Year : 2020 | Volume
: 3 | Issue : 1 | Page : 34--36
An unusual cause for hypokalemic metabolic alkalosis with medullary nephrocalcinosis
Sudarsan Krishnasamy, Priyanka Khandelwal, Aditi Sinha, Pankaj Hari, Arvind Bagga
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi
Bartter syndrome is a rare inherited tubulopathy characterized by hypokalemic metabolic alkalosis, polyuria, growth retardation, and often, medullary nephrocalcinosis. Many disorders present with similar clinical and metabolic features and pose diagnostic dilemma. We describe a young infant girl with growth retardation, hypokalemic metabolic alkalosis, and medullary nephrocalcinosis but without polyuria or urinary chloride wasting. Clinical exome sequencing revealed compound heterozygous variations in SLC26A3 (c.1514+5G > A and c.168del), the gene implicated in congenital chloride diarrhea. This case highlights the utility of genetic testing for definitive diagnosis and specific management in cases where Bartter syndrome is suspected.
|How to cite this article:|
Krishnasamy S, Khandelwal P, Sinha A, Hari P, Bagga A. An unusual cause for hypokalemic metabolic alkalosis with medullary nephrocalcinosis.Asian J Pediatr Nephrol 2020;3:34-36
|How to cite this URL:|
Krishnasamy S, Khandelwal P, Sinha A, Hari P, Bagga A. An unusual cause for hypokalemic metabolic alkalosis with medullary nephrocalcinosis. Asian J Pediatr Nephrol [serial online] 2020 [cited 2020 Nov 24 ];3:34-36
Available from: https://www.ajpn-online.org/text.asp?2020/3/1/34/288148
Bartter syndrome is a genetically heterogeneous group of tubular disorders characterized by defective salt reabsorption in the thick ascending limb of the loop of Henle, resulting in salt wasting, hypokalemia, and metabolic alkalosis. Patients with cystic fibrosis, congenital chloride diarrhea, apparent mineralocorticoid excess, and pyloric stenosis often present with identical clinical and biochemical features and are collectively termed “pseudo-Bartter syndrome.” Congenital chloride diarrhea, a rare autosomal recessive disorder with an incidence of 1:30,000 in Finland, is characterized by polyhydramnios, premature delivery, failure to thrive, neonatal onset of diarrhea with hyponatremia, hypokalemia, and hypochloremic metabolic alkalosis. Mutations in the solute carrier family 26 member 3 (SLC26A3) gene, encoding a Cl −/HCO3− exchanger expressed in the brush border of the intestinal epithelia causes excessive fecal chloride loss. We describe an infant with congenital chloride diarrhea with clinical and biochemical parameters mimicking Bartter syndrome.
A 3.5-month-old girl, born at term with a birth weight of 2.7 kg, presented with recurrent episodes of dehydration requiring intravenous fluids from the second day of life. Perinatal history was unremarkable, except for history of antenatal polyhydramnios. The second and third episodes of dehydration occurred at 1 and 2 months of age, when poor growth and polyuria were noticed. She was fifth-born of third degree consanguineous marriage; one brother and sister each had succumbed at 4.5 and 18 months of age, respectively, due to recurrent dehydration and poor growth. The siblings had been evaluated at another center, and the details of evaluation were not available.
At presentation, the child was severely undernourished, with weight-for-age standard deviation score (SDS) − 5.0 and length-for-age SDS − 5.1. Blood pressure records were between 50th and 75th percentile for age, gender, and height. Blood investigations showed pH 7.46–7.54, bicarbonate 29–34 mEq/L, sodium 114–133 mEq/L, potassium 2.3–2.8 mEq/L, and chloride 84–94 mEq/L. Blood levels of creatinine were 0.1–0.4 mg/dL, calcium 10.1–10.7 mg/dL, phosphate 4.7–6.1 mg/dL, alkaline phosphatase 443–486 U/L, uric acid 3.1–4.2 mg/dL, and serum magnesium 2.3 mg/dL. Urine calcium excretion was 4.3 mg/kg/day (normal <4 mg/kg/day). Ultrasound revealed bilateral medullary nephrocalcinosis.
During hospital stay, it was observed that the child was passing very dilute, watery stools, which were mistaken by the family as urine. When quantified by catheterization, the urine output was normal (0.8 L/m 2/day) and urine chloride was 14–19 mEq/L (normal <20 mEq/L). Levels of stool chloride were 84–96 mEq/L (normal <30 mEq/L) on multiple occasions; sweat chloride was 27 mEq/L (normal <40 mEq/L). In view of neonatal-onset hypokalemic metabolic alkalosis with borderline-high stool chloride levels and no urinary wasting, a diagnosis of congenital chloride diarrhea was made.
Clinical exome sequencing revealed two heterozygous variants in SLC26A3 gene, including a single base pair deletion in exon 16 (c. 1686del), which led to frameshift and premature truncation of the protein 14 amino acids downstream to codon 562 (p.F562LfsX14), and a splice site variant in intron 13 (c. 1514 + 5G > A). The two variants were absent in the 1000 genomes and ExAC databases, were conserved across species, and were predicted to be damaging on in silico prediction by MutationTaster2 (www.mutationtaster.org). The former variant was classified as pathogenic, whereas the latter was attributed unknown significance, upon classification by the 2015 criteria of the American College of Medical Genetics and Genomics. Parental testing to confirm allele segregation could not be performed.
Given findings consistent with a diagnosis of congenital chloride diarrhea, nutritional rehabilitation and electrolyte replacement were advised. However, the family did not return for follow-up and the patient succumbed to the illness at home 3 months later.
