Complement factor H deficiency (CFHD) can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3 (120700), and a decrease in other ... Complement factor H deficiency (CFHD) can manifest as several different phenotypes, including asymptomatic, recurrent bacterial infections, and renal failure. Laboratory features usually include decreased serum levels of factor H, complement component C3 (120700), and a decrease in other alternative pathway components, indicating activation of the alternative complement pathway. Homozygotes and heterozygotes may show increased susceptibility to meningococcal infections. In addition, a number of renal diseases have been associated with factor H defect or deficiency, including atypical hemolytic-uremic syndrome (aHUS; 235400), membranoproliferative glomerulonephritis type II (MPGN II), and nonspecific hematuria or nephritis (Ault, 2000). See also complement factor I deficiency (610984), which shows phenotypic overlap with this disorder. Welch (2002) discussed the role of complement in renal disease. - Membranoproliferative Glomerulonephritis type II Abrera-Abeleda et al. (2006) summarized features of MPGN relevant to the complement cascade. MPGN type II, also known as dense deposit disease, causes chronic renal dysfunction that progresses to end-stage renal disease in about half of patients within 10 years of diagnosis. MPGN types I and III are variants of immune complex-mediated disease; MPGN II, in contrast, has no known association with immune complexes (Appel et al., 2005). MPGN II accounts for less than 20% of cases of MPGN in children and only a fractional percentage of cases in adults. Both sexes are affected equally, with the diagnosis usually made in children between the ages of 5 and 15 years who present with nonspecific findings such as hematuria, proteinuria, acute nephritic syndrome, or nephrotic syndrome. More than 80% of patients with MPGN II are positive for serum C3 nephritic factor (C3NeF), an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. C3NeF prolongs the half-life of C3 convertase. Patients with MPGN type II without C3NeF often have mutations in the CFH gene, which also results in prolonged activation of C3 convertase.
Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. ... Wyatt et al. (1982) reported 2 families with partial factor H deficiency and glomerulonephritis. In 1 family, of Polish origin, a teenaged male had vasculitis, thrombocytopenia, proteinuria, and depressed levels of serum factor H and complement component C3. The mother, maternal uncle, and a cousin had depressed H levels. The second family was of English-Irish extraction living in Kentucky; 3 persons in 3 generations had H levels about half normal. The index case had depressed serum factors H and B levels and IgA nephropathy (161950) which progressed to renal failure. A sister also had IgA nephropathy and depressed serum H and C3 levels. Levy et al. (1986) reported a consanguineous Algerian family in which 2 brothers had early-onset glomerulonephritis with C3 deposits and low levels (less than 10% of normal) of complement factor H. The factor H deficiency was defined by undetectable complement hemolytic activity by the classic (CH50) and alternate (AP50) pathways, and low levels of C3 and factor B (138470). The unaffected first-cousin parents and 2 healthy sibs, presumed heterozygotes, had half-normal H values. Renal disease was discovered at 14 and 4 months of age in the elder and younger brother, respectively. The elder had recurrent episodes of macroscopic hematuria occurring during the course of infections but did not seem to have an excessive number of infections; the younger had repeated upper and lower respiratory tract infections and nearly persistent macroscopic hematuria. Electron microscopy of renal biopsies from both patients were typical for intramembranous dense deposit disease, but immunofluorescence microscopy showed an atypical pattern with abundant granular C3 deposits within the mesangium and along the capillary walls. Lopez-Larrea et al. (1987) studied a family in which 3 female sibs had undetectable levels of factor H and C3 nephritic factor, low levels of factor B, C3, and C5 (see 120500), and normal levels of C4-binding protein (120830), factor I (217030), and classic pathway factors. C4 (see 120810) levels were low in 1 patient. Two of the sibs had Neisseria meningitidis sepsis; all 3 developed membranoproliferative glomerulonephritis. Brai et al. (1988) and Misiano et al. (1993) described a consanguineous Italian family in which 3 sibs had deficiency of factor H and its spliced isoform FHL1. The proband had systemic lupus erythematosus (152700) with chronic renal failure and had highly reduced C3 serum levels and low concentrations of C5-C9. She had suffered from skin lesions (chronic