Pediatric Bartter syndrome: The therapeutic challenge

Bartter syndrome is a rare genetic disorder characterized by hypokalemia, hypochloremia, alkalosis, and normal or low blood pressure. There are three main clinical forms of Bartter syndrome, and a variant form including neonatal Bartter syndrome, classical pediatric Bartter syndrome, adult Bartter syndrome and a variant form (Gitelman syndrome) which is generally milder than neonatal and classic pediatric forms of Bartter syndrome [1-3].


Introduction
Bartter syndrome is a rare genetic disorder characterized by hypokalemia, hypochloremia, alkalosis, and normal or low blood pressure. There are three main clinical forms of Bartter syndrome, and a variant form including neonatal Bartter syndrome, classical pediatric Bartter syndrome, adult Bartter syndrome and a variant form (Gitelman syndrome) which is generally milder than neonatal and classic pediatric forms of Bartter syndrome [1][2][3].
Children with classic Bartter syndrome generally became symptomatic in the fi rst two years of life, but they are usually diagnosed at school age or later. Children with classic Bartter syndrome also develop polyuria, polydipsia, and a tendency to dehydration, but they generally have normal urinary calcium excretion or mild hypercalciuria without signifi cant tendency to develop kidney stones [1].

Other features of Bartter syndrome include [1]:
 Vomiting and growth retardation.  Excess production of prostaglandins by the kidneys is often found.
There is no curative therapy for many of the rare genetic disorders such as Bartter syndrome. Many patients with such disorders will be treated to a large extent with symptomatic therapies, and many of them will continue to have some symptoms, and growth and mental retardation despite the traditional therapies generally known by the treating physician.
Because of the rarity of such disorders, many specialist physicians may have limited experience with treatment of https://www.peertechz.com/journals/archives-of-clinical-nephrology Citation: Al Mosawi AJ (2020) Pediatric Bartter syndrome: The therapeutic challenge. Arch Clin Nephrol 6(1): 005-009. DOI: https://dx.doi.org/10.17352/acn.000038 such disorders and treatment side effects may be sometimes encountered. It is hoped that advances arising from the accumulating research evidence can contribute to improving treatment of such conditions [1,4,5].

Materials and methods
A unique case of classical pediatric Bartter syndrome associated with low set ears and mental retardation that was treated unsatisfactorily was studied. The medical literatures were reviewed for the recent research evidence that may help in improving the therapeutic services for patients with Bartter syndrome.

Results
The occurrence the rare genetic disorder Bartter syndrome in Iraq has not been documented. A unique case of Bartter syndrome associated with low set ears and mental retardation in an Iraqi girl. The girl was treated before referral by some of the traditional therapies that improved her symptoms and condition, but she experienced some side effects of treatment and growth and mental retardation. The girl was fi rst seen at the pediatric psychiatry clinic at about the age of fi ve years during June, 2018 as a known case of Bartter syndrome with poor speech development. She was also delayed in achieving motor mile stones. However, currently she can walk and run. The child had slow growth, episodes of vomiting, polydipsia, polyuria, and history of spasms. She has been treated with oral potassium supplementation (30mEq per day in divided doses) and indomethacin (12.5mg daily) which had to be stopped for some time before few months because of the development of serious gastric side effects with abdominal pain and vomiting.
Despite treatment, she had chronic hypokalemia as serum potassium was low in all the previously available performed tests (Table 1).
Although the girl had low set ears ( Figure 1) and poor speech development, she was responding to her name, and had good eye contact. She responded when she asked to take the pen and try to copy a line, but she couldn't hold the pen perfectly right nor could she copy the line. This Iraqi girl had been treated traditionally by potassium supplement and indomethacin, but persistent correction of hypokalemia couldn't be achieved.

Bartter syndrome treatment research progress
Bartter syndrome was originally treated by the physicians who fi rst reported the condition, initially with potassium chloride supplements, and later they performed partial adrenalectomy. Symptoms were relieved for several months without potassium supplements after partial adrenalectomy, but serum potassium remained low (3.3-2.8mEq/L). Fifteen months after partial adrenalectomy, signifi cant hypokalemia (Serum potassium: 2 mEq/L) and tetany returned [1,6,7].
George T Bryan and colleagues reported that spironolactone with low-sodium diet increased serum potassium to normal level in Bartter syndrome. They also reported that infusion of albumin was associated with a rapid increase in serum potassium and a reduction in aldosterone secretion rate [8].
The work of Kornerup and colleagues suggested that longterm treatment with indomethacin may be ineffective in maintaining normal potassium balance in Bartter syndrome [9]. Konomi, et al., reported the occurrence of pseudotumor cerebri in Bartter syndrome during indomethacin therapy [14].
Gill JR, et al., reported that treatment with ibuprofen which is an inhibitor of prostaglandin synthetase having   Normal plasma aldosterone level and normal urinary aldosterone excretion.
 Normal blood pressure.
The initial treatment of the patient with oral potassium was not satisfactory.
Treatment with acetylsalicylic acid was associated with some effect, and an allergic reaction led withdrawal of treatment. Treatment with the angiotensin converting enzyme inhibitor captopril and oral potassium was associated with clinical and biochemical improvement.

Discussion
Bartter syndrome was probably fi rst described by Pacita Pronove, Ross C MacCardle and Frederic Crosby Bartter in 1960.
They reported a fi ve-year old boy with hypokalemia, alkalosis, primary aldosteronism, normal blood pressure, unique renal lesion which is hyperplasia of the juxtaglomerular apparatus.  Plasma rennin activity consistently increased after kaliuretics, while a marked reduction occurred in response to anti-prostaglandin agents. There is also convincing evidence that the addition of enalapril can be of value in improving treatment in this Iraqi patient [30].

Conclusion
Literature review helped in recommending an evidencebased opinion suggesting the replacement of one drug with a safer one, and the addition of another evidence-based effective therapy.