We report a 3.5-month-old girl who presented with polyhydramnios and neonatal onset of metabolic alkalosis, hyponatremia, and hypokalemia and was diagnosed with congenital chloride diarrhea due to novel, likely compound heterozygous, variants in the SLC26A3 gene. The presence of nephrocalcinosis and hypercalciuria, mimicking antenatal Bartter syndrome, was unique in this patient.
The SLC26A3 g ene encodes for the Cl −/HCO3− transporter in the distal ileum and colon, and mutations in the gene lead to fecal losses of chloride, sodium and potassium, and osmotic diarrhea. Inadequate secretion of bicarbonate in the gut leads to metabolic alkalosis, in contrast to other inherited enteropathies that typically cause metabolic acidosis. More than 55 mutations have been identified in SLC26A3 gene all over its 21 exons. While the majority of variants, detected chiefly in consanguineous Finnish, Arab, and Polish populations, are missense or minor deletions that affect exons 3–6 or 12–15, splice site variants are also described. The present patient had a single base pair deletion and a splice site variant in a novel location. Compound heterozygous variations have previously been reported as causative of this phenotype. Due to loss to follow-up, we were unable to perform allele segregation in parents to confirm their pathogenicity in the present patient.
Congenital chloride diarrhea mimics Bartter syndrome because the large volume watery stools are often mistaken for polyuria in infancy. Furthermore, the stool chloride levels might be fallaciously low at presentation due to intravascular volume depletion, thereby complicating the diagnosis. Similarly, the index patient had borderline-low stool chloride values at presentation that rose to >90 mEq/L after rehydration. Cystic fibrosis and apparent mineralocorticoid excess are other rare mimics of Bartter syndrome that present during infancy with hypokalemic metabolic alkalosis; these can be differentiated clinically, as well as based on elevated sweat chloride and blood pressure, respectively, apart from genetic testing.
Early onset of hypercalciuria and medullary nephrocalcinosis in the present case was unique. Nephrocalcinosis was described in patients with chloride diarrhea by Holmberg et al. in 1977 and subsequently reported during long-term follow-up in multiple series.,, Nephrocalcinosis was present in 8.5% and 7.7% of cases in patients followed in Finland and Japan, respectively., It is hypothesized that reduced paracellular reabsorption of calcium, together with hypovolemia and low urinary flow, might promote urine supersaturation and crystal precipitation that causes medullary nephrocalcinosis. Adverse renal outcome, seen in a significant proportion of patients during long-term follow-up, is attributed chiefly to chronic hypovolemia and nephrocalcinosis., With early diagnosis and careful attention to fluid and electrolyte supplementation, outcomes have improved, and majority of cases survive beyond infancy.
The present case highlights the necessity of a high index of suspicion for congenital chloride diarrhea in a setting of hypochloremic metabolic alkalosis, even in infants presenting with medullary nephrocalcinosis. Determination of urinary chloride level during metabolic alkalosis guides further diagnostic evaluation. Stool chloride level may be useful in the setting of diarrhea or when losses from urine and sweat have been ruled out. Genetic testing is useful for definitive diagnosis, management, and genetic counseling. Gene panels for targeted exome sequencing in patients presenting with features of Bartter syndrome should include SLC26A3 g ene.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
|1||Höglund P, Auranen M, Socha J, Popinska K, Nazer H, Rajaram U, et al. Genetic background of congenital chloride diarrhea in high-incidence populations: Finland, Poland, and Saudi Arabia and Kuwait. Am J Hum Genet 1998;63:760-8.|
|2||Höglund P, Haila S, Socha J, Tomaszewski L, Saarialho-Kere U, Karjalainen-Lindsberg ML, et al. Mutations of the down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet 1996;14:316-9.|
|3||Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.|
|4||Wedenoja S, Pekansaari E, Höglund P, Mäkelä S, Holmberg C, Kere J. Update on SLC26A3 mutations in congenital chloride diarrhea. Hum Mutat 2011;32:715-22.|
|5||Rodríguez-Herrera A, Navas-López VM, Redondo-Nevado J, Gutiérrez G. Compound heterozygous mutations in the SLC26A3 gene in 2 Spanish siblings with congenital chloride diarrhea. J Pediatr Gastroenterol Nutr 2011;52:106-10.|
|6||Holmberg C. Electrolyte economy and its hormonal regulation in congenital chloride diarrhea. Pediatr Res 1978;12:82-6.|
|7||Najafi M, Kordi-Tamandani DM, Behjati F, Sadeghi-Bojd S, Bakey Z, Karimiani EG, et al. 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. Orphanet J Rare Dis 2019;14:41.|
|8||Holmberg C, Perheentupa J, Pasternack A. The renal lesion in congenital chloride diarrhea. J Pediatr 1977;91:738-43.|
|9||Kamal NM, Khan HY, El-Shabrawi MH, Sherief LM. Congenital chloride losing diarrhea: A single center experience in a highly consanguineous population. Medicine (Baltimore) 2019;98:e15928.|
|10||Wedenoja S, Ormälä T, Berg UB, Halling SF, Jalanko H, Karikoski R, et al. The impact of sodium chloride and volume depletion in the chronic kidney disease of congenital chloride diarrhea. Kidney Int 2008;74:1085-93.|
|11||Konishi KI, Mizuochi T, Yanagi T, Watanabe Y, Ohkubo K, Ohga S, et al. Clinical features, molecular genetics, and long-term outcome in congenital chloride diarrhea: A nationwide study in Japan. J Pediatr 2019;214:151-70.e6.|
|12||Hihnala S, Höglund P, Lammi L, Kokkonen J, Ormälä T, Holmberg C. Long-term clinical outcome in patients with congenital chloride diarrhea. J Pediatr Gastroenterol Nutr 2006;42:369-75.|