Cases reported "Bartter Syndrome"

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1/40. Gitelman disease associated with growth hormone deficiency, disturbances in vasopressin secretion and empty sella: a new hereditary renal tubular-pituitary syndrome?

    Gitelman disease was diagnosed in two unrelated children with hypokalemic metabolic alkalosis and growth failure (a boy and a girl aged 7 mo and 9.5 y, respectively, at clinical presentation) on the basis of mutations detected in the gene encoding the thiazide-sensitive NaCl cotransporter of the distal convoluted tubule. GH deficiency was demonstrated by specific diagnostic tests in both children. Hypertonic saline infusion tests showed a partial vasopressin deficiency in the girl and delayed secretion of this hormone in the boy. magnetic resonance imaging revealed an empty sella in both cases. Up to now, hypomagnesemia and hypocalciuria have been considered obligatory criteria for the diagnosis of Gitelman disease; however, our two patients had hypomagnesemia and hypocalciuria in less than half the determinations. GH replacement treatment was associated with a good clinical response in both children. It appears that these cases represent a new phenotype, not previously described in Gitelman disease, and that the entity may be considered a new complex hereditary renal tubular-pituitary syndrome.
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2/40. Identification of a novel R642C mutation in Na/Cl cotransporter with Gitelman's syndrome.

    Gitelman's syndrome, a variant of Bartter's syndrome, is an inherited disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria, and these abnormalities have recently been linked to the thiazide-sensitive Na/Cl cotransporter (TSC) gene. We evaluated three unrelated patients affected with this syndrome whose diagnosis was made based on clinical and biochemical features. The data of clearance studies in these patients were compatible with Gitelman's syndrome. We then investigated possible mutations of the TSC gene. In one patient whose parents are consanguineous, we identified a novel missense mutation in the TSC gene, which causes alteration of arginine to cysteine at codon 642 (R642C mutation) located in the cytoplasmic tail of the product. This mutation results in the loss of an MspI site in exon 15 of the TSC gene. MspI digestion analysis of genomic dna fragments from the family was consistent with the autosomal recessive inheritance of the disorder, and presence of this mutation correlated with the clinical manifestations. Such mutation was not detected in 47 normal healthy subjects. In the second patient, we found another missense mutation in one allele of the TSC gene, which results in alteration of arginine to glutamine at codon 955. In the third patient, no mutation causing amino acid substitution was found in the TSC gene. These results indicate that the R642C mutation in TSC is critically important for impairment of this cotransporter function and also suggest the necessity of further investigations in the genetic background of Gitelman's syndrome.
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3/40. Phenotypic variability in bartter syndrome type I.

    Limited phenotypic variability has been reported in patients with bartter syndrome type I, with mutations in the Na-K-2Cl cotransporter gene (BSC). The diagnosis of this hereditary renal tubular disorder is usually made in the antenatal-neonatal period, due to the presence of polyhydramnios, premature delivery, hypokalemia, metabolic alkalosis, hypercalciuria, and nephrocalcinosis. Among nine children with hypercalciuria and nephrocalcinosis, we identified new mutations consistent with a loss of function of the mutant allele of the BSC gene in five. Three of the five cases with BSC gene mutations were unusual due to the absence of hypokalemia and metabolic alkalosis in the first years of life. The diagnosis of incomplete distal renal tubular acidosis was considered before molecular evaluation. Three additional patients with hypokalemia and hypercalciuria, but without nephrocalcinosis in the first two and with metabolic acidosis instead of alkalosis in the third, were studied. Two demonstrated the same missense mutation A555T in the BSC gene as one patient of the previous group, suggesting a single common ancestor. The third patient presented with severe hypernatremia and hyperchloremia for about 2 months, and a diagnosis of nephrogenic diabetes insipidus was hypothesized until the diagnosis of bartter syndrome type I was established by molecular evaluation. We conclude that in some patients with bartter syndrome type I, hypokalemia and/or metabolic alkalosis may be absent in the first years of life and persistent metabolic acidosis or hypernatremia and hyperchloremia may also be present. Molecular evaluation can definitely establish the diagnosis of atypical cases of this complex hereditary tubular disorder, which, in our experience, may exhibit phenotypic variability.
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4/40. Gitelman's syndrome (familial hypokalemia-hypomagnesemia).

