|Year : 2017 | Volume
| Issue : 1 | Page : 1-10
Clinical and laboratory study of infants and children with Bartter syndrome attending Alexandria University Children’s Hospital (10 years experience)
Mohamed Thabet1, Ola A Sharaki2, Hanan M Fathy1, Ahmed Z.Z Ayoub1
1 Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt
|Date of Submission||20-Nov-2016|
|Date of Acceptance||15-Feb-2017|
|Date of Web Publication||12-Jul-2017|
Hanan M Fathy
Department of Pediatrics, Faculty of Medicine, Alexandria University, Alexandria, 01666
Source of Support: None, Conflict of Interest: None
Background Bartter syndrome (BS) is a group of inherited, salt-losing tubulopathies presenting as metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. It is a consequence of abnormal function of the kidneys, which become unable to properly regulate the volume and composition of body fluids because of defective reabsorption of NaCl in loop of Henle. A first consequence of the tubular defect in BS is polyuria, which is responsible for particular complications of pregnancy − that is, polyhydramnios and premature delivery. Low potassium levels in the blood may result from overactivity of the renin–angiotensin II–aldosterone hormone system that is essential in controlling blood pressure. To date, at least five genes have been linked to BS, and they characterize five types of BS.
Aim The aim of this work is to study the clinical and laboratory data of infants and children with BS attending Alexandria University Children’s Hospital during a 10-year period (January 2004–December 2013).
Participants and methods A retrospective analysis of children diagnosed with BS attending Alexandria University Children’s Hospital during a 10-year period (January 2004–December 2013) was carried out. On the basis of the clinical, biochemical features, and ultrasonographic findings, 20 children were diagnosed with BS. Their demographic, clinical, biochemical, and hormonal profiles were analyzed. Follow-up data and outcomes were recorded.
Results The majority of cases had perinatal history of polyhydraminos. All cases had high urinary chloride in spot urine analysis. The mainstay of treatment in BS is potassium supplementation and indomethacin. Correction of hypokalemia and hyperprostaglandinemia are mandatory for improving the symptoms (vomiting, polyuria) and chronic sequalae such as FTT and growth retardation.
Conclusions According to this study, BS should be suspected in any child with a history of failure to thrive and metabolic alkalosis. Early diagnosis and treatment with NSAIDs are life-saving.
Keywords: bartter syndrome, hypokalemia, hyperreninemia, hyperaldosteronism, hypercalciuria, hypomagnesemia, metabolic alkalosis, nephrocalcinosis
|How to cite this article:|
Thabet M, Sharaki OA, Fathy HM, Ayoub AZ. Clinical and laboratory study of infants and children with Bartter syndrome attending Alexandria University Children’s Hospital (10 years experience). Alex J Pediatr 2017;30:1-10
|How to cite this URL:|
Thabet M, Sharaki OA, Fathy HM, Ayoub AZ. Clinical and laboratory study of infants and children with Bartter syndrome attending Alexandria University Children’s Hospital (10 years experience). Alex J Pediatr [serial online] 2017 [cited 2019 Mar 18];30:1-10. Available from: http://www.ajp.eg.net/text.asp?2017/30/1/1/210438
| Introduction|| |
Bartter syndrome (BS) was originally described by Bartter et al. in 1962 . It is a primary tubulopathy that presents with failure to thrive (FTT), fatigue, polyuria, polydipsia, nocturia, generalized weakness, salt cravings, dehydration, vomiting, muscle weakness, muscle spasm, tetany, mental confusion, and short stature .
It is an inherited disorder (autosomal recessive) characterized by hypokalemia, hypochloremic metabolic alkalosis, hyperreninemia, hyperprostaglandinism, normal blood pressure, with an increased urinary loss of sodium (Na), chloride (Cl), potassium (K), calcium (Ca), and prostaglandins .
BS is rare, and estimates of its occurrence vary from country to country. In the USA, the estimated prevalence is one per million .
In Kuwait, the prevalence in the general population is 1.7 cases per 100 000 persons. In Palestine, evaluation of an affected family member (12) revealed phenotypic features of both Gitelman syndrome and classic BS, whereas in United Arab Emirates two cases of BS among nationals were observed. In Saudi Arabia, nine patients (the father and eight siblings) had biochemical features of BS .
