease (CKD) occurred in 7/19 (37%) suggesting that the long term prognosis can be unfavorable (4 CKD stage II, 3 CKD stage III). Of note 2 patients with CKD had impaired renal function since diagnosis while the remaining 5 progressed gradually during followup. Conclusion WES is useful in dealing with the phenotypic heterogeneity of Bartter syndrome. Our results emphasize the need for early diagnosis, regular followup and appropriate treatment in order to maintain normal renal function and achieve normal final height and weight.

Annals of Clinical and Medical Case Reports

1.1. Objective: Gitelman syndrome (GS) is an autosomal recessive tubular disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. GS is mostly caused by inactivating mutations of the SLC12A3 gene. The purpose of this study was to describe the clinical features of a GS patient and investigate the underlying mutations of SLC12A3 gene in the pedigree. 1.2. Methods: A patient suffering from muscle weakness was clinically diagnosed as GS. Clinical data of the proband were studied retrospectively. All of his family members were screened for SLC12A3 gene mutations. 26 exons and exon-intron boundaries of SLC12A3 gene were amplified by Polymerase Chain Reaction(PCR). PCR products were sequenced directly. 1.3. Results: The proband had hyperreninemia but hypoaldosteronemia, which was distinct from the cases previously reported. The proband and his sick brother were found to have the same compound heterozygous mutations (c.917C>T and IVS 14-8T>C) of SLC12A3 gene. Each mutation was detected in paternal and maternal genomic DNA, respectively. The proband’s healthy brother had one mutation (c.917C>T) only. IVS 14-8T>C was a novel splicing site mutation that had never been reported. 1.4. Conclusion: Hypoaldosteronemia was found in a GS patient. A novel heterozygous splicing site mutation of the SLC12A3 gene was reported, expanding the spectrum of SLC12A3 gene mutations.

POS-084 A RARE GENETIC DISORDER PRESENTING AS RECURRENT URINARY TRACT INFECTION IN CHILDREN

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive renal tubular disorder. The incidence is <1/1,000,000 individuals and >50% cases develop chronic kidney disease (CKD) by 2nddecade of life. It presents with non-specific symptoms like failure to thrive, abdominal pain, polydipsia, polyuria and clinical features of urinary tract infection (UTI). To the best of our knowledge, only 5 case reports have been published from the Indian sub-continent and none describing long term follow up.

Gitelman Syndrome: a Сlinical and Molecular Overview

Gitelman syndrome (OMIM #263800) is an autosomal recessive renal tubular disorder due to loss of function mutations of SLC12A3 gene, encoding the thiazide-inhibitable, electroneutral Na+-Cl– cotransporter (NCC) of the distal convoluted tubule. Clinical consequences include chronic normotensive hypokalemic alkalosis, hypomagnesemia, hypocalciuria, polyuria/nocturia, chronic asthenia, muscular cramps, chondrocalcinosis and rarely cardiac arrhythmias.Impaired reabsorption of glomerular filtrate through NCC drives compensatory reabsorption of Na+ in more distal tubular segments (connecting and cortical collecting tubules) via both the «electrogenic» channel ENa (which also enhances tubular secretion of potassium and protons, explaining the hypokalemic alkalosis), and pendrin-dependent electroneutral NaCl reabsorption. Thus volume depletion is seldom severe in these patients.There exists wide variability and severity of clinical symptoms between subjects, ranging from an almost asymptomatic disease to a severely disabling one. More than 400 SLC12A3 mutations have been so far described, evenly distributed along the protein sequence and without any hot spot. Mutation detection rate by gene sequencing actually is about 80 %. There are no genotype-phenotype correlations.Commonly considered a benign condition, Gitelman syndrome may be associated with reduced quality of life, increased medicalization and high hospitalization rate.

