NEONATAL BARTTER SYNDROME TYPE 1
Hajer Aloulou*, Salma Ben Ameur*, Imen Zouch, Amira Bouraoui*, Sonia AbdelHak**, Rosa Vargas Poussou***, Thouraya Kammoun*, Mongia Hachicha*
*Department of Pediatrics, Sfax, Tunisia**, Laboratory of genetics-Pasteur Institut, Tunis ,Tunisia, *** Department of Genetics, European Hospital ,George, Pompidou.
Address for Correspondence
H Aloulou, Hospital Hedi Chaker, 3029 SFAX, TUNISIA, France.
Email
hajer_aloulou@yahoo.fr
Abstract
Bartter's syndrome is heterogeneous renal tubular disorder affecting sodium, potassium, chloride reabsorption in the thick ascending limb of Henle's loop. It is characterized by urinary potassium loss and metabolic alkalosis. BS type 1 also referred to as antenatal or neonatal BS, is caused by mutations in the SLC12A1 gene encoding bumetanide-sensitive-sodium-potassium-chloride cotransporter (NKCC2). In antenatal BS, abnormality begins in utero with fetal polyuria resulting in polyhydramnios and premature delivery. Another hallmark of this variant is a marked hypercalciuria and as a secondary consequence, the development of nephrocalcinosis and osteopenia. A 45 day old-boy born following a pregnancy complicated by severe polyhydramnios at a gestational age of 29 weeks, presented with fractures of upper limbs, dehydration, persistent hypokalemia, hypochloremic metabolic alkalosis with normal blood pressure, elevated plasma renin activity and nephrocalcinosis. Genetic study showed homozygosity mutations in the SLC12A1 gene.
Keywords
Bartter syndrome, prematurity, nephrocalcinosis, NKCC2, SLC12A1 gene
Introduction
Bartter syndrome (BS) is an autosomal recessive, heterogeneous, renal tubular disorder in which one of the key transport proteins involved in transcellular Na-K-CL transport in the thick ascending limb of Henle's loop or distal convoluted tubule is impaired [1, 2]. The antenatal hypercalciuric variant of BS, also termed "hyperprostaglandin E syndrome is the more severe condition of polyuric loop dysfunction [2] shares common features (hypokalemia, metabolic alkalosis, and hyper-reninemic hyperaldosteronism with normal blood pressure) with the other types of BS [3]. In this report, we describe a child with typical manifestations of neonatal Bartter syndrome including polyhydramnios, prematurity, hypokalemia, metabolic alkalosis and nephrocalcinosis who improved with potassium supplements and indomethacin.
Case Report
A baby boy was born to consanguineous healthy parents of Arabic origin (Lybie) at 29 week of gestation. The parents had already given birth to 2 low premature infants after pregnancy complicated by hydramnios, however, they died of unexplained etiology at 10 and 15 days of life respectively. The birth weight of this child was 1150 g (25th centile for gestational age). The pregnancy course was also complicated by severe maternal polyhydramnios. He was initially admitted in neonatal intensive care unit in Lybie because of prematurity and suspected feto-maternal infection for 45 days. At home, parents noticed tumefaction in upper limbs. Therefore, they consulted in Tunisia and the child was admitted in our department. On examination, the child weighed 2500g (-4SD), had a length of 45 cm (-4SD) with head circumference of 34cm. He was dehydrated with a triangular face, tumefaction of upper limbs and normal blood pressure. Urine output was 5 ml/kg /hour. Investigations showed hypokalemic hypochloremic metabolic alkalosis (serum potassium = 2.5mEq/L , chloride = 96 mEq/L, bicarbonate = 28 mEq /L, PH =7.6); normal serum levels of creatinine, calcium and magnesium with increased urinary loss of calcium (calciuria = 10mmol/kg/day). Plasma aldosterone level was elevated (1083 ng/dl, normal values = 100 to790 ng/dl) as well as plasma renin activity (18.12 µg/ml/h, normal values = 9.7±1.7 ng/ml/h). Serial parathyroid hormone values were elevated (681ng/l, normal value = 3 to 5 ng/l). Radiography of limb showed bone demineralization and fracture of humerus. Ultrasonogram of the abdomen revealed nephrocalcinosis in the both kidney. Electric response audiometry of the brain stem was normal. In view of the prenatal manifestation, as well as postnatal profound polyuria, hypokalemic hypochloremic metabolic alkalosis and nephrocalcinosis, neonatal Bartter's syndrome was considered and treatment was done by correction of electrolytes and dehydration along with indomethacin. The drug was well tolerated and the infant showed correction of electrolyte imbalance. Analysis of the SLC12A gene showed two mutations (C.626T > A in exon 3) and (C.1875G > T in exon 14). Genetic study demonstrated that his parents had this mutations in the heterozygous state. On follow up at ten months, the child was asymptomatic with satisfactory weight gain. Characteristic facies with thin, triangular face, prominent forehead, large eyes and drooping mouth was evident. He is on indomethacin (2 mg/kg/day), potassium chloride supplementation (4 mmol/kg/d) and magnesium sulphate (0.5mmol/kg/d). The serum electrolytes and creatinine clearance are within the normal range.
Discussion
The hallmark of antenatal BS is polyhydramnios, prematurity, followed by postnatal polyuria and hypercalciuria [4]. Three different genes are found to be responsible of this condition : the SLC12A1(NKCC2) gene which resides in chromosome 15q15-q21 (type 1 BS), the ROMK (KCNJ1) gene located on 11q24-25(type 2) and BSND gene which encodes the common accessory -SUBMIT Barttin for CIC-Ka and CIC-Kb chloride channels (type 4) [4,5,6,7]. Several mutations of the gene SLC12A1 were reported [3]. Our patient had mutations in the SLC12A1(NKCC2) gene.