In Egypt, there is no estimated prevalence of BS.
Thick ascending loop of Henle (TALH) has channels, coded by a specific gene. Any mutation in the gene results in impaired channel function and hence defective electrolyte reabsorption (Na+ K+, Cl−, and Ca2+) in the TALH and delivery of large volumes of urine with a high content of Na+, K+, Cl−, and Ca2+ to the distal tubule ,. In the distal tubule, part of the delivered Na+ will be reabsorbed in exchange for intracellular K+. Hence, K wasting occurs . Impaired Na absorption in TALH will result in increased levels of prostaglandin E2. Increased PGE2 will exacerbate primary defect of Cl transport in TALH, which will stimulate renin–angiotensin–aldosterone axis causing hypokalemia (because of hyperaldosteronism), and impede water reabsorption in collecting ducts leading to hyposthenuria. Hyperaldosteronism increases K wasting and stimulates exchange of intracellular H ions for K ions for intraluminal K (distal tubule and collecting duct) resulting in exaggeration of metabolic alkalosis ,.
Etiology and types
BS is a hereditary disease, with an autosomal recessive (BS types I–IV) or autosomal dominant (BS type V) mode of transmission . To date, at least five genes have been linked to BS, and they characterize five types of BS  ([Table 1]).
|Table 1 Genetics and presentation (clinical and lab) of Bartter syndrome |
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Most cases of BS are usually symptomatic early in life, although occasional patients (mostly BS type III and rare patients with BS types IV and V) may continue into adulthood with few, if any, manifestations .
Mothers of fetus with BS often present with unexplained polyhydramnios between 24 and 30 weeks of gestation. Intrauterine growth restriction may also be associated with the inability of the kidney tubule to retain salt and water, resulting in fetal polyuria. Infants are usually born preterm ,,.
After birth, rapid weight loss, lethargy and poor feeding, FTT, fatigue, polyuria, polydipsia, nocturia, generalized weakness, salt cravings, dehydration, vomiting, muscle weakness, muscle spasm, tetany, mental confusion, and short stature (if untreated) were observed ,,,,.
Facial features such as triangular face, prominent forehead, large eyes, protruding ears, and drooping mouth may be present. Sensorineural deafness is seen in type IV BS. Strabismus, convulsions, and increased susceptibility to infections are also reported ,.
Patients with antenatal BS (types I and II) fail to establish an adequate transepithelial voltage gradient to drive Ca and magnesium absorption, giving rise to hypercalciuria and hypermagnesiuria, which increase predisposition to nephrocalcinosis .
Clinically, BS types III and V appear to be less severe than types I, II, and IV despite similar biochemical indices .
Untreated infants fail to thrive and may die in a few days as a result of dehydration, poor feeding, or severe electrolyte disturbance. Mild mental retardation is linked to delay in diagnosis and treatment .
The important complications of BS include hypercalciuria leading to nephrocalcinosis, growth retardation, FTT, and developmental delay in untreated patients. Sensorineural deafness is associated with BS IV. Cardiac arrhythmia and sudden death may result from electrolyte imbalances. There was a significant decrease in bone mineral density. Very rarely progressive renal disease, renal failure, and interstitial nephritis can occur. Acute renal failure from rhabdomyolysis due to hypokalemia has also been reported ,,,.
The diagnosis of BS is largely one of exclusion, made in patients who present with unexplained hypokalemia and metabolic alkalosis with a normal or low blood pressure, and in whom other, more common, etiologies are ruled out.
The most helpful laboratory test is measurement of the urine Cl concentration, which is usually greater than 40 mmol/l in patients with BS in whom Cl excretion is equal to dietary Cl intake .
Measurement of urinary Ca excretion, which is usually high-normal or elevated in patients with BS, is another diagnosis method. Urinary Ca excretion can be determined with a 24 h urine collection or estimated from the calcium-to-creatinine (Ca/Cr) ratio in a spot urine specimen. The range of normal values for these measurements is more than 4 mg/kg/day or more than 0.21 urinary Ca/Cr ratio .
