Complement factor H deficiency D84.8

Complement factor H deficiency (CFHD) has a variable phenotype.

Some patients develop recurrent infections, including increased susceptibility to meningococcal infections.

Other patients with complement factor H deficiency develop chronic kidney disease, primarily manifesting as C3 glomerulopathy. Affected individuals usually present with nonspecific findings such as hematuria in the first decades of life. The disease may progress to chronic renal failure with the need for renal transplantation.

Since complement factor H is the major regulator of the alternative pathway of the complement system, CFH deficiencyleads to uncontrolled activation of the alternative complement pathway.

The renal phenotype is now defined as a form of C3 glomerulopathy (C3G), a pathological entity in which C3 is deposited within the renal glomerulus in the mesangial or intramembranous space. These deposits occur in the absence of immune complexes or immunoglobulins.

Synonymous terms used to describe this condition include:

• Membranoproliferative glomerulonephritis type II (MPGN II).
• Mesangial Glomerulonephritis
• Dense Deposit Disease (DDD)
• C3 glomerulonephritis (see Ault et al. 2000; Riedl et al. 2017, Wong et al. 2018).

Serum levels of factor H are decreased due to the genetic defect. Secondarily, complement component C3 (120700) and other components of the alternative pathway are decreased. This is due to consumption of these factors.

Several reviews (Ito et al., 2017, Riedl et al., 2017, Wong et al. 2018) have noted that the definition and classification of C3G is constantly evolving. In the past, C3G was referred to as type II membranoproliferative glomerulonephritis (MPGN) or dense deposit disease (DDD) with mesangial or intramembranous deposits of electron-dense material.

In contrast, MPGN types I and III, which are usually associated with immune complex deposits, tend to show subendothelial and subepithelial electron-dense deposits. However, there is considerable variability, and the differentiation and distinction between these terms is often unclear. Welch (2002) also discussed the role of complement in renal disease.

A subset of patients with MGPN II who do not have mutations in the CFH gene are positive for serum C3 nephritic factor (C3NeF), an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. The presence of C3NeF prolongs the half-life of C3 convertase, which also leads to inappropriate activation of the complement cascade (S. Abrera-Abeleda et al. 2006).

Vogt et al (1995) reported on a 6-year-old boy who presented with hypocomplementemic hypertensive kidney disease at 13 months of age. Renal biopsy showed changes diagnosed as membranoproliferative glomerulonephritis, with deposits of type III collagen (120180) and segmental deposits of complement C3 in the capillary loops. Decreased concentrations of serum C3 and factor B, but normal concentrations of serum C4 and factor I were noted. Factor H was undetectable (radial immunodiffusion analysis).

Both parents had slightly decreased levels of factor H. The siblings had normal levels. Ault et al (1997) reported that the child originally described by Vogt et al (1995) underwent renal transplantation at age 7 years; serum C3 levels remained low thereafter, as did factor H levels.

Licht et al (2006) reported on two girls born to 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 deposits of C3. Laboratory analysis showed activation of both the alternative and classical complement pathways, and both the patients and their asymptomatic mother had autoantibodies to C3 nephritic factor (C3Nef). Genetic analysis revealed a homozygous mutation in the CFH gene (134370.0014) in the patients; both parents were heterozygous for the mutation.

1. Abrera-Abeleda MA et al (2006) Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet 43: 582-589.
2. Ault BH et al (1997) Human factor H deficiency: mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem 272: 25168-25175.
3. Ault BH (2000) Factor H and the pathogenesis of renal diseases. Pediat Nephrol 14: 1045-1053.
4. Ito N et al (2017) C3 glomerulopathy and current dilemmas. Clin Exp Nephrol 21: 541-551.
5. Licht C et al.(2006) Deletion of lys224 in regulatory domain 4 of factor H reveals a novel pathomechanism for dense deposit disease (MPGN II). Kidney Int 70: 42-50.
6. Riedl M et al (2017) C3 glomerulopathy. Pediat. Nephrol. 32: 43-57.
7. Vogt BA et al.(1995) Inherited factor H deficiency and collagen type III glomerulopathy. Pediat. Nephrol 9: 11-15.
8. Welch TR (2002) Complement in glomerulonephritis. Nature Genet. 31: 333-334.
9. Wong EKS et al (20187) Diseases of complement dysregulation--an overview. Semin. Immunopath. 40: 49-64.