Case Report
iMedPub Journals Journal of Rare Disorders: Diagnosis & Therapy 2019 www.imedpub.com ISSN 2380-7245 Vol.5 No.2:4
DOI: 10.36648/2380-7245.5.2.196
Congenital Chloride Diarrhea in a Bartter Maria Helena Vaisbich*, Juliana Caires de Oliveira Syndrome Misdiagnosed Brazilian Patient Achili Ferreira, Ana Carola Hebbia Lobo Messa and Abstract Fernando Kok The differential diagnosis in children with hypokalemic hypochloremic alkalosis Department of Pediatric Nephrology, include a group of an inherited tubulopathies, such as Bartter Syndrome (BS) Instituto da Criança, University of São Paulo, and Gitelman Syndrome (GS). However, some of the clinically diagnosed São Paulo, Brasil patients present no pathogenic mutation in BS/GS known genes. Therefore, one can conclude that a similar clinical picture may be caused by PseudoBartter Syndrome (PBS) conditions. PBS include acquired renal problems (ex.: use of diuretics) as well as genetic or acquired extrarenal problems such as cystic *Corresponding author: fibrosis or cyclic vomiting, respectively. The accurate diagnosis of BS/GS needs Maria Helena Vaisbich a rational investigation. First step is to rule out PBS and confirm the primary renal tubular defect. However, it is not easy in some situations. In this sense, Department of Pediatric Nephrology, we reported a patient that was referred to our service with the diagnosis Instituto da Criança, University of São Paulo, of BS, but presented no mutation in BS/GS known genes. The whole-exome São Paulo, Brasil. sequencing detected a SCL26A3 likely pathogenic mutation leading to the final diagnosis of Congenital Chloride Diarrhea (CCD). Reviewing the records, the [email protected] authors noticed that liquid stools were mistaken for urine. In addition, urinary and fecal samples were collected at an inappropriate time. The fecal sample taken during dehydration led to a low fecal chloride level and urine taken soon Tel: +55-11-99940-3433 after sodium and potassium chloride infusion led to a high urinary chloride fractional excretion. Based on this data, BS was misdiagnosed. Our goal is to report the first Brazilian CCD patient initially misdiagnosed as BS and discuss Citation: Vaisbich MH, Ferreira JCDOA, the difficulties to achieve the correct diagnosis in clinical practice. Messa ACHL, Kok F (2019) Congenital Chloride Keywords: Alkalosis; Child; Bartter syndrome; Gitelman syndrome; Congenital Diarrhea in a Bartter Syndrome Misdiagnosed chloride diarrhea; Hypokalemia Brazilian Patient. J Rare Disord Diagn Ther. Vol.5 No.2:4 Abbreviations: BS: Bartter Syndrome; GS: Gitelman Syndrome; PBS: PseudoBartter Syndrome; CCD: Congenital Chloride Diarrhea; CFTR: Cystic Fibrosis Transmembrane Conductance Regulator
Received: August 16, 2019; Accepted: November 11, 2019; Published: November 18, 2019
Introduction aldosterone in childhood include a group of an autosomal recessive salt-loss tubulopathies, such as Bartter Syndrome General pediatricians are frequently the first professionals to (BS) and Gitelman Syndrome (GS) [3]. However, variants in detect metabolic and electrolyte disturbances in childhood known BS/GS genes have not been identified in some patients and they should be aware of the differential diagnosis. In cases [4] suggesting other rare diseases may cause a PseudoBartter of persistent hypochloremic hypokalemic metabolic alkalosis, Syndrome (PBS). Table 1 summarizes the main differential acquired situations such as cyclic vomiting, chloride-intake diagnosis of this metabolic and electrolyte disturbance and deficiency, laxative abuse, diuretics use or nephrotoxic agents provides some details of the etiologies. The clinical diagnosis of have to be investigated [1]. However, the late diagnosis could be BS can be achieved with a rational investigation excluding PBS harmful to patients with some rare genetic diseases [2]. In this and confirming the primary renal tubular dysfunction. However, context, the differential diagnosis of persistent hypochloremic