Prenatal diagnosis can be made by the high Cl content of the amniotic fluid ,, and mutational analysis of genomic DNA extracted from cultured amniocytes obtained by amniocentesis .
The main differential diagnosis is with Gitelman syndrome, also known as the hypocalciuric variant of BS. Gitelman syndrome is an autosomal recessive disorder that presents with hypokalemia, metabolic alkalosis, hypomagnesemia, hypocalciuria, and normal blood pressure ,,,.
In contrast to the typically early clinical presentation in BS, Gitelman syndrome is usually not diagnosed until late childhood or adulthood , although presentation in infancy has been described .
Other causes of unexplained hypokalemia and metabolic alkalosis associated with a normal or low blood pressure must be excluded before making the diagnosis of BS or Gitelman syndrome. The most common disorders that have a similar presentation and must be excluded are unexplained vomiting and diuretic use. It is not uncommon for patients to have both vomiting and diuretic abuse.
Measurement of the urine Cl concentration usually distinguishes unexplained self-induced vomiting from BS and Gitelman syndrome ,.
The urine Cl concentration is usually less than 25 mmol/l in patients with vomiting due to both hypovolemia and hypochloremia. In contrast, the urine Cl concentration is typically much higher (usually >40 mmol/l) in patients with BS or Gitelman syndrome .
In the case of long use of diuretics, appropriate drug history and demonstration of the diuretic in the urine will establish the diagnosis ,.
Other disorders that cause volume depletion but do not affect renal tubular function can partially mimic BS. These conditions have sometimes been called ‘pseudo-BS’ including cyclic vomiting, congenital Cl diarrhea, cystic fibrosis, and pyloric stenosis.
The tubular defects in BS or Gitelman syndrome cannot be corrected. As a result, treatment, which must be life-long, is aimed at minimizing the effects of the secondary increases in prostaglandin, renin, and aldosterone production and at correcting the volume deficit and electrolyte abnormalities.
The primary aim of the treatment of BS is correction of hypokalemia and alkalosis. Therefore, administration of KCl is always necessary. The dose of KCl supplementation should individually be titrated in accordance with the patient’s needs and must balance the amount lost by the kidney. However, this mode of supplementation therapy is almost totally ineffective by itself, as administered K is lost through the kidney in a short period of time .
K-sparing agents such as spironolactone or triamterine would be an effective additive to supplementation therapy at this stage. Indeed, these groups of medication offer an effective but transient control of hypokalemia .
Neutralizing the amplification effect of prostaglandins on the features of BS has long been the mainstay of drug therapy of this syndrome. Prostaglandin synthetase inhibitors are the main group of drugs recommended in this respect. Among many prostaglandin synthetase inhibitors, indomethacin is the most widely used .
The recommended dose of indomethacin is 2–3 mg/kg/day in two or three divided doses. Indomethacin decreases salt wasting and the degree of hypokalaemic alkalosis, and also partially corrects the impaired urine concentrating ability .
Other drugs used are acetylsalicylic acid (100 mg/kg/day), ibuprofen (30 mg/kg/day), or ketoprofen (20 mg/kg/day).
Renal transplantation has primarily been performed in isolated case reports of patients who developed end-stage renal disease because of coexisting renal disease or because of complications related to volume depletion, electrolyte abnormalities, drug-related side effects, and/or nephrocalcinosis. Renal transplantation should correct the transport abnormalities in BSs. Recurrence of the disease in the transplanted kidney should not occur and has not been described ,,.
| Aim|| |
The aim of this work was to study the clinical and laboratory data of infants and children with BS attending Alexandria University Children’s Hospital (AUCH) during a 10-year period (January 2004–December 2013).
| Participants and methods|| |
A retrospective study was used. Ethics committee approval has been obtained before starting the study.
The study was carried out at the nephrology clinic in the AUCH.
The target population of the study was BS cases attending the nephrology clinic at the AUCH.
All records of patients diagnosed as BS in AUCH from 2004 to 2013 were reviewed. Only 20 patients were identified and fulfilled the criteria of BS.
Data collection methods
The following data were collected from patient files:
- Personal characteristics:
- File number and sex.
