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Cystic Fibrosis Presenting as Pseudo-Bartter Syndrome: An Important Diagnosis that is Missed!

Article in The Indian Journal of Pediatrics · June 2020 DOI: 10.1007/s12098-020-03342-8

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REVIEW ARTICLE

Cystic Fibrosis Presenting as Pseudo-Bartter Syndrome: An Important Diagnosis that is Missed!

Mohsin Raj Mantoo1 & Madhulika Kabra1 & S. K. Kabra1

Received: 14 January 2020 /Accepted: 6 May 2020 # Dr. K C Chaudhuri Foundation 2020

Abstract Cystic fibrosis (CF), an autosomal recessive disorder, occurs due to mutations in CFTR gene resulting in impaired cystic fibrosis transmembrane conductance regulator (CFTR) function in various epithelia. In addition to the well-known pulmo- nary and pancreatic morbidities, CF is characterized by electrolyte and acid-base abnormalities- hypochloremia, hyponatremia, and metabolic . These are collectively known as Pseudo-Bartter syndrome, as similar abnormalities are seen in Bartter syndrome- an inherited affecting thick ascending limb of . There may be a significant clinical overlap between the Classic Bartter syndrome, and CF presenting as Pseudo-Bartter syndrome, especially in early childhood. This review focuses on Pseudo-Bartter syndrome in CF, its pathogenesis and differentiation from Bartter/Gitelman syndrome. Other causes of metabolic abnormalities resembling Bartter syndrome are also highlighted.

Keywords Cystic fibrosis . Hypokalemia . Hyponatremia .

