1 September 2009
C1q nephropathy associated with deletion of long arm of chromosome 7
A 9-year-old boy with known chromosome 7q31.2-q32 deletion was referred with 6 months of asymptomatic microhaematuria and recent development of proteinuria, lethargy and anorexia.
He was initially admitted to a regional hospital with a skin infection, and microhaematuria was incidentally detected, with raised anti-DNAse-B and anti-streptolysin-O titer. A urinary tract ultrasound was normal.
He represented 2 months later with lethargy and anorexia. Urinalysis showed proteinuria and haematuria, with borderline hypertension (110/80). He was transferred to our service for further investigation, which yielded normal results for serum C3, C4, ANF, Anti-ds-DNA, UEC, FBP, plasma calcium, magnesium, phosphate and coagulation profile. A urine albumin/creatinine ratio was 73.2 (range <2.5) and calcium/creatinine ratio of 0.24 (0.04–0.70). Renal biopsy showed mesangioproliferative changes, normal tubulointerstitial pattern and no pathological vascular changes. Immunofluorescence revealed diffuse global, predominantly mesangial immunoglobulin G (IgG) and C3 deposition with extension into the capillary loops in some glomeruli. There was moderate C1q and sparse immunoglobin A (IgA) deposition (Fig. 1).
Electron microscopy showed diffuse mesangial proliferation with extensive electron dense deposits in the mesangium and peripheral subepithelial basement membrane, with tubuloreticular inclusions.
The histological findings in the absence of clinical, haematological and immunological signs of lupus was consistent with a diagnosis of C1q nephropathy. He has remained asymptomatic with no need for immunosuppression to date.
This boy has previously been diagnosed with a de novo deletion of chromosome 7q31.2-32 by G-banded karyotype. He has learning problems, attention-deficit disorder with hyperactivity, seizures, dental abnormalities, a nephropathy and Wolf–Parkinson–White syndrome (WPWS). Previous published cases of deletions with similar breakpoints have language impairment because of Forkhead box protein P2 gene involvement, developmental delay and dysmorphic features,1 but there are no reports of nephropathy or WPWS with this deletion.
No specific gene has been implicated in C1q nephropathy. Lim et al. reported a 3-year-old boy with C1q nephropathy and a family history of Dent disease, with the X-linked CLCN5 gene mutation. The significance of Dent disease to the development of the C1q nephropathy is unknown.2
Genes associated with proteinuria and nephrotic syndrome include NPHS1, NPHS2, WT1, LAMB2 and PLCE1. There are no known genes linked with nephrotic syndrome in the 7q region. The NOS3 gene in the 7q36 region has been implicated in causing hypertension and microalbuminaemia. Genetic regions on chromosomes 7q, 18q and 22q, contain genes determining variations in urinary albumin excretion, or susceptibility to proteinuria in families who have type 2 diabetes3
Whether the C1q nephropathy in our patient is related to the chromosome deletion remains to be elucidated. It is possible that this may be a chance observation.
C1q nephropathy was first described in 1985 by Jennette and Hipp4 who outlined criteria for diagnosis as C1q deposits in the mesangium on immunofluorescence, corresponding mesangial or paramesangial electron-dense deposits on electron microscopy, and no evidence of systemic lupus erythematosus. The underlying aetiology is unknown.
Children with C1q nephropathy commonly present with nephrotic syndrome or proteinuria. Kersnik et al. reported 12 paediatric patients: eight presented with nephrotic syndrome, one with nephrotic range proteinuria and three with non-nephrotic proteinuria associated with microhaematuria, hypertension and renal insufficiency.5 Vizjak et al. report on 72 C1q nephropathy patients (28 children). Clinical presentations included asymptomatic haematuria and or proteinuria (22%), frequently relapsing nephrotic syndrome with minimal change disease (63%) and nephrotic syndrome in all focal segmental glomerular sclerosis (FSGS) patients.6
Hatae et al.4 examined the results of 2221 children aged 1–15 years who underwent renal biopsy between 1975 and 2002. Thirty were diagnosed with C1q nephropathy based on the criteria of Jennette and Hipp. The C1q patients were divided into asymptomatic urinary abnormalities (18) and nephrotic group (12). Light microscopy showed minimal change disease (MCD) in 73%, mesangial proliferative glomerulonephritis in 20%, and FSGS in 7%.
The natural history of C1q nephropathy in children suggests a good prognosis where the histological findings are of MCD, while children with FSGS progress to end-stage disease. Children with C1q nephropathy presenting with nephrotic syndrome are less likely to respond to corticosteroids and relapse frequently.4,6
In summary, this is the first report noting an association between a deletion on the long arm of chromosome 7 and C1q nephropathy, suggesting that the relationship needs to be further investigated if other cases are identified.