Eight novel KCNJ1 variants and parathyroid hormone overaction or resistance in 5 probands with Bartter syndrome type 2

PurposeBartter syndrome type 2 (BS2) is an autosomal recessive renal tubular disorder, which is caused by the mutations in KCNJ1. This study was designed to analyze and describe the genotype and clinical features of five Chinese probands with BS2. MethodsIdentify KCNJ1 gene variants by the next generation sequencing and evaluate their mutation effects according to 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines. ResultsTen variants including eight novel ones of KCNJ1 gene were found, the most common type was missense variant. The common symptoms and signs from high to low incidence were: polydipsia and polyuria (5/5), one of them (1/5) presented with diabetes insipidus; maternal polyhydramnios and premature delivery (4/5); growth retardation (3/5). Two patients presented with hypochloremic metabolic alkalosis and hypokalemia; whereas the acid-base disturbance was absent in the others. One patient had evident parathyroid hormone (PTH) resistance (hypocalcemia, hyperphosphatemia and markedly elevated PTH levels), three presented with PTH overacting (hypercalcemia, hypophosphatemia and mild elevated PTH levels), and one showed normal blood calcium and phosphorus concentrations with high-normal PTH levels. All patients had nephrocalcinosis and/or hypercalciuria, and one of them complicated with nephrolithiasis. Indomethacin has significant therapeutic effect on the growth retardation, polydipsia and polyuria and treatment was associated with a decrease in urine calcium excretion, normalization of electrolyte disturbance and PTH parameters. ConclusionsTen variants of KCNJ1 gene were identified in five Chinese probands. These patients had atypical BS phenotype lacking evident metabolic alkalosis and/or manifesting with PTH overaction/resistance, which reminds clinicians to carefully differentiate BS2 with other parathyroid disorders. This is the first report of BS2 from Chinese populations.

SUN-LB133 Analysis of Clinical Characteristics and Gene Mutation in Four Cases of Gitelman Syndrome

Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by renal salt wasting with secondary hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria. GS was found to be caused by mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter (NCCT) on the apical membrane of distal convoluted tubule. The prevalence worldwide is estimated at approximately 1:40,000, making it one of the most frequent inherited renal tubular disorders. To date, over 400 mutations scattered throughout SLC12A3 have been identified in GS patients. The majority of patients are compound heterozygous for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation. The type of the SLC12A3 mutation may be a determinant factor in the severity of GS. The purpose of this study is to analyze clinical characteristics and gene mutation in four cases of GS. Methods: Four patients with closely resembling Gitelman syndrome was selected. Results: Six SLCl2A3 gene mutations were found in these four patients. There were one SLCl2A3 homozygous mutation in case 1 and case 3, and two SLCl2A3 heterozygous mutations in case 2 and case 4, respectively. This six gene mutations include missense mutations, frameshift mutations, and nonsense mutations. Four patients were diagnosed with Gitelman syndrome. Case 4 is the most severe with severe hypokalemia, accompanied by ventricular arrhythmias, which may be related to the presence of two SLC12A3 gene mutations in the patient. Conclusions: Four patients in this study were diagnosed with Gitelman syndrome based on their clinical characteristics and genetic testing results. For patients with hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria need to exclude Gitelman syndrome.Key words: Gitelmen Syndrome, Mutations, SlC12A3 gene

A novel compound heterozygous mutation of SLC12A3 gene in a Chinese pedigree with Gitelman syndrome.

Gitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterized by salt wasting and hypokalemia resulting from loss-of-function mutations in the solute carrier family 12A3 (SLC12A3) gene encoding the thiazide-sensitive NaCl cotransporter (NCC). Here, we investigated the clinical manifestations and genetic features of a Chinese pedigree with GS. Next-generation sequencing and Sanger sequencing analysis were performed to define and confirm the SLC12A3 gene mutations of the patient (proband II:1) and this pedigree. Clinical manifestations and biochemical parameters were collected and analyzed. Genetic analysis of the SLC12A3 gene identified two novel mutations in the proband, heterozygous (c.2842delT) and heterozygous (c.1569_1586del) mutation, respectively. Additionally, heterozygous (c.2842delT) mutation in SLC12A3 gene was found in his father and younger brother. The other heterozygous (c.1569_1586del) mutation in SLC12A3 gene was carried by his mother. Two novel mutations may be related to the occurrence of the GS in the pedigree. However, additional studies are particularly required to explore the underlying molecular mechanisms.