it is not easy in some situations. Congenital Chloride Diarrhea hypokalemic metabolic alkalosis with high serum renin and (CCD), a disease characterized by fecal chloride waste, can © Under License of Creative Commons Attribution 3.0 License | This article is available from: https://raredisorders.imedpub.com 1 Journal of Rare Disorders: Diagnosis & Therapy 2019 ISSN 2380-7245 Vol.5 No.2:4 tubular reabsorption. tubular reabsorption. tubular reabsorption. + + Treatment There is no specific treatment. There Treatment is based on electrolytes prostaglandin and supplementation inhibitors objectingpolyuria. AARS to inhibitors can employed reduce be in selective cases with close monitoring of renal function and blood pressure. Spironolactone can also be used to K increase Electrolytes supplementation Electrolytes Electrolytes Electrolytes supplementation and preferably inhibitor, prostaglandin COX 2 selective one. Inhibitors of AARS can be employed monitoring renal function and blood pressure. Spironolactone can be K increase used to FE; isothenuria/ - FE, ↑Cl + FE, + FE, ↑Na FE FE, ↑Na - + + Lab Findings Similar to BS type 1, but newborns acidosis. metabolic hyperkalemic transient can present BS type 1 Similar to hyposthenuria. hyposthenuria. ↑Cl ↑ plasmatic renin and aldosterone; hypercalciuria; hypercalciuria; aldosterone; and renin plasmatic ↑ ↑K Similar to BS type 1 Similar to Nephrocalcinosis Nephrocalcinosis is uncommon and, patientscan and hypercalciuria. hypomagnesemia present ↑ plasmatic aldosterone and renin; and aldosterone ↑ plasmatic ↑ K Genetic Diseases Genetic Renal Genetic Diseases Genetic Renal Similar to BS type 1, but less severe alkalosis. hypokalemic In addition to the metabolic electrolyte and disturbances deafness. patients sensorineural present Polyhydramnios Polyhydramnios (fetal and prematurity. polyuria) Life-threatening electrolyte disturbances; nephrocalcinosis. early In addition to the metabolic electrolyte and disturbances deafness. patients sensorineural present Classic to manifestations: thrive, vomiting, failure polydipsia, episodes polyuria, hypotension fever of about 6 – and 12 months of age. However, there is a phenotype great overlap among classic forms. and antenatal Early Early manifestation with polyhydramnios and severe prematurity; high mortality rate. Notably, survivors the evolving with complete resolution. clinical
- - , + -Cl Special Clinical Manifestations Special Clinical , K + + , and -K + + and Cl + , K / CLCNKB + (Xp11.21), , K + (15q15-q21) Differential diagnosis of persistent hypochloremic hypokalemic metabolic alkalosis in childhood. alkalosis metabolic hypokalemic hypochloremic diagnosis of persistent Differential , encoding CLC- CLCNKA . - MAGED2 MAGED2 SLC12A1 urinary waste - Table 1 Table encoding Na encoding Pathogenic loss of Pathogenic functionin mutations Summary of GeneticsPathogenesis and pathogenic loss of pathogenic function mutation(11q24), KCNJ1 in encodes ROMK, which leading to Na+, K+, Cl- urinary losses Pathogenic mutation in BSND (1p31) encoding barttin a subunit ofCLC- Kb, responsible for its activation Compound heterozygous mutation in Na leading to cotransporter cotransporter (NKCC2), Na leading to urinary waste and Cl Cl Pathogenic Pathogenic mutations in which MAGE-D2 in the implicated and ofregulation NKCC2 encodes protein NCC, leading to severe of BS. form antenatal Pathogenic Pathogenic mutations in CLCNKB leading to and (1p36) Kb urinary losses of Na Data data) reported unknown unknown unknown unknown Unknown Few cases cases Few da Criança – da Criança evaluated at at evaluated the Instituto (unpublished was the most the most was Unknown, but Unknown, BS/GS patients BS/GS patients Epidemiological Epidemiological common type in common HCFMUSP, Brazil Brazil HCFMUSP, DR AR AR AR 1/ 2/ 4a/ 4b/ BS Type BS Type BS Type BS Type BS Type BS Type - BS type AR 3/ BS type 5/ BS BS (transient BS) BS (transient X-linked recessive X-linked Classic BS associated associated MAGED2 Disease/Inheritance Antenatal Antenatal