    Gitelman's syndrome (GS) is a heritable renal disorder characterized by hypomagnesemia, hypokalemia and hypocalciuria, and distinct from Bartter's syndrome (BS). As compared to those with BS, patients with GS present at an older age, and they have a milder clinical picture, normal or slightly decreased concentrating ability, reduced urinary excretion of calcium, and permanently decreased serum magnesium level. GS is caused by defective NaCl transport in the distal convoluted tubule, and linked to the gene encoding the thiazide sensitive Na-Cl-cotransporter located on chromosome 16q. patients with BS, on the other hand, have mutations in the transporters in the thick ascending loop of henle (NKCC2, ROMK, and C1C-Kb). Treatment of GS consists of magnesium salt replacement. Long term prognosis in terms of maintaining growth, preserving renal function and life expectancy is excellent.
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5/40. Placental pathology in fetal bartter syndrome.

    bartter syndrome, which presents clinically with polyuria, urinary potassium loss, hypokalemia, hypercalciuria, and alkalosis, is an autosomal recessive disorder with mutations in genes encoding the Na-K-2Cl cotransporter, the chloride channel CLC-NKB, and the potassium channel ROMK. prenatal diagnosis of bartter syndrome is now possible; however, there are no reports of the placental pathology associated with fetal bartter syndrome. We present the placental pathologic findings in two siblings with fetal bartter syndrome. Both pregnancies were complicated by polyhydramnios and preterm delivery. The first pregnancy delivered at 30 weeks, and bartter syndrome was diagnosed in the perinatal period. The subsequent pregnancy required periodic therapeutic amniocentesis secondary to massive polyhydramnios and delivered at 32 weeks gestation. The suspicion of fetal bartter syndrome was very high in this second pregnancy, and the infant was confirmed to have bartter syndrome subsequently. Both placentas were large for gestational age, weighing greater than the 95th percentile. Microscopic examination showed extensive subtrophoblastic basement membrane mineralization (special stains positive for iron and calcium) in the chorionic villi. This striking finding was present in both placentas. Subtrophoblastic mineralization has been described in the literature in placentas of fetuses with abnormalities including anencephaly, trisomy 21, and other congenital abnormalities; however, it has also been described in normal pregnancies. Mechanisms of calcification in the placenta are not well understood, but these striking cases suggest that defects in fetal renal excretion of ions can lead to dystrophic calcification within the placenta, particularly in a subtrophoblastic pattern.
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6/40. Attenuated renal excretion in response to thiazide diuretics in Gitelman's syndrome: a case report.

    Gitelman's syndrome is a variant of Bartter's syndrome characterized by hypocalciuria and hypomagnesemia. The administration of thiazide diuretics may induce a subnormal increase of urinary Na and Cl- excretion in patients with Gitelman's syndrome, consistent with the hypothesis that less Na and Cl- than normal is reabsorbed by the thiazide-inhibitable transporter in Gitelman's syndrome. Specific mutations of NaCl cotransporter, coupled with mutant NaCl cotransporter expression studies clearly demonstrated that many of the characteristics of individuals with Gitelman's syndrome are explained by lack of function of NaCl cotransporter. We recently diagnosed a patient with Gitelman's syndrome by performing the thiazide and furosemide tests, and it is suggested that the clearance studies by diuretic administration may be of diagnostic help in Gitelman's syndrome.
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7/40. Functional characterization of a calcium-sensing receptor mutation in severe autosomal dominant hypocalcemia with a Bartter-like syndrome.

