Indian J Pediatr DOI 10.1007/s12098-014-1379-6
CLINICAL BRIEF
Genetic Analysis in Bartter Syndrome from India Pradeep Kumar Sharma & Bhaskar Saikia & Rachna Sharma & Kumar Ankur & Praveen Khilnani & Vinay Kumar Aggarwal & Hae Cheong
Received: 21 August 2013 / Accepted: 13 February 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. Around 150 cases have been reported in literature till now. Mutations leading to salt losing tubulopathies are not routinely tested in Indian population. The authors have done the genetic analysis for the first time in the Bartter syndrome on two cases from India. First case was antenatal Bartter syndrome presenting with massive polyuria and hyperkalemia. Mutational analysis revealed compound heterozygous mutations in KCNJ1(ROMK) gene [p(Leu220Phe), p(Thr191Pro)]. Second case had a phenotypic presentation of classical Bartter syndrome however, genetic analysis revealed only heterozygous novel mutation in SLC12A gene p(Ala232Thr). Bartter syndrome is a clinical diagnosis and genetic analysis is recommended for prognostication and genetic counseling.
Keywords Bartter syndrome . Genetic analysis . India P. K. Sharma : B. Saikia : R. Sharma : P. Khilnani Department of Pediatric Intensive Care Unit, B L Kapur Super Speciality Hospital, New Delhi, India K. Ankur Department of Neonatal Intensive Care Unit, B L Kapur Super Speciality Hospital, New Delhi, India V. K. Aggarwal Department of Pediatric Nephrology, B L Kapur Super Speciality Hospital, New Delhi, India H. Cheong Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea P. K. Sharma (*) Flat No 48, Pocket 7, Sector 21, Rohini, New Delhi 110086, India e-mail: [email protected]
Introduction Bartter syndrome is a group of rare autosomal-recessive disorders with a unifying pathophysiology consisting of severe reductions in, or losses of, salt absorption by the thick ascending limb of loop of Henle (TAL) and or Distal convoluted tubule (DCT). Mutations in five genes that are expressed in the TAL/DCT have been identified in Bartter syndrome [1].
Case Reports Case 1 A 1,870 g boy was delivered at 35 wk of gestation through cesarean section. There is no history of consanguinity. During 2nd trimester, mother had polyhydraminos with amniotic fluid index of 24.6. At 25 wk of gestation mother underwent amniocentesis. Chromosomal analysis was normal. At birth, no facial dysmorphism was present and postnatal urine output was 20 mL/kg/h. Blood urea and creatinine were 12 mg/dL and 0.3 mg/dL respectively. Serum sodium, potassium, calcium and chloride at Day 1 were 135 mmol/L, 5.1 mmol/L, 7.9 mg/dL and 96 mmol/L respectively. Urinary sodium, potassium, calcium and chloride were 129 mmol/L, 4.2 mmol/L, 6.6 mg/dL and 123 mmol/L respectively. Urinary calcium /creatinine ratio was 1.19 (5 y
Bartter syndrome type I
SLC12A1
NKCC2
TAL
Perinatal
Bartter syndrome type II
KCNJ1
ROMK
TAL + CCD
Perinatal
Bartter syndrome type III
CLCNKB
CIC-Kb
TAL + DCT
0–5 y
Bartter syndrome type IV A BSND Barttin (β-subunit TAL + DCT of CIC-Ka and Type IV B CLCNKA/CLCNKB CIC-Kb) Bartter syndrome type Vc CASR CaR protein TAL
Perinatal
variable
Hypokalemia, hypomagnesemia, alkalosis, hypocalciuria, growth retardation Polyhydramnios, polyuria, hypochloremia, alkalosis, hypokalemia, nephrocalcinosis Polyhydramnios, polyuria, hypochloremia, alkalosis, hyperkalemia initially, hypokalemia later, nephrocalcinosis Hypokalemia, hypochloremia, alkalosis, failure to thrive Polyhydramnios, polyuria, hypochloremia, alkalosis, hypokalemia, sensorineural deafnessb Hypocalcemia, low parathyroid hormone levels, hypercalciuria, uncommon cause of Bartter syndrome
CIC-Ka Chloride channel Ka; CIC-Kb Chloride channel Kb; NCCT Thiazide-sensitive sodium–chloride cotransporter; NKCC2 Furosemide-sensitive sodium–potassium–chloride cotransporter; ROMK Renal outer medullary potassium channel; BSND Bartter syndrome with sensorineural deafness; CASR Calcium sensing receptor; TAL Thick ascending limb of loop of henle; CCD Cortical collecting duct; DCT Distal convoluted tubule a
This terminology is based on the chronological order of gene discovery
b
Sensorineural deafness occurs because CIC-Ka and CIC-Kb are highly expressed in the inner ear and interact with other transport proteins (e.g., NKCC1) to maintain the high potassium concentration in the endolymph that is required for normal hearing c