- Date of birth and time of presentation of the child.
- Consanguinity, perinatal history, and family history of a similar condition.
- Initial clinical presentation:
- The initial presentation such as polyuria, polydipsia, vomiting, FTT, recurrent dehydration, and developmental delay were recorded.
- Growth parameters:
- Weight and height were collected from files. Child growth standards issued by the WHO  were used to classify the children’s weight for age, height for age, and weight for height in terms of a cutoff point of −2 SD below the median using growth reference curves. Children included in the study according to the above classification and who measured below −2 SD for the reference were considered growth retarded .
- Laboratory investigations:
- Initial biochemical findings (blood urea nitrogen, Cr, Ca, phosphorus, ALP, Cl, Na, K, uric acid).
- Arterial blood gases (pH, HCO3, PCO2).
- Spot urine analysis (Na, K, Cl, Ca/Cr ratio).
- Other investigations:
- Hearing assessment to identify cases of bilateral sensorineural hearing loss.
- Renal ultrasound (for nephrocalcinosis).
- Complications and outcome:
- Complications such as growth retardation and chronic renal impairment were collected from data.
- The results of some anthropometric measurements of BS cases at diagnosis and on follow-up visits were compared.
- K syrup, indomethacin, aldactone, and brufen were used.
- Operational definitions:
- Hypokalemia: It is a condition in which the level of K in serum is below the normal serum range 
- Newborn 3.7–5.9 mmol/l.
- Infant 4.1–5.3 mmol/l.
- Child 3.4–4.7 mmol/l.
- Hypochloremia: It is an electrolyte disturbance in which there is an abnormally decreased level of the Cl ion in the blood. The normal serum range for Cl is 97–107 mmol/l .
- Hypercalciuria: It is defined as more than 4 mg/kg/day or more than 0.21 urinary Ca/Cr ratio .
Normal spot urine analysis values were defined as follows:
- Cl 15–40 mmol/l 
- K 20–60 mmol/l .
- Na 20–230 mmol/l .
| Results|| |
This study was conducted on cases of pediatric BS diagnosed at AUCH from January 2004 to December 2013. It included 20 patients.
As regards sex distribution, male patients represent 70% of total cases, making male-to-female ratio 2.3 : 1.
The average age of patients was 24 months (range: 1.0–132.0 months), whereas the average age at presentation was 2 months (range: 0.0–12.0 months).
Positive family history was found in 35% of cases, perinatal history of polyhydramnios was found in 70% of cases, whereas consanguinity of patients and parents was observed in 40% ([Table 2]).
|Table 2 Distribution of Bartter syndrome cases according to personal data, perinatal history, family history, and consanguinity|
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Out of all BS cases, 70% presented with recurrent dehydration, 45% with vomiting, 45% with FTT, and 15% with polyuria ([Figure 1]).
|Figure 1 Distribution of Bartter syndrome cases according to their clinical presentation.|
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[Figure 2] illustrates that the majority of patients were normotensive (70%), hypotensive (25%), and 5% of patients are hypertensive (one patient) according to blood pressure percentile for age and sex.
|Figure 2 Distribution of Bartter syndrome cases according to blood pressure (mmHg).|
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In the studied patient, it was found that average serum Na level was 124.5 mmol/l, average serum K was 2.03 mmol/l, average serum Cl was 78.5 mmol/l, average serum Ca was 9.15 mg/dl, and average serum magnesium was 1.9 mg/dl.
Arterial blood gas analysis of studied cases revealed that pH ranged from 7.5 to 7.73 with a mean of 7.6±0.1, serum HCO3 ranged from 32 to 45.2 mmol/l with a mean of 37.6±3.8, and serum PCO2 ranged from 22.0 to 47.2 mmHg with a mean of 30.6±7.5.
Regarding spot urine analysis, the mean urinary Na was 67.1±31.3 mmol/l, mean urinary K was 46.5±27.6 mmol/l, and mean urinary Cl was 82.2±36.5 mmol/l ([Table 3]).
|Table 3 Distribution of Bartter syndrome cases according to initial biochemical findings|
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It was found that 55% of patients have high Ca/Cr ratio, 30% of patients have normal Ca/Cr ratio, and 15% of patients have low Ca/Cr ratio ([Figure 3]).
|Figure 3 Distribution of Bartter syndrome cases according to calcium-to-creatinine ratio.|
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Basically all the patients were treated by K syrup. Most of the patients need other adjuvant treatments as follows: 45% indomethacin, 30% aldactone, 5%, brufen, and 5% minirin ([Figure 4]).
