British Journal of Dermatology 2000; 142: 521±524. Systemic lupus erythematosus with C1q deficiency N.M.STONE, A.WILLIAMS,* J.D.WILKINSON² AND G.BIRD* Department of Dermatology, *Department of Immunology, Oxford Radcliffe Hospital, Old Road, Headington, Oxford OX3 7LJ, U.K. ²Department of Dermatology, Amersham General Hospital, South Buckinghamshire NHS Trust, Whielden Street, Amersham HP7 0JD, U.K. Accepted for publication 20 October 1999 Summary We report a case of systemic lupus erythematosus associated with C1q deficiency. Our patient presented at the age of 6 years with cutaneous lupus. She later developed Raynaud's phenomenon, non-scarring alopecia, oral ulceration and grand mal seizures due to cerebral vasculitis. Complement C3 and C4 levels were consistently normal during flares of her lupus and haemolytic activity of her complement was absent, suggesting a deficiency of an early component of the complement cascade. No C1q could be detected. Key words: C1q deficiency, cutaneous lupus, systemic lupus erythematosus Homozygous C1q deficiency is exceptionally rare with only 41 previously reported cases. Thirty-eight of these patients developed a lupus-like illness. Systemic lupus erythematosus (SLE) in association with C1q deficiency presents at an early age and has an increased association with glomerulonephritis and cerebral vasculitis, and hence a poor prognosis. Diagnosis of a complement deficiency is important so that appropriate immunization and prompt treatment of infections can be ensured. Genetic counselling can be given and other potential treatments considered. The close association of SLE with C1q deficiency provides an interesting insight into the pathogenesis of SLE. Case report A 6-year-old girl presented with a facial rash following a family holiday to Pakistan. She was the third child of consanguineous parents of Asian origin. She had previously been well, had no developmental problems and took no medication. Her three siblings were in good health. Examination revealed a scaly erythematous rash, with follicular plugging, affecting both cheeks (Fig. 1a). A clinical diagnosis of lupus was made and confirmed by skin biopsy. Histologically, there was basal layer damage, a periadnexal inflammatory infiltrate and follicular plugging. Immunological tests were performed (Table 1), which revealed a positive speckled antinuclear antibody titre at 1/640. The C3 and C4 levels and renal function were normal. q 2000 British Association of Dermatologists Antiphospholipid antibodies were negative. She was treated with potent topical steroids and sun-blocks. A `butterfly type' facial rash continued to appear in the summer months. She also developed a diffuse nonscarring alopecia and an erythematous scaly rash on the dorsae of the hands (Fig. 1b). Control was maintained with topical steroids and intermittent courses of oral hydroxychloroquine. At the age of 10 years she developed Raynaud's phenomenon and suffered recurrent oral ulceration requiring treatment with systemic steroids. This was complicated on one occasion by a herpes zoster infection of the third thoracic dermatome. At age 11 years she complained of headaches and suffered grand mal seizures. A magnetic resonance image scan of the brain revealed a left frontal lobe infarct which was presumed to be secondary to cerebral vasculitis. She was treated with oral prednisolone, azathioprine and anticonvulsant medication and made a full recovery. The immunosuppressive drugs and anticonvulsants were slowly weaned off. Owing to her young age of presentation and the severity of her lupus she was reviewed in the joint Dermatology/Immunology clinic at Wycombe Hospital. The immunologists noted that during each flare of her lupus the C3 and C4 levels remained normal, suggesting the possibility of coexistent complement deficiency. A functional test for complement (CH50) was performed which assessed the ability of the patient's serum to lyse IgM sensitized sheep red blood cells. No lysis of the cells occurred, suggesting a defect 521 522 N.M.STONE et al. Table 1. Immunological investigations Test Our patient Normal % Reported in other known cases of C1q deficiency1 ANA dsDNA Sm Ro La RNP 1/640 Negative Positive Negative Negative Negative , 1/20 Negative Negative Negative Negative Negative 71% positive (24/34) 21% positive (5/24) in one of the early components of the complement cascade. Quantification of the early complement components was then performed by double immunodiffusion using sheep polyclonal antibodies. No precipitin line was seen for C1q, thereby confirming an absence of C1q in our patient's serum. On further questioning she admitted to suffering from several respiratory infections, recurrent tonsillitis and infection of her ear lobes following piercing. She was fully immunized, including meningococcal and pneumococcal vaccines, and any infections were treated promptly with high antibiotic doses and prolonged treatment regimens. Her immediate family were tested for C1q deficiency; however, all were found to have normal levels of haemolytic complement and immunochemically detectable C1q. Following the diagnosis of C1q deficiency, the patient developed a Proteus pyelonephritis which required intravenous antibiotics. She also suffered another flare of her cutaneous lupus following a visit to Pakistan, despite taking prophylactic low-dose oral prednisolone and use of topical sunscreen agents. She has had two further grand mal seizures and is currently receiving oral sodium valproate, azathioprine and oral prednisolone for control. Her renal function has been consistently normal. C1q is synthesized by bone marrow-derived monocytes and macrophages. Treatment with a bone marrow transplant has therefore been considered for our patient; however, no suitable family human leukocyte antigen matches have been found. 