Some experts classify the mild salt-losing effect of gain-of-function mutations in the calcium-sensing receptor as Bartter syndrome type V
polyuria, polydipsia, vomiting, constipation, salt craving, and a tendency to dehydration. No mutation could be identified in some cases [4]. Type IV or BSND variant presents with features of antenatal variety associated with sensorineural deafness [1, 4]. Mutation p(Leu220Phe) and mutation at locus p(Thr191) in KCNJ1(ROMK) gene, as identified here have been reported previously [5, 6]. Transient hyperkalemia and metabolic acidosis is usually seen with type II Bartter syndrome which resembles the clinical picture of pseudohypoaldosteronism type I. It is postulated that postnatal maturation of potassiumregulating mechanisms, including Na-K-ATPase, may explain the transient nature of the hyperkalemia [7, 8]. Although nephrocalcinosis is common but it may be absent in antenatal Bartter syndrome [5, 9]. The second case had a clinical picture of classical Bartter syndrome; however gene study revealed only one heterozygous mutation in SLC12A3 gene. Genotype-phenotype dissociation may be explained due to non-identification of second mutation in CIC-Kb or SCL12A3 gene. Further studies for larger deletions or duplications are required to find second mutation in SLC12A3 gene. The functional analysis of detected mutation (Ala232Thr) with standard tools predicted significant structural and/or functional damage on the protein. Also, Ala232 is highly conserved in mammalians. Mutations
leading to salt losing tubulopathies are not routinely tested in Indian population. Genetic analysis helps in providing accurate diagnosis and genetic counseling. All forms of Bartter syndrome are autosomal recessive in nature, thus carrying a 25 % risk of recurrence in siblings. Prenatal diagnosis can be offered to desired couple based on the mutations identified at 11 wk of pregnancy. Treatment of Bartter syndrome is directed at preventing dehydration, maintaining nutritional status, and correcting hypokalemia. Potassium supplementation and indomethacin (prostaglandin inhibitors) is the mainstay of treatment [10]. Bartter syndrome is very rare; a combination of failure to thrive and metabolic alkalosis should arouse a suspicion. Early diagnosis and treatment are life saving. Bartter syndrome is a clinical diagnosis. Genetic analysis is recommended for prognostication and genetic counseling.
Contributions PKS and BS: Collected the data, prepared, critically revised and finally approved the manuscript; RS and KA: Collected the data, prepared the manuscript; PK and VKA: Critically revised and finally approved the manuscript; HC: Did the genetic analysis and provided the interpretation of the same. PK will act as guarantor for the paper. Conflict of Interest None. Role of Funding Source None.
Indian J Pediatr
References 6. 1. Seyberth HW. An improved terminology and classification of Bartter like syndromes. Nat Clin Pract Nephrol. 2008;4: 560–7. 2. Bartter FC, Pronove P, Gill JR, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis, a new clinical syndrome. Am J Med. 1962;33:811–28. 3. Sampathkumar K, Muralidharan U, Kannan A, Ramakrishnan M, Ajeshkumar R. Childhood Bartter’s syndrome: An Indian case series. Indian J Nephrol. 2010;20:207–10. 4. Amirlak I, Dawson KP. Bartter syndrome: An overview. Q J Med. 2000;93:207–15. 5. Puricelli E, Bettinelli A, Borsa N, Sironi F, Mattiello C, Tammaro F, et al; Italian Collaborative Group for Bartter Syndrome. Long-term
7. 8.
9.
10.
follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant. 2010;25:2976–81. Vollmer M, Koehrer M, Topaloglu R, Strahm B, Omran H, Hildebrandt F. Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome. Pediatr Nephrol. 1998;12:69–71. Fremont OT, Chan JCM. Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr. 2012;8:25–30. Peters M, Jeck N, Reinalter S, Leonhardt A, Tonshoff B, Klaus G, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med. 2002;112:183–90. Vaisbich MH, Fujimura MD, Koch VH. Bartter syndrome: Benefits and side effects of long-term treatment. Pediatr Nephrol. 2004;19: 858–63. Ataoglu E, Civilibal M, Ozkul AA, Varal IG, Oktay ER, Murat E. Indomethacin-induced colon perforation in Bartter’s syndrome. Indian J Pediatr. 2009;76:322–3.
