Intrafamilial phenotype variability in patients with Gitelman syndrome having the same mutations in their thiazide-sensitive sodium/chloride cotransporter.
BACKGROUND
Gitelman syndrome (GS) most often results from mutations in the thiazide-sensitive sodium chloride cotransporter (NCC). Although the severity of symptoms may vary in patients who have the same mutations, a markedly different clinical presentation in family members with identical mutations is truly rare.


METHODS
Five patients (3 women and 2 men) belonging to 2 unrelated Chinese families were investigated. All had chronic hypokalemia, renal potassium (K+) wasting, metabolic alkalosis, and normal blood pressure. Direct sequencing of both the NCC and CLCNKB genes were performed.


RESULTS
The probands in each family were men. They had very severe hypokalemia and were symptomatic with episodes of paralysis. They had normal plasma magnesium concentrations, normal calcium excretion rates, and impaired maximal urine concentrating ability. In contrast, female family members were asymptomatic. They had laboratory findings typical of GS--less severe hypokalemia, hypomagnesemia, hypocalciuria, and intact maximal renal concentrating ability. Nevertheless, all patients had the same novel pair of NCC mutations and no mutations detected in CLCNKB.


CONCLUSIONS
Differences in sex may help explain the different clinical presentations in these 2 Chinese families with novel NCC mutations. Hypomagnesemia and hypocalciuria are not always present in patients with GS.
Lin
Shih-Hua
SH
Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan. l521116@ndmctsgh.edu.tw
Cheng
Nai-Lin
NL
Hsu
Yu-Juei
YJ
Halperin
Mitchell L
ML
D000328:Adult; D000471:Alkalosis / Q000235:genetics*; D027321:Anion Transport Proteins / Q000235:genetics*; D044466:Asian People; D001477:Bartter Syndrome / Q000235:genetics; D002118:Calcium / Q000652:urine; D002352:Carrier Proteins / Q000235:genetics*; D018118:Chloride Channels / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007008:Hypokalemia / Q000235:genetics*; D007674:Kidney Diseases / Q000235:genetics*; D008274:Magnesium / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011955:Receptors, Drug; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000235:genetics*; D013577:Syndrome
D027321:Anion Transport Proteins; C412733:CLCNKB protein, human; D002352:Carrier Proteins; D018118:Chloride Channels; D008565:Membrane Proteins; D011955:Receptors, Drug; C578874:SLC12A3 protein, human; D015222:Sodium Channels; D049992:Sodium Chloride Symporters; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; C064415:thiazide receptor; D008274:Magnesium; D002118:Calcium