Wegener granulomatosis is a necrotizing granulomatous small- and medium-vessel vasculitis predominantly affecting the upper airways, lungs and the kidneys. The disorder is rare in children and most publications are based on case reports and small patient series (1,2). The etiology of WG is unknown but existing evidence suggests an autoimmune process, with predominantly neutrophilic inflammation in early lesions and increasing titers of c-ANCA directed against proteinase-3 (3). Children with WG have similar sites of organ system involvement when compared to adults with a higher incidence of subglottic stenosis in children.
The most common manifestations of WG in children and adults are because of upper and lower respiratory tract involvement (3). Patients typically present with epistaxis, sinusitis, otitis, hearing loss, stridor, hoarseness and lower respiratory symptoms including cough, wheezing, dyspnea or hemoptysis. CT scanning is superior to chest x-ray in establishing the diagnosis and defining the extent of parenchymal disease (4). Multiple lung nodules or masses are the most common imaging findings, seen in 70% of patients. Other common findings include air space opacification, thickening of the airway walls and narrowing of the lumen. Less frequent findings include interstitial fibrosis, pleural disease and enlarged mediastinal lymph nodes (4).
Renal involvement is the second most common and often the most serious manifestation of WG. Patients may be asymptomatic despite the presence of significant renal disease. Necrotizing crescentic glomerulonephritis is frequently identified on biopsy. Ocular manifestations are common and include episcleritis, conjunctivitis, uveitis, optic neuritis and pseudotumor cerebri. Cutaneous manifestations range from erythematous or purpuric macules to necrotizing vasculitic ulcerations and gangrene.
Gastrointestinal involvement is rare in WG, and patients infrequently present primarily with GI symptoms. The literature is limited to case reports and to our knowledge there has only been 1 prior pediatric case report with isolated gastrointestinal symptoms as the initial manifestation (3,5). Patients with GI involvement may present with abdominal pain, rectal bleeding, diarrhea, and intestinal perforation mimicking IBD or infectious colitis. Other gastrointestinal manifestations include gastritis, colitis and perirectal abscess. The extraintestinal manifestations of Crohn disease and WG may overlap. Pulmonary complications of IBD include bronchiolitis obliterans, interstitial lung disease and granulomatous lung disease (6,7). IBD can also present with renal manifestations including hematuria because of renal calculi or rarely glomerulonephritis.
Our patient presented with abdominal pain and weight loss and had gastric, duodenal and colonic erosions at endoscopy. These findings in conjunction with the biopsy changes and a positive ASCA were highly suggestive of Crohn disease. In addition, he had a dramatic improvement with initiation of prednisone and 5-ASA therapy. The subsequent development of dyspnea, hemoptysis and review of his full-thickness appendectomy specimen led to the diagnosis of WG.
The diagnosis of WG is usually suggested by a typical pattern of organ involvement and confirmed by histopathological evidence of vasculitis, granulomatous inflammation and necrosis (8). Antineutrophilic cytoplasmic antibodies (ANCA), specifically c-ANCA, are elevated in up to 90% of patients with WG. The targeted antigen has been identified as PR-3. Proteinase-3 is a neutral serine protease localized in the azurophilic granules of the neutrophils and myeloperoxidase-positive monocytes. It is involved in the enzymatic degradation of elastin, hemoglobin, type IV collagen, fibronectin and laminin (9). The specificity of c-ANCA in WG varies from 80%-100% (10). Elevated levels of ANCA may be seen in other pediatric diseases including cystic fibrosis (c-ANCA) juvenile idiopathic arthritis, ulcerative colitis (p-ANCA) and Crohn disease (p-ANCA) (10-14). An elevated c-ANCA is suggestive of WG but is insufficient to establish the diagnosis and histopathological confirmation is required in patients with an atypical presentation (10). In our patient, the positive c-ANCA PR-3 helped establish the diagnosis of WG. This test was particularly helpful in a patient whose initial gastrointestinal symptoms were suggestive of IBD and who was ASCA positive. ASCA recognize mannose sequences inthe cell wall mannan of S. cerevisiae and is a non-autoantigen in IBD (15). Although the reason why patients with Crohn disease develop ASCA positivity is unknown, this antibody is thought to be highly specific for Crohn disease (13,15-17). Although WG has been associated with positive ANCA testing, to our knowledge it has not been associated with false positive ASCA testing. ASCA positivity is not 100% specific for Crohn disease with positive tests occurring in some patients with celiac disease, autoimmune hepatitis and in healthy relatives of patients with Crohn disease (15,16).
Initial therapy of WG includes steroids and cyclophosphamide in severe cases. Methotrexate is an alternative in patients with less severe disease and has been used with good results in pediatric patients (18,19). Originally WG in adults had a high mortality with an average survival of only 5 months. Treatment with glucocorticoids and cyclophosphamide has improved the mean survival to more than 80% at 5 years. A recent retrospective study in adults demonstrated that treatment with cyclophosphamide and corticosteroids resulted in a 10-year survival rate of 75%, but therapy did not prevent severe organ damage (20). Morbidity and mortality data in pediatric patients indicate that treatment with glucocorticoids and cyclophosphamide results in a 5-year survival rate of 94% (1). In pediatric patients chronic renal failure is the major cause of long-term morbidity (2,21). Permanent morbidity from nasal deformities and subglottic stenosis seems to be more frequent in children than in adults (1,21).
Wegener granulomatosis is an uncommon disorder in pediatric patients which may present primarily with gastrointestinal complaints mimicking IBD. The pathological findings may be similar to Crohn disease with patchy intestinal involvement and granulomas on biopsy. WG may initially respond to the medication used to treat IBD. Therefore, a high index of suspicion is required to diagnose WG. Sinopulmonary or renal symptoms in a patient with suspected IBD should raise the possibility of WG. An elevated c-ANCA proteinase-3 in an appropriate clinical setting is strongly suggestive ofWG. Examination of full-thickness biopsy specimens, if available, may also help to establish the diagnosis. It isimportant for pediatric gastroenterologists to differentiate these 2 conditions, as appropriate initiation of cyclophosphamide therapy appears to significantly improve long-term outcome in patients with WG.
The authors would like to thank Martha Yearsley, MD, for assistance in manuscript preparation.
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