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COMPLEMENT COMPONENT 3 DEFICIENCY, AUTOSOMAL RECESSIVE; C3D

COMPLEMENT COMPONENT 3 DEFICIENCY, AUTOSOMAL RECESSIVE; C3D

Alternative titles; symbolsC3 DEFICIENCY, AUTOSOMAL RECESSIVE▼ DescriptionThe main clinical manifestation of primary C3 deficiency is childhood-onset of recurren...

Alternative titles; symbols

  • C3 DEFICIENCY, AUTOSOMAL RECESSIVE

▼ Description
The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus (see 152700), and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by Reis et al., 2006).

▼ Clinical Features
Alper et al. (1972) described a patient with a striking susceptibility to pyogenic infection who was apparently homozygous for C3 deficiency. Her C3 levels were one-thousandth or less of normal. Many relatives, including both parents, had approximately half-normal levels.

Pussell et al. (1980) described a family in which 3 children had homozygous C3 deficiency and both parents and 2 other children were heterozygous for a C3 null gene. The family was of Palestinian-Lebanese origin, living in Kuwait; the parents were thought to be cousins. The homozygous and heterozygous children were susceptible to infection. Proteinuria and/or microscopic hematuria were present in all 3 homozygous children, and a heterozygous child had membranoproliferative glomerulonephritis. The only child with normal complement had neither nephritis nor increased susceptibility to infection.

Sano et al. (1981) reported 2 sisters with C3 deficiency and systemic lupus erythematosus (SLE; 152700)-like symptoms.

Berger et al. (1983) and Borzy et al. (1988) observed C3-deficient homozygotes who developed mesangiocapillary glomerulonephritis. The association of C3 deficiency with nephritis was thought to be due to failure of a second physiologic activity of the complement system, that of promoting the disposal of immune complexes to the mononuclear phagocytic system.

Nilsson et al. (1992) described 3 sisters who were compound heterozygotes for a null allele inherited from the father and a dysfunctional C3 allele inherited from the mother. Alternative pathway complement function was absent, but classic pathway complement function was partially intact. One of the sisters, the proband, had an SLE-like disease. The proband's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathways, but completely resistant to alternative pathway, convertase-dependent cleavage.

Botto et al. (1990) studied a 10-year-old boy who had recurrent attacks of otitis media during the first 3 years of life. Between 5 and 8 years of age, he had more than 20 episodes of rash which affected his face, forearms, and hands and resembled the target lesions of erythema multiforme. Attacks were normally preceded by an upper respiratory infection, and a group A beta-hemolytic Streptococcus was isolated from his throat during 2 episodes. The parents were consanguineous ('share a common great-grandparent'). C3 could not be detected by RIA of serum from the patient.

▼ Other Features
McLean and Hoefnagel (1980) observed an association between partial lipodystrophy and familial C3 deficiency. A 16-year-old girl with familial C3 deficiency developed partial lipodystrophy affecting the face, arms and upper torso. The pattern was reminiscent of that observed in patients with acquired partial lipodystrophy who do not have familial C3 deficiency (608709).

▼ Molecular Genetics
By segregation of C3S and C3F allotypes within a family in which a child had C3 deficiency, Botto et al. (1990) confirmed the presence of a null C3 allele (120700.0003), for which the patient was homozygous. Both parents were heterozygous for the null allele.

In an Afrikaner patient with C3 deficiency described by Alper et al. (1972), Botto et al. (1992) demonstrated homozygosity for a partial deletion of the C3 gene (120700.0004) as the molecular basis of the deficiency.

In a 22-year-old Japanese male patient with C3 deficiency and systemic lupus erythematosus, born of consanguineous parents, Tsukamoto et al. (2005) identified a homozygous splice site mutation in the C3 gene (120700.0009). Complement assay detected no C3 in serum and only a trace amount of C3 hemolytic activity. Both parents and 2 sibs were heterozygous for the mutation, and all had reduced levels of C3 hemolytic activity. The patient had suffered from photosensitivity, recurrent fever, and facial erythema from childhood.

Tags: 19p13.3