In this study, it was found that 55% of patients presented with severe symptoms, whereas 45% have mild symptoms ([Figure 5]).
[Table 4] illustrates that, among patients who presented early (<2 ms), 33.3% of children were underweight at presentation, whereas only 11.1% were underweight at follow-up. In addition, it shows that 22.2% of children were of short stature at presentation, whereas only 11.1% were of short stature at follow-up.
|Table 4 Comparison between some anthropometric measurements at presentation and on follow-up visits in different age groups|
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In the age group that presented late (>2 ms), 36.4% of children were underweight at presentation and 27.3% were underweight at follow-up visit, whereas 27.3% of children were of short stature at presentation and 18.2% were of short stature at follow-up visit.
In both groups, there was no significant statistical difference in patients’ growth parameters at presentation and on follow-up visits.
[Table 5] shows that there was a significant statistical difference in the patients’ growth parameters before and after receiving indomethacin.
|Table 5 Comparison between some anthropometric measurements before and after receiving indomethacin|
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In all, 44.4% were underweight before indomethacin treatment, whereas 22.2% were underweight after receiving indomethacin.
In all, 22.2% were of short stature before indomethacin treatment, with improvement of all patients after receiving indomethacin.
[Table 6] shows that all mild cases of BS survived, whereas 81.8% of severe cases survived with no significant statistical difference.
|Table 6 Relation between severityof Bartter syndrome cases and fate, age at presentation, and response to medication|
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It was observed that 54.5% of patients who presented early (<2 ms) had severe symptoms in comparison with 45.5% of patients who presented later (≥2 ms), with no significant statistical difference.
[Table 6] reveals that all patients of BS received K syrup, 63% of severe cases received indomethacin in comparison with 22.2% of mild cases, and 27.3% of severe cases received aldactone in comparison with 33% mild cases.
It was observed that 22.2% of patients who presented early (<2 ms) died, whereas no deaths were observed in patients who presented later (>2 ms) ([Table 7]).
|Table 7 Relation between age at presentation and fate of Bartter syndrome cases|
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| Discussion|| |
BS is an autosomal recessive disorder with a characteristic set of metabolic abnormalities ,. These include hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus (the source of renin in the kidney), hyperaldosteronism, and, in some patients, hypomagnesemia .
This research included 14 male and six female patients, with a male : female ratio of 2.3 : 1.0. This observation is similar to a study conducted by Sampathkumar et al. , on seven children diagnosed as BS in India during an 8-year period from 2001 to 2009, which shows a male-to-female ratio of 3.0 : 1.0, whereas in the study by Abdel-Al et al.  in Kuwait had female predominance with a male-to-female ratio (1 : 1.6) and the stud by Dillon et al.  showed equal sex distribution.
The age of BS cases who attended the hospital ranged from 1 month to 11 years, with a median of 24 months. The mean age of patients was 9.3 months (range: 2–32 months) in the study conducted by Abdel-Al et al. .
Sampathkumar et al.  revealed that age of patients ranged from 2 to 15 months, with the mean age of 6.45 months. Mean age at presentation was 3.0±4.0 months, which is close to the results of Dillon et al. . Delayed diagnosis may be due to lack of awareness of renal tubular diseases (RTD) among general physicians and to a lesser extent to lack of diagnostic facilities, especially for the underlying metabolic diseases. In the present studied group, consanguinity rate was 40% and positive family history was observed among only 35% of cases. In the study by Abdel-Al et al. , both consanguinity and familial history among the patients were high (69 and 54%, respectively). Parental consanguinity rate in India is reported to be around 28.5% . The significant difference in the consanguinity rate in RTD may be due to the autosomal recessive inheritance characteristics of the most common tubular disorders .