discoid plaques on sun-exposed areas), with ulcerations and central nervous system involvement with psychosis. Her 2 affected brothers showed a similar serum complement profile. They had suffered from 3 and 1 episodes, respectively, of meningococcal meningitis, without autoimmune disease. Factor H was undetectable in all affected sibs, and both parents presented serum concentrations of factor H that were about 50% of normal. Western blot analysis showed the absence of both factor H and FHL1 in the affected sibs. The father and 2 of the H-deficient sibs, including the proband, also had a partial C2 deficiency (217000). Nielsen et al. (1989) described a 15-year-old girl with a complete deficiency of factor H. Both parents had half normal levels. The girl had 2 episodes of meningococcal disease. The degree of H reduction was sufficient to cause increased, spontaneous activation of the alternative complement pathway. Fijen et al. (1996) described a Dutch family in which both heterozygous and homozygous factor H deficiency was observed. The proband of the family suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis. Western blot analysis showed complete factor H deficiency. Among 21 relatives of the proband encompassing 3 generations, 10 had low factor H levels, including 2 children of the proband, indicating heterozygosity. Serum studies showed decreased levels of components of the alternative complement pathway. Vogt et al. (1995) reported a 6-year-old Native American (Sioux) boy who presented at age 13 months with hypocomplementemic hypertensive renal disease. Renal biopsy showed changes consistent with membranoproliferative glomerulonephritis, deposition of type III collagen (120180), and segmental complement C3 deposition in capillary loops. Decreased levels of serum C3 and factor B but normal levels of serum C4 and factor I were found; factor H was undetectable by radial immunodiffusion analysis. Slightly depressed levels of factor H were present in both parents; his sibs had normal levels. Ault et al. (1997) reported that the child originally described by Vogt et al. (1995) underwent renal transplantation at age 7; serum C3 concentrations remained low thereafter, as did factor H levels. Western blot analysis of the patient's plasma before and after renal transplantation showed slightly increased concentration of the 45-kD factor H and no detectable 150-kD factor H when compared with 7 normal plasma samples. Ault et al. (1997) demonstrated that the patient's fibroblasts retained 155-kD factor H protein, which was not degraded even after 12 hours, and showed that factor H was retained in the endoplasmic reticulum. Licht et al. (2006) reported 2 girls, born of consanguineous Turkish parents, with early onset of membranoproliferative glomerulonephritis type II. Renal biopsies showed thickening of the glomerular basement membrane caused by dense deposits in the lamina densa. Immunohistochemistry showed deposition of C3. Laboratory analysis showed activation of both the alternative and classical complement pathway, and both patients and their asymptomatic mother also had autoantibodies to C3 nephritic factor (C3Nef). Genetic analysis identified a homozygous mutation in the CFH gene (134370.0014) in the patients; both parents were heterozygous for the mutation. Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation, which the authors termed 'glomerulonephritis C3.' Heterozygous mutations in complement regulatory genes were identified in 4 of 6 unrelated patients with glomerulonephritis C3, including 2 patients each with mutations in the CFH (see, e.g., 134370.0017) and CFI genes (see, e.g., 217030.0007), respectively. In addition, 1 of 13 unrelated patients with glomerulonephritis with MPGN also had a heterozygous CFH mutation. The findings indicated that dysregulation of the complement alternative pathway is associated with a wide spectrum of diseases ranging from HUS to MPGN with C3 deposits.
In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene.
... In a Native American boy reported by Vogt et al. (1995) who had factor H deficiency and membranoproliferative glomerulonephritis, Ault et al. (1997) identified compound heterozygosity for 2 mutations (134370.0002 and 134370.0003) in the CFH gene. In 3 affected sibs of a consanguineous Italian family with complement factor H deficiency reported by Brai et al. (1988) and Misiano et al. (1993), Sanchez-Corral et al. (2000) identified a homozygous nonsense mutation in the CFH gene (134370.0006). In 1 of the brothers reported by Levy et al. (1986), Dragon-Durey et al. (2004) identified a homozygous mutation in the CFH gene (134370.0010). Dragon-Durey et al. (2004) identified homozygous mutations in the CFH gene in 3 additional patients with MPGN, including 2 Turkish brothers (134370.0013).