CLINICAL BRIEF
Genetic Analysis in Bartter Syndrome from India Pradeep Kumar Sharma & Bhaskar Saikia & Rachna Sharma & Kumar Ankur & Praveen Khilnani & Vinay Kumar Aggarwal & Hae Cheong
Received: 21 August 2013 / Accepted: 13 February 2014 # Dr. K C Chaudhuri Foundation 2014
Abstract Bartter syndrome is a group of inherited, salt-losing tubulopathies presenting as hypokalemic metabolic alkalosis with normotensive hyperreninemia and hyperaldosteronism. Around 150 cases have been reported in literature till now. Mutations leading to salt losing tubulopathies are not routinely tested in Indian population. The authors have done the genetic analysis for the first time in the Bartter syndrome on two cases from India. First case was antenatal Bartter syndrome presenting with massive polyuria and hyperkalemia. Mutational analysis revealed compound heterozygous mutations in KCNJ1(ROMK) gene [p(Leu220Phe), p(Thr191Pro)]. Second case had a phenotypic presentation of classical Bartter syndrome however, genetic analysis revealed only heterozygous novel mutation in SLC12A gene p(Ala232Thr). Bartter syndrome is a clinical diagnosis and genetic analysis is recommended for prognostication and genetic counseling.
Keywords Bartter syndrome . Genetic analysis . India P. K. Sharma : B. Saikia : R. Sharma : P. Khilnani Department of Pediatric Intensive Care Unit, B L Kapur Super Speciality Hospital, New Delhi, India K. Ankur Department of Neonatal Intensive Care Unit, B L Kapur Super Speciality Hospital, New Delhi, India V. K. Aggarwal Department of Pediatric Nephrology, B L Kapur Super Speciality Hospital, New Delhi, India H. Cheong Department of Pediatrics, Seoul National University Children’s Hospital, Seoul, South Korea P. K. Sharma (*) Flat No 48, Pocket 7, Sector 21, Rohini, New Delhi 110086, India e-mail: [email protected]
Introduction Bartter syndrome is a group of rare autosomal-recessive disorders with a unifying pathophysiology consisting of severe reductions in, or losses of, salt absorption by the thick ascending limb of loop of Henle (TAL) and or Distal convoluted tubule (DCT). Mutations in five genes that are expressed in the TAL/DCT have been identified in Bartter syndrome [1].
Case Reports Case 1 A 1,870 g boy was delivered at 35 wk of gestation through cesarean section. There is no history of consanguinity. During 2nd trimester, mother had polyhydraminos with amniotic fluid index of 24.6. At 25 wk of gestation mother underwent amniocentesis. Chromosomal analysis was normal. At birth, no facial dysmorphism was present and postnatal urine output was 20 mL/kg/h. Blood urea and creatinine were 12 mg/dL and 0.3 mg/dL respectively. Serum sodium, potassium, calcium and chloride at Day 1 were 135 mmol/L, 5.1 mmol/L, 7.9 mg/dL and 96 mmol/L respectively. Urinary sodium, potassium, calcium and chloride were 129 mmol/L, 4.2 mmol/L, 6.6 mg/dL and 123 mmol/L respectively. Urinary calcium /creatinine ratio was 1.19 (5 y
Bartter syndrome type I
SLC12A1
NKCC2
TAL
Perinatal
Bartter syndrome type II
KCNJ1
ROMK
TAL + CCD
Perinatal
Bartter syndrome type III
CLCNKB
CIC-Kb
TAL + DCT
0–5 y
Bartter syndrome type IV A BSND Barttin (β-subunit TAL + DCT of CIC-Ka and Type IV B CLCNKA/CLCNKB CIC-Kb) Bartter syndrome type Vc CASR CaR protein TAL
Perinatal
variable
Hypokalemia, hypomagnesemia, alkalosis, hypocalciuria, growth retardation Polyhydramnios, polyuria, hypochloremia, alkalosis, hypokalemia, nephrocalcinosis Polyhydramnios, polyuria, hypochloremia, alkalosis, hyperkalemia initially, hypokalemia later, nephrocalcinosis Hypokalemia, hypochloremia, alkalosis, failure to thrive Polyhydramnios, polyuria, hypochloremia, alkalosis, hypokalemia, sensorineural deafnessb Hypocalcemia, low parathyroid hormone levels, hypercalciuria, uncommon cause of Bartter syndrome
CIC-Ka Chloride channel Ka; CIC-Kb Chloride channel Kb; NCCT Thiazide-sensitive sodium–chloride cotransporter; NKCC2 Furosemide-sensitive sodium–potassium–chloride cotransporter; ROMK Renal outer medullary potassium channel; BSND Bartter syndrome with sensorineural deafness; CASR Calcium sensing receptor; TAL Thick ascending limb of loop of henle; CCD Cortical collecting duct; DCT Distal convoluted tubule a
This terminology is based on the chronological order of gene discovery
b
Sensorineural deafness occurs because CIC-Ka and CIC-Kb are highly expressed in the inner ear and interact with other transport proteins (e.g., NKCC1) to maintain the high potassium concentration in the endolymph that is required for normal hearing c
