Mixed Bartter-Gitelman syndrome: an inbred family with a heterogeneous phenotype expression of a novel variant in the CLCNKB gene
© Al-Shibli et al.; licensee Springer. 2014
Received: 28 January 2014
Accepted: 10 February 2014
Published: 18 February 2014
Patients with renal diseases associated with salt-losing tubulopathies categorized as Gitelman and classic form of Bartter syndrome have undergone genetic screening for possible mutation capture in two different genes: SLC12A3 and CLCNKB. Clinical symptoms of these two diseases may overlap.
Bartter syndrome and Gitelman syndrome are autosomal recessive salt-losing tubulopathies with hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus, hyperaldosteronism, and, in some patients, hypomagnesemia.
Here we describe four patients from an inbred family with a novel missense variant in the CLCNKB gene. All of patients are asymptomatic; yet they have the typical metabolic abnormality of salt losing tubulopathies. One of those patients had hypomagnesaemia while others not. Clinical and laboratory data of all patients was described. All 4 patients have a homozygous c.490G > T missense variant in exon 5 of the CLCNKB gene. This variant alters a glycine into a cysteine on amino acid position 164 of the resulting protein (p.Gly164Cys). The c.490G > T variant is a novel variant not previously described in other patients nor controls. Polyphen analysis predicts the variation to be possibly damaging. Analysis of SLC12A3 was normal.
Here in we are describing a novel homozygous c.490G > T missense variation was identified in exon 5 of the CLCNKB gene was identified in an Emirati patients with a mild manifestation of Bartter - Gitelman syndrome.
KeywordsBartter syndrome Gitelman syndrome Mutation Phenotype CLCNKB gene
Bartter syndrome (BS) and Gitelman syndrome (GS) are autosomal recessive disorders with a characteristic set of metabolic abnormalities (Amirlak and Dawson 2000; Konrad et al. 2000; Naesens et al. 2004). These include hypokalemia, metabolic alkalosis, hyperreninemia, hyperplasia of the juxtaglomerular apparatus (the source of renin in the kidney), hyperaldosteronism, and, in some patients, hypomagnesemia. (Amirlak and Dawson 2000; Naesens et al. 2004).
Genetics and presentation of Bartter and Gitelman syndromes
Bartter syndrome type I
Antenatal Bartter syndrome (Hyperprostaglandin E syndrome)
Bartter syndrome type II
Antenatal Bartter syndrome
Bartter syndrome type III
Hypochloremia., mild hypomagnesemia, FTT in infancy
Bartter syndrome type IVA
Barttin (B-subunit of CLC-Ka and CLC-Kb)
Antenatal Bartter syndrome (Hyperprostaglandin E syndrome) and sensorineural deafness
Bartter syndrome type IVB
CLCNKA and CLCNKB
CLC-Ka and CLC-Kb
Antenatal Bartter syndrome (Hyperprostaglandin E syndrome) and sensorineural deafness
Bartter syndrome type V•
Bartter syndrome with hypocalcemia
NCC (thiazide- sensitive NaCl co-transporter).
Hypomagnesemia, hypocalcuria, growth retardation
Here in, we described a case series with mild and heterogeneous phenotype, all had novel mutation in the CLCNKB gene.
The first patient (proband1) was a 14 years old girl was presented with prolonged hypokalemia after an attack of acute gastroenteritis. Review of all systems was negative. There was no significant perinatal history, her birth history records revealed full-term by normal spontaneous delivery and normal birth weight of 3,400 grams without antenatal polyhydramnios. There was no history of chronic drug ingestion. She was doing well in school and had normal actively level, normal hearing and vision.
On presentation her height (160 cm) and body weight (58 kg) both were around the 50th percentile. Blood pressure was 114/75 mmHg, heart rate 96 beats/min and respiratory rate 22/min. The remainder of the physical examination was unremarkable. Family history was negative for chronic diseases and sudden death.
