Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome.
BACKGROUND
Ante/neonatal Bartter syndrome (BS) is a hereditary salt-losing tubulopathy due to mutations in genes encoding proteins involved in NaCl reabsorption in the thick ascending limb of Henle's loop. Our aim was to study the frequency, clinical characteristics and outcome of each genetic subtype.


METHODS
Charts of 42 children with mutations in KCNJ1 (n = 19), SLC12A1 (n = 13) CLCNKB (n = 6) or BSND (n = 4) were retrospectively analysed. The median follow-up was 8.3 [0.4-18.0] years.


RESULTS
We describe 24 new mutations: 10 in KCNJ1, 11 in SLC12A1 and 3 in CLCNKB. The onset of polyhydramnios, birth term, height and weight were similar for all groups; three patients had no history of polyhydramnios or premature birth and had CLCNKB mutations according to a less severe renal sodium wasting. Contrasting with these data, patients with CLCNKB had the lowest potassium (P = 0.006 versus KCNJ1 and P = 0.034 versus SLC12A1) and chloride plasma concentrations (P = 0.039 versus KCNJ1 and P = 0.024 versus SLC12A1) and the highest bicarbonataemia (P = 0.026 versus KCNJ1 and P = 0.014 versus SLC12A1). Deafness at diagnosis was constant in patients with BSND mutations; transient neonatal hyperkalaemia was present in two-thirds of the children with KCNJ1 mutations. Nephrocalcinosis was constant in KCNJ1 and SLC12A1 but not in BSND and CLCNKB patients. In most cases, water/electrolyte supplementation + indomethacin led to catch-up growth. Three patients developed chronic renal failure: one with KCNJ1 mutations during the second decade of age and two with CLCNKB and BSND mutations and without nephrocalcinosis during the first year of life.


CONCLUSIONS
We confirmed in a large cohort of ante/ neonatal BS that deafness, transient hyperkalaemia and severe hypokalaemic hypochloraemic alkalosis orientate molecular investigations to BSND, KCNJ1 and CLCNKB genes, respectively. Chronic renal failure is a rare event, associated in this cohort with three genotypes and not always associated with nephrocalcinosis.
Brochard
Karine
K
Hôpitaux de Toulouse, Université Paul Sabathier, Département de Pédiatrie, Centre de Référence des Maladies Rénales Rares, Toulouse F31000, France.
Boyer
Olivia
O
Blanchard
Anne
A
Loirat
Chantal
C
Niaudet
Patrick
P
Macher
Marie-Alice
MA
Deschenes
Georges
G
Bensman
Albert
A
Decramer
Stéphane
S
Cochat
Pierre
P
Morin
Denis
D
Broux
Françoise
F
Caillez
Mathilde
M
Guyot
Claude
C
Novo
Robert
R
Jeunemaître
Xavier
X
Vargas-Poussou
Rosa
R
D000293:Adolescent; D000350:Africa, Central; D000352:Africa, Northern; D001477:Bartter Syndrome / Q000208:ethnology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D003638:Deafness / Q000208:ethnology / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D006947:Hyperkalemia / Q000208:ethnology / Q000235:genetics; D007223:Infant; D008297:Male; D009154:Mutation / Q000235:genetics*; D009397:Nephrocalcinosis / Q000208:ethnology / Q000235:genetics; D010641:Phenotype; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D012189:Retrospective Studies; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics*; D064466:Solute Carrier Family 12, Member 1; D014421:Turkey; D044465:White People / Q000208:ethnology / Q000235:genetics
C440005:BSND protein, human; C412733:CLCNKB protein, human; D018118:Chloride Channels; C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; C578714:SLC12A1 protein, human; D028021:Sodium-Potassium-Chloride Symporters; D064466:Solute Carrier Family 12, Member 1