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Factor H deficiency(CFHD)

MedGen UID:
96024
Concept ID:
C0398777
Disease or Syndrome
Synonyms: CFH DEFICIENCY; CFHD; COMPLEMENT FACTOR H DEFICIENCY
SNOMED CT: Factor H deficiency (234622003)
 
Gene (location): CFH (1q31.3)
 
Monarch Initiative: MONDO:0012350
OMIM®: 609814

Disease characteristics

Excerpted from the GeneReview: C3 Glomerulopathy
C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity. [from GeneReviews]
Authors:
Bertha Martín  |  Richard JH Smith   view full author information

Additional descriptions

From OMIM
Complement factor H deficiency (CFHD) has a variable phenotype. Some patients present with recurrent infections, including increased susceptibility to meningococcal infections, whereas others develop renal disease manifest primarily as C3 glomerulopathy. Affected individuals usually present in the first decades of life with nonspecific findings such as hematuria and may progress to chronic renal failure. As complement factor H is the key regulator of the alternative pathway of the complement system, CFH deficiency results in inappropriate activation of the alternative complement pathway. Laboratory features usually include decreased serum levels of factor H, due to the genetic defect, as well as secondarily decreased levels of complement component C3 (120700) and other alternative pathway components, consistent with consumption of these factors. The renal phenotype is now considered to be a form of C3 glomerulopathy (C3G), which is a pathologic entity in which C3 is deposited within the kidney glomerulus in the mesangial or intramembranous space; this occurs in the absence of immune complexes or immunoglobulins. Terms used to describe this disease include membranoproliferative glomerulonephritis type II (MPGN II), mesangial glomerulonephritis, dense deposit disease (DDD), and C3 glomerulonephritis (summary by Ault, 2000, reviews by Riedl et al., 2017 and Wong and Kavanagh, 2018). Nomenclature and Classification Several reviews (Ito et al., 2017, Riedl et al., 2017, Wong and Kavanagh, 2018) have noted that the definition and classification of C3G continues to evolve. Historically, C3G has been referred to as type II membranoproliferative glomerulonephritis (MPGN) or dense deposit disease (DDD) with mesangial or intramembranous deposition of electron dense material. In contrast, MPGN types I and III, which are usually associated with immune complex deposition, tend to show subendothelial and subepithelial electron dense deposits. However, there is significant variability, and the differentiation and distinction between these terms is often unclear. Welch (2002) also discussed the role of complement in renal disease. A subgroup of patients with MGPN II who do not have mutations in the CFH gene are positive for serum C3 nephritic factor (C3NeF), which is an autoantibody directed against C3bBb, the convertase of the alternative pathway of the complement cascade. Presence of C3NeF prolongs the half-life of C3 convertase, which also results in inappropriate activation of the complement cascade (summary by Abrera-Abeleda et al., 2006). Genetic Heterogeneity of C3G C3G2 (610984) is caused by mutation in the CFI gene (217030) on chromosome 4q25, and C3G3 (614809) is caused by mutation in the CFHR5 gene (608593) on chromosome 1q31.  http://www.omim.org/entry/609814
From MedlinePlus Genetics
Researchers have identified two major forms of C3 glomerulopathy: dense deposit disease and C3 glomerulonephritis. Although the two disorders cause similar kidney problems, the features of dense deposit disease tend to appear earlier than those of C3 glomerulonephritis, usually in adolescence. However, the signs and symptoms of either disease may not begin until adulthood.

The kidney problems associated with C3 glomerulopathy tend to worsen over time. About half of affected individuals develop end-stage renal disease (ESRD) within 10 years after their diagnosis. ESRD is a life-threatening condition that prevents the kidneys from filtering fluids and waste products from the body effectively.

One of the two forms of C3 glomerulopathy, dense deposit disease, can also be associated with other conditions unrelated to kidney function. For example, people with dense deposit disease may have acquired partial lipodystrophy, a condition characterized by a lack of fatty (adipose) tissue under the skin in the upper part of the body. Additionally, some people with dense deposit disease develop a buildup of yellowish deposits called drusen in the light-sensitive tissue at the back of the eye (the retina). These deposits usually appear in childhood or adolescence and can cause vision problems later in life.

C3 glomerulopathy is a group of related conditions that cause the kidneys to malfunction. The major features of C3 glomerulopathy include high levels of protein in the urine (proteinuria), blood in the urine (hematuria), reduced amounts of urine, low levels of protein in the blood, and swelling in many areas of the body. Affected individuals may have particularly low levels of a protein called complement component 3 (or C3) in the blood.  https://medlineplus.gov/genetics/condition/c3-glomerulopathy

Clinical features

From HPO
Hematuria
MedGen UID:
5488
Concept ID:
C0018965
Disease or Syndrome
The presence of blood in the urine. Hematuria may be gross hematuria (visible to the naked eye) or microscopic hematuria (detected by dipstick or microscopic examination of the urine).
Thickened glomerular basement membrane
MedGen UID:
488906
Concept ID:
C0445347
Finding
Prominent glomerular basement membrane (GBM), reflecting an increase in thickness (subjective estimate) of the basal lamina of the glomerulus of the kidney.
Chronic kidney disease
MedGen UID:
473458
Concept ID:
C1561643
Disease or Syndrome
Functional anomaly of the kidney persisting for at least three months.
Glomerular subendothelial electron-dense deposits
MedGen UID:
1370779
Concept ID:
C4476539
Anatomical Abnormality
Electron dense deposits at the glomerular basement membrane,
Recurrent bacterial infections
MedGen UID:
334943
Concept ID:
C1844383
Finding
Increased susceptibility to bacterial infections, as manifested by recurrent episodes of bacterial infection.
Depletion of components of the alternative complement pathway
MedGen UID:
369958
Concept ID:
C1969220
Finding
An abnormal reduction in the components of the alternative complement pathway, such as the C3 protein or its cleavage products.
Decreased circulating complement factor H concentration
MedGen UID:
409784
Concept ID:
C1969222
Finding
Concentration of the complement component factor H in the blood circulation below the lower limit of normal.