Atypical presentation of familial hypomagnesemia with hypercalciuria and nephrocalcinosis in a patient with a new claudin-16 gene mutation

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder caused by mutations in genes that encode renal tight junction proteins claudin-16 or claudin-19, which are responsible for magnesium and calcium paracellular reabsorption in the thick ascending limb of Henle’s loop. Progressive renal failure is frequently present, and most of the patients require renal replacement therapy still during adolescence. In this case report, we describe a new homozygous missense mutation on CLDN16 gene (c.592G>C, Gly198Arg) in a 24-year-old male patient diagnosed with FHHNC after clinical investigation due to incidental detection of altered routine laboratorial tests, who was firstly misdiagnosed with primary hyperparathyroidism. In addition, it illustrates an atypical presentation of this disease, with late onset of chronic kidney disease, improving the phenotype-genotype knowledge of patients with FHHNC.

Complicated Gitelman syndrome and autoimmune thyroid disease: a case report with a new homozygous mutation in the SLC12A3 gene and literature review

BackgroundGitelman syndrome (GS) is an inherited autosomal recessive renal tubular disorder characterized by low levels of potassium and magnesium in the blood, decreased excretion of calcium in the urine, and elevated blood pH. GS is caused by an inactivating mutation in the SLC12A3 gene, which is located on the long arm of chromosome 16 (16q13) and encodes a thiazide-sensitive sodium chloride cotransporter (NCCT).Case presentationA 45-year-old man with Graves’ disease complicated by paroxysmal limb paralysis had a diagnosis of thyrotoxic periodic paralysis for 12 years. However, his serum potassium level remained low despite sufficiently large doses of potassium supplementation. Finally, gene analysis revealed a homozygous mutation in the SLC12A3 gene. After his thyroid function gradually returned to normal, his serum potassium level remained low, but his paroxysmal limb paralysis resolved.ConclusionsGS combined with hyperthyroidism can manifest as frequent episodes of periodic paralysis; to date, this comorbidity has been reported only in eastern Asian populations. This case prompted us to more seriously consider the possibility of GS associated with thyroid dysfunction.

A unique finding of normal aldosterone level in Bartter’s syndrome

Background: Bartter’s syndrome is a rare autosomal recessive renal tubular disorder characterized by hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronemia with normotension. Bartter syndrome has five types; type 1 (mutation in sodium/potassium chloride transporter), type 2 (mutation in voltage gated potassium channel), type 3 (mutation on chromosome 1 that encodes Barttin and makes only kidney-specific chloride channel B non-functional), type 4 ( mutation in BSND gene encoding Barttin and makes both kidney-specific chloride channels A & B non-functional) and type 5 (L125P gain in function mutation in calcium-sensing receptor). Case Presentation: A 28-year-old male was hospitalized for evaluation of nausea, vomiting, generalized weakness and persistent chronic hypokalemia. Bartter’s syndrome was suspected based on clinical and laboratory evidence, however serum aldosterone level was normal. Further genetic testing confirmed the diagnosis of Bartter’s syndrome type 3. Conclusions: We report a case of Bartter’s syndrome type 3 with a unique finding of normal aldosterone level.

Gitelman syndrome in a South African family presenting with hypokalaemia and unusual food cravings

BackgroundGitelman syndrome (GS) is an autosomal recessive renal tubular disorder characterised by renal salt wasting with hypokalaemia, metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is caused by mutations in SLC12A3 encoding the sodium-chloride cotransporter on the apical membrane of the distal convoluted tubule. We report a South African family with five affected individuals presenting with hypokalaemia and unusual food cravings.MethodsThe affected individuals and two unaffected first degree relatives were enrolled into the study. Phenotypes were evaluated through history, physical examination and biochemical analysis of blood and urine. Mutation screening was performed by sequencing of SLC12A3, and determining the allele frequencies of the sequence variants found in this family in 117 ethnically matched controls.ResultsThe index patient, her sister, father and two aunts had a history of severe salt cravings, fatigue and tetanic episodes, leading to consumption of large quantities of salt and vinegar. All affected individuals demonstrated hypokalaemia with renal potassium wasting. Genetic analysis revealed that the pseudo-dominant pattern of inheritance was due to compound heterozygosity with two novel mutations: a S546G substitution in exon 13, and insertion of AGCCCC at c.1930 in exon 16. These variants were present in the five affected individuals, but only one variant each in the unaffected family members. Neither variant was found in any of the controls.ConclusionsThe diagnosis of GS was established in five members of a South African family through clinical assessment, biochemical analysis and mutation screening of the SLC12A3 gene, which identified two novel putative pathogenic mutations.

