Mimicry and well known genetic friends: molecular diagnosis in an Iranian cohort of suspected Bartter syndrome and proposition of an algorithm for clinical differential diagnosis

Abstract

Background Bartter Syndrome is a rare, genetically heterogeneous, mainly autosomal recessively inherited condition characterized by hypochloremic hypokalemic metabolic alkalosis. Mutations in several genes encoding for ion channels localizing to the renal tubules including SLC12A1, KCNJ1, BSND, CLCNKA, CLCNKB, MAGED2 and CASR have been identified as underlying molecular cause. No genetically defined cases have been described in the Iranian population to date. Like for other rare genetic disorders, implementation of Next Generation Sequencing (NGS) technologies has greatly facilitated genetic diagnostics and counseling over the last years. In this study, we describe the clinical, biochemical and genetic characteristics of patients from 15 Iranian families with a clinical diagnosis of Bartter Syndrome. Results Age range of patients included in this study was 3 months to 6 years and all patients showed hypokalemic metabolic alkalosis. 3 patients additionally displayed hypercalciuria, with evidence of nephrocalcinosis in one case. Screening by Whole Exome Sequencing (WES) and long range PCR revealed that 12/17 patients (70%) had a deletion of the entire CLCNKB gene that was previously identified as the most common cause of Bartter Syndrome in other populations. 4/17 individuals (approximately 25% of cases) were found to suffer in fact from pseudo-Bartter syndrome resulting from congenital chloride diarrhea due to a novel homozygous mutation in the SLC26A3 gene, Pendred syndrome due to a known homozygous mutation in SLC26A4 , Cystic Fibrosis (CF) due to a novel mutation in CFTR and apparent mineralocorticoid excess syndrome due to a novel homozygous loss of function mutation in HSD11B2 gene. 1 case (5%) remained unsolved. Conclusions Our findings demonstrate deletion of CLCNKB is the most common cause of Bartter syndrome in Iranian patients and we show that age of onset of clinical symptoms as well as clinical features amongst those patients are variable. Further, using WES we were able to prove that nearly 1/4 patients in fact suffered from Pseudo-Bartter Syndrome, reversing the initial clinical diagnosis with important impact on the subsequent treatment and clinical follow up pathway. Finally, we propose an algorithm for clinical differential diagnosis of Bartter Syndrome. Electronic supplementary material The online version of this article (10.1186/s13023-018-0981-5) contains supplementary material, which is available to authorized users.

A Rare Cause of Chronic Hypokalemia with Metabolic Alkalosis: Case Report and Differential Diagnosis

“…Recently, Najafi et al described a cohort of 17 children presenting with hypokalemic metabolic alkalosis, low birth weight and failure to thrive, 4 of them were clinically misdiagnosed as having Bartter Syndrome. Using Whole Exome Sequencing, different diagnoses were discovered in 4 of these patients including cystic fibrosis, congenital chloride diarrhea and AME [8]. In their patients, as in ours, diagnosis was delayed because blood pressure monitoring had not been routinely performed, highlighting the difficulties of getting accurate blood pressure measurements in small infants.…”

“…However, the clinical presentation of our patient demonstrates that hypokalemia and metabolic alkalosis can be present at birth and that growth delay can occur also before birth with IUGR. Data from other authors show a variable age at onset/diagnosis of hypertension, in most cases in childhood and adolescence [7][8][9]. Unfortunately, in our case, the exact time of onset of hypertension is unknown because blood pressure readings were not taken until the patient was nine months old, when she was referred to our unit.…”

“…In their patients, as in ours, diagnosis was delayed because blood pressure monitoring had not been routinely performed, highlighting the difficulties of getting accurate blood pressure measurements in small infants. Nevertheless, even when hypertension is detected, a diagnosis of AME can be delayed for many years [7][8][9]. For example, Morineau et al reported a mean age at clinical diagnosis of hypertension of about 5 years of life in a cohort of patients with AME, while in the same cohort the mean age at diagnosis of AME was approximately 15 years [7].…”

“…Algorithm of the causes of hypokaliemic metabolic alkalosis. Most of these disorders are rare, with a potentially insidious clinical presentation and diagnosis is often delayed or missed [7,8]. In addition, age at onset can be variable, with the most severe forms usually being detected in early childhood.…”

Genetic spectrum of Brazilian suspected Bartter Syndrome Patients

“…However, before the establishment of BS clinical hypothesis, acquired or genetic pseudo-Bartter conditions, renal or extrarenal, should be ruled out [4][5][6][7]. Among them Gitelman Syndrome (GS; OMIN 263800) is an important differential diagnosis.…”