title: Retrospective cohort study of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis due to CLDN16 mutations.
abstract: BACKGROUND
  Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare autosomal recessive tubular disorder exhibiting a high risk for progressive chronic kidney disease (CKD).
  
  
  METHODS
  This is a retrospective multicentre study of 25 paediatric cases with FHHNC in Poland. Median age at diagnosis was 4 years and median follow-up time was 4.8 years.
  
  
  RESULTS
  All cases of FHHNC carried recessive mutations in CLDN16. The founder mutation in CLDN16, Leu151Phe, was the most frequent cause of FHHNC in Polish patients, with 13 (52%) cases being homozygous and 5 (20%) carrying Leu151Phe allele in compound heterozygosity. All cases showed nephrocalcinosis, increased urinary fractional excretion of magnesium and hypercalciuria. Other disease features included hypomagnesaemia (76%), hyperparathyroidism (76%), hyperuricaemia (56%) and hypocitraturia (60%). Treatment with thiazides effectively reduced hypercalciuria in most cases. During follow-up, renal function declined in 60% of patients; 12% of patients reached CKD stage 3 or 4 and one patient developed end-stage renal failure.
  
  
  CONCLUSIONS
  We report one of the largest cohorts of FHHNC cases caused by CLDN16 mutations. A missense variant of CLDN16, Leu151Phe, is the most common mutation responsible for FHHNC in Poland. Additionally, we found that normomagnesaemia does not exclude FHHNC and the calculation of fractional excretion of Mg can be diagnostic in the setting of normomagnesaemia. We also demonstrate the efficacy of a treatment with thiazides in terms of hypercalciuria in the majority of patients.
authors.affiliation: Department of Pediatric Nephrology, Medical University of Lublin, Poland.
authors.forename: Przemysław
authors.initials: P
authors.lastname: Sikora
authors.affiliation: Children's Hospital, Poznań, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Zaniew
authors.affiliation: Department of General Pediatrics, Pediatric Nephrology, University Children's Hospital, Münster, Germany.
authors.forename: Lea
authors.initials: L
authors.lastname: Haisch
authors.affiliation: Center of Pediatrics and Oncology, Chorzów, Poland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pulcer
authors.affiliation: Department of Pediatrics in Zabrze, Medical University of Silesia, Katowice, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Szczepańska
authors.affiliation: Department of Pediatric Nephrology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Moczulska
authors.affiliation: Nephrology Division, Department of Pediatrics and Immunology, Polish Mothers Memorial Hospital Research Institute, Lódź, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Rogowska-Kalisz
authors.affiliation: Department of Pediatric Nephrology, Medical University of Lublin, Poland.
authors.forename: Beata
authors.initials: B
authors.lastname: Bieniaś
authors.affiliation: Nephrology Division, Department of Pediatrics and Immunology, Polish Mothers Memorial Hospital Research Institute, Lódź, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Tkaczyk
authors.affiliation: Department of Pediatric Cardiology and Nephrology, University of Medical Sciences, Poznań, Poland.
authors.forename: Danuta
authors.initials: D
authors.lastname: Ostalska-Nowicka
authors.affiliation: Department of Pediatric Nephrology, Jagiellonian University Medical College, Kraków, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Zachwieja
authors.affiliation: Center of Pediatrics and Oncology, Chorzów, Poland.
authors.forename: Lidia
authors.initials: L
authors.lastname: Hyla-Klekot
authors.affiliation: Department of General Pediatrics, Pediatric Nephrology, University Children's Hospital, Münster, Germany.
authors.forename: Karl Peter
authors.initials: KP
authors.lastname: Schlingmann
authors.affiliation: Department of General Pediatrics, Pediatric Nephrology, University Children's Hospital, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Konrad
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D057167:Claudins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D053565:Hypercalciuria / Q000453:epidemiology / Q000235:genetics*; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009397:Nephrocalcinosis / Q000453:epidemiology / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D015995:Prevalence; D015499:Renal Tubular Transport, Inborn Errors / Q000453:epidemiology / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D057167:Claudins; C502010:claudin 16
keywords: CLDN16; FHHNC; hypercalciuria; hypomagnesaemia; nephrocalcinosis