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- and Cl + , K + ENaC inhibitors as amiloride triamtere and supplementations are necessary. are supplementations Thiazides diuretics can to be used decrease also hypercalciuria and increase supplementation can also calcemia. option. be an PTH Calcium and vitamin D. Na supplementation No specifictreatment, just inhibition AARS to reduce urinary proteinuria; alkalization citrate or (potassium potassium/magnesium citrate) to nephrocalcinosis; thiazide avoid diuretics or to aggravate decrease the calcium waste. urinary Sodium, chloride and and electrolytes rich diet potassium supplementation FE); ↑ ++ decade of life decade th to 5 rd . ↑renin and aldosterone. . ↑renin - and Cl FE, + + , K + FE; + FE, ↑Na FE; FE - + + ↑ urinary hypercalciuria, and at low least one of the following molecular sings: weight hypophosphatemia, protein; but nephrocalcinosis, also proteinuria with glomerular insufficiency about the 3 and nephrolithiasis, glomerulosclerosis; renal ↓ Na urinary Na ↑Cl Hypocalcemia Hypocalcemia and hypercalciuria (↑Ca ↓ PTH. 35% nephrocalcinosis; present patients the of 10% calcification basal ganglia plasmatic aldosterone and renin; and aldosterone plasmatic ↑ K ↑ plasmatic aldosterone and renin; and aldosterone ↑ plasmatic ↑ K Genetic Diseases Genetic others genetic diseases genetic others The disease manifests in childhood as failure hematuria, sometimes rickets, to and thrive, patients can polyuria, present and glomerulosclerosis. proteinuria Dent type 2: manifestations, Beyond the renal present patients mild intellectual cataract subclinical hypotonia, deficit, can Generally Generally hypocalcemia, but there are cases present with seizures with or tetany, hypercalciuria, asymptomatic normal serum have PTH concentrations low- and have oftenwith hypoparathyroidism. been diagnosed hypertension hypertension in children, adults and young adolescents, in specially familial cases; failure to thrive in infants Symptoms Symptoms are children < 6 years old; more uncommon often occur in in adolescents is often. adults; hypotension and young
, , + , K - CLCN5 , Cl , + urinary SCNN1G + OCRL1 A few patients do not present mutations in CLCN5 or OCRL; this suggests other genes can also be involved can also be genes other CLCN5 or OCRL; this suggests in mutations do not present patients A few encodes encodes a , hypocalciuria . (3q13.3-q21.1), + and ++ exchanger exchanger ClC-5, + /H and H - + which phosphatidylinositol bisphosphate 5-phosphatase (PIP2) (associated with Lowe Syndrome). Pathogenic 1: Pathogenic type Dent mutations in (Xp11.22), the electrogenic encodes Cl which wasting can be due to ROMK direct inhibition or due to electrogenic potentialgradient. differential and Mg and hypomagnesemia and hypomagnesemia which belongs to CLC the family of chloride (Cl-) channels. 2: pathogenic type Dent mutations in Pathogenic gain of gain Pathogenic function variants CASR in which encodes CaSR, a calcium sensible the receptor. Therefore, even when the serum calcium low, the is hypercalciuria persists. The K Pathogenic loss of Pathogenic function variants encodes which , SLC12A3 in excessive to leading NCC, Na of loss urinary Pathogenic gain of gain Pathogenic function variants SCNN1B in encoding encoding ENaC, leading to excessive reabsorption, sodium excessive urinary loss of K and unknown unknown Prevalence Prevalence Prevalence 1-9:100.000 <1: 1.000.000 AD AR AD (pseudo (pseudo with BS / Hypocalcemia Hypocalcemia Dent Disease / Dent Liddle Syndrome Liddle Syndrome X-linked recessive X-linked autosomal dominant dominant autosomal Gitelman Syndrome/ Gitelman hyperaldosteronism)/ © Under License of Creative Commons Attribution 3.0 License 3 Journal of Rare Disorders: Diagnosis & Therapy 2019 ISSN 2380-7245 Vol.5 No.2:4 physiotherapy; physiotherapy; Sodium, chloride and supplementation; potassium be bomb can inhibitor Proton decreases action its