Gitelman syndrome: A case report of hypokalemic seizures in an adolescent male

Gitelman syndrome (GS) is an autosomal recessive tubular disorder with an incidence of 1 in 40,000. It is characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, with secondary hyperreninemia, which can easily be managed with a potassium (K+) sparing diuretic if correctly recognized, and with an understanding of the pathophysiology. A 17-year-old male patient presented to the emergency department after an episode of tonic-clonic seizure activity and subsequent loss of consciousness. Diagnosis of GS was made following persistent hypokalemia despite adequate repletion and further laboratory analysis. The patient was placed on a K+-sparing diuretic and had no further seizure activity. This case illustrates the importance of proper clinical and diagnostic evaluation of electrolyte abnormalities in all patients, especially in younger patients in whom early diagnosis can be crucial in preventing future complications. The following core competencies are addressed in this article: Medical knowledge, Patient care.

Genotype/Phenotype Analysis in 67 Chinese Patients with Gitelman's Syndrome

Background: Gitelman's syndrome (GS) is an autosomal recessive renal tubular disorder, which is caused by the mutations in SLC12A3. This study was designed to analyze the characteristics of the genotype and phenotype, and follow-up in the largest group of Chinese patients with GS. Methods: Sixty-seven patients with GS underwent SLCl2A3 analysis, and their clinical characteristics and biochemical findings as well as follow-up were reviewed, aiming to achieve a better description of GS. Additionally, the association of genotype and phenotype was explored. Results: Forty-one different mutations were identified within these 67 GS patients, including 11 novel mutations and 5 recurrent ones. Typical hypocalciuria and hypomagnesemia were not found in 6 (9%) and 8 (11.9%) patients, respectively. Male patients and those harboring severe mutations in both alleles had significant higher urinary fractional excretion (FE) of potassium, magnesium and chlorine. In addition, there were 2 patients who had chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m²) and 32 patients with abnormal glucose metabolism. Conclusions: We identified 41 mutations related to GS, containing 11 novel variants and 5 high-frequency ones, which should facilitate earlier and more accurate diagnosis of GS. FE of electrolytes in urine may be more sensitive in the phenotype evaluation and differential diagnosis than corresponding serum electrolytes. Hypokalemia and hypomagnesemia in GS were difficult to correct; however, spironolactone might be helpful for hypokalemia to some degree. Compared with normal people, patients with GS were at higher risk of developing type 2 diabetes.

Gitelman's Syndrome: An unusual cause of Recurrent Attack of Quadriparesis

Gitelman'?s syndrome, discovered in 1966 by Gittleman,Graham and Welt, is an autosomal recessive renal tubular disorder and characterized by hypokalemic metabolic alkalosis, hypomagnesaemia, hypocalciuria. This is a rare cause of hypokalemia which has an autosomal recessive inheritance. Here we are reporting a case of a 35 years old lady presented with recurrent attacks of quadriparesis due to hypokalemia and pain in multiple joints. Later we diagnosed the case as Gitelman?'s syndrome.DOI: http://dx.doi.org/10.3329/jom.v16i1.22407 J MEDICINE 2015; 16 : 59-60

Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations.

