Wegener’s Granulomatosis Occurring In Father and Son
Barsam SJ, Seevaratnam M
Wegener’s Granulomatosis (WG) is a rare necrotising vasculitis. There is an ongoing debate regarding the importance of genetics and environment in the aetiology of WG. Our review of the literature for familial clustering and HLA matching in systemic vasculitides reveals an absence of significant evidence of familial aggregation. Our case report of Wegener’s Granulomatosis in a father and son supports the anecdotal evidence for genetic influences.
The diagnosis of Wegener’s Granulomatosis (WG) is based on characteristic clinical and pathological findings and is supported by a positive cANCA. The clinical features can, however, be vague and it is therefore important to have a high index of clinical suspicion in order to treat the condition before it progresses to a life threatening stage.
A detailed search via Dialogue and PubMed was carried out. Familial clustering of WG is rare and may be due to: shared genetic susceptibility; common environmental influences; chance; or a combination of these. Evidence for both genetic and environmental influences in WG is mostly observational and anecdotal. As yet there has been no consistent gene, HLA antigen or environmental agent directly associated with WG identified in the literature.
We present a case of a gentleman with WG whose son was known to suffer with an advanced systemic WG, thus supporting the observational evidence for a genetic component to WG.
Key Words: Wegener’s Granulomatosis, familial clustering, systemic vasculitides
A 73 year old gentleman was admitted via the Emergency Department with weakness, malaise, four stones weight loss over the previous 9 months and shortness of breath on exertion. Two weeks prior to admission he had an episode of epistaxis and nasal discharge with crusts, which resolved within 24hours. He had a one year history of diarrhoea and was diagnosed with collagenous colitis on colonoscopy and biopsy. He was treated with 5mg prednisolone, with minimal improvement in symptoms. Over the preceding 3 years he was investigated for normocytic anaemia and had gastric atrophy diagnosed on gastroscopy. He denied arthralgia, cough or coryzal symptoms. His past medical history included a stroke 9 months earlier, transient ischaemic attacks, benign prostatic hypertrophy, hypertension and childhood asthma. Our patient was married with one son who was diagnosed with WG at 39 years old. There was no other family history of vasculitis or of autoimmune disease. He was a retired patent attorney and had never smoked.
On examination he was thin, pale and afebrile with normal cardiovascular and respiratory systems. He had generalised lower abdominal tenderness with normal bowel sounds and mucous on rectal examination. Neurological examination revealed mild left sided weakness with preserved reflexes and tone. Joints, eyes and skin were normal.
Results from investigations showed increased inflammatory markers with C-reactive protein (CRP) 97mg/dl (normal range [NR] <5), erythrocyte sedimentation rate (ESR) 132mm/h (NR 1-10) and white cell count 26.5 x109/L (NR 4-11) with a neutrophilia 21.2 x 109/L (NR 2-7), albumin 23g/L (NR 35-50) and all other liver function, renal function, electrolytes and coagulation tests normal. Dipstick urine microscopy was normal and 24h urine protein collection 0.38g and creatinine clearance 81mL/min. Chest XR and CT thorax showed bronchiectasis of both apices. Ultrasound scan of his abdomen was normal and a CT of his abdomen showed a thickened colon wall.
Antinuclear antibodies were weakly positive, anti-smooth muscle antibodies were positive and anti-neutrophilic cytoplasmic antibody (cANCA) were strongly positive at >100, measured by indirect immunoflourescence. Anti-proteinase 3 (PR3) antibodies were strongly positive and myeloperoxidase antibodies were negative.
A diagnosis of WG was made and he was immediately commenced on prednisolone 60mg once a day. A nasal biopsy, performed after 3 days of steroid treatment, showed non-specific chronic inflammation.
Our patient made a complete clinical recovery associated with normalisation of CRP, ESR and cANCA PR3. The steroid dose was reduced and he remains in remission, although has suffered with recent septic arthritis.
Our patient’s son had developed severe arthralgia at 30 years old and had renal involvement from presentation. His respiratory tract was relatively well preserved with mild coryzal symptoms. He had histological evidence of WG on renal biopsy and strongly positive CANCA and PR3. He is currently on renal dialysis, having received 5 years of steroids and cyclphosphamide treatment. The father and son had lived in the same house for 16 years then in the same village for a further 8 years.
