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Van der Woude syndrome

Van Der Woude syndrome consists of the following characteristics: cleft lip and palate, missing teeth and lip pits.


It is caused by mutations in the IRF6 gene. (Popliteal pterygium syndrome is also caused by mutations in this gene.)

VACTERL association
Van der Woude syndrome
Van Goethem syndrome
Varicella Zoster
Variegate porphyria
Vasovagal syncope
VATER association
Velocardiofacial syndrome
Ventricular septal defect
Viral hemorrhagic fever
Vitamin B12 Deficiency
VLCAD deficiency
Von Gierke disease
Von Hippel-Lindau disease
Von Recklinghausen disease
Von Willebrand disease


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Respiratory failure in ANCA-associated vasculitis - antineutrophil cytoplasmic autoantibodies
From CHEST, 8/1/96 by Jan C. ter Maaten

Objective: To assess the prevalence, clinical manifestations, and course of respiratory failure in all patients who tested positive for antineutrophil cytoplasmic autoantibodies (ANCA) in our clinics in the period between January 1985 and January 1993.

Design: Case-series analysis.

Setting: Three teaching hospitals in the Netherlands.

Patients: Two hundred twenty consecutive patients suspected of having vasculitis and/or glomerulonephritis who tested positive for ANCA by indirect immunofluorescence and enzyme-linked immunosorbent assay.

Results: Sixty-two patients had pulmonary involvement. Acute respiratory failure developed in nine.

Respiratory failure was related to infections in two of them and to ANCA-associated vasculitis in seven. These seven patients uniformly presented with pulmonary hemorrhage and diffuse pulmonary infiltrates. The diagnosis of systemic vasculitis was supported by the presence of a pulmonary-renal syndrome in all patients, and by detection of antibodies to the proteinase 3 or myeloperoxidase antigen in all but one patient. Antiglomerular basement membrane antibodies were absent. The mortality was high due to hypoxic respiratory failure, pulmonary superinfections, and concomitant renal failure.

Conclusions: Acute respiratory failure due to vasculitis developed in one of every nine patients with ANCA-associated pulmonary disease. Patients usually present with pulmonary infiltrates and hemoptysis. A diagnosis of vasculitis may be further supported by analysis of the urinary sediment and determination of the ANCA target antigen. It remains to be proved that early detection of ANCA favorably affects the outcome.

Key words: acute respiratory failure; antineutrophil cytoplasmic autoantibodies; vasculitis

Abbreviations: ANCA=antineutrophil cytoplasmic autoantibodies; aMPO=antibodies against myeloperoxidase; aPR3=antibodies against proteinase 3; C-ANCA=cytoplasmic ANCA; ELISA=enzyme-linked immunosorbent assay; IIF=indirect immunofluorescence; P-ANCA=perinuclear ANCA; RF = respiratory failure

Respiratory failure (RF) is a serious complication of systemic vasculitis. Few cases with RF in systemic vasculitis or Wegener's granulomatosis have been described, usually associated with pulmonary hemorrhage and diffuse pulmonary infiltrates.(1),(2),(3),(4),(5),(6),(7),(8),(9),(10),(11) The presence of RF is not explicitly mentioned in most series, and thus, its exact prevalence is unknown. The percentage of patients with systemic vasculitis who die due to pulmonary hemorrhage can more easily be recognized: 6 to 13% in large series.(12),(13),(14) The fact that RF in systemic vasculitis is seldomly reported suggests that the diagnosis is exceptional or difficult to make. Indeed, a certain diagnosis of pulmonary vasculitis can often be made only by open lung biopsy specimens.(15)

Recently, antineutrophil cytoplasmic autoantibodies (ANCA) have been shown to be of diagnostic value in the work-up of systemic vasculitis.(13),(16),(17),(18) ANCA are directed against lysosomal enzymes of neutrophils and are considered sensitive markers for Wegener's granulomatosis, microscopic polyarteritis, and related systemic necrotizing vasculitis.(13),(16),(17),(18) Two main patterns of ANCA are recognized by indirect immunofluorescence (IIF) microscopy: a cytoplasmic (C-ANCA) and a perinuclear (P-ANCA) staining.(19) Almost all C-ANCA sera are directed to proteinase 3.(20),(21) The major target antigen of P-ANCA is myeloperoxidase, but many other antigen specificities have been described.(22),(23),(24) Antibodies to proteinase 3 (aPR3) and myeloperoxidase (aMPO) are strongly associated with idiopathic (systemic) vasculitis.(18),(23) Patients with antibodies to other antigens than PR3 and MPO usually have nonvasculitic syndromes such as chronic inflammatory bowel disease, rheumatic diseases, autoimmune liver disease, and certain infections.(23)

Recently, the clinical relevance of testing for ANCA in patients with respiratory tract symptoms has been shown.(25) Now that the availability of the ANCA test may facilitate the difficult diagnosis of pulmonary vasculitis, we wondered how often RF occurred in patients with ANCA-associated pulmonary disease. Therefore, we studied the prevalence, the clinical manifestations, and the course of RF in all patients who tested positive for ANCA.

