Online Mendelian Inheritance in Man (OMIM) (original) (raw)

# 601678

BARTTER SYNDROME, TYPE 1, ANTENATAL; BARTS1

Alternative titles; symbols

HYPOKALEMIC ALKALOSIS WITH HYPERCALCIURIA 1, ANTENATAL

HYPERPROSTAGLANDIN E SYNDROME 1

SNOMEDCT: 700107006; ORPHA: 112, 620217; DO: 0110142;

Phenotype-Gene Relationships

TEXT

A number sign (#) is used with this entry because antenatal Bartter syndrome type 1 (BARTS1) is caused by homozygous or compound heterozygous mutation in the sodium-potassium-chloride cotransporter-2 gene (SLC12A1; 600839) on chromosome 15q21.

Description

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.

Clinical Features

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; and 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. Fever, vomiting, and occasional diarrhea associated with the disorder 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).

Clinical Variability

Kurtz et al. (1997) studied a cohort of 20 Costa Rican patients, previously described by Madrigal et al. (1997), who had a congenital syndrome that bore strong similarities to antenatal Bartter syndrome type 1 but also had several distinct features. In all patients, pregnancy was complicated by polyhydramnios, and 7 of the 9 patients were born prematurely. Six of 9 patients studied in detail were presented for evaluation within the first year of life. One was not diagnosed until the age of 10 years and another was 4.5 years old at the time of diagnosis. All affected children had experienced recurrent episodes of vomiting and dehydration, dating from the first few weeks of life. The phenotype was remarkable for a peculiar facies in 7 of 9 children, characterized by a triangularly shaped face, protruding ears, and drooping mouth; in addition, 5 of 9 had strabismus, and there was evidence of sensorineural hearing loss by audiogram testing in 2 of 9. All had hypokalemic metabolic alkalosis, hyposthenuria, and failure to thrive, with growth parameters less than the 3rd centile for age. Hypercalciuria with associated sonographic evidence of nephrocalcinosis was demonstrated in 7 children. The other 2 children had evidence of nephrocalcinosis but normal urine calcium excretion. Renal function was well preserved in all but 1 patient, who developed renal insufficiency and progressed to end-stage renal disease by 16 years of age. Although the development of tubulointerstitial disease leading to a progressive decline in renal function had been described both in patients treated with long-term indomethacin and in patients with classic Bartter syndrome, this patient was not treated with indomethacin, and the etiology of her end-stage renal disease remained unexplained. Kurtz et al. (1997) noted that the Costa Rican patients had a milder clinical course than other antenatal Bartter syndrome patients with NKCC2 (SLC12A1) mutations.

Gross et al. (2015) reported a 5-month-old boy, born of consanguineous Arab Muslim parents with an unusual presentation of BARTS1. The delivery was complicated by polyhydramnios, and he was diagnosed with nephrocalcinosis in the neonatal period. After treatment with antibiotics for a febrile illness at age 3 months, he developed severe diarrhea with weight loss. Laboratory studies at age 5 months showed increased serum calcium, hypercalciuria, and hyperparathyroidism, but other electrolytes were normal. Specifically, he did not have hypokalemia or metabolic alkalosis. Head and neck ultrasound did not show a parathyroid adenoma. Treatment with potassium citrate was effective for the biochemical abnormalities, but he showed significant developmental delay with hypotonia at age 10 months. Gross et al. (2015) suggested that the abnormality in renal calcium homeostasis may have triggered changes in parathyroid hormone (PTH; 168450) secretion. Whole-exome sequencing identified a homozygous frameshift mutation in the SLC12A1 gene, confirming the diagnosis.

Li et al. (2016) reported 2 African American brothers with BARTS1 associated with hyperparathyroidism, hypercalcemia, hypercalciuria, and nephrocalcinosis. Both pregnancies were complicated by polyhydramnios and premature delivery. The proband's brother died of multiorgan failure at 9 weeks, and postmortem examination showed multigland parathyroid hyperplasia. The 12-year-old proband continued to have persistent hypercalciuria and increased PTH levels with normal bone density. Other electrolytes were only mildly disturbed: he had mildly low sodium, potassium, chloride, and magnesium, and mildly increased bicarbonate. Plasma renin, vasopressin, and urinary prostaglandin E2 were increased. He was treated with cinacalcet and potassium citrate. Neck ultrasound did not reveal a parathyroid adenoma.

