Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation.
BACKGROUND
cblC disease is a cause of hemolytic uremic syndrome (HUS), which has been primarily described in neonates and infants with severe renal and neurological lesions.


METHODS
Two sisters aged 6 and 8.5 years presented with a latent hemolytic process characterized by undetectable or low plasma haptoglobin, respectively, associated with renal failure and gross proteinuria. Renal biopsies performed in both patients found typical findings of thrombotic microangiopathy suggesting the diagnosis of HUS. Both patients were free of neurologic signs.


RESULTS
Biochemical investigations found a cobalamin processing deficiency of the cblC type. Search for additional factors susceptible to worsen endothelial damage revealed homozygosity 677C--> T mutation in the methylenetetrahydrofolate reductase gene as well as heterozygosity for a 3254T--> C mutation in factor H in the patient with the most severe clinical presentation. Long-term subcutaneous administration of hydroxocobalamin in combination with oral betaine and folic acid resulted in clinical and biological improvement in both patients.


CONCLUSIONS
cblC disease may be a cause of chronic HUS with delayed onset in childhood. Superimposed mutation of factor H gene might influence clinical severity.
Guigonis
Vincent
V
Department of Pediatric Nephrology, Hôpital Armand-Trousseau, Paris, France.
Frémeaux-Bacchi
Véronique
V
Giraudier
Stéphane
S
Favier
Rémi
R
Borderie
Didier
D
Massy
Ziad
Z
Mougenot
Béatrice
B
Rosenblatt
David S
DS
Deschênes
Georges
G
D000740:Anemia / Q000209:etiology; D001622:Betaine / Q000031:analogs & derivatives / Q000627:therapeutic use; D002648:Child; D003131:Combined Modality Therapy; D017242:Complement Factor H / Q000235:genetics*; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006242:Haptoglobins / Q000172:deficiency; D006463:Hemolytic-Uremic Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy; D006801:Humans; D006879:Hydroxocobalamin / Q000627:therapeutic use*; D006973:Hypertension / Q000209:etiology; D007668:Kidney / Q000098:blood supply / Q000473:pathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000209:etiology; D010951:Plasma Exchange; D017354:Point Mutation; D011507:Proteinuria / Q000209:etiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl; D006435:Renal Dialysis; D014805:Vitamin B 12 / Q000378:metabolism*
C493495:CFH protein, human; D006242:Haptoglobins; D011518:Proto-Oncogene Proteins; C018229:betaine citrate; D001622:Betaine; D017242:Complement Factor H; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D050721:Proto-Oncogene Proteins c-cbl; C119570:CBLC protein, human; D014805:Vitamin B 12; D006879:Hydroxocobalamin