Introduction child was sent to authors’ hospital for further management. In view of one episode of pneumonia and history of frequent Cystic fibrosis and Bartter syndrome are rare inherited disor- foul-smelling stools, a diagnosis of cystic fibrosis was consid- ders. Overlapping of some clinical manifestations like dehy- ered and sweat chloride was performed. Cystic fibrosis was dration and failure to thrive, and similar electrolyte abnormal- confirmed with sweat chloride of 130 mEq/L and CFTR mu- ities in the two conditions may create a diagnostic confusion. tation analysis revealed homozygous for delta F 508 mutation. This is more common during infancy and early childhood. The infant was treated with intravenous infusion of normal saline, potassium and other supportive care for cystic fibrosis. Electrolyte abnormalities, metabolic alkalosis, blood urea and Representative Case creatinine improved in 36 h. The infant was again hospitalized later with dehydration and similar electrolyte abnormalities. This case highlights the overlapping clinical symp- Case N, a 4-month-old female infant, presented with failure to toms, electrolyte abnormalities and the diagnostic confu- thrive, recurrent dehydration and one episode of pneumonia; sion. This is further compounded by the lack of aware- requiring hospitalization thrice. Infant was severely malnour- ness about both illnesses in pediatricians and limited ished with weight of 2.6 kg. Chest X-ray was normal; blood availability of diagnostic tests (sweat test and molecular investigations revealed significant abnormalities in electrolyte diagnosis for Bartter syndrome and cystic fibrosis). and acid base balance (serum sodium 126 mEq/L, potassium Therefore, it is important to improve the knowledge of 1.8 mEq/L, blood pH 7.52 and bicarbonate 32 mmol/L) along pediatricians about these two diagnoses and how to dif- with raised urea and creatinine (urea 76 mg/dl and creatinine ferentiate between them. 1.4 mg/dl). A diagnosis of Bartter syndrome was made and the Cystic fibrosis (CF) is the single most common life- limiting monogenetic disease in the Caucasian population * S. K. Kabra with the estimated incidence of 1 in 3000 in white- [email protected] Americans [1]. The prevalence is CF in Indian population is – 1 estimated between 1 in 40,000 100,000 [2]. The pathogenesis Department of Pediatrics, All India Institute of Medical Sciences, of CF stems from mutations in CFTR gene (7q31.2) which New Delhi 110029, India Indian J Pediatr encodes cystic fibrosis transmembrane conductance regulator absorption from sweat as it passes through the ducts of sweat (CFTR) chloride (Cl−) channel [3]. Abnormal CFTR function glands results in significant loss of NaCl on to the skin surface. in the sweat glands leads to defective reabsorption and hence This forms the basis of doing sweat Cl test and is the reason why loss of NaCl in the sweat [4]. This forms the basis of sweat these patients have a salty taste on kiss. These NaCl losses are chloride test widely used in the diagnosis of CF. Excessive exacerbated in any condition that results in excessive sweating loss of NaCl in the sweat in patients of CF leads to the char- including fever, high ambient temperature or physical exertion. acteristic acid-base and electrolyte abnormalities mimicking In the airway epithelia, the direction of movement of these − − those of Bartter syndrome (an inherited renal tubulopathy). ions is different- CFTR mediates secretion of Cl and HCO3 while ENaC is responsible for Na+ absorption. This is impor- tant for maintaining the properties of airway surface liquid Molecular Defect in Cystic Fibrosis: A Defect (ASL) which prevents the ciliated epithelium from desiccation and forms part of mucociliary clearance mechanism. In CF, in Electrolyte Transport − − defect in CFTR (Cl and HCO3 secretion) and unopposed + Cystic fibrosis transmembrane conductance regulator (CFTR) Na absorption mediated by ENaC results in ASL depletion belongs to ATP-binding cassette (ABC) family of proteins. The and hyperviscosity of airway secretions. This forms the path- channel is formed by two membrane spanning domains (MSD1 ophysiologic basis of mucus plugging, recurrent pneumonias and 2), two nucleotide binding domains (NBD 1 and 2) that bind and bronchiectasis which are the major CF morbidities. ATP and a regulatory (R) domain which contains sites for phos- phorylation [5]. CFTR functions as an anion channel for Cl− and − HCO3 , allowing movement of these anions down their electro- Electrolyte and Acid-Base Abnormalities chemical gradient [4]. The direction of ion movement differs in in Cystic Fibrosis- Pseudo Bartter Syndrome different epithelia depending on their particular function (absorp- tion or secretion) as depicted in Fig. 1. As explained above, defective CFTR results in excessive loss In the sweat glands, the primary secretion is isotonic, which of NaCl in the sweat. This results in salt depletion in these becomes hypotonic as it passes through the duct on to the skin infants and the compensatory activation of -angiotensin- surface for evaporative cooling. Na+ and Cl− are absorbed via system (RAAS) [6–9]. Compensatory Na+ reab- epithelial Na+ channels (ENaC) and CFTR channels, respective- sorption by aldosterone results in secretion of K+ and H+ in the ly, present in the apical membrane of duct epithelial cells. The renal collecting ducts, resulting in hypokalemia and metabolic gradient for this transport is created by the Na+ K+ ATPase alkalosis. This constellation of abnormalities- hyponatremia, present in the basolateral membrane. In cystic fibrosis, CFTR hypochloremia, hypokalemia and metabolic alkalosis are re- are either reduced in number or defective, which blocks the ferred to as Pseudo-Bartter syndrome (PBS). Based on a sys- reabsorption of Cl− directly and Na+ indirectly (Lack of move- tematic review [10], these electrolyte abnormalities occurred ment of Cl− from lumen to ductal epithelial cells results in de- most commonly in <2.5-y-old age group and may be subacute polarization of the membrane to a more positive potential which or chronic. The electrolyte abnormalities may be recurrent inhibits movement of Na+ into the cell). This lack of NaCl even before the clinical diagnosis of CF is considered.

Fig. 1 Dysfunctional CFTR leads to NaCl wasting in sweat in patients with cystic fibrosis. CFTR Cystic fibrosis transmembrane conductance regulator; ENaC Epithelial Na+ channels Indian J Pediatr

