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C4 Deficiency

MedGen UID:
859438
•Concept ID:
C3899844
•
Disease or Syndrome

Definition

Lack of production of functional C4 protein, due to a genetic defect requiring homozygous loss of both the C4A and C4B genetic paralogs. Approximately 75% of patients with a C4 deficiency will develop a severe systemic lupus erythematosus at an early age. Patients also present with frequent sinopulmonary infections often with Streptococcus pneumoniae. [from NCI]

Professional guidelines

PubMed

Technical and theoretical considerations in the HLA typing of amniotic fluid cells for prenatal diagnosis and paternity testing.
Pollack MS, Heagney SD, Braun D Jr, O'Neill GJ
Prenat Diagn 1981 Jul;1(3):183-95. doi: 10.1002/pd.1970010304. PMID: 6981107

Recent clinical studies

Etiology

Classical pathway deficiencies - A short analytical review.
Truedsson L
Mol Immunol 2015 Nov;68(1):14-9. Epub 2015 May 30 doi: 10.1016/j.molimm.2015.05.007. PMID: 26038300
Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations.
Boteva L, Morris DL, Cortés-Hernández J, Martin J, Vyse TJ, Fernando MM
Am J Hum Genet 2012 Mar 9;90(3):445-56. Epub 2012 Mar 1 doi: 10.1016/j.ajhg.2012.01.012. PMID: 22387014Free PMC Article
The intricate role of complement component C4 in human systemic lupus erythematosus.
Yang Y, Chung EK, Zhou B, Lhotta K, Hebert LA, Birmingham DJ, Rovin BH, Yu CY
Curr Dir Autoimmun 2004;7:98-132. doi: 10.1159/000075689. PMID: 14719377
Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.
Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A
Medicine (Baltimore) 2003 Jul;82(4):274-81. doi: 10.1097/01.md.0000085055.63483.09. PMID: 12861105
Complement deficiency and autoimmunity.
Sullivan KE
Curr Opin Pediatr 1998 Dec;10(6):600-6. doi: 10.1097/00008480-199810060-00011. PMID: 9848020

Diagnosis

Hereditary and acquired angioedema.
Patel G, Pongracic JA
Allergy Asthma Proc 2019 Nov 1;40(6):441-445. doi: 10.2500/aap.2019.40.4267. PMID: 31690390
C1 inhibitor deficiency: consensus document.
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D
Clin Exp Immunol 2005 Mar;139(3):379-94. doi: 10.1111/j.1365-2249.2005.02726.x. PMID: 15730382Free PMC Article
Genetic deficiencies of the complement system and association with disease--early components.
Kölble K, Reid KB
Int Rev Immunol 1993;10(1):17-36. doi: 10.3109/08830189309051169. PMID: 8340675
Inherited deficiencies of complement and complement-related proteins.
Fries LF, O'Shea JJ, Frank MM
Clin Immunol Immunopathol 1986 Jul;40(1):37-49. doi: 10.1016/0090-1229(86)90067-x. PMID: 2941192
The hereditary and acquired deficiencies of complement.
Nusinow SR, Zuraw BL, Curd JG
Med Clin North Am 1985 May;69(3):487-504. doi: 10.1016/s0025-7125(16)31028-8. PMID: 3892188

Therapy

Post-transplant hypocomplementemia: A novel marker of cardiovascular risk in kidney transplant recipients?
Maestro de la Calle G, Fernández-Ruiz M, López-Medrano F, Polanco N, González E, San Juan R, Ruiz-Merlo T, Origüen J, Paz-Artal E, Andrés A, Aguado JM
Atherosclerosis 2018 Feb;269:204-210. Epub 2018 Jan 27 doi: 10.1016/j.atherosclerosis.2018.01.021. PMID: 29407595
C1 inhibitor deficiency: consensus document.
Gompels MM, Lock RJ, Abinun M, Bethune CA, Davies G, Grattan C, Fay AC, Longhurst HJ, Morrison L, Price A, Price M, Watters D
Clin Exp Immunol 2005 Mar;139(3):379-94. doi: 10.1111/j.1365-2249.2005.02726.x. PMID: 15730382Free PMC Article
Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.
Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A
Medicine (Baltimore) 2003 Jul;82(4):274-81. doi: 10.1097/01.md.0000085055.63483.09. PMID: 12861105
Inherited complement deficiency states and SLE.
Rynes RI
Clin Rheum Dis 1982 Apr;8(1):29-47. PMID: 6288318
Diagnosis and management of hereditary angioedema (HAE).
Atkinson JP
Ann Allergy 1979 Jun;42(6):348-52. PMID: 378041

