Ten Year Retrospective Review of Bartter Syndrome at Sheikh Hospital 2008-2018

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Introduction
In 1962, Bartter et al. identified a new syndrome characterized by hypokalemia and metabolic alkalosis with hyperaldosteronism and hyperplasia of the juxtaglomerular apparatus (JGA) [1]. Those patients were different from the typical patients with hyperaldosteronism because they were younger, had normal blood pressure, also had growth retardation. Bartter syndrome (BS) is currently recognized as a rare inherited renal tubular disorder that affects around 1 in 1,000,000 of the population. It is, caused by defective salt reabsorption in the thick ascending limb (TAL) of the loop of Henle, resulting in salt wasting, hypokalemia and metabolic alkalosis with relatively low levels of serum chloride [2]. Impairment in the sodium-potassium-chloride cotransporter (NKCC2) or the potassium channel (ROMK) affects the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). This results in increased distal delivery of these ions, where only some sodium is reabsorbed, and potassium is secreted [3].
BS is a heterogeneous disorder, both clinically and genetically, that can be classified into two clinical variants, antenatal BS (aBS) and classic BS (cBS), according to the onset age. Also, BS can be classified into at least five genetic subtypes according to the underlying mutant gene, all of which are expressed in the tubular epithelial cells of the thick ascending limb of the loop of Henle [2].
Types of Bartter syndrome: i. Type I results from mutations in the sodium chloride/potassium chloride cotransporter gene (NKCC2). ii.
Type II results from mutations in the ROMK gene. iii.
Type III results from mutations in the chloride channel gene (CLC-Kb). iv.
Type IV results from the loss-of-function mutations in the gene encoding Barttin [4,5]. v.
Type V results from mutations in extracellular calcium ionsensing receptor and in the genes that encode the chloride channel subunits, ClC-Ka and ClC-Kb.
Bartter syndrome is usually seen in children and adolescents who also have stunted growth and complaints of polyuria, polydipsia, cramps, vomiting, dehydration, constipation, growth delays, and failure to thrive. A family history of nephrocalcinosis and detailed personal history ruling out the possibility of surreptitious vomiting and diuretic abuse should be practiced before making the diagnosis. Patients are usually emaciated with a prominent forehead, large eyes, strabismus, protruding ears, sensorineural deafness, and drooping mouth. Normal or low blood pressures are usually recorded. Long-standing cases may present with elevated blood pressures. Offspring with antenatal Bartter syndrome present with polyhydramnios secondary to intrauterine polyuria and are usually delivered prematurely. Fever, sensorineural deafness, profound polyuria, vomiting, and diarrhea leading to dehydration are common observations after birth [6]. Diagnosis is made by pertinent findings in the background and physical exam, potentiated with specific laboratory abnormalities. Bartter syndrome is associated with electrolyte and acidbase abnormalities, including hypokalemia and metabolic alkalosis in almost all cases [7].

I Ethical Considerations
This study was approved by the institutional review board of Mashhad University of Medical sciences. Informed consent was obtained from all patients or their parents.

II Inclusion Criteria
A total of 14 patients who were admitted to Sheikh Hospital with a diagnosis of Bartter syndrome from 2008 to 2018 have participated.

III Study Design
The information of all those 14 patients such as age, gender, clinical features and laboratory findings were abstracted from their files and evaluated.

IV Statistical Analyses
Data are expressed as mean ± SD. All analyses were performed using standard statistical software. The clinical backgrounds of the patients were compared using the Mann-Whitney, one-way ANOVA, one sample t-test and Student's t-tests, as appropriate. A P-value of <0.05 was considered statistically significant.

Results
Our study aimed to review and evaluate ten-year information of patients with Bartter syndrome in Sheikh Hospital to diagnose this disease sooner and to help patients have a faster recovery. A total of 14 patients admitted to Sheikh Hospital with diagnosis of Bartter syndrome between 2008 and 2018 were included. The minimum age of participants was 36 weeks and the maximum age was 192 weeks. Also, 6 patients were male, and 8 patients were female. The minimum age of diagnosis was at week 2 and the maximum age was at week 132 of birth. The most important clinical features of patients were growth retardation, nausea, polyuria, fever and weakness ( Table 2). Growth retardation was a common disorder in female patients (4 out of 6 newborns) while in male patients, weakness and nausea were more common.

I Polyuria and Polydipsia
Polyuria and polydipsia were found in just two patients as their chief complaint.

II Nausea and Vomiting
Nausea and vomiting were found in four patients, and analysis shows that there is no significant difference between the neonates' gender and this complication (P=0.594).

III Mental Retardation
Mental retardation is one of the most important symptoms in Bartter syndrome and it was found in one female newborn. There is no significant difference between the neonates' gender and this complication (P=0.175).

IV Malnutrition
Malnutrition was found in two female neonates.

V Weakness
Weakness also found in two male and three female neonates, and there is no significant difference between the neonates' gender and this complication (P=0.657).

VI Preterm Labor
Preterm labor was found in one male and three female neonates, and there is no significant difference between the neonates' gender and this complication (P=0.604).

VII Polyhydramnios
Polyhydramnios is an important sign in Bartter syndrome and was found in two neonates. There is no significant difference between the neonates' gender and this complication. As polyhydramnios is an obvious manifestation of Bartter syndrome it reminds the necessity of gestational ultrasonography.