Wongsaengsak et al. (2017) reported 4 patients from 3 unrelated families of Hispanic descent with genetically confirmed BARTS1 associated with hyperparathyroidism, hypercalcemia, nephrocalcinosis, and nephrogenic diabetes insipidus. All had classic features of the disorder, including polyhydramnios and hypokalemic metabolic alkalosis, and most had increased renin activity. Additional features included poor overall growth, failure to thrive, respiratory insufficiency, and gastroesophageal reflux. One patient was noted to have dysmorphic facial features with triangular facies and prominent forehead, and 2 were noted to have developmental delay. Treatment strategies included indomethacin, cinacalcet, potassium supplementation, and chlorothiazide, with variable responses.

Mapping

In 5 consanguineous kindreds with antenatal Bartter syndrome, Simon et al. (1996) excluded linkage to the region of chromosome 16 where the NCCT gene (SLC12A3; 600968) involved in Gitelman syndrome (263800) is located. Using multipoint linkage analysis, Simon et al. (1996) demonstrated linkage of Bartter syndrome in these families to the NKCC2 gene on chromosome 15, which encodes a sodium/potassium/chloride transporter that mediates reabsorption of sodium chloride in the thick ascending loop of Henle. In each of the 5 families, all affected offspring of consanguineous union were homozygous for alleles of each marker; in addition, while the affected subject in 1 family was not known to be the product of a consanguineous union, she too was homozygous for all markers tested in the NKCC2 segment.

Inheritance

The transmission pattern of BARTS1 in the families reported by Simon et al. (1996) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 families with antenatal Bartter syndrome, Simon et al. (1996) identified frameshift or nonconservative missense mutations in the NKCC2 gene that cosegregated with the disease (see 600839.0001-600839.0003).

In 9 patients from 7 Costa Rican families with a variant form of antenatal Bartter syndrome type 1, Kurtz et al. (1997) analyzed the SLC12A1 gene and identified homozygosity for a nonsense mutation (600839.0003) in 3 patients; in 3 additional patients, the mutation was only detected on 1 allele. The mutant allele was contained on a single common haplotype, suggesting that most patients with antenatal Bartter syndrome in Costa Rica share a single common ancestor.

Nozu et al. (2009) reported a 7-year-old Japanese girl with Bartter syndrome type 1 who was compound heterozygous for mutations in the SLC12A1 gene (600839.0004 and 600839.0005). The authors stated that this was the first study to perform mutation analysis in inherited kidney disease using noninvasive methods, i.e., with cells from urinary sediment rather than renal biopsy.

In 2 brothers, born of African American parents, with BARTS1, Li et al. (2016) identified compound heterozygous mutations in the SLC12A1 gene (600839.0006 and 600839.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed. The presentation in these boys was unusual in that they had significant hyperparathyroidism, hypercalcemia, hypercalciuria, and nephrocalcinosis. Li et al. (2016) noted that SLC12A1 is not expressed in the parathyroid gland, suggesting that loss of SLC12A1 function is unlikely to affect parathyroid function directly. The authors hypothesized that increased prostaglandin E2 may be responsible for increased serum PTH.

In 4 patients from 3 unrelated families of Hispanic descent with BARTS, Wongsaengsak et al. (2017) identified biallelic mutations in the SLC12A1 gene (see, e.g., 600839.0008-600839.0010). The mutations were found by whole-exome sequencing; functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function. In addition to classic features of the disorder, the patients had hyperparathyroidism, hypercalcemia, nephrocalcinosis, and nephrogenic diabetes insipidus. Wongsaengsak et al. (2017) postulated that the calcium and parathyroid abnormalities in these patients may be due to modulation of CaSR (601199) function.

