Alternative titles; symbols
SNOMEDCT: 700109009; ORPHA: 112, 620220; DO: 0110143;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 11q24.3 | Bartter syndrome, type 2 | 241200 | Autosomal recessive | 3 | KCNJ1 | 600359 |
A number sign (#) is used with this entry because antenatal Bartter syndrome type 2 (BARTS2) is caused by homozygous or compound heterozygous mutation in the potassium channel ROMK gene (KCNJ1; 600359) on chromosome 11q24.
Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).
Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012).
For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.
The antenatal form of Bartter syndrome is a life-threatening disorder in which both renal tubular hypokalemic alkalosis and profound systemic symptoms are manifest (Seyberth et al., 1985; Deschenes et al., 1993; Proesmans et al., 1985). The abnormalities begin in utero with marked fetal polyuria that leads to polyhydramnios between 24 and 30 weeks of gestation and, typically, premature delivery (Ohlsson et al., 1984). The amniotic fluid contains high chloride levels but normal concentrations of sodium, potassium, calcium, and prostaglandin E2. Affected neonates have severe salt wasting and hyposthenuria, moderate hypokalemic metabolic alkalosis, hyperprostaglandinuria, and failure to thrive. The International Collaborative Study Group for Bartter-like Syndromes (1997) noted that an essential manifestation of the antenatal variant is marked hypercalciuria, and as a secondary consequence, affected infants develop nephrocalcinosis and osteopenia.
Peters et al. (2002) found that 9 of 14 patients with antenatal Bartter syndrome caused by mutations in the ROMK gene developed transient hyperkalemia within the first month of life, which was in contrast to those patients with NKCC2 mutations. The phenotype in the ROMK patients resembled the clinical picture of pseudohypoaldosteronism type I (264350). Finer et al. (2003) reported 12 infants with mutations in the ROMK gene, affecting all 3 protein isoforms, who showed transient hyperkalemia as high as 9.0 mmol/L without acidosis within the first few weeks of life. Two patients developed ventricular arrhythmias and 1 patient died while hyperkalemic at age 8 days. The authors suggested that postnatal maturation of potassium-regulating mechanisms, including Na-K-ATPase, may explain the transient nature of the hyperkalemia. By functional analysis of channel conductance defects caused by different ROMK mutations, Jeck et al. (2001) suggested that patients with mutations that affect all 3 ROMK isoforms may show transient neonatal hyperkalemia, most likely due to defects affecting the cortical collecting duct.
Fever, vomiting, and occasional diarrhea associated with the antenatal Bartter syndrome have been attributed to the stimulation of renal and systemic prostaglandin E2 activity in affected infants; these symptoms are effectively treated with inhibitors of prostaglandin synthesis. Based on these clinical features, the antenatal form of Bartter syndrome has been referred to as the hyperprostaglandin E syndrome (Seyberth et al., 1987).
Fellman et al. (1996) described an infant with severe hyperprostaglandin E syndrome in whom hyperthyroidism was diagnosed at the age of 12 weeks. The hyperthyroidism was thought to have been induced by PGE2. The PGE2 stimulus was also thought to explain the recurrent acute crises of polyuria, dehydration, fever, and diarrhea in this patient. They considered the extensive and abnormal crying of the patient to be an indicator of pain caused by endogenous PGE2, since it could be abolished with indomethacin or a very high dose of fentanyl.
There may be a form of hyperprostaglandin E syndrome that is separate from the antenatal Bartter syndrome due to mutation of the SLC12A1 or KCNJ1 gene. Kockerling et al. (1996) stated that hyperprostaglandin E syndrome is characterized by its severe prenatal manifestation, leading to fetal polyuria, development of polyhydramnios, and premature birth. The disorder mimics furosemide treatment with hypokalemic alkalosis, hypochloremia, isosthenuria, and impaired renal conservation of both calcium and magnesium. Therefore, the thick ascending limb of the loop of Henle seems to be involved in the disorder. Kockerling et al. (1996) demonstrated that sensitivity to furosemide is completely maintained in patients with Bartter syndrome and Gitelman syndrome. The diuretic, saluretic, and hormonal responses were similar to those of the control group of healthy children, indicating an intact function of the thick ascending limb of the loop of Henle in BS/GS. In contrast, however, patients with hyperprostaglandin E syndrome had a marked resistance to this loop diuretic. The authors concluded that a defect in electrolyte reabsorption in the thick ascending limb of the loop of Henle plays a major role in hyperprostaglandin E syndrome.
