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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

Acquired generalized lipodystrophy associated with autoimmune hepatitis and low serum C4 level.
Eren E, Özkan TB, Çakır ED, Sağlam H, Tarım Ö
J Clin Res Pediatr Endocrinol 2010;2(1):39-42. Epub 2010 Feb 6 doi: 10.4274/jcrpe.v2i1.39. PMID: 21274335Free PMC Article
Complement deficiency and autoimmunity.
Sullivan KE
Curr Opin Pediatr 1998 Dec;10(6):600-6. doi: 10.1097/00008480-199810060-00011. PMID: 9848020
Genetic risk factors for aPL syndrome.
Wilson WA, Gharavi AE
Lupus 1996 Oct;5(5):398-403. doi: 10.1177/096120339600500513. PMID: 8902769
Serum protein markers in systemic lupus erythematosus.
Rantapää Dahlqvist S, Beckman G, Beckman L
Hum Hered 1988;38(1):44-7. doi: 10.1159/000153753. PMID: 3258268
Anti-C4 in the serum of a transfused C4-deficient patient with systemic lupus erythematosus.
Giles CM, Swanson JL
Vox Sang 1984;46(5):291-9. doi: 10.1111/j.1423-0410.1984.tb00089.x. PMID: 6730425

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
A tale of two rashes.
Richmond BW, Cole MB, Dash A, Eyler A, Boomershine CS
Am J Med 2011 May;124(5):414-7. doi: 10.1016/j.amjmed.2011.01.003. PMID: 21531230
Inherited deficiencies of complement in rheumatic diseases.
Ratnoff WD
Rheum Dis Clin North Am 1996 Feb;22(1):75-94. doi: 10.1016/s0889-857x(05)70263-5. PMID: 8907066
Hereditary angioedema: a case with ascites yet no symptoms in the family.
Shinzato T, Nakamura H, Kuniyoshi T, Higashionna A, Uehara T, Oshiro J, Uechi H, Shikiya K, Sakugawa H, Kinjo F
Intern Med 1992 May;31(5):633-5. doi: 10.2169/internalmedicine.31.633. PMID: 1504426
Diagnosis and management of hereditary angioedema (HAE).
Atkinson JP
Ann Allergy 1979 Jun;42(6):348-52. PMID: 378041

Therapy

A tale of two rashes.
Richmond BW, Cole MB, Dash A, Eyler A, Boomershine CS
Am J Med 2011 May;124(5):414-7. doi: 10.1016/j.amjmed.2011.01.003. PMID: 21531230
T cells and in situ cryoglobulin deposition in the pathogenesis of lupus nephritis.
Cohen RA, Bayliss G, Crispin JC, Kane-Wanger GF, Van Beek CA, Kyttaris VC, Avalos I, Yu CY, Tsokos GC, Stillman IE
Clin Immunol 2008 Jul;128(1):1-7. doi: 10.1016/j.clim.2008.04.004. PMID: 18565470Free PMC Article
Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus.
Speirs C, Fielder AH, Chapel H, Davey NJ, Batchelor JR
Lancet 1989 Apr 29;1(8644):922-4. doi: 10.1016/s0140-6736(89)92506-3. PMID: 2565418
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

Subacute cutaneous lupus erythematosus: 25-year evolution of a prototypic subset (subphenotype) of lupus erythematosus defined by characteristic cutaneous, pathological, immunological, and genetic findings.
Sontheimer RD
Autoimmun Rev 2005 Jun;4(5):253-63. Epub 2004 Nov 12 doi: 10.1016/j.autrev.2004.10.003. PMID: 15990071
Serum complement C4 levels during acute malarial infection and post-treatment period.
Siddique ME, Ahmed S
Indian J Pathol Microbiol 1995 Oct;38(4):335-9. PMID: 9726139
Partial C4 deficiency in two children with systemic lupus erythematosus.
Bakkaloğlu A, Pascual M, Schifferli JA, Ozen S, Beşbaş N, Saatçi U
Turk J Pediatr 1995 Apr-Jun;37(2):147-51. PMID: 7597765
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
Acute and rapidly progressive forms of glomerulonephritis in the elderly.
Montoliu J, Darnell A, Torras A, Revert L
J Am Geriatr Soc 1981 Mar;29(3):108-16. doi: 10.1111/j.1532-5415.1981.tb01971.x. PMID: 7204803

Clinical prediction guides

Clinical characteristics of chronic idiopathic thrombocytopenia in Chinese children.
Wong MS, Chan GC, Ha SY, Lau YL
J Pediatr Hematol Oncol 2002 Nov;24(8):648-52. doi: 10.1097/00043426-200211000-00009. PMID: 12439037
Effects of pesticide exposure on serum immunoglobulin and complement levels.
Undeğer U, Başaran N
Immunopharmacol Immunotoxicol 2001 Aug;23(3):437-43. doi: 10.1081/iph-100107342. PMID: 11694033
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
Partial C4 deficiency in subacute sclerosing panencephalitis.
Rittner C, Meier EM, Stradmann B, Giles CM, Köchling R, Mollenhauer E, Kreth HW
Immunogenetics 1984;20(4):407-15. doi: 10.1007/BF00345615. PMID: 6490109
Activation of the classical pathway of complement by Hageman factor fragment.
Ghebrehiwet B, Silverberg M, Kaplan AP
J Exp Med 1981 Mar 1;153(3):665-76. doi: 10.1084/jem.153.3.665. PMID: 7252410Free PMC Article

Recent systematic reviews

Human Inborn Errors of Immunity in Pyoderma Gangrenosum: A Systematic Review.
Oprea Y, Antohi DR, Vague M, Delbourgo Patton C, Wu B, Ortega-Loayza AG
Am J Clin Dermatol 2024 Sep;25(5):701-716. Epub 2024 Jul 1 doi: 10.1007/s40257-024-00875-y. PMID: 38951460
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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