C2 Deficiency

C2 deficiency is the commonest inherited complement deficiency in people of European descent, with an autosomal recessive pattern. It increases the risk of invasive pyogenic infection and lupus like disease, but about half of affected people remain well.

Pathophysiology. C2 is needed to form the C3 convertase of the classical activation sequence, so the classical route to C3 deposition fails. Alternative activation partly compensates, which explains the milder course than with C1q or C3 loss.

Most cases (type I) carry a 28 kb deletion in the C2 gene on an ancestral HLA haplotype (HLA-B18, DR2). Homozygous deficiency occurs in about 1 in 10,000 people, and about 1 in 100 are heterozygous carriers.

Disease may begin in childhood or adulthood.

• Recurrent pneumococcal pneumonia, meningitis and bacteraemia, and occasionally neisserial and Haemophilus infection
• Lupus like disease: photosensitive and discoid rash, arthritis, mouth ulcers, often with negative antinuclear antibody
• Glomerulonephritis and vasculitis
• Dermatomyositis, polymyositis, and inflammatory bowel disease in some
• Atherosclerosis and early cardiovascular disease
• Half of homozygotes have no symptoms

• Total haemolytic complement (CH50): absent or very low, with normal alternative activation (AH50).
• C2 level: absent by immunoassay, with normal or low C4 and normal C3.
• Genetic testing of C2 (including the common 28 kb deletion), with family testing.
• Autoantibodies: antinuclear antibody and anti-Ro are often present; anti-dsDNA is less often positive.
• Lupus and vasculitis workup with full blood count, creatinine, urinalysis, and skin or renal biopsy as indicated.
• Immunoglobulins and specific antibody responses to pneumococcal polysaccharide.

Differential diagnosis.

• Other early classical complement deficiencies (C1q, C1r/C1s, C4)
• Systemic lupus erythematosus without complement deficiency
• C3 deficiency and terminal complement deficiencies
• Antibody deficiency and splenic hypofunction
• Hereditary angio oedema
• Acquired complement consumption

• Vaccination: pneumococcal conjugate vaccine, then pneumococcal polysaccharide vaccine at least 8 weeks later, meningococcal ACWY and B vaccines, Haemophilus influenzae type b vaccine, and yearly inactivated influenza vaccine. Recheck pneumococcal titres 4 to 6 weeks after vaccination.
• Antibiotic prophylaxis after an invasive infection or with repeated infection: phenoxymethylpenicillin 250 mg orally twice daily (children under 6 years 125 mg twice daily; 6 to 11 years 250 mg twice daily), for at least adolescence and often longer.
• Acute fever or illness: this is possible sepsis. After blood cultures, give ceftriaxone 2 g intravenously (children 50 to 80 mg/kg, maximum 2 g) without waiting for results.
• Lupus like disease:
  • Hydroxychloroquine 200 to 400 mg orally daily, not over 5 mg/kg of actual body weight daily, with eye screening at baseline and yearly after 5 years of use.
  • Prednisolone 0.5 to 1 mg/kg orally daily (maximum 60 mg) for flares, tapered to the lowest effective dose.
  • Mycophenolate mofetil 1 g orally twice daily for nephritis.
• Cardiovascular risk: control blood pressure, lipids and smoking.
• Fresh frozen plasma is not given routinely; it is considered only in life threatening infection while antibiotics are given.
• Counselling: carriers (about 1 in 100) are usually well and need no treatment.

Special groups.

• Relatives of a patient: test siblings, because up to a quarter may be homozygous and unaware.
• Pregnancy: lupus like disease and anti-Ro antibodies need joint rheumatology and obstetric care.

Monitoring. Yearly clinical review for infection, rash, joint and renal symptoms. Urinalysis and creatinine yearly. Pneumococcal titres every 3 to 5 years.

Referral and escalation. Refer to immunology. Urgent for fever, meningism, new rash with joint pain, or haematuria.