In utero, fetal polyuria can cause polyhydramnios between 24 and 30 wk of gestation followed typically by premature delivery like in our case [1,3,7]. Postnatally, affected infants present with the typical pattern of impaired tubular reabsorption in the thick ascending limb of Henle's loop including salt-wasting, isosthenuric or hyposthenuric polyuria, and hypercalciuria [8]. In addition to iso- or hyposthenuric polyuria, newborns lose large amounts of sodium and chloride through the urine, causing hyponatremia and hypochloremia. Increased sodium delivery to the distal tubule, particularly when combined with activation of renin-angiotensin-aldosterone system, enhances excretion of potassium and hydrogen ions, causing hypokalemic alkalosis [6,8].

Within the first months of life, nearly all patients develop medullary nephrocalcinosis in parallel with persistent hypercalciuria [6,9]. Urinary excretion of calcium can be used to distinguish Bartter's from Gitelman's syndrome, which is a similar condition characterized by hypomagnesemia and increased urinary loss of magnesium and hypocalciuria [5, 6, 9]. Our patient presented with nephrocalcinosis and bone demineralization consequence of hypercalciuria, the serum level of magnesium was normal. Generalised symptoms such as fever, vomiting, diarrhea and failure to thrive had been attributed to increased systemic prostaglandin formation [7,8,9].

Therapeutic efforts should be directed to correct dehydration and electrolyte imbalance. Apart from potassium and magnesium supplementation, treatment with cyclo-oxygenase inhibitors effectively reduces polyuria, ameliorates hypokalemia, and improves growth [4]. Indomethacin at a dose of 1-5 mg/kg/day is most frequently used and well tolerated [4,8]. It was beneficial in our case to correct the electrolyte abnormalities and the impairment of urinary concentration. Treatment with COX-2 inhibitors such as rofecoxib compared with classical nonsteroidal anti-inflammatory drugs such as indomethacin may be superior in terms of gastrointestinal side effects and specificity [7]. Recent studies suggest that long-term exposure to rofecoxib may carry a higher cardiovascular risk compared with non selective inhibitors [6]. On follow up at two months, our patient was asymptomatic with satisfactory weight gain. However, the long-term prognosis is guarded; lack of satisfactory control may lead to morbidity, growth failure and renal insufficiency [5].

Early diagnosis is important, because treatment with indomethacin may result in correction of the hypercalciuria, a decrease in nephrocalcinosis, and preservation of renal function. Prenatal diagnosis can be made by the high chloride content of the amniotic fluid and mutational analysis of genomic DNA extracted from cultured amniocytes obtained by amniocentesis [5,8].
References :
  1. Starremans PG, Kersten FF, Van Den Heuvel LP, Knoers NV, Bindels RJ. Dimeric architecture of the human bumetanide-sensitive Na-K-Cl Co-transporter. J Am Soc Nephrol. 2003; 14: 3039-3046.
  2. Seyberth HW. An improved terminology and classification of Bartter-like syndromes. Nat Clin Pract Nephrol. 2008; 4: 560-567.
  3. Vargas-Poussou R, Feldmann D, Vollmer M, Konrad M, Kelly L, van den Heuvel LP, et al. Novel molecular variants of the Na-K-2Cl cotransporter gene are responsible for antenatal Bartter syndrome. Am J Hum Genet. 1998; 62: 1332-1340.
  4. Adachi M, Asakura Y, Sato Y, Tajima T, Nakajima T, Yamamoto T, et al. Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Endocr J. 2007; 54: 1003-1007.
  5. Kumar PS, Deenadayalan M, Janakiraman L, Vijayakumar M. Neonatal Bartter syndrome. Indian Pediatr. 2006; 43: 735-737.
  6. Jeck N, Schlingmann KP, Reinalter SC, Komhoff M, Peters M, Waldegger S, et al. Salt handling in the distal nephron: lessons learned from inherited human disorders. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R782-795
  7. Reinalter SC, Jeck N, Brochhausen C, Watzer B, Nusing RM, Seyberth HW, et al. Role of cyclooxygenase-2 in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Kidney Int. 2002; 62: 253-260
  8. Konrad M, Leonhardt A, Hensen P, Seyberth HW, and Kockerling A. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics. 1999; 103: 678-683.
  9. Asteria C. Molecular basis of Bartter's syndrome: new insights into the correlation between genotype and phenotype. Eur J Endocrinol. 1997; 137: 613-615.
Last Updated : Saturday, August 01, 2009 Vol 6 Issue 8 Art #43
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Aloulou H, Ameur B S, Zouch I, Bouraoui A, AbdelHak S, Poussou V R, Kammoun T, Hachicha M. NEONATAL BARTTER SYNDROME TYPE 1. Pediatric Oncall [serial online] 2009[cited 2009 August 1];6. Art #43. Available From : http://www.pediatriconcall.com/Journal/Article/FullText.aspx?artid=249&type=J&tid=&imgid=&reportid=111&tbltype=
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