Prenatal Diagnosis
For prenatal diagnosis, Matsushita et al. (1999) 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. The authors suggested that the latter parameters may allow prediction of fetal Bartter syndrome during the prenatal period.
Konrad et al. (1999) reviewed the clinical and laboratory findings during pregnancy and the neonatal period in 2 sibs affected with the hyperprostaglandin E syndrome. Compound heterozygosity at the KCNJ1 (600359) locus (D74Y/P110L) confirmed the clinical diagnosis of antenatal Bartter syndrome type 2 at 26 weeks of gestation (see MOLECULAR GENETICS).
In a 26-week-old fetus with a confirmed diagnosis of hyperprostaglandin E syndrome, Konrad et al. (1999) found that indomethacin therapy from 26 to 31 weeks prevented further progression of polyhydramnios without major side effects. In contrast to his 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. Thus, progression of polyhydramnios with extreme prematurity can be prevented by prenatal therapy; postnatally the early diagnosis allows the effective water and electrolyte substitution before severe volume depletion occurs.
Kleta et al. (2000) noted that the clinical problems in patients with Bartter syndrome are to a large extent caused by elevated levels of prostaglandins. Treatment options have included indomethacin, a nonselective cyclooxygenase (COX) inhibitor, but this drug has a broad range of side effects and therefore requires extensive monitoring. Kleta et al. (2000) reported successful results with a selective and specific inhibitor of COX2 (600262). This isoenzyme seems to be responsible for the elevated levels of inducible prostaglandins from the macula densa and the thick ascending limb of the loop of Henle.
The transmission pattern of BARTS2 in the families reported by Simon et al. (1996) was consistent with autosomal recessive inheritance.
The potassium channel gene ROMK (KCNJ1; 600359) is believed to be a regulator of cotransporter activity; it is an ATP-sensitive potassium channel that 'recycles' reabsorbed potassium back to the tubule lumen. In 4 kindreds, Simon et al. (1996) found mutations in the ROMK gene that cosegregated with antenatal Bartter syndrome and disrupted ROMK function (600359.0001-600359.0006). The disorder has since been designated antenatal Bartter syndrome type 2. Thus, antenatal Bartter syndrome is genetically heterogeneous.
The International Collaborative Study Group for Bartter-like Syndromes (1997) reported mutations in the KCNJ1 gene (600359.0007-600359.0009) in 3 kindreds and 5 sporadic cases with antenatal Bartter syndrome type 2. Functional coupling of ROMK and the luminal Na-K-2Cl cotransporter is crucial for NaCl reabsorption. Therefore, loss of function in ROMK, as well as in NKCC2, would be predicted to disrupt electrogenic chloride reabsorption in the medullary thick ascending limb of the loop of Henle.
Using targeted mutations, Lopes et al. (2002) established that mutations in KCNJ1 residues associated with Bartter syndrome decreased the strength of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). They concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Bartter syndrome when these mutations are present in patients.
Deschenes, G., Burguet, A., Guyot, C., Hubert, P., Garabedian, M., Dechaux, M., Loirat, C., Broyer, M. Forme antenatale de syndrome de Bartter. Ann. Pediat. 40: 95-101, 1993. [PubMed: 8457138]
Fellman, V., Pihko, H., Majander, A., Seyberth, H. W. Severe hyperprostaglandin E syndrome with hyperthyroidism: studies of pathogenetic mechanisms. J. Inherit. Metab. Dis. 19: 687-694, 1996. [PubMed: 8892027] [Full Text: https://doi.org/10.1007/BF01799846]
Finer, G., Shalev, H., Birk, O. S., Galron, D., Jeck, N., Sinai-Treiman, L., Landau, D. Transient neonatal hyperkalemia in the antenatal (ROMK defective) Bartter syndrome. J. Pediat. 142: 318-323, 2003. [PubMed: 12640382] [Full Text: https://doi.org/10.1067/mpd.2003.100]
