Table 2.
Genetic and acquired complement abnormalities in 200 families in which one member (sporadic form) or more than one member (familial form) met the criteria for atypical hemolytic uremic syndrome
| aHUS | All Patients (n=214) | Familial Forma (n=28) | Sporadic Form (n=172) | P Value for Familial versus Sporadic Forms | Familial and Sporadic Forms (n=200) |
|---|---|---|---|---|---|
| Genetic/acquired abnormality | |||||
| CFH | 59 | 10 (35.7) | 45 (26.1) | 0.27 | 54 (27.0) |
| MCP | 20 (9.3) | 4 (14.3) | 15 (8.7) | 0.36 | 20 (10.0) |
| CFI | 18 (8.4) | 0 | 18 (10.4) | 18 (9.0) | |
| C3 | 18 (8.4) | 3 (10.7) | 13 (7.6) | 0.57 | 16 (8.0) |
| CFB | 4 (1.9) | 1 (3.6) | 2 (1.2) | 0.53 | 3 (1.5) |
| Anti-CFH antibodies | 14 (6.5) | 0 | 14 (8.1) | 14 (7.0) | |
| Combined | 9 (42.) | 2 (7.1) | 6 (3.5) | 0.27 | 8 (4.0) |
| THBDb | 0 | 0 | 0 | 0 | |
| Complement-mediated disease | 142 (66.3) | 20 (71.4) | 113 (65.7) | 0.67 | 132 (66.0) |
| Undetermined/incomplete | 72 (33.6) | 8 (4/4) (28.6) | 59 (34.3) | 0.55 | 68 (34.0) |
Values are expressed as the number (percentage) of patients. Undetermined: no anti-CFH antibodies and no genetic abnormalities were identified in the six tested genes; incomplete: families in which a mutation was identified in one member with aHUS but not in another member who also had aHUS (sister or brother of the index case). In four families, we identified a mutation in one affected patient (in CFH, C3, or CFI), but not in another affected relative (incomplete). Combined: patients with ≥2 genetic abnormalities, including (1) in familial cases: MCP (p.Arg103Trp; R69W)/CFI (p.Pro50Ala) and CFH (p.R1210C)/MCP (p.Tyr29×)/ and additional CFI (p.Pro553Ser) in one member of the family); (2) in sporadic cases: C3 (p.Pro1114Leu)/CFI (p.Asp524Val), CFH (c.2300–2301insA, p.Asn767LysfsX7)/CFI (p.His183Arg), CFH (p.R341H)/C3 (p.Arg161Trp), CFI (p.Tyr459Ser)/CFB (p.Val455Ile), MCP (IVS2+2; T>G)/CFI (p.H118R), CFI (p.Gly119Arg; G101R)/CFI (p.Gly424Asp; G406D). The two variants, H183R and P553S, in the CFI gene were identified in the single-nucleotide polymorphism database. aHUS, atypical hemolytic uremic syndrome; CFH, complement factor H; MCP, membrane cofactor protein; CFI, complement factor I; CFB, complement factor B; THBD, thrombomodulin.
Forty-two of 214 patients (19.6%) had familial aHUS. Among the 28 familial cases of aHUS, the disease occurred in siblings in 14 families, with a dominant trait in 7 other families (father/children) and an incomplete penetrance in the remaining 7 families (cousins, aunt/nephew, grandmother/granddaughter). The mutations in the familial forms were heterozygous in all but one case.
Two variants (A43T and P501L) in the THBD gene were identified in four patients who also had a mutation in the CFH gene (n=3) or CFB gene (n=1). These patients were arbitrarily included in the group of corresponding identified mutations.