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder exhibiting a high risk for progressive chronic kidney disease (CKD). This is a retrospective multicentre study of 25 paediatric cases with FHHNC in Poland. Median age at diagnosis was 4 years and median follow-up time was 4.8 years. All cases of FHHNC carried recessive mutations in CLDN16. The founder mutation in CLDN16, Leu151Phe, was the most frequent cause of FHHNC in Polish patients, with 13 (52%) cases being homozygous and 5 (20%) carrying Leu151Phe allele in compound heterozygosity. All cases showed nephrocalcinosis, increased urinary fractional excretion of magnesium and hypercalciuria. Other disease features included hypomagnesaemia (76%), hyperparathyroidism (76%), hyperuricaemia (56%) and hypocitraturia (60%). Treatment with thiazides effectively reduced hypercalciuria in most cases. During follow-up, renal function declined in 60% of patients; 12% of patients reached CKD stage 3 or 4 and one patient developed end-stage renal failure. We report one of the largest cohorts of FHHNC cases caused by CLDN16 mutations. A missense variant of CLDN16, Leu151Phe, is the most common mutation responsible for FHHNC in Poland. Additionally, we found that normomagnesaemia does not exclude FHHNC and the calculation of fractional excretion of Mg can be diagnostic in the setting of normomagnesaemia. We also demonstrate the efficacy of a treatment with thiazides in terms of hypercalciuria in the majority of patients.

Hypokalemic paralysis in a middle-aged female with classic Bartter syndrome

Inherited classic Bartter syndrome (cBS) is an autosomal recessive renal tubular disorder resulting from inactivating mutations in the asolateral chloride channel (C1C-Kb) and usually presents in early infancy or childhood with mild to moderate hypokalemia. Profound hypokalemic paralysis in patients with cBS is extremely rare, especially in middle age. A 45-year-old Chinese female patient was referred for evaluation of chronic severe hypokalemia despite regular K+ supplementation (1 mmol/kg/d). She had had two episodes of muscle paralysis due to severe hypokalemia (K+ 1.9 - 2.1 mmol/l) in the past 3 years. She denied vomiting, diarrhea, or the use of laxatives or diuretics. Her blood pressure was normal. Biochemical studies showed hypokalemia (K+ 2.5 mmol/l) with renal potassium wasting, metabolic alkalosis (HCO3- 32 mmol/l), normomagnesemia (Mg2+ 0.8 mmol/l), hypercalciuria (calcium to creatinine ratio 0.5 mmol/mmol; normal < 0.22 mmol/mol), high plasma renin activity, but normal plasma aldosterone concentration. Abdominal sonography revealed neither renal stones nor nephrocalcinosis. Acquired causes of cBS such as autoimmune disease and drugs were all excluded. Molecular analysis of the CLCNKB gene, encoding ClC-Kb, and SLC12A3, encoding the thiazide-sensitive sodium chloride cotransporter (NCC), revealed compound heterozygous mutations in CLCNKB (L335P and G470E) inherited from her parents; her SLC12A3 was normal. These two mutations were not identified in 100 healthy subjects. Her plasma K+ concentration rose to 3 - 3.5 mmol/l after the addition of spironolactone. Inherited cBS may present with hypokalemic paralysis and should be considered in adult patients with hypokalemia and metabolic alkalosis.

A man with a worrying potassium deficiency

SummaryHypokalaemia may present as muscle cramps and Cardiac arrhythmias. This is a condition commonly encountered by endocrinologists and general physicians alike. Herein, we report the case of a 43-year-old gentleman admitted with hypokalaemia, who following subsequent investigations was found to have Gitelman's syndrome (GS). This rare, inherited, autosomal recessive renal tubular disorder is associated with genetic mutations in the thiazide-sensitive sodium chloride co-transporter and magnesium channels in the distal convoluted tubule. Patients with GS typically presents at an older age, and a spectrum of clinical presentations exists, from being asymptomatic to predominant muscular symptoms. Clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia. Treatment of GS consists of long-term potassium and magnesium salt replacement. In general, the long-term prognosis in terms of preserved renal function and life expectancy is excellent. Herein, we discuss the biochemical imbalance in the aetiology of GS, and the case report highlights the need for further investigations in patients with recurrent hypokalaemic episodes.Learning points Recurrent hypokalaemia with no obvious cause warrants investigation for hereditary renal tubulopathies.GS is the most common inherited renal tubulopathy with a prevalence of 25 per million people.GS typically presents at an older age and clinical suspicion should be raised in those with hypokalaemic metabolic alkalosis associated with hypomagnesaemia.Confirmation of diagnosis is by molecular analysis for mutation in the SLC12A3 gene.