Prognosis

Post-transplant hypocomplementemia: A novel marker of cardiovascular risk in kidney transplant recipients?
Maestro de la Calle G, Fernández-Ruiz M, López-Medrano F, Polanco N, González E, San Juan R, Ruiz-Merlo T, Origüen J, Paz-Artal E, Andrés A, Aguado JM
Atherosclerosis 2018 Feb;269:204-210. Epub 2018 Jan 27 doi: 10.1016/j.atherosclerosis.2018.01.021. PMID: 29407595
Partial C4 deficiency in juvenile idiopathic arthritis patients.
Gilliam BE, Wolff AE, Moore TL
J Clin Rheumatol 2007 Oct;13(5):256-60. doi: 10.1097/RHU.0b013e318156b9e3. PMID: 17921792
Autoantibodies and lymphoproliferative diseases in acquired C1-inhibitor deficiencies.
Cicardi M, Zingale LC, Pappalardo E, Folcioni A, Agostoni A
Medicine (Baltimore) 2003 Jul;82(4):274-81. doi: 10.1097/01.md.0000085055.63483.09. PMID: 12861105
C4 isotype deficiency in IgA nephropathy.
Welch TR, Berry A, Beischel LS
Pediatr Nephrol 1987 Apr;1(2):136-9. doi: 10.1007/BF00849283. PMID: 3153269
The hereditary and acquired deficiencies of complement.
Nusinow SR, Zuraw BL, Curd JG
Med Clin North Am 1985 May;69(3):487-504. doi: 10.1016/s0025-7125(16)31028-8. PMID: 3892188

Clinical prediction guides

Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis.
Lintner KE, Patwardhan A, Rider LG, Abdul-Aziz R, Wu YL, Lundström E, Padyukov L, Zhou B, Alhomosh A, Newsom D, White P, Jones KB, O'Hanlon TP, Miller FW, Spencer CH, Yu CY
Ann Rheum Dis 2016 Sep;75(9):1599-606. Epub 2015 Oct 22 doi: 10.1136/annrheumdis-2015-207762. PMID: 26493816Free PMC Article
Clinical characteristics of IgA nephropathy associated with low complement 4 levels.
Zhu B, Zhu CF, Lin Y, Perkovic V, Li XF, Yang R, Tang XL, Zhu XL, Cheng XX, Li Q, Chen HY, Sun Y, Chen QW, Wang YJ
Ren Fail 2015 Apr;37(3):424-32. Epub 2014 Dec 24 doi: 10.3109/0886022X.2014.994408. PMID: 25539484
Cutaneous vasculitis and glomerulonephritis associated with C4 deficiency.
Kosaka S, Osada S, Kaneko T, Nishimura S, Kawana S
Clin Exp Dermatol 2013 Jul;38(5):492-5. doi: 10.1111/j.1365-2230.2012.04423.x. PMID: 23777490
The intricate role of complement component C4 in human systemic lupus erythematosus.
Yang Y, Chung EK, Zhou B, Lhotta K, Hebert LA, Birmingham DJ, Rovin BH, Yu CY
Curr Dir Autoimmun 2004;7:98-132. doi: 10.1159/000075689. PMID: 14719377
Genetic deficiencies of the complement system and association with disease--early components.
Kölble K, Reid KB
Int Rev Immunol 1993;10(1):17-36. doi: 10.3109/08830189309051169. PMID: 8340675

Recent systematic reviews

AA Amyloidosis Secondary to Primary Immune Deficiency: About 40 Cases Including 2 New French Cases and a Systematic Literature Review.
Delplanque M, Galicier L, Oziol E, Ducharme-Bénard S, Oksenhendler E, Buob D, Grateau G, Boutboul D, Georgin-Lavialle S
J Allergy Clin Immunol Pract 2021 Feb;9(2):745-752.e1. Epub 2020 Sep 30 doi: 10.1016/j.jaip.2020.09.023. PMID: 33007500

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