since beneficial, chloride secretion the gastric Chest Chest hypertonic antibiotics saline prevent to bronchopulmonary inhalation; treat and inhaled infections; dornase modulating therapies used isolated alfa; or in CFTR- combinationthe type of according mutation: Potentiators to of and CFTR correctors of lumacaftor). (ataluren, protein CFTR defects Supplementation (Ivacaftor) ofvitamins. fat-soluble (classes I,II,II,IV,IV,V (classes I,II,II,IV,IV,V CFTR etiology children. concentration (> 60 mmol/L); - exhaustion among others. exhaustion FE + confirmation is done genetic by showing test pathogenic a mutation in leading to is available screening and VI). Neonatal diagnosis in 95% of patients. ↑ plasmatic renin and aldosterone; ↑ plasmatic chloride ↑ fecal (> 90mmol/L) ↓ K ↑ sweat Cl
nasogastric tube suctioning in hospitalized children. tube suctioning in hospitalized nasogastric - Infants inadvertently fed chloride-deficient formula; chloride-deficient fed inadvertently Infants syndrome; delayed gastric emptying, hypertrophic pyloric stenosis. pyloric emptying, hypertrophic gastric delayed syndrome; Examples: aminoglycosides, amphotericin B, and heavy metal intoxication. metal and heavy B, amphotericin aminoglycosides, Examples: Genetic Diseases Genetic Acquired conditions Acquired loop diuretic (mimicking Bartter syndrome) or a thiazide diuretic (mimicking Gitelman syndrome) Gitelman (mimicking or a thiazide diuretic syndrome) (mimicking Bartter loop diuretic Primary hyperhidrosis –characterized by overactive sweat glands. The pathophysiology is still unknown. is glands. The pathophysiology sweat overactive by –characterized Primary hyperhidrosis This is an uncommon situation in neonates and infants, but is an important differential diagnosis in older constipated constipated diagnosis in older differential but is an important and infants, in neonates situation This is an uncommon Gastroesophageal reflux; surreptitious vomiting and bulimia (more common in adolescents); childhood cyclic vomiting cyclic childhood common in adolescents); (more vomiting and bulimia surreptitious reflux; Gastroesophageal Secondary hyperhidrosis – several diseases can cause excessive sweat such as hyperthyroidism, anxiety disorders or heat or heat disorders anxiety such as hyperthyroidism, sweat excessive cause diseases can – several hyperhidrosis Secondary impair mucociliary in clearance the CF manifests in newborns early (meconium ileus); later forms childhood and observed. are CF is characterized of thick by mucus in accumulation the airway and epithelia pancreatic and sweat ducts. These disturbances can result insufficiency, in pancreatic increase sweat in Cl Polyhydramnios Polyhydramnios watery diarrhea and beginning in utero and persistent during life; poor prematurity; growth and electrolytes weight gain; life-threatening disturbances and metabolic concentration, male intestinal infertility, and airway obstructions. Mutations in CFTR lung, which bacterial facilitates infection increasing the lung damage that results in lung insufficiency. mortality are related to Morbidity the severity of and involvement. bronchopulmonry
/ - channel
SLC26A3 + , encoding encoding , exchanger cystic fibrosis - 3 CFTR HCO Pathogenic loss of Pathogenic function in (ROMK-2) (ROMK-2) and the outwardly rectifying chloride channel. in colonic and ileal in colonic epithelial gene, gene, encoding Cl Pathogenic loss of Pathogenic functionin variants the transmembrane regulator a chloride channel (CFTR), expressed variety in of epithelia, in implicated a chloride transport, protein with also but and processing traffic, secretion of ATP and control of the ENaC, the renal secretory K condition 10.000. unknown Prevalence: in Brazil the in Brazil Laxative abuse Laxative and African; and African; Cyclic vomiting Cyclic In general, is In general, Arabia, Kwait Kwait Arabia, more often in often more More often in often More unknown, but unknown, incidence is 1: Finland, Saudit text). In Brazil is In Brazil text). Caucasians; less Caucasians; and Poland (see and Poland some areas as in some areas Nephrotoxic agents Nephrotoxic common in Asian common Chloride-intake deficiency Chloride-intake Surreptitious diuretics use diuretics Surreptitious Excessive and persistent sweating and persistent Excessive AR AR diarrhea/ Congenital chloride Congenital Cystic fibrosis (CF) / fibrosis Cystic