62% had one extractable nuclear antigen Positive (15/24) Discussion C1q deficiency is an extremely rare, autosomal recessively inherited, complement deficiency with only 41 cases reported worldwide.1 Thirty-eight of these reported cases are associated with a lupus-like illness. Our patient is a classical case of SLE associated with C1q deficiency (Table 2). She presented at an early age. Cutaneous lupus was her presenting complaint and is a recurrent problem. She developed central nervous system involvement, oral ulceration and Raynaud's phenomenon. Her antinuclear antibody has been raised with a high titre, but antidouble-stranded DNA antibodies have been consistently negative. She has suffered several bacterial and viral infections. Cutaneous lupus is the major clinical feature in patients with lupus associated with C1q deficiency. Glomerulonephritis and cerebral involvement, usually presenting with grand mal seizures, are common complications.1,2 Recurrent bacterial and viral infections occur. The disease is equally described in males and females, and has a characteristically early age of onset, with a median age of 6 years. Antidoublestranded DNA antibodies are uncommon. Several patients have died in early childhood due to septicaemia or renal failure.1±4 Homozygous complement deficiency occurs in approximately 1% of patients with SLE.5 These inherited deficiencies are rare, C2 deficiency being the most common in white Caucasians. Acquired Table 2. Clinical features Clinical features Age of onset Cutaneous disease Glomerulonephritis Grand mal seizures Alopecia Oral ulceration Raynaud's Recurrent bacterial infections Our patient % Reported in other known cases of C1q deficiency1 5 years Yes No Yes Yes Yes Yes Yes Median 6 years 36/41 (89%) 16/41 (39%) 5/41 (12%) 8/41 (20%) 9/41 (22%) 1/41 (2%) 13/41 (32%) q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 521±524 SLE WITH C1q DEFICIENCY 523 Figure 1. (a) Erythematous scaly rash affecting both cheeks, age 6 years. (b) Similar rash affecting dorsum of fingers, with periungual involvement. complement deficiencies in SLE are, however, very common. Reduced levels of C3 are routinely used as a marker of disease activity. C1q is the first molecule in the classical complement cascade. There is a hierarchy of association of homozygous complement deficiency with SLE.1,5 C3-deficient patients rarely develop a lupus-type disease. One-third of patients with C2 deficiency develop a lupus-type disease. There is a high prevalence of SLE in patients with C4, C1r and C1s deficiency. C1q deficiency is the strongest disease susceptibility gene, with 98% of patients developing SLE. Recently, the molecular basis for C1q deficiency has been addressed in 13 families. In all those examined so far, single base mutations leading to premature stop codons, frameshifts or an exchange of amino acid residues have been identified.6 The classical complement cascade is known to be involved in the clearance of immune complexes. A failure of immune complex clearance in C1q deficiency has been the traditional explanation for the strong association of lupus in these patients. This does not explain why C1q deficiency is associated with such a specific clinical disease, rather than any number of different autoimmune diseases. Korb and Ahearn7 have suggested an alternative explanation. When keratinocytes are rendered apoptotic, via ultraviolet (UV) irradiation, they develop `surface blebs' which contain the different cytoplasmic and nuclear components, to which lupus patients develop antibodies. Korb and Ahearn demonstrated that keratinocytes rendered apoptotic with UV light are able to bind C1q directly to the surface blebs, in the absence of antibodies. This suggests a new role for C1q, and possibly the classical complement cascade, in the clearance of apoptotic cells from the epidermis. This is an attractive hypothesis as it may explain the prevalence of photosensitive cutaneous involvement in these patients. A defect in clearance of these apoptotic cells could also explain the development of autoantibodies. Walport et al.1 have developed strains of C1q knock-out mice. They have noted that the mice which develop glomerulonephritis have large numbers of apoptotic cells in their glomeruli. It is important to check the early pathway complement levels in patients with an early age of onset of SLE and also in patients where the C3 and C4 levels remain normal during acute flares. The total haemolytic activity of complement (CH50 or 100) is a good screening test. Diagnosis is important due to the potentially poor prognosis associated with lupus in these patients. Prompt treatment with antibiotics of high, prolonged dose and full immunization, can help to decrease the severity and number of infective episodes. Prophylactic antibiotics may be advisable if infections are recurrent. Replacement of C1q with fresh frozen plasma (FFP) has been used as a temporary treatment in some patients.2,8 Urticaria has been noted q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 521±524 524 N.M.STONE et al. as a complication of FFP treatment due to the development of C1q antibodies.2 Genetic counselling should be given to these patients and their families. Bone marrow transplantation could offer a permanent cure for this potentially fatal disease. References 1 Walport MJ, Davies KA, Botto M. C1q and systemic lupus erythematosus. Immunobiology 1998; 199: 265±85. 2 Bowness P, Davies KA, Norsworthy PJ et al. Hereditary C1q deficiency and systemic lupus erythematosus. Q J Med 1994; 87: 455±64. 3 Berkel AI, Petry F, Sanal K et al. Development of systemic lupus erythematosus in a patient with selective complete C1q deficiency. Eur J Pediatr 1997; 156: 113±15. 4 Chapuis RM, Hauptmann G, Grosshans E, Isliker H. Structural and functional studies in C1q deficiency. J Immunol 1982; 129: 1509±12. 5 Walport MJ, Davies KA, Morley BJ, Botto M. Complement deficiency and autoimmunity. Ann NY Acad Sci 1997; 815: 267±81. 6 Petry F, Molecular Basis of Hereditary C.1q Deficiency. Immunobiology 1998; 199: 286±94. 7 Korb LC, Ahearn JM. C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes: complement deficiency and systemic lupus erythematosus revisited. J Immunol 1997; 158: 4525±8. 8 Orihara T, Tsuchiya K, Yamasaki S, Furuya T. Selective C1q deficiency in a patient with systemic lupus erythematosus. Br J Dermatol 1987; 117: 247±54. q 2000 British Association of Dermatologists, British Journal of Dermatology, 142, 521±524