Clinical features in all patients
Case 1 (index)
Age in years on presentation/follow up
Weight centile on presentation/follow up
Height centile on presentation/follow up
History of polyuria and polydipsia
Laboratory features of all patients
30-40 ng/L (resting)
400-620 ng/24 hours
Bartter and Gitelman syndromes are genotypic and phenotypic heterogeneous diseases. Clinical manifestation and laboratory findings might be misleading in proposing diagnosis and managing appropriate treatment. (Jeck et al. 2000).
Our patients were having the typical metabolic abnormalities of BS/GS tubulopathy. Urine Na, K, and Cl were significantly high, TTKG was high in the presence of hypokalemia indicateing renal loss. Their parents and other heterozygous siblings are normal and they don’t have electrolytes abnormalities.
Features differentiating Bartter and Gitelman syndromes
Classic Bartter syndrome
Age at onset
Childhood or later
Normal or high
Urine prostaglandins (PGE2)
High or normal
In our patient Gitelman was initially diagnosed based on the clinical and laboratory findings and so Genetic analysis for SLC12A3 gene was done and it was normal; CLCNKB gene showed a novel mutation in the exon 5. Co-segregation of this missense variant in an inbred family with 4 affected patients suggest that this variant is pathogenic.
Clinical symptoms and biochemical markers of GS and classic form of Bartter syndrome (type III) may overlap and thus genetic analysis may specify the real cause of symptoms. (Brochard et al. 2009) Our patient had hypomagnesaemia which is due to renal loss based on the high Mg in the urine in the presence of hypomagnesaemia and the high FeMg. Mg supplement was needed for the index patient but not for the others; however other patients may develop hypomagnesaemia in the future as transition phenotypes from classical BS (cBS) to GS have also been described. (Cruz and Castro 2013 Jan).
There is a difference in both clinical and biochemical expression of CLCNKB mutations in both GS and type III BS syndromes between patients who share the same mutations suggests. (Briet et al. 2006; Uchida 2000) A modifier effect from genetic and/or environmental factors as it has been often reported in other cases of CLCNKB mutation (Dong Yan et al. 2010; Nozu et al. 2007) Sep and other human diseases such as polycystic kidney disease (Fain et al. 2005). However, the genotype–phenotype relation is variable, and mutations in the CLCNKB gene may cause overlapping phenotypes of classic/antenatal BS, cBS/GS, and GS (Cruz and Castro 2013; Fain et al. 2005; Peters et al. 2002). Several former studies tried to focus on the correlation between specific DNA mutation and phenotypic clinical outcome. In a study by Coto, many individuals carrying exactly the same mutation coming from unrelated families did not correlate in values of ionic composition in blood and urine. Their clinical symptoms also differed. (Coto et al. 2004) To date, more than 30 CLCNKB variants have been reported (Pierre Robitaille et al. 2011; Israel et al. 2003; Fukuyama et al. 2003; Fukuyama et al. 2004; Rodriguez et al. 2005; Yu et al. 2010; Xiumin et al. 2013; Gorgojo et al. 2006; Lee et al. 2012; Toshihiro et al. 2006; Enriquez et al. 2010; Konrad et al. 2000a) in patients with classical BS phenotype, atypical BS or mixed Bartter-Gitelman phenotypes as found in our patients. Our family shows that even patients and even siblings with the same DNA variants could present differences in clinical symptoms, and even mimic a different syndromes. This was the case in a study by Zelikovic, where a large Bedouin family sharing CLCNKB variant presented clinical characteristics specific for Gitelman syndrome, on the one side of the spectrum, to classic Bartter syndrome, on the other. (Zelikovic et al. 2003) Therefore, there is an indication for screening the CLCNKB gene in those patients with the Gitelman phenotype who do not have variants in the SLC12A3 gene. (Konrad and Weber 2003).
Our findings demonstrate intrafamilial phenotypic heterogeneity, namely the presence of Gitelman syndrome and classic Bartter syndrome phenotypes in kindred’s with CLCNKB c.490G > T mutation.
Written informed consent was obtained from the patients' parents for the publication of this report and any accompanying images.
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