Circulating renin and aldosterone levels are almost always aldosterone-mediated reabsorption of Na+ in exchange for elevated. The features of PBS were associated with dehydra- K+ and H+. This results in hypokalemia and metabolic alka- tion, excessive sweating, fever, chest infections, vomiting and losis. Increased delivery of NaCl to macula densa activates the failure to thrive [10]. tubuloglomerular feedback and increased production of pros- The genesis of the electrolyte abnormalities in Pseudo- taglandins (PGE2). The paracellular reabsorption of Ca++ and Bartter syndrome are depicted in Fig. 2. These abnormalities Mg++ is also impaired resulting in and hypo- show striking resemblance to those of inherited tubulopathies magnesemia [15]. known as Bartter syndrome and Gitelman syndrome, the same Another similar renal tubular disorder is the Gitelman syn- is being discussed in next section. drome which results from a defective thiazide-sensitive NaCl cotransporter (NCC) in the distal convoluted tubule (DCT) [16]. This results in NaCl wasting, hypocalcemia and hypo- magnesemia in addition to hypokalemic metabolic alkalosis. Bartter Syndrome: A Brief Overview The age of symptom onset is variable and most common man- ifestations include salt craving, fatigue, muscle weakness, This syndrome was originally described by Bartter and co- and low blood pressure [17]. workers in two patients with without hy- Laghmani et al., recently reported an interesting disorder pertension but with characteristic abnormalities of hyperplasia with severe and transient Bartter syndrome of juxtaglomerular apparatus (JGA) and hypokalemic metabol- due to mutation in MAGED2 gene present on X chromosome ic alkalosis [11]. Bartter syndrome results from defective NaCl [18]. The authors describe total 13 infants in whom pregnancy absorption in the thick ascending limb (TAL) of loop of Henle was complicated by severe polyhydramnios and prematurity. – [12 14]. NaCl absorption in TAL is mediated by - All surviving patients (11) had resolution of symptoms later in + + − sensitive Na K 2Cl cotransporter (NKCC2), renal outer life. MAGED2 encodes a protein, melanoma-associated anti- + medullary K (ROMK) channel on the apical membrane and gen D2, which is involved in normal expression and localiza- chloride channels (ClCN-Kb and ClCN-Ka) on the basolateral tion of both NKCC2 in TAL and NCC in DCT. This results in membrane. The electrochemical gradient for the NaCl absorp- severe NaCl wasting and polyuria. The transient nature of this + + tion is created by Na K ATPase present on the basolateral tubulopathy is still intriguing. membrane. Ca and Mg are absorbed via paracellular pathways The above discussed renal tubular disorders are summa- in TAL as a result of electrical gradient created due to NaCl rized in Table 1. reabsorption. Mutation in the genes encoding NKCC2, ROMK In addition to these inherited tubulopathies, various other and Barttin (a subunit of Cl channels ClCN-Kb and ClCN-Ka) entities (Table 2) have been described to produce Bartter syn- results in Bartter syndrome type I, II and IV, respectively. The drome like metabolic abnormalities. Loop abuse/ Bartter syndrome types I, II, and IV present early with antenatal excess can produce exactly same picture and needs to be ruled polyhydramnios and severe symptoms in neonatal period. out before making a diagnosis of Bartter syndrome [19, 20]. Bartter syndrome type III (Classic Bartter syndrome) is due to Nephrotoxic agents (like aminoglycosides, amphotericin B mutation in gene encoding ClCN-Kb and may present in early etc.) can produce similar phenotype [15]. Extra renal NaCl childhood with less severe symptoms. loss can also produce similar electrolyte abnormalities as The defective NaCl reabsorption in TAL results in in- discussed above in CF. Gastro-intestinal losses including creased delivery of NaCl to the distal tubules and hence vomiting and diarrhea (as in congenital hypertrophic pyloric stenosis, congenital chloride diarrhea) also produce hypochloremia, hypokalemia and metabolic alkalosis [21]. In addition, Bartter syndrome like abnormalities have also been reported in diabetes and vasculitis [22, 23] Therefore, any disorder that causes loss of sodium and/or chloride in vomitus, loose stools, urine or sweat can lead to a phenotype that resembles Bartter or Gitelman syndrome. When faced with hypokalemia, metabolic alkalosis and low-normal blood pressure, one should carefully rule out more common causes before considering the above discussed renal tubulopathies. This is done by thorough clinical assessment and certain basic lab parameters. A meticulous history taking can exclude gastrointestinal losses. In addition, spot urinary Fig. 2 Genesis of Pseudo-Bartter syndrome. CFTR Cystic fibrosis trans- membrane conductance regulator; ECF Extracellular fluid; RAAS Renin- chloride concentration < 10 mEq/L suggests an extra renal angiotensin-aldosterone system loss of Cl as in excess vomiting, congenital chloride diarrhea Indian J Pediatr