Demography, Clinical Features & Investigations
WG usually presents in the 4th or 5th decade with equal sex incidence and more commonly in Caucasians.
WG is a primary small vessel vasculitis with a characteristic histolopathological triad of necrotising granulomatous inflammation, focal segmental glomerulonephritis and necrotising vasculitis. However, a limited form of WG is recognised, involving predominantly the head and neck.
85% of people have respiratory system involvement, more commonly the upper respiratory tract with epistaxis, rhinorrhoea, saddle nose, hoarse voice, conductive hearing loss and subglottic stenosis. The lower respiratory tract is also affected presenting as cough, haemoptysis, dyspnoea. 70% of patients have renal involvement, although only 18% present with renal disease, manifest as oedema or haematuria.
29% of patients have ocular disease including sleritis, corneal ulcer, retro-orbital mass. 25% have musculoskeletal non- specific symptoms with myalgia and non-erosive arthritis. 14% have skin changes ranging from petechiae to necrotising ulcer. 10% have gastrointestinal symptoms mostly bloody diarrhoea.
Usually a preceding period of systemic upset with weight loss, anorexia, fever occurs.
Blood tests would be expected to reveal a leucocytosis, thrombocytosis and increased CRP and ESR. Urinalysis is sensitive for renal involvement and proteinuria is common. A chest XR is important to detect cavities, nodules or haemorrhages.
PR3 has a high specificity of >99% during active disease and >95% sensitive, but during quiescent disease state it is 63% sensitive.
The gold standard diagnostic investigation is a nasal, transbronchial or renal biopsy, showing the triad of histological characteristics.
Immunogenetics may have a significant aetiopathological role in WG. 90% of active WG are c-ANCA positive and 90% of these are PR3. PR3 expression is genetically determined and is overexpressed in WG, due to poymorphism in the PR3 promoter region and defective genotypes of PR3 inhibitor alpha-1 antitrypsin. C-ANCA recognises the over-expression of proteinase 3 (PR3) on endothelial cells of WG, they prime auto-reactive T helper cells to interact with auto-reactive B cells to produce more c-ANCA. Auto-T helper cells trigger cytotoxic T cells to destroy endothelial cells with excess PR3. PR3 primed macrophages degranulate, releasing free radicals thus leading to further cell damage.
Treatment is in 2 phases: induction and maintenance. Induction is achieved with
prednisolone high dose, often with pulsed or continuous cyclophosphamide. Maintenance
therapy is with prednisolone, methotrexate or azathioprine and new evidence
is now emerging about the benefits of co-trimoxazole 1.
Monitoring should continue until full response is achieved, determined by clinical features and normal ESR and/or c-ANCA.
Genetics vs Environment in Pathogenesis
Familial clustering of WG is rare and may be due to: shared genetic susceptibility; common environmental influences; chance; or a combination of these.
Evidence for both genetic and environmental influences in WG is mostly observational and anecdotal.
Propylthiouracil, dust and silica have been reported to trigger small vessel systemic vasculitides (SV) 2,3,4. Nasal carriage of Staphylococcus aureus increases the risk of relapse with WG 5. In a reported family Hepatitis B infection is related to the development of polyarteritis nodosa 6. Further support for the role of the environment is gained from the observation that no cases of WG have been reported in first degree family members living in separate environments, there are more published twins discordant for WG than concordant, the first degree relatives with WG reported to date all live in close communities together, and there are cases of identical twins reported in whom one developed WG and the other remained disease free 7. Nagibov et al,1987 described a married couple with c-ANCA positive WG living in a village in Russia 8.
There are observational reports of familial clustering of WG and of other SV, although aggregation of different SV is rare. In some families HLA typing has been done, but the HLA studies of related and unrelated individuals with WG have failed to consistently identify unique genetic markers 9,10. HLA-B8 was found in both father and stepson with c-ANCA positive WG 11 and another sibling pair with generalised WG 12. HLA- DR2 is shown to be associated with severe renal involvement in WG 13.