REFERENCES

1. 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]
2. 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\]
3. Gross, I., Siedner-Weintraub, Y., Simckes, A., Gillis, D.Antenatal Bartter syndrome presenting as hyperparathyroidism with hypercalcemia and hypercalciuria: a case report and review. J. Pediat. Endocr. Metab. 28: 943-946, 2015. [PubMed: 25741940] [Full Text: https://doi.org/10.1515/jpem-2014-0188\]
4. 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\]
5. Kurtz, C. L., Karolyi, L., Seyberth, H. W., Koch, M. C., Vargas, R., Feldmann, D., Vollmer, M., Knoers, N. V. A. M., Madrigal, G., Guay-Woodford, L. M.A common NKCC2 mutation in Costa Rican Bartter's syndrome patients: evidence for a founder effect. J. Am. Soc. Nephrol. 8: 1706-1711, 1997. [PubMed: 9355073] [Full Text: https://doi.org/10.1681/ASN.V8111706\]
6. Li, D., Tian, L., Hou, C., Kim, C. E., Hakonarson, H., Levine, M. A.Association of mutations in SLC12A1 encoding the NKCC2 cotransporter with neonatal primary hyperparathyroidism. J. Clin. Endocr. Metab. 101: 2196-2200, 2016. [PubMed: 26963954] [Full Text: https://doi.org/10.1210/jc.2016-1211\]
7. Madrigal, G., Saborio, P., Mora, F., Rincon, G., Guay-Woodford, L. M.Bartter syndrome in Costa Rica: a description of 20 cases. Pediat. Nephrol. 11: 296-301, 1997. [PubMed: 9203176] [Full Text: https://doi.org/10.1007/s004670050280\]
8. Nozu, K., Iijima, K., Kawai, K., Nozu, Y., Nishida, A., Takeshima, Y., Fu, X. J., Hashimura, Y., Kaito, H., Nakanishi, K., Yoshikawa, N., Matsuo, M.In vivo and in vitro splicing assay of SLC12A1 in an antenatal salt-losing tubulopathy patient with an intronic mutation. Hum. Genet. 126: 533-538, 2009. [PubMed: 19513753] [Full Text: https://doi.org/10.1007/s00439-009-0697-7\]
9. 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\]
10. Proesmans, W., Devlieger, H., Van Assche, A., Eggermont, E., Vandenberghe, K., Lemmens, F., Sieprath, P., Lijnen, P.Bartter syndrome in two siblings: antenatal and neonatal observations. Int. J. Pediat. Nephrol. 6: 63-70, 1985. [PubMed: 3888887]
11. Seyberth, H., Koniger, S., Rascher, W., Kuhl, P., Schweer, H.Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders. Pediat. Nephrol. 1: 491-497, 1987. [PubMed: 3153322] [Full Text: https://doi.org/10.1007/BF00849259\]
12. 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\]
13. 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\]
14. Simon, D. B., Karet, F. E., Hamdan, J. M., Di Pietro, A., Sanjad, S. A., Lifton, R. P.Bartter's syndrome, hypokalemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nature Genet. 13: 183-188, 1996. [PubMed: 8640224] [Full Text: https://doi.org/10.1038/ng0696-183\]
15. Wongsaengsak, S., Vidmar, A. P., Addala, A., Kamil, E. S., Sequeira, P., Fass, B., Pitukcheewanont, P.A novel SLC12A1 gene mutation associated with hyperparathyroidism, hypercalcemia, nephrogenic diabetes insipidus, and nephrocalcinosis in four patients. Bone 97: 121-125, 2017. [PubMed: 28095294] [Full Text: https://doi.org/10.1016/j.bone.2017.01.011\]

Contributors:

Cassandra L. Kniffin - updated : 02/28/2017
Marla J. F. O'Neill - updated : 8/12/2010
Cassandra L. Kniffin - reorganized : 12/2/2002
Victor A. McKusick - updated : 9/26/2000
Victor A. McKusick - updated : 4/16/1999
Victor A. McKusick - updated : 7/14/1997
Victor A. McKusick - updated : 4/1/1997

Creation Date:

Victor A. McKusick : 2/12/1997

Edit History:

carol : 11/08/2022
alopez : 07/12/2018
alopez : 03/01/2017
ckniffin : 02/28/2017
carol : 05/12/2016
carol : 5/12/2016
carol : 5/11/2016
carol : 4/22/2013
wwang : 8/12/2010
mgross : 10/15/2009
carol : 5/26/2005
ckniffin : 8/24/2004
carol : 12/2/2002
ckniffin : 11/21/2002
carol : 11/18/2002
terry : 9/26/2000
carol : 4/19/1999
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carol : 6/25/1998
mark : 7/16/1997
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alopez : 7/10/1997
jenny : 4/1/1997
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jamie : 2/18/1997
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