Claudin-19 Mutations and Clinical Phenotype in Spanish Patients with Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive tubular disorder characterized by excessive renal magnesium and calcium excretion and chronic kidney failure. This rare disease is caused by mutations in the CLDN16 and CLDN19 genes. These genes encode the tight junction proteins claudin-16 and claudin-19, respectively, which regulate the paracellular ion reabsortion in the kidney. Patients with mutations in the CLDN19 gene also present severe visual impairment. Our goals in this study were to examine the clinical characteristics of a large cohort of Spanish patients with this disorder and to identify the disease causing mutations. We included a total of 31 patients belonging to 27 unrelated families and studied renal and ocular manifestations. We then analyzed by direct DNA sequencing the coding regions of CLDN16 and CLDN19 genes in these patients. Bioinformatic tools were used to predict the consequences of mutations. Clinical evaluation showed ocular defects in 87% of patients, including mainly myopia, nystagmus and macular colobomata. Twenty two percent of patients underwent renal transplantation and impaired renal function was observed in another 61% of patients. Results of the genetic analysis revealed CLDN19 mutations in all patients confirming the clinical diagnosis. The majority of patients exhibited the previously described p.G20D mutation. Haplotype analysis using three microsatellite markers showed a founder effect for this recurrent mutation in our cohort. We also identified four new pathogenic mutations in CLDN19, p.G122R, p.I41T, p.G75C and p.G75S. A strategy based on microsequencing was designed to facilitate the genetic diagnosis of this disease. Our data indicate that patients with CLDN19 mutations have a high risk of progression to chronic renal disease.

Calcium Unresponsive Hypocalcemic Tetany: Gitelman Syndrome with Hypocalcemia

Introduction. Gitelman's syndrome (GS) is autosomal recessive renal tubular disorder characterized by hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis, and hyperreninemic hyperaldosteronism. It is usually associated with normal serum calcium. We report a patient presented with hypocalcemic tetany, and evaluation showed Gitelman's syndrome with hypocalcemia. Case Report. A 28-year-old woman presented with cramps of the arms, legs, fatigue, and carpal spasms of one week duration. She has history of similar episodes on and off for the past two years. Her blood pressure was 98/66 mmHg. Chvostek's sign and Trousseau's sign were positive. Evaluation showed hypokalemia, hypocalcemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. Self-medication, diuretic use, laxative abuse, persistent vomiting, and diarrhoea were ruled out. Urinary prostaglandins and genetic testing could not be done because of nonavailability. To differentiate Gitelman syndrome from Bartter's syndrome (BS), thiazide loading test was done. It showed blunted fractional chloride excretion. GS was confirmed and patient was treated with spironolactone along with magnesium, calcium, and potassium supplementation. Symptomatically, she improved and did not develop episodes of tetany again. Conclusion. In tetany patient along with serum calcium measurement, serum magnesium, serum potassium, and arterial blood gases should be measured. Even though hypocalcemia in Gitelman syndrome is rare, it still can occur.

Antenatal Bartter Syndrome: A Review

Antenatal Bartter syndrome (ABS) is a rare autosomal recessive renal tubular disorder. The defective chloride transport in the loop of Henle leads to fetal polyuria resulting in severe hydramnios and premature delivery. Early onset, unexplained maternal polyhydramnios often challenges the treating obstetrician. Increasing polyhydramnios without apparent fetal or placental abnormalities should lead to the suspicion of this entity. Biochemical analysis of amniotic fluid is suggested as elevated chloride level is usually diagnostic. Awareness, early recognition, maternal treatment with indomethacin, and amniocentesis allow the pregnancy to continue. Affected neonates are usually born premature, have postnatal polyuria, vomiting, failure to thrive, hypercalciuria, and subsequently nephrocalcinosis. Hypokalemia, metabolic alkalosis, secondary hyperaldosteronism and hyperreninaemia are other characteristic features. Volume depletion due to excessive salt and water loss on long term stimulates renin-angiotensin-aldosterone system resulting in juxtaglomerular hyperplasia. Clinical features and electrolyte abnormalities may also depend on the subtype of the syndrome. Prenatal diagnosis and timely indomethacin administration prevent electrolyte imbalance, restitute normal growth, and improve activity. In this paper, authors present classification, pathophysiology, clinical manifestations, laboratory findings, complications, and prognosis of ABS.