Fremont, O. T., Chan, J. C. M. Understanding Bartter syndrome and Gitelman syndrome. World J. Pediat. 8: 25-30, 2012. [PubMed: 22282380] [Full Text: https://doi.org/10.1007/s12519-012-0333-9]
International Collaborative Study Group for Bartter-like Syndromes. Mutations in the gene encoding the inwardly-rectifying renal potassium channel, ROMK, cause the antenatal variant of Bartter syndrome: evidence for genetic heterogeneity. Hum. Molec. Genet. 6: 17-26, 1997. Note: Erratum: Hum. Molec. Genet. 6: 650 only, 1997. [PubMed: 9002665] [Full Text: https://doi.org/10.1093/hmg/6.1.17]
Jeck, N., Derst, C., Wischmeyer, E., Ott, H., Weber, S., Rudin, C., Seyberth, H. W., Daut, J., Karschin, A., Konrad, M. Functional heterogeneity of ROMK mutations linked to hyperprostaglandin E syndrome. Kidney Int. 59: 1803-1811, 2001. [PubMed: 11318951] [Full Text: https://doi.org/10.1046/j.1523-1755.2001.0590051803.x]
Kleta, R., Basoglu, C., Kuwertz-Broking, E. New treatment options for Bartter's syndrome. (Letter) New Eng. J. Med. 343: 661-662, 2000. [PubMed: 10979805] [Full Text: https://doi.org/10.1056/NEJM200008313430915]
Kockerling, A., Reinalter, S. C., Seyberth, H. W. Impaired response to furosemide in hyperprostaglandin E syndrome: evidence for a tubular defect in the loop of Henle. J. Pediat. 129: 519-528, 1996. [PubMed: 8859258] [Full Text: https://doi.org/10.1016/s0022-3476(96)70116-6]
Konrad, M., Leonhardt, A., Hensen, P., Seyberth, H. W., Kockerling, A. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics 103: 678-683, 1999. [PubMed: 10049979] [Full Text: https://doi.org/10.1542/peds.103.3.678]
Lopes, C. M. B., Zhang, H., Rohacs, T., Jin, T., Yang, J., Logothetis, D. E. Alterations in conserved Kir channel-PIP(2) interactions underlie channelopathies. Neuron 34: 933-944, 2002. [PubMed: 12086641] [Full Text: https://doi.org/10.1016/s0896-6273(02)00725-0]
Matsushita, Y., Suzuki, Y., Oya, N., Kajiura, S., Okajima, K., Uemura, O., Suzumori, K. Biochemical examination of mother's urine is useful for prenatal diagnosis of Bartter syndrome. Prenatal Diag. 19: 671-673, 1999. [PubMed: 10419618] [Full Text: https://doi.org/10.1002/(sici)1097-0223(199907)19:7<671::aid-pd571>3.0.co;2-o]
Ohlsson, A., Sieck, U., Cumming, W., Akhtar, M., Serenius, F. A variant of Bartter's syndrome: Bartter's syndrome associated with hydramnios, prematurity, hypercalciuria and nephrocalcinosis. Acta Paediat. Scand. 73: 868-874, 1984. [PubMed: 6395627] [Full Text: https://doi.org/10.1111/j.1651-2227.1984.tb17793.x]
Peters, M., Jeck, N., Reinalter, S., Leonhardt, A., Tonshoff, B., Klaus, G., Konrad, M., Seyberth, H. W. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am. J. Med. 112: 183-190, 2002. [PubMed: 11893344] [Full Text: https://doi.org/10.1016/s0002-9343(01)01086-5]
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Seyberth, H. W., Rascher, W., Schweer, H., Kuhl, P. G., Mehls, O., Scharer, K. Congenital hypokalemia and hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J. Pediat. 107: 694-701, 1985. [PubMed: 3863906] [Full Text: https://doi.org/10.1016/s0022-3476(85)80395-4]
Simon, D. B., Bindra, R. S., Mansfield, T. A., Nelson-Williams, C., Mendonca, E., Stone, R., Schurman, S., Nayir, A., Alpay, H., Bakkaloglu, A., Rodriguez-Soriano, J., Morales, J. M., Sanjad, S. A., Taylor, C. M., Pilz, D., Brem, A., Trachtman, H., Griswold, W., Richard, G. A., John, E., Lifton, R. P. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nature Genet. 17: 171-178, 1997. [PubMed: 9326936] [Full Text: https://doi.org/10.1038/ng1097-171]
Simon, D. B., Karet, F. E., Rodriguez-Soriano, J., Hamdan, J. H., DiPietro, A., Trachtman, H., Sanjad, S. A. Lifton, R. P.: Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nature Genet. 14: 152-156, 1996. [PubMed: 8841184] [Full Text: https://doi.org/10.1038/ng1096-152]