Table 1 Summary of Bartter and Gitelman syndromes

Disorder Gene Protein Defect Presentation

Bartter syndrome I SLC12A1 Na+ K+ 2Cl− cotransporter Defective Na+,K+ and Cl− Antenatal Bartter syndrome; (NKCC2) reabsorption in TAL. polyhydramnios; ; failure to thrive Bartter syndrome II KCNJ1 Renal outer medullary K+ Defective Na+,K+ and Cl− Antenatal Bartter syndrome; (ROMK) channel reabsorption in TAL. polyhydramnios; nephrocalcinosis; failure to thrive Bartter syndrome III CLCNKB ClCN-Kb channel Defective Na+,K+ and Cl− Classic Bartter syndrome; presents in reabsorption in TAL and DCT. early childhood, failure to thrive, polyuria, normal serum magnesium Bartter syndrome IV BSND Barttin Defective Na+ and Cl− reabsorption in Antenatal Bartter syndrome; TAL and DCT. polyhydramnios; sensorineural hearing loss Gitelman syndrome SLC12A3 NaCl cotransporter (NCC) Defective Na+ and Cl− reabsorption in Usually presents in late childhood; DCT. fatigue; weakness; polyuria; hypocalciuria; hypokalemia; hypomagnesemia and metabolic alkalosis. MAGED 2 variant MAGED2 Melanoma-associated antigen Defective Na+ and Cl− reabsorption in Severe polyhydramnios; Transient (Bartter and Gitelman overlap) D2 TAL and DCT. Antenatal Bartter syndrome

ClCN-Ka Chloride channel-kidney a; ClCN-Kb Chloride channel-kidney b; DCT Distal convoluted tubule; TAL Thick ascending limb of loop of Henle

or cystic fibrosis [24]. Bartter and Gitelman syndromes have Table 3 summarizes the key differences between urinary chloride in excess of 20 mEq/L. In addition, patients Pseudo-Bartter syndrome and Bartter syndrome. Bartter with metabolic alkalosis and high blood pressure should drive syndrome types I, II and IV (Antenatal Bartter syn- workup on lines of primary hyperaldosteronism, Liddle syn- drome) have severe phenotypes which manifest in neo- drome, apparent mineralocorticoid excess, glucocorticoid re- natal period. Type III or Classic Bartter syndrome pre- mediable aldosteronism etc. [24]. sents in early childhood with relatively mild phenotype and is to be clinically differentiated from Gitelman syn- drome and the Pseudo-Bartter syndrome. Patients with Differentiating Pseudo-Bartter Syndrome Classic Bartter usually present at a younger age as com- of CF and Bartter Syndrome paredtoGitelmanorPseudo-Bartterandtendtohave more severe metabolic alkalosis along with higher frac- Given that the Pseudo-Bartter syndrome can be the initial tional excretion of sodium and chloride (FeNa and manifestation of CF [10, 25–28], one needs to keep CF as FeCl) [14]. Hypomagnesemia and hypocalciuria are a differential diagnosis of an infant with unexplained hy- more common in Gitelman syndrome, though the same pokalemia, hypochloremia and metabolic alkalosis in ad- may be seen in Bartter and Pseudo-Bartter syndromes as dition to salt losing tubulopathies. In addition, Pseudo- well. Hence, a clinician may need genetic testing to Bartter syndrome should also be considered in patients clearly distinguish between these overlapping clinical with CF who have failure to thrive despite treatment. entities.

Table 2 Causes of Pseudo- Bartter syndrome other than cys- Urinary loss of sodium/chloride Diuretic excess tic fibrosis Nephrotoxic drugs like amphotericin B

Gastrointestinal loss of sodium/chloride Vomiting e.g., congenital hypertrophic pyloric stenosis Congenital chloride diarrhea abuse