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cause similar biochemical abnormalities and, in these patients, room due to watery diarrhea. However, as CCD diagnosis criteria diarrhea can be confounded with polyuria, making this disease includes fecal chloride > 90 mEq/l and low urinary chloride [7] difficult to be suspected [5]. According to a recent publication of this hypothesis was ruled out and the patient was referred to Ben-David et al., there are 13 case reports in literature about CCD our pediatric nephrology service with provisional diagnosis of patients initially misdiagnosed as BS, 10 from Middle East, 2 from BS. Supporting this possible diagnosis, the patient presented Japan and 1 Serbian [6]. In this paper, the authors report the first polyhydramnios, premature delivery, reported polyuria and Brazilian patient with CCD who was misdiagnosed as BS and the characteristic lab findings. Unfortunately, the diagnosis ofBS diagnosis was achieved just by Whole-Exome Sequencing (WES). was accepted and new urinary electrolytes were not measured. Our goal is to discuss the difficulties to achieve the diagnosis in She was treated with potassium chloride, indomethacin clinical practice. (later replaced by celecoxib) and omeprazole to avoid gastric symptoms. During follow up she presented rare episodes of mild Case Report diarrhea, metabolic and electrolyte control, adequate growth and A female patient was born from healthy non-consanguineous weight gain. We performed genetic evaluation of our clinically parents at 36 weeks of gestation with an appropriate birth weight diagnosed BS/GS patients, including the following genes: GLA, of 3420 g. She had non-remarkable familial history. In the third CLCNKA, CLCNKB, BSND, KCNJ1, SLC12A1, CTNS, AQP2, AVPR2, trimester of gestation, polyhydramnios was observed. Hospital SLC12A3, CLDN19, CNNM2, CLDN16, TRPM6, SCNN1G, SCNN1B, records reported polyuria and episodes of vomiting. At the fourth ATP6V1B1, ATP6V0A4, SLC4A4. She had no mutation detected day of life she developed jaundice and the exams showed indirect and WES was done revealing a homozygous mutation (c.1487 bilirubin of 23 mg/dl and blood type O Rh+, while maternal T>G; p.Leu496Arg) in the solute carrier family 26 (SLC26A3) on chromosome 7q31, encoding for a transmembrane Cl-/HCO - blood type was A Rh+. ABO incompatibility was diagnosed 3 and exsanguinous transfusion indicated. For this reason, other exchanger mainly expressed in the apical brush border of ileum exams were collected and unexpectedly showed metabolic and colonic epithelium [8]. This variant was confirmed by Sanger sequencing. This mutation is likely pathogenic and was reported alkalosis (pH= 7.6 pCO2= 36.5 mmHg HCO3- = 36.3 mEq/L BE= +15.1), hyponatremia (125 mEq/L), hypokalemia (2.9 mEq/L) at least once related to CCD in a family from Hong Kong [8]. and hypochloremia (90 mEq/L). Unfortunately, simultaneous Celecoxib was withdrawn and the patient has evolved well under urinary electrolyte concentration was not checked. A surgical oral potassium chloride supplementation and omeprazole. She problem was ruled out. She was discharged on the 21st day of has no sign of renal dysfunction. life, after jaundice resolution and serum sodium, potassium and chloride improvement with oral supplementation. The patient Discussion was followed up on an outpatient basis, being treated with oral The differential diagnosis of persistent hypochloremic potassium chloride supplementation (2 – 3 mEq/kg/day) with hypokalemic metabolic alkalosis in childhood include some serum potassium range of 