Some experts classify the mild salt-losing effect of gain-of-function mutations in the calcium-sensing receptor as Bartter syndrome type V
polyuria, polydipsia, vomiting, constipation, salt craving, and a tendency to dehydration. No mutation could be identified in some cases [4]. Type IV or BSND variant presents with features of antenatal variety associated with sensorineural deafness [1, 4]. Mutation p(Leu220Phe) and mutation at locus p(Thr191) in KCNJ1(ROMK) gene, as identified here have been reported previously [5, 6]. Transient hyperkalemia and metabolic acidosis is usually seen with type II Bartter syndrome which resembles the clinical picture of pseudohypoaldosteronism type I. It is postulated that postnatal maturation of potassiumregulating mechanisms, including Na-K-ATPase, may explain the transient nature of the hyperkalemia [7, 8]. Although nephrocalcinosis is common but it may be absent in antenatal Bartter syndrome [5, 9]. The second case had a clinical picture of classical Bartter syndrome; however gene study revealed only one heterozygous mutation in SLC12A3 gene. Genotype-phenotype dissociation may be explained due to non-identification of second mutation in CIC-Kb or SCL12A3 gene. Further studies for larger deletions or duplications are required to find second mutation in SLC12A3 gene. The functional analysis of detected mutation (Ala232Thr) with standard tools predicted significant structural and/or functional damage on the protein. Also, Ala232 is highly conserved in mammalians. Mutations
leading to salt losing tubulopathies are not routinely tested in Indian population. Genetic analysis helps in providing accurate diagnosis and genetic counseling. All forms of Bartter syndrome are autosomal recessive in nature, thus carrying a 25 % risk of recurrence in siblings. Prenatal diagnosis can be offered to desired couple based on the mutations identified at 11 wk of pregnancy. Treatment of Bartter syndrome is directed at preventing dehydration, maintaining nutritional status, and correcting hypokalemia. Potassium supplementation and indomethacin (prostaglandin inhibitors) is the mainstay of treatment [10]. Bartter syndrome is very rare; a combination of failure to thrive and metabolic alkalosis should arouse a suspicion. Early diagnosis and treatment are life saving. Bartter syndrome is a clinical diagnosis. Genetic analysis is recommended for prognostication and genetic counseling.
Contributions PKS and BS: Collected the data, prepared, critically revised and finally approved the manuscript; RS and KA: Collected the data, prepared the manuscript; PK and VKA: Critically revised and finally approved the manuscript; HC: Did the genetic analysis and provided the interpretation of the same. PK will act as guarantor for the paper. Conflict of Interest None. Role of Funding Source None.
Indian J Pediatr
References 6. 1. Seyberth HW. An improved terminology and classification of Bartter like syndromes. Nat Clin Pract Nephrol. 2008;4: 560–7. 2. Bartter FC, Pronove P, Gill JR, MacCardle RC. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis, a new clinical syndrome. Am J Med. 1962;33:811–28. 3. Sampathkumar K, Muralidharan U, Kannan A, Ramakrishnan M, Ajeshkumar R. Childhood Bartter’s syndrome: An Indian case series. Indian J Nephrol. 2010;20:207–10. 4. Amirlak I, Dawson KP. Bartter syndrome: An overview. Q J Med. 2000;93:207–15. 5. Puricelli E, Bettinelli A, Borsa N, Sironi F, Mattiello C, Tammaro F, et al; Italian Collaborative Group for Bartter Syndrome. Long-term
7. 8.
9.
10.
follow-up of patients with Bartter syndrome type I and II. Nephrol Dial Transplant. 2010;25:2976–81. Vollmer M, Koehrer M, Topaloglu R, Strahm B, Omran H, Hildebrandt F. Two novel mutations of the gene for Kir 1.1 (ROMK) in neonatal Bartter syndrome. Pediatr Nephrol. 1998;12:69–71. Fremont OT, Chan JCM. Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr. 2012;8:25–30. Peters M, Jeck N, Reinalter S, Leonhardt A, Tonshoff B, Klaus G, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med. 2002;112:183–90. Vaisbich MH, Fujimura MD, Koch VH. Bartter syndrome: Benefits and side effects of long-term treatment. Pediatr Nephrol. 2004;19: 858–63. Ataoglu E, Civilibal M, Ozkul AA, Varal IG, Oktay ER, Murat E. Indomethacin-induced colon perforation in Bartter’s syndrome. Indian J Pediatr. 2009;76:322–3.