From this series, patients with ANCA-positive vasculitis and RF seem to have a relatively bad prognosis with an early (2 month) mortality in four of the seven patients. This mortality rate compares to the fatal outcome of disease in four of eight patients with ANCA-associated glomerulonephritis and systemic vasculitis who had massive pulmonary hemorrhage.(13) Early in the course, patients will die of hypoxic respiratory failure due to pulmonary vasculitis. Late fatalities are due to opportunistic superinfections. In addition, the development of multiple organ failure contributes to the unfavorable outcome. Indeed, the outcome of ANCA-positive patients compares with the results in other immunocompromised patients needing ventilatory assistance, and in patients with multiorgan failure.(36),(37),(38),(39)

The gain of a specific diagnosis by detection of ANCA seems at best questionable, considering the bad prognosis in our patients. The unfavorable outcome may have been facilitated by the fact that immunosuppressive treatment was not started until RF was imminent or present. The delay in treatment could have been shortened by prompt detection of an active urinary sediment, and earlier recognition of the presence of a pulmonary-renal syndrome. Nevertheless, early diagnosis in our patients was hampered by the short interval between the onset of pulmonary symptoms and the development of RF.

A pitfall in the approach of an ANCA-positive patient with respiratory tract symptoms is the occurrence of "false-positive ANCA" tests. These have been found in patients with pulmonary infection, fibrotic lung disease, connective tissue disease, malignancy, and pulmonary emboli.(25),(30),(40) Most of these patients have the P-ANCA staining pattern on ethanol-fixed leukocytes. The specificity of ANCA for idiopathic vasculitis is high when antibodies against PR3 or MPO are found with an ELISA.(30),(41),(42) Furthermore, the presence of coexistent renal disease and, thus, a pulmonary-renal syndrome appears to support the true-positive character of the ANCA test for systemic vasculitic disease.(40) Therefore, analysis of the urinary sediment is a useful diagnostic tool in a patient with ANCA-associated pulmonary disease.

Probably, the finding of a positive ANCA, RF, and diffuse pulmonary infiltrates is insufficient information for the institution and continuation of combined cyclophosphamide and corticosteroid therapy. Thus, histologic evidence of vasculitis is needed. Institution of immunosuppressive therapy, however, can be justified by the presence of a high suspicion of systemic vasculitis when other organs are involved as well, eg, glomerulonephritis.

In conclusion, acute RF is not rare in patients with ANCA-associated pulmonary disease. The presence of an active urinary sediment gives a simple clue to this diagnosis. The disease is associated with a severe course with imminent RF and a significant mortality. Determination of the ANCA target antigen results in a more specific diagnosis. However, it remains to be proved that early detection of ANCA favorably affects the prognosis in these patients with severe pulmonary vasculitis.


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(2) Thomashow BM, Felton CP, Navarro C. Diffuse intrapulmonary hemorrhage, renal failure and a systemic vasculitis. Am J Med 1980; 68:299-304

(3) Hensley MJ, Feldman NT, Lazarus JM, et al. Diffuse pulmonary hemorrhage and rapidly progressive renal failure. Am J Med 1979; 66:894-98

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(9) Scully RE, Mark EJ, McNeely WF, et al. Case records of Massachusetts General Hospital. N Engl J Med 1986; 314:1170-84

(10) Scully RE, Mark EJ, McNeely WF, et al. Case records of Massachusetts General Hospital. N Engl J Med 1993; 328:951-58

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(12) Haworth SJ, Savage COS, Carr D, et al. Pulmonary haemorrhage complicating Wegener's granulomatosis and microscopic polyarteritis. BMJ 1985; 290:1775-78

(13) Falk RJ, Hogan S, Carey TS, et al. Glomerular disease collaborative network: clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. Ann Intern Med 1990; 113:656-63

(14) Gaskin G, Pusey CD. Systemic vasculitis. In: Cameron S, Davison AM, Grunfeld JP, et al, eds. Oxford textbook of clinical nephrology. Oxford: Oxford University Press, 1992; 612-33

(15) Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener's granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116:488-98

(16) Nolle B, Specks V, Ludemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener's granulomatosis. Ann Intern Med 1989; 111:28-40

(17) Cohen Tervaert JW, van der Woude FJ, Fauci AS, et al. Association between active Wegener's granulomatosis and anticytoplasmic antibodies. Arch Intern Med 1989; 149:2461-65

(18) Kallenberg CGM, Brouwer E, Weening JJ, et al. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46:1-15