2.5 to 3.2 mEq/L. During follow up, acquired conditions as well as genetic diseases that pediatricians she was appropriately oral fed and the mother reported that the must be aware of, in which the precise diagnosis is essential patient had pasty stools without blood or mucus about 2 times/ due to the life-threatening situation. The lack of knowledge of day and polyuria. No mental or other congenital defects were the differential diagnosis and an inappropriate investigation of observed. She evolved with failure to thrive, but with adequate this metabolic electrolyte disturbance can lead to misdiagnosis neuropsychomotor development. The investigation showed and, consequently, incorrect treatment and complications. normal chloride levels in the sweat and normal functional This is exactly what happened to this patient that received coprology. Infectious diarrhea and food allergy or intolerance indomethacin or celecoxib. This mistake could have led to renal was ruled out. At 16 months of age, she was presented at dysfunction [9].Table 1 shows possible diagnosis of this condition emergency service with severe watery diarrhea, vomiting and and details some factors that can guide the investigation. The dehydration, and the exams showed serum (s) Na+= 130 mEq/L, diagnosis can vary according to the age and the clinical and + - - sK = 2.5 mEq/L, sCl = 91mEq/L, blood pH= 7.58 and HCO3 = familial history can rule out possibilities such as drug effects. 44 mEq/l. At this time, an investigation about the pathway of Figure 1 suggests a way to investigate these patients. Especially electrolyte waste was finally proposed. Then, a sample of stool in neonates and infants, information about prenatal and delivery was collected, and the fecal electrolyte measurements were: conditions are important. For instance, gastric suction can cause Na+= 9.5 mEq/L, K+= 8.95 mEq/L and Cl-= 40.3 mEq/L. The patient metabolic alkalosis. Polyhydramnios associated with dilation received sodium and potassium chloride infusion. Immediately of bowel loop in gestational ultrasonography can lead to CCD after volume recovery, a urine sample was taken for examination suspicion [10]. Metabolic alkalosis in neonates and young infants and showed: Na+= 77 mEq/L, K+= 68 mEq/L and Cl- = 61mEq/L. The can be due to surgical problems such as hypertrophic pyloric investigation detected elevated plasma renin= 15 ng/ml (normal: stenosis and these issues must be ruled out at presentation [11]. 0.51-2.64) and aldosterone= 95 ng/dL (normal: up to 39,2). All The presence of early manifestations such as premature labor, this information was obtained from the medical records, checking polyhydramnios, and failure to thrive increases the probability the time of each procedure, and can be susceptible to error. CCD of genetic causes. The basis of the investigation is to identify the was suspected since the patient was being treated for chronic pathway of electrolyte waste. This includes electrolyte serum hypochloremic metabolic alkalosis and was in the emergency and urinary measurements, but these have to be done after © Under License of Creative Commons Attribution 3.0 License 5 Journal of Rare Disorders: Diagnosis & Therapy 2019 ISSN 2380-7245 Vol.5 No.2:4
Loss of Acid from the Extracellular Fluid ↑ Bicarbonate Concentration in the Extracellular Fluid
Loss of H+ from GI fluid. Acid loss from the extracellular fluid. excessive chloride Alkali administration: Drugs Metabolism from Renal loss of H+: loss in the sweat. -overnutrition, -use of Mg-hydroxide bicarbonate precursors: Intracellular - ↓ Na+, K+ and Cl- reabsorption: -excessive alkalinization containing antacid citrate, acetate, and lactate. + transfer of H - ↑ Na+ reabsorption with of acidosis, binds, -massive transfusions, hypervolemia and hypertension -milk–alkali syndrome -parenteral high-dose -infusion of large volume of -anticids. penicillin salts fresh frozen plasma, administration. -use of citrate as an anticoagulant.
Metabolic Alkalosis