WG is a debilitating yet treatable multisystemic disease that commonly affects
the upper respiratory tract and is associated with significant morbidity and
It is crucial to have a high index of clinical suspicion in order to diagnose WG early, allow for optimum treatment and prevent disease progression. A thorough family history may help in making the diagnosis. The exact aetiology of WG is unknown but as more evidence emerges, the complex interaction between genetic susceptibility and environmental influences can be revealed and scientific conclusions can subsequently be made. Our case report adds to the limited observational studies and case reports in the literature which support the theory of a genetic component to WG.
Dr SJ Barsam, SHO Department of General Medicine
Queen Elizabeth II Hospital, Welwyn Garden City, Herts AL7 4HQ
Dr M Seevaratnam, Consultant Elderly Care and General Physician
Queen Elizabeth II Hospital, Welwyn Garden City, Herts AL7 4HQ
Dr Sarah Barsam, MA (Cantab), MBBS
45 Cotleigh Road, London NW6 2NN
Phone No: 0777 978 8497
1) Stegeman CA, Tervaert JW, de Jonge PE, Kallenberg CG. 1996. Co-trimmoxazole for the prevention of relapses of Wegener’s Granulomatosis. New England Journal of Medicine. Vol 335(1), 265-270.
2) Savage CO, Harper L, Holland M. 2002. New findings in the pathogenesis of antineutrophil cytoplasmic antibody associated vasculitis. Current Opinion Rheumatology. Vol. 14 (1), 15-22.
3) Granel B, Serratrice J, Disdier P, Abdul S, Gras R, Martin F, Swaider L, Weiller PJ. 2002. Dust exposure: a missed environmental factor of Wegener’s Granulomatosis. Annals of Rheumatological Disease. Vol 61(12), 1113.
4) Nuyts GD, Van V, Lem E, De Vos A, Daelemans RA, Rorive G, Elseviers MM, Schurgers M, Segaert M, D’Haese PC, De Bree ME. 1995. Wegener’s Granulomatosis is associated to exposure to silicon compounds. Nephrology Dialysis Transplant. Vol 10 (7), 1162-65.
5) Stegeman CA, Tervaert JW, Sluiter WJ, Manson WL, de Jonge PE, Kallenberg CG. 1994. Association of chronic nasal carriage of Staphylococcus aureus infection and higher relapse rates in Wegener’s Granulomatosis. Annals of Internal Medicine. Vol 120 (1), 12-17.
6) Rottem M, Cotch MF, Faucia AS, Hoffman GS. 1994. Familial vasculitis: report of 2 families. Journal of Rheumatology. Vol 21 (3), 561-3.
7) Weiner SR, Kwan LW, Paulus HE, Carox J, Weisbart RH. 1986. Twins discordant for Wegener’s Granulomatosis. Clinical Experimental Rheumatology. Vol 4(4), 389-90.
8) Nagibov VM, Cheranov EA. 1987. A case of Wegener’s Granulomatosis in married couples. Vestn Otorinolaryngol. Vol 2, 72-73. Russian
9) Nowak R, Lehmann H, Flores-Suarez LF, Nanhou A, van der Woude FJ. 1999. Familial occurrence of systemic vasculitis and rapidly progressive glomerulonephritis. American Journal of Kidney Diseases. Vol 34(2).
10) Fietta P. 2004. Systemic Vasculitides: immunogenetics and familial clustering. Clinical and Experimental Rheumatology. Vol22, 238-51.
11) Barrett TG, Taylor CM, Thomason P. 1993. Environmental trigger for anti-neutrophil cytoplasmic antibodies? Lancet. Vol 342, 369-70.
12) Hay EM, Beaman M, Ralston AJ, Ackrill P, Bernstein RM, Holt PJL. 1991. Wegener’s Granulomatosis occurring in siblings. British Journal of Rheumatology. Vol 30, 144-5.
13) Sewell RF, Hamilton DV. 1992. Time-associated Wegener’s Granulomatosis in 2 members of a family. Nephrology Dialysis Transplant. Vol 7, 882.
14) Perez VL, Chavala SH, Ahmed M, Chu D, Zafirakis P, Baltatzis S, Ocampo V, Foster S. 2004. Ocular Manifestations and Concepts of Systemic Vasculitides. Survey of Ophthalmology. Vol 49 (4), 399-418.