Others Diet deficient in chloride Diabetes Vasculitis Indian J Pediatr

Table 3 Key differences between Pseudo-Bartter syndrome and Bartter syndrome

Characteristic Pseudo-Bartter in CF Bartter syndrome

Mutation CFTR gene Genes encoding NKCC2, ROMK, ClCN-Kb, ClCN-Ka, Barttin Inheritance Autosomal recessive Autosomal recessive* Basic defect Excessive loss of NaCl in sweat Defective NaCl reabsorption in TAL Clinical manifestations Prematurity, low birth weight, meconium ileus, failure Prematurity, polyhydramnios, failure to thrive, polyuria, to thrive, upper respiratory involvement (rhinosinusitis, , hypokalemia, hypochloremia, metabolic alkalosis, nasal polyposis), lower respiratory tract involvement hypocalcemia (tetany, seizures), hypomagnesemia, (Recurrent or persistent pneumonia), pancreatic leading to nephrocalcinosis, deafness (in Type insufficiency; diabetes mellitus, rectal prolapse, IV Bartter) cirrhosis, male infertility, nephrocalcinosis, aquagenic wrinkling, Pseudo-Bartter syndrome Antenatal ultrasonography Hyper-echogenic bowel, meconium peritonitis Polyhydramnios Electrolyte and blood gas abnormalities Hyponatremia, hypochloremia, Hyponatremia, hypochloremia, hypokalemia, hypocalcemia, hypokalemia, metabolic alkalosis hypomagnesemia, metabolic alkalosis RAAS Elevated renin activity and aldosterone Elevated renin activity and aldosterone Urinary PGE2 [29] Normal Elevated Sweat chloride Abnormal Normal Urine Na excretion Low High FeNa and FeCl Low High Response to loop ** Normal Blunted Treatment IV rehydration; salt supplementation and other KCl supplements, NSAIDs, aldosterone receptor blockers supportive care

*Autosomal dominant hypercalciuric hypocalcemia, caused by mutation in calcium sensing receptor, CaSR is sometimes called as Type V Bartter syndrome **Testing response to diuretics is no longer recommended (risk of marked diuresis) CF Cystic fibrosis; CFTR Cystic fibrosis transmembrane conductance regulator; ClCN-Ka Chloride channel-kidney a; ClCN-Kb Chloride channel- kidney b; FeCl Fractional excretion of chloride; FeNa Fractional excretion of sodium; NKCC2 Na+ K+ 2Cl− cotransporter; NSAIDs Non-steroidal anti- inflammatory drugs; RAAS Renin-angiotensin-aldosterone system; ROMK Renal outer medullary K+ channel; TAL Thick ascending limb of loop of Henle

Utility of Pseudo-Bartter Syndrome only be made after confirmation by sweat chloride or in the Diagnostic Algorithm of CF CFTR gene analysis. Caution while interpreting the findings of Pseudo- The diagnostic criteria for CF have been elaborated and include Bartter syndrome is needed as the electrolyte abnormali- thepresenceofoneormoretypical clinical characteristics or a ties are very non-specific. Besides Bartter syndrome, oth- positive newborn screen or a diagnosis of CF in a sibling with a er acquired causes of renal tubular damage or even any laboratory evidence of CFTR defect in the form of elevated extra-renal NaCl loss (e.g., diarrhea, vomiting) can result sweat chloride or two abnormal CFTR alleles or abnormal nasal in hypochloremic hypokalemic metabolic alkalosis. As potential difference [30]. The sweat chloride remains the gold highlighted above, there can be a significant clinical over- standard test for CF. With more than 2000 mutant alleles iden- lap between Classic Bartter syndrome, Gitelman syn- tified [31], all of which are not disease-causing, genetic analysis drome and CF presenting as Pseudo-Bartter syndrome of CFTR gene sometimes reveals unclear results. The CFTR which may be difficult to tell apart even after basic lab gene analysis is especially helpful in cases with intermediate tests like blood pH, urine electrolytes and sweat chloride. sweat chloride results (30–59 mmol/L). In that scenario, genetic testing including next generation The issues faced by pediatricians managing such sequencing may be helpful. cases in the developing countries were previously highlighted [32]. Non-availability of sweat chloride test- ing and CFTR mutation analysis add to the already poor Prevention and Management awareness about CF. In such scenarios, certain ancillary of Pseudo-Bartter Syndrome tests have been suggested by the CF experts from India, including testing for electrolyte abnormalities of Pseudo- The salt content of human breast milk (<7 mmol/L) or standard Bartter syndrome, stool examination for fat globules and infant formula (<15 mmol/L) may be inadequate in infants with testing the respiratory specimens for Pseudomonas CF. Infants with CF are sodium depleted irrespective of weather aeruginosa [2]. However, the diagnosis of CF should [6, 33, 34]. Hence the latest ESPEN-ESPGHAN guidelines Indian J Pediatr recommend routine sodium supplementation for all infants with 9. Legris GJ, Dearborn D, Stern RC, et al. Sodium space and intra- CF. Sodium supplementation may be started at 1–2 mmol/kg/d vascular volume: dietary sodium effects in cystic fibrosis and healthy adolescent subjects. Pediatrics. 1998;101:48–56. followed by monitoring of urine Na excretion. Goal is to keep 10. 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