Professional guidelines

PubMed

Sucker C, Hetzel GR, Farokhzad F, Dahhan F, Schmitz M, Kurschat C, Grabensee B, Maruhn-Debowski B, Zotz R, Scharf R
Nephrol Dial Transplant 2007 May;22(5):1347-50. Epub 2007 Feb 27 doi: 10.1093/ndt/gfl753. PMID: 17327284
Goodship TH
Kidney Int 2006 Jul;70(1):12-3. doi: 10.1038/sj.ki.5001612. PMID: 16810287
Bosch T, Wendler T
Ther Apher 2001 Jun;5(3):182-5. PMID: 11467754

Recent clinical studies

Therapy

Zanchi C, Locatelli M, Cerullo D, Aumiller V, Corna D, Rottoli D, Schubert S, Noris M, Tomasoni S, Remuzzi G, Zoja C, Benigni A
Mol Immunol 2024 Apr;168:10-16. Epub 2024 Feb 17 doi: 10.1016/j.molimm.2024.02.010. PMID: 38368725
Morigi M, Locatelli M, Rota C, Buelli S, Corna D, Rizzo P, Abbate M, Conti D, Perico L, Longaretti L, Benigni A, Zoja C, Remuzzi G
Sci Rep 2016 Jun 27;6:28445. doi: 10.1038/srep28445. PMID: 27345360Free PMC Article
Alfandary H, Davidovits M
Pediatr Nephrol 2015 Dec;30(12):2129-34. Epub 2015 Aug 20 doi: 10.1007/s00467-015-3166-7. PMID: 26289290
Noone D, Waters A, Pluthero FG, Geary DF, Kirschfink M, Zipfel PF, Licht C
Pediatr Nephrol 2014 May;29(5):841-51. Epub 2013 Nov 20 doi: 10.1007/s00467-013-2654-x. PMID: 24249282
Kavanagh D, Goodship TH
Curr Opin Hematol 2010 Sep;17(5):432-8. doi: 10.1097/MOH.0b013e32833cae86. PMID: 20613506

Prognosis

Phuong LK, Cheung A, Agrawal R, Butters C, Buttery J, Clark J, Connell T, Curtis N, Daley AJ, Dobinson HC, Frith C, Hameed NS, Hernstadt H, Krieser DM, Loke P, Ojaimi S, McMullan B, Pinzon-Charry A, Sharp EG, Sinnappurajar P, Templeton T, Wen S, Cole T, Gwee A
Pediatr Infect Dis J 2023 Oct 1;42(10):908-913. Epub 2023 Jul 7 doi: 10.1097/INF.0000000000004004. PMID: 37463351
Laskowski J, Renner B, Pickering MC, Serkova NJ, Smith-Jones PM, Clambey ET, Nemenoff RA, Thurman JM
J Clin Invest 2020 Aug 3;130(8):4039-4054. doi: 10.1172/JCI135105. PMID: 32369457Free PMC Article
De Vriese AS, Sethi S, Van Praet J, Nath KA, Fervenza FC
J Am Soc Nephrol 2015 Dec;26(12):2917-29. Epub 2015 Jul 16 doi: 10.1681/ASN.2015020184. PMID: 26185203Free PMC Article
Smith RJ, Harris CL, Pickering MC
Mol Immunol 2011 Aug;48(14):1604-10. Epub 2011 May 24 doi: 10.1016/j.molimm.2011.04.005. PMID: 21601923Free PMC Article
Loirat C, Niaudet P
Pediatr Nephrol 2003 Nov;18(11):1095-101. Epub 2003 Sep 17 doi: 10.1007/s00467-003-1289-8. PMID: 13680331

Clinical prediction guides

Laskowski J, Renner B, Pickering MC, Serkova NJ, Smith-Jones PM, Clambey ET, Nemenoff RA, Thurman JM
J Clin Invest 2020 Aug 3;130(8):4039-4054. doi: 10.1172/JCI135105. PMID: 32369457Free PMC Article
De Vriese AS, Sethi S, Van Praet J, Nath KA, Fervenza FC
J Am Soc Nephrol 2015 Dec;26(12):2917-29. Epub 2015 Jul 16 doi: 10.1681/ASN.2015020184. PMID: 26185203Free PMC Article
Pickering MC, Cook HT
Clin Exp Immunol 2008 Feb;151(2):210-30. doi: 10.1111/j.1365-2249.2007.03574.x. PMID: 18190458Free PMC Article
Loirat C, Niaudet P
Pediatr Nephrol 2003 Nov;18(11):1095-101. Epub 2003 Sep 17 doi: 10.1007/s00467-003-1289-8. PMID: 13680331
Williams DG
Pediatr Nephrol 1997 Feb;11(1):96-8. doi: 10.1007/s004670050241. PMID: 9035182

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