1/240. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. OBJECTIVE: To describe prenatal genetic diagnosis in hyperprostaglandin E syndrome (HPS) and the effect of indomethacin therapy on the course of the disease before birth and in the neonatal period. methods: Mutational analysis of the ROMK channel gene (KCNJ1) from amniocytes by single-strand conformational analysis and direct sequencing. review of the clinical and laboratory findings during pregnancy and the neonatal period in two siblings affected with HPS. RESULTS: Compound heterozygosity of the fetus in KCNJ1 (D74Y/P110L) confirmed the clinical diagnosis of HPS at 26 weeks of gestation. indomethacin therapy from 26 to 31 weeks prevented further progression of polyhydramnios without major side effects. In contrast to the elder brother, who had been diagnosed at the age of 2 months, the neonatal course was uncomplicated. Hypovolemic renal failure after excessive renal loss of salt and water could be prevented and severe nephrocalcinosis did not occur. CONCLUSIONS: Genetic diagnosis of HPS and subsequent prenatal indomethacin therapy seems to have a beneficial effect on the natural course of HPS, especially progression of polyhydramnios; therefore, extreme prematurity could be prevented. Also, postnatally the early diagnosis allows the effective water and electrolyte substitution before severe volume depletion. ( info) |
2/240. Recombinant human growth hormone and Gitelman's syndrome. Gitelman's syndrome is a primary renal tubular disorder with hypokalemic metabolic alkalosis, hypocalciuria, and magnesium deficiency. Short stature is one of clinical manifestations in children. The pathogenesis of short stature in Gitelman's syndrome is not known. To evaluate whether growth hormone (GH) is deficient and whether recombinant human GH (rhGH) improves growth rate, rhGH therapy was tried in a child with Gitelman's syndrome. Both height and body weight were less than the third percentile. Laboratory and radiologic findings suggested GH deficiency. During the first 6 months, rhGH therapy with potassium supplement markedly elevated growth rate from 3.8 cm/yr to 12.0 cm/yr. After cessation of rhGH, height increment markedly decreased to the pretreatment level of 3.6 cm/yr during the second 6 months. Additionally, hypomagnesemia was corrected after rhGH therapy. Accordingly, GH deficiency may contribute to short stature in children with Gitelman's syndrome, and rhGH therapy would be an excellent adjunctive treatment for short children with Gitelman's syndrome whose condition is resistant to conventional therapies in terms of growth. ( info) |
| bartter syndrome is characterized by renal potassium and chloride loss, hypokalaemia, hypochloraemic metabolic alkalosis and increased plasma renin activity along with elevated angiotensin ii and hyperaldosteronism. For diagnosis we conducted biochemical examinations of both amniotic fluid and the mother's urine. Except for potassium, amniotic fluid electrolytes in a mother with a fetus with bartter syndrome were high. Urinary chloride, sodium and calcium were very low. Thus, the latter parameters may allow prediction of fetal bartter syndrome during the prenatal period. ( info) |
4/240. 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. ( info) |
5/240. Increased transforming growth factor-beta2 expression in the glomerular arteriole of the juxtaglomerular apparatus in a Bartter's-like syndrome. Although transforming growth factor-beta (TGF-beta) has been shown to participate in regulating hormone synthesis and release, little is known about involvement of individual human TGF-beta isoforms, TGF-beta1, -beta2, and -beta3, in renin synthesis and release. We examined expression of these TGF-beta isoforms in a 50-year-old man with a Bartter's-like syndrome whose renal biopsy specimen showed hyperplasia of the juxtaglomerular apparatus (GA), mild mesangial hypercellularity, focal tubular atrophy, and interstitial fibrosis. Immunoreactivity for renin and marked expression of TGF-beta2 mRNA were noted in the glomerular arteriole of the JGA, whereas mRNA expression for TGF-beta1 was only slight and that for TGF-beta3 was still more faint. Expression of mRNAs for all 3 TGF-beta isoforms was increased in the fibrotic interstitium. This expression pattern suggests that TGF-beta2 may be involved in inducing renin synthesis and/or release in the glomerular arteriole of the JGA. ( info) |
6/240. 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. ( info) |
7/240. Dose related growth response to indometacin in gitelman syndrome. Growth failure is a recognised feature of gitelman syndrome, although it is not as frequent as in bartter syndrome. Indometacin is reported to improve growth in bartter syndrome, but not in gitelman syndrome, where magnesium supplements are recommended. This paper presents 3 sisters with gitelman syndrome who could not tolerate magnesium supplements, and whose hypotension and polyuria were eliminated by taking 2 mg/kg/day indometacin, but who grew poorly. However, increasing the indometacin dose to 4 mg/kg/day improved their growth significantly, without changing their symptoms or biochemistry. Gastrointestinal haemorrhage necessitated the use of misoprostol. ( info) |
| The neonatal form of bartter syndrome is characterized by intrauterine onset of polyuria leading to severe polyhydramnios. We report a patient with the early onset of the syndrome and a similar history in a previous sibling who died in early neonatal life. The patient is a female product of 33 weeks of gestation complicated by severe polyhydramnios. Her birth weight was 2,100 g. polyuria led to severe dehydration on the 3rd day of life. Laboratory studies showed hypokalemia, hyponatremia, and elevated plasma levels of renin and aldosterone. hypercalciuria was associated with echographic evidence of nephrocalcinosis. indomethacin therapy resulted in a significant reduction in urine volume and correction of biochemical abnormalities. growth and development are satisfactory after 4 years of indomethacin therapy, but nephrocalcinosis remains unchanged. ( info) |
9/240. Bartter's syndrome in pregnancy: a case report and review. Bartter's syndrome is a rare renal tubular disorder, involving juxtaglomerular cells hyperplasia, characterized by normotensive hyper-reninism and secondary hyperaldosteronism, marked renal loss of potassium and profound hypokalaemia. Both clinical and biochemical features are heterogeneous, ranging from the incidental finding in an asymptomatic patient to marked clinical features of hypokalaemia. Inheritance is likely to be an autosomal recessive. We present a case of Bartter's syndrome complicating pregnancy in a Chinese woman. We documented an increasing demand for potassium supplement during pregnancy which stabilized by mid-trimester. The absence of pregnancy complications such as polyhydramnios indicated that the fetus was unlikely to be affected by the condition. ( info) |
10/240. 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. ( info) |