    The extracellular Ca(2 )-sensing receptor (CaSR) plays an essential role in extracellular Ca(2 ) homeostasis by regulating the rate of parathyroid hormone (PTH) secretion and the rate of calcium reabsorption by the kidney. Activation of the renal CaSR is thought to inhibit paracellular divalent cation reabsorption in the cortical ascending limb (cTAL) both directly and indirectly via a decrease in NaCl transport. However, in patients with autosomal dominant hypocalcemia (ADH), caused by CaSR gain-of-function mutations, a defect in tubular NaCl reabsorption with renal loss of NaCl has not been described so far. This article describes a patient with ADH due to a gain-of-function mutation in the CaSR, L125P, associated with a Bartter-like syndrome that is characterized by a decrease in distal tubular fractional chloride reabsorption rate and negative NaCl balance with secondary hyperaldosteronism and hypokalemia. The kinetics of activation of the L125P mutant receptor expressed in HEK-293 cells, assessed by measuring CaSR-stimulated changes in intracellular Ca(2 ) and ERK activity, showed a dramatic reduction in the EC(50) for extracellular Ca(2 ) compared with the wild-type and a loss-of-function mutant CaSR (I40F). This study describes the first case of ADH associated with a Bartter-like syndrome. It is herein proposed that the L125P mutation of the CaSR, which represents the most potent gain-of-function mutation reported so far, may reduce NaCl reabsorption in the cTAL sufficiently to result in renal loss of NaCl with secondary hyperaldosteronism and hypokalemia.
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8/40. association between activating mutations of calcium-sensing receptor and Bartter's syndrome.

    Bartter's syndrome is a heterogeneous disorder characterised by deficient renal reabsorption of sodium and chloride, and hypokalaemic metabolic alkalosis with hyper-reninaemia and hyperaldosteronaemia. Mutations in several ion transporters and channels have been associated with the pathogenesis of Bartter's syndrome. We describe two hypocalcaemic patients with deficient parathyroid hormone secretion who also showed characteristics of Bartter's syndrome. We found activating mutations of the gene for the calcium-sensing receptor (CASR) in both patients. Activation of this calcium-sensing receptor inhibits the activity of a renal outer-medullary potassium channel that is mutated in type 2 Bartter's syndrome. We therefore suggest that some activating mutations of CASR could provide new mechanisms for the development of Bartter's syndrome.
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9/40. Heterozygous mutations of the gene for Kir 1.1 (ROMK) in antenatal bartter syndrome presenting with transient hyperkalemia, evolving to a benign course.

    Bartter-like syndrome encompasses a set of inherited renal tubular disorders associated with hypokalemic metabolic alkalosis, renal salt wasting, hyperreninemic hyperaldosteronism, and normal blood pressure. Antenatal bartter syndrome, a subtype of Bartter-like syndrome, is characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. Mutations in the bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) and ATP-sensitive inwardly rectifying potassium channel (ROMK) of the thick ascending limb of Henle's loop have been identified in the antenatal bartter syndrome. We report the identification of two heterozygous mutations of the gene for Kir 1.1 (ROMK) from an antenatal bartter syndrome patient who presented at birth with mild salt wasting and a biochemical findings that mimicked primary pseudohypoaldosteronism type 1, such as hyperkalemia and hyponatremia, and evolved to a relatively benign course. We have identified amino acid exchanges Arg338Stop and Met357Thr in the gene exon 5 for ROMK by PCR and direct sequencing. Both mutations alter the C-terminus of the ROMK protein, and can affect channel function.
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10/40. Abnormalities of erythrocyte sodium transport systems in Bartter's syndrome.

    The basic tubular alteration present in Bartter's syndrome is still a subject of controversy. The possibility that a generalized defect in the transmembrane ion transport underlies the disease has been extensively investigated. Previous evaluations of cellular sodium metabolism in Bartter patients showed extremely variable findings. We have examined in the red blood cells of two patients with Bartter's syndrome the intracellular Na and K concentrations, the activity of the ouabain-sensitive Na /K pump, furosemide-sensitive Na /K cotransport, Na /Li countertransport and the rate constant of Na and K passive permeability. We have compared these values with those of healthy subjects and patients with chronic hypokalemia produced by conditions other than Bartter's syndrome. ouabain-sensitive Na /K pump activity was decreased in both patients, whereas Na /Li countertransport was activated. One of the patients also exhibited markedly decreased intraerythrocyte K concentration and decreased furosemide-sensitive Na /K cotransport. The other had increased Na /K cotransport activity and Na passive permeability. Intracellular Na and passive permeability to K were normal in both subjects. Neither oral potassium supplementation (100 mEq/day) nor indomethacin treatment (150 mg/day) could correct these abnormalities. Our results are partially consistent with previous observations and indicate the existence of heterogenous abnormalities of erythrocyte sodium transport systems in patients with Bartter's syndrome which are not a consequence of chronic hypokalemia.
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