(19) Rasmussen N, Wiik A, Hoier-Madsen M, et al. Anti-neutrophil cytoplasm antibodies 1988. Lancet 1988; 1:706-07

(20) Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D, et al. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophophate-binding protein in the lysosomes of normal human neutrophils. J Clin Invest 1989; 84:1577-87

(21) Jennette JC, Hoidal JH, Falk RJ. Specificity of antineutrophil cytoplasmic autoantibodies for proteinase 3. Blood 1990; 78:2263-64

(22) Goldschmeding R, Cohen Tervaert JW, Gans ROB, et al. Different immunological specificities and disease associations of c-ANCA and p-ANCA. Neth J Med 1990; 36:114-16

(23) Kallenberg CGM, Mulder AHL, Cohen Tervaert JW. Antineutrophil cytoplasmic antibodies: a still growing class of autoantibodies in inflammatory disorders. Am J Med 1992; 93:675-82

(24) Gross WL, Schmitt WH, Csernok E. ANCA and associated diseases: immunodiagnostic and pathogenetic aspects. Clin Exp Immunol 1993; 91:1-12

(25) Davenport A, Lock RJ, Wallington TB, et al. Clinical significance of anti-neutrophil cytoplasm antibodies detected by a standardized indirect immunofluorescence assay. QJ Med 1994; 87:291-99

(26) Cohen Tervaert JW, Limburg PC, Elema JD, et al. Detection of autoantibodies against myeloid lysosomal enzymes: a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis. Am J Med 1991; 91:59-66

(27) Gans ROB, Kuizinga MC, Goldschmeding R, et al. Clinical features and outcome in patients with glomerulonephritis and antineutrophil cytoplasmic autoantibodies. Nephron 1993; 64:182-88

(28) Jennette JC, Falk RJ. Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides. Am J Kidney Dis 1991; 18:184-87

(29) Cordier JF, Valeyre D, Guillevin L, et al. Pulmonary Wegener's granulomatosis: a clinical and imaging study of 77 cases. Chest 1990; 97:906-12

(30) Franssen CFM, Gans ROB, Arends AJ, et al. Differences between anti-myeloperoxidase- and anti-proteinase 3-associated renal disease. Kidney Int 1995; 47:193-99

(31) Bosch X, Font J, Mirapeix E, et al. Antimyeloperoxidase autoantibody-associated necrotizing alveolar capillaritis. Am Rev Respir Dis 1992; 146:1326-29

(32) Bosch X, Mirapeix E, Font J, et al. Prognostic implication of antineutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol 1991; 36:107-13

(33) Jayne DRW, Marshall PD, Jones SJ, et al. Autoantibodies to GBM and neutrophil cytoplasm in rapidly progressive glomerulonephritis. Kidney Int 1990; 37:965-70

(34) Bygren P, Rasmussen N, Isaksson B, et al. Anti-neutrophil cytoplasm antibodies, anti-GBM antibodies and anti-dsDNA antibodies in glomerulonephritis. Eur J Clin Invest 1992; 22:783-92

(35) Gal AA, Salinas FF, Staton GW. The clinical and pathological spectrum of antineutrophil cytoplasmic autoantibody-related pulmonary disease: a comparison between perinuclear and cytoplasmic antineutrophil cytoplasmic autoantibodies. Arch Pathol Lab Med 1994; 118:1209-14

(36) Cameron JS. Acute renal failure in the intensive care unit today. Intensive Care Med 1986; 12:64-70

(37) Dees A, Ligthart JL, van Putten WLJ, et al. Mechanical ventilation in cancer patients: analysis of clinical data and outcome. Neth J Med 1990; 37:183-88

(38) Lloyd-Thomas AR, Wright I, Lister TA, et al. Prognosis of patients receiving intensive care for lifethreatening medical complications of haematological malignancy. BMJ 1988; 296:1025-29

(39) Torrecilla C, Cortes JL, Chamorro C, et al. Prognostic assessment of the acute complications of bone marrow transplantation requiring intensive therapy. Intensive Care Med 1988; 14:393-98

(40) Davenport A, Lock RJ, Wallington TB. Clinical relevance of testing for antineutrophil cytoplasm antibodies (ANCA) with a standard indirect immunofluorescence ANCA test in patients with upper or lower respiratory tract symptoms. Thorax 1994; 49:213-17

(41) DeRemee RA, Homburger HA, Specks U. Lesions of the respiratory tract associated with the finding of anti-neutrophil cytoplasmic autoantibodies with a perinuclear staining pattern. Mayo Clin Proc 1994; 69:819-24

(42) Bosch X, Lopez-Soto A, Mirapeix E, et al. Antineutrophil cytoplasmic autoantibody-associated alveolar capillaritis in patients presenting with pulmonary hemorrhage. Arch Pathol Lab Med 1994; 118:517-22

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