VIII Fever
Four male and five female neonates showed fever during the disease, but there was no significant difference between the neonates' gender and this complication (P=0.657).

IX Seizure
Seizure almost found in association with fever in one male and three female neonates.

X Nephrocalcinosis
Nephrocalcinosis was reported in only two female neonates. There was no significant difference between the neonates' gender and nephrocalcinosis (P=0.308).

XI Hearing Loss
Hearing loss was found in two infants.

XII Diarrhea
One male and three female neonates showed diarrhea as their chief complaint.

XIII Mortality
All patients were treated, and one female neonate died due to the complications.

XIV Drugs
Drugs used for 13 survived patients included potassium chloride, normal saline, Aldactone and ibuprofen.

XV Genetic Evaluation
A genetic evaluation was performed on a few patients and two Bartter syndrome cases were confirmed, and one Pseudo Bartter syndrome (congenital diarrhea with chloride excretion) was reported.

XVI Sonography Findings
Sonography findings showed no abnormality in the kidneys of five patients, while the rest had nephrocalcinosis and nephrolithiasis as one of the complications. Due to the 65% prevalence of these complications the necessity for ultrasound examination of these patients is indicated.

XVII Biochemical Laboratory Findings
Biochemical factors measured in our study include urea, creatinine, sodium, potassium, calcium, phosphor, and fasting blood sugar, RBC and WBC in urine, urine calcium, urine protein, urine pH, blood pH, pCO2, HCO3, and hemoglobin (Table 1).

XVIII Potassium
Potassium normal range in children is 3.5-5.5 mEq/l, while the potassium range in Bartter syndrome patients in our study is 2-4.5 mEq/l. This finding shows that the potassium level in participants is significantly less than the normal population (P=0.0001).

XIX Urea
The normal range of urea in children is 5.4-24.3 mmol/l. Our study demonstrates that urea is significantly higher than normal in participants (15-151 mmol/l), and blood urea nitrogen has a significant increase in neonates with Bartter syndrome (P=0.0001).

XX Sodium
Our findings showed that serum sodium levels in participants have no significant difference with that of the normal population. The normal sodium level in neonates is 135-145 mEq/l and in our participants, it is 110-142 mEq/l.

XXI Blood pH
One of the most important findings in Bartter syndrome is metabolic alkalosis. In this study, the bicarbonate serum levels in participants ranged from 17 to 37 mEq/l while the normal range in children is 17-28 mEq/l. Although the bicarbonate range in patients was higher than normal, it is not statistically significant.

XXII Family History
Given the genetic status of Bartter syndrome as an autosomal recessive disease, the history of 4 out of 14 patients revealed a positive family history of the disease.

Discussion
Bartter syndrome is an autosomal recessive genetic disorder. Impairment in the sodium-potassium-chloride cotransporter (NKCC2) or the potassium channel (ROMK) affects the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). Bartter syndrome affects neonates and causes preterm labor in infants with this disorder. The most prevalent complications include polyuria, polydipsia, polyhydramnios, metabolic alkalosis and fever.
In a study conducted by Simon. B D et al., they demonstrate Bartter's syndrome, featuring hypercalciuria, hypokalemia, metabolic alkalosis and early presentation with severe volume depletion. They also discussed the link between the Bartter's syndrome and the renal Na-K-2Cl co transporter gene NKCC2 and identified frame-shift or nonconservative missense mutations for this gene that co-segregate with the disease [8]. Similar to our study, the potassium level in all participants was significantly lower than the normal range.
In another study, N Takahashi et al. showed that Bartter syndrome can cause polyuria and polydipsia in all humans and animals' samples. They demonstrated that disease complications become more severe as a result of a mutation in renal the Na-K-2Cl cotransporter gene [9]. Similarly, two participants in our study were diagnosed with polyuria and polydipsia. According to these findings, gene therapy can be a suitable treatment for these patients.
In another research by Seik UV et al., the case of a woman with recurrent hydramnios in three pregnancies, whose only surviving infant was later found to have Bartter's syndrome, was described. The finding of maternal hydramnios in the present case and 12 other reported cases of Bartter's syndrome suggests that increased fetal voiding is the most likely causative factor in the development of increased amniotic fluid volume. They also indicate that early-onset hydramnios might signify Bartter's syndrome in the offspring in families with an index case [9]. In line with our study, polyhydramnios was found in two participants.
The study conducted by Hannsjörg W. Seyberth et al., turned out that a congenital hypokalemic tubular disorder is described with many features resembling Bartter syndrome. Additional features include prenatal onset with polyhydramnios and premature labor, failure to thrive, episodes of fever, vomiting, diarrhea, and renal electrolyte and water wastage, hypercalciuria, nephrocalcinosis, and osteopenia [10]. Similar to our study, the potassium level in all participants was significantly lower than the normal range, in addition, nephrocalcinosis was found in two patients diagnosed with Bartter syndrome.

Conclusion
Based on our findings, resulting from the history and information taken from the patients diagnosed with Bartter syndrome in Sheikh Hospital in the last 10 years, the most important clinical features of Bartter syndrome consist of growth retardation, hypokalemia, increased blood urea nitrogen, and nephrocalcinosis and kidney microlithiasis according to laboratory findings and sonography. In addition, some patients have complications such as preterm labor, seizure, nausea and vomiting, diarrhea and polyhydramnios. Considering these findings, we can