It was found that perinatal history of polyhydramnios is positive in 70% of our studied patients. Shalev et al.  from Israel analyzed retrospectively the data from 13 infants with BS and nerve deafness who were born during a 20-year period. They found that all pregnancies were complicated by polyhydramnios and premature birth , whereas polyhydramnios and prematurity were present in two (28.5%) patients in the study conducted by Sampathkumar et al. .
The most common presenting symptoms were recurrent dehydration (70%), vomiting (45%), FTT (48%), and polyuria (44%). The most common presenting symptoms varied in different literatures. Polyuria/dehydration (33%) and growth retardation (25%) were the most common presenting symptoms explained by Zelikovic et al. . The most common symptoms noticed in Sampathkumar et al.  study were FTT (85.7%), vomiting (57%), and dehydration (57%).
The present study shows that the majority of cases (70%) are normotensive according to blood pressure percentile for age and sex; Sampathkumar et al.  found that all patients are normotensive.
Hypokalemia was a constant feature among patients of BS (100%). Hypochloremia and metabolic alkalosis are also noticed in 100% of patients with BS. The studies by Sampathkumar et al.  and Abdel-Al et al.  also showed hypokalemia and hypochloremia in all the patients.
Hyperreninemia was present in 100% of patients, whereas hyperaldosteronism was present in 83.4% (one patient had normal aldosterone level). This may be due to lab error. The studies by Sampathkumar et al.  and Abdel-Al et al.  also showed hyperreninemia and hyperaldosteronism in all the patients.
Hypercalciuria and nephrocalcinosis were described in the study by Garel et al.  which recorded hypercalciuria in 33% and nephrolithiasis in 8%. In present study, hypercalciuria was found in 55% of studied patients, but no data were available about nephrocalcinosis. Hypocalciuria (urinary Ca/Cr ratio between 0.01 and 0.10)  was found in 30% of patients.
At the nephrology unit of AUCH, the mainstay of therapy in BS cases is K replacement. In all, 100% of studied cases receive K supplementation, but only 30% receive aldactone.
Most of our patients (45%) need another adjuvant therapy, which is considered now as a cornerstone medication in the management of BS. Among prostaglandin synthetase inhibitors, indomethacin is the most widely used ,,,,.
Dillon et al.  used indomethacin in 60% of his patients. Similarly, 63% of severe cases in the present study received indomethacin, whereas Abdel-Al et al.  used it in all cases diagnosed as BS.
After successful therapy, a relative improvement in anthropometric measurements of the patients was observed. However, it was not statistically significant. However, in patients who received indomethacin, there was a significant catch-up growth when compared with a sex- and age-matched normal population. Abdel-Al et al.  showed significant catch-up growth in 30.76% of patients, whereas the study by Dillon et al.  showed catch-up growth in all patients treated with indomethacin therapy with remarkable clinical and biochemical improvement .
As regards the long-term prognosis, usually prognosis in many cases is good, with patients being able to lead a fairly normal life . The death rate was 10% of total cases (two patients), which is close to that in the study by Abdel-Al et al. , 7.69% (one patient).
Genetic studies were not conducted in any of our children because of nonavailability of such specialized laboratories in our region. There is no direct correlation between the clinical phenotype and the underlying genotypic abnormality, even with well-characterized defects in a single transporter. However, more severe and earlier clinical manifestations may be seen with mutations leading to defects in Na–K–2Cl cotransporter and the luminal K channel .
There were no available data about cases that are complicated by renal failure or nephrocalcinosis.
| Conclusion|| |
From this study we concluded the following:
- BS is an uncommon RTD.
- The majority of cases had perinatal history of polyhydraminos.
- The most common presenting symptoms were recurrent dehydration (70%), vomiting (45%), FTT (45%), and polyuria (15%).
- The majority of BS cases were normotensive.
- All cases had metabolic alkalosis, hypokalemia, and hypochloremia.
- All cases had high urinary Cl in spot urine analysis.
- Although all cases were spotted early and adequately treated, as evidenced by improvement of symptomatology and lab parameters, yet this did not show significant statistical difference as regards improvement in growth parameter during follow-up.
- The mainstay of treatment in BS is K supplementation and indomethacin.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]