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Case report and self assessment
phocyte clones illuminate pathogenesis and affect therapy of experimental arthritis. Arthritis Rheum. 28:841-845. 2. Cremer, M. A., A. D. Hernandez, A. S. Townes, J. M. Stuart, and A. H. Kang. 1983. Collagen-induced arthritis in rats: antigen-specific suppression of arthritis and immunity by intravenously injected native type II collagen. J. Immunol. 131:2995. 3. Eugui, E. M., and R. H. Houssay. 1975. Passive transfer of unresponsiveness of lymph node cells, studies on adjuvant disease. Immunology. 28:703-710. 4. Griffiths, M. M., and C. W. I)eWitt. 1981. Immunogenetic control of experimental collagen-induced arthritis (ECIA) in rats. II. ECIA susceptibility and immune response to type II collagen (calf) are linked to RTI. J. Immunogenet. (Oxf.). 8:463. 5. Helfgott, S. M., R. A. DynesiusTrentham, D. E. Trentham. 1985. Collagen-induced arthritogenic factor in the rat. Arthritis Rheum. 27:$35. 6. Holoshitz, J., Y. Naparstek, A. BenNun, and I. R. Cohen. 1983. Lines of T lymphocytes induce or vaccinate against autoimmune arthritis. Science (Wash: DC). 219:56. 7. Kaibara N., T. Hotokebuchi, K. Takagishi, I. Katsuki, M. Morinaga, C. Arita, and S. Jingushi. 1984. Pathogenetic difference between collagen arthritis and adjuvant arthritis. J. Exp. Med. 159:1388. 8. Kerwar, S. S., M. E. Englert, R. A. McReynoids, M. J. Landes, J. M. Lloyd, A. L. Oronsky, and F. J. Wilson. 1983. Type II collageninduced arthritis: studies with purified anticollagen immunoglobulin. Arthritis Rheum. 26:1120. 9. Klareskog, L., R. Holmdahi, E. Larsson, and H. Wigzeli. 1983. Role of T lymphocytes in collagen II induced arthritis in rats. Clin. Exp. Immunol. 51:117. 10. Kohashi, O., K. Aihara, A. Ozawa, S. Kotani, and I. Azuma. 1982. New model of a synthetic adjuvant MDP-
induced arthritis. Clinical and histologic studies in athymic nude and euthymic rats. Lab. Invest., 47:27-36. 11. Pearson, C. M. 1956. Development of arthritis, periarthritis, and periostitis in rats given adjuvants. Proc. Soc. Exp. Biol. Med. 91:95. 12. Pearson, C. M., B. H. Waksman, and J. T. Sharp. 1961. Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant. J. Exp. Med. 113:485. 13. Pearson, C. M., and F. D. Wood. 1964. Passive transfer of adjuvant arthritis by lymph node and spleen cells. J. Exp. Med. 120:547. 14. Pearson, C. M., and Y. H. Chang. 1979. Adjuvant disease: Pathology and immune reactivity. (Workshop on aetiopathogenic factors in Reiter's syndrome). Ann. Rheum. Dis. (Suppl.) 38:102- 110. 15. Rosenbaum, J. T. 1981. Why HLA-B27: An analysis based on two animal models. Ann. Intern. Med. 94:261 - 263. 16. Sehoen R. T., M. I. Greene, D. E. Trentham. 1982. Antigen-specific suppression of type II collagen-induced arthritis by collagen-coupled spleen cells. J. Immunol. 128:717. 17. Stuart, J. M., and F. J. Dixon. 1983. Serum transfer of collagen-induced arthritis in mice. J. Exp. Med. 158:378. 18. Stuart, J. M., K. Tomoda, T. J. Yoo, A. S. Townes, and A. H. Kang. 1983. Serum transfer of collageninduced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats. Arthritis Rheum. 26:1237. 19. Takagishi, N., T. Kaibara, K. Arai, et al. 1985. Serum transfer of collagen arthritis in congenitally athymic nude rats. J. Immunol. 134:3864. 20. Taurog, J. D., G. P. Sandberg, and M. L. Mahowaid. 1983. The cellular basis of adjuvant arthritis. I. Enhancement of cell-mediated passive transfer by concanavalin A and by immunosuppressive pretreatment of the recipients. Cell. Immunol. 75:271.
21. Taurog, J. D., G. P. Sandberg, and M. L. Mahowald. 1983. The cellular basis of adjuvant arthritis. II. Characterization of the cells mediating passive transfer. Cell. Immunol. 80:198. 22. Taurog, J. D., S. S. Kerwar, R. A. McReynolds, G. P. Sandberg, S. L. Leary, and M. L. Mahowald. 1985. Synergy between adjuvant arthritis and collagen-induced arthritis in rats. J. Exp. Med. (in press). 23. Terato, K., K. A. Hasty, M. A. Cremer, J. M. Stuart, A. S. Townes, A. H. Kang. 1985. Collagen-induced arthritis in mice. Localization of an arthritogenic determinant to a fragment of the type II collagen molecule. J. Exp. Med. 162:637. 24. Trentham, D. E. 1982. Collagen arthritis as a relevant model for rheumatoid arthritis. Evidence pro and con. Arthritis Rheum. 25:911. 25. Trentham, D. E., A. S. Townes, and A. H. Kang. 1977. Autoimmunity to type 11 collagen: an experimental model of arthritis. J. Exp. Med. 146:857. 26. van Eden, W., J. Holoshitz, Z. Nero, A. Frenkel, A. Kiajam, I. R. Cohen. 1985. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc. Nat. Acad. Sci. USA. 82:5117. 27. Waksman, B. H., and C. Wennersten. 1963. Passive transfer of adjuvant arthritis in rats with living lymphoid cells of sensitized donors. Int. Arch. Allergy Appl. Immunol. 23:129. 28. Wooley, P. H., H. S. Luthra, J. M. Stuart, and C. S. David. 1981. Type II collagen-induced arthritis in mice. 1. Major histocompatibility complex (I region) linkage and antibody correlates. J. Exp. Med. 154:688. 29. Wooley, P. H., H. S. Luthra, S. K. Singh, H. R. Huse, J. M. Stuart, C. S. David. 1984. Passive transfer of arthritis to mice by injection of human anti-type II collagen antibody. Mayo Clin. Proc. 59:737.
Case Report and Self Assessment
An 8-year-old boy, belonging to the third percentile in height, weight, and occipito-frontal circumference, had been born full term, with a birth weight of 3.27 kg, by normal vaginal delivery. H e ' d had hypotonia during the neonatal period. No other siblings were affected. At 2 months old, he had shown failure to thrive, pneu-
monia, diarrhea, and steatorrhea. Markedly reduced activities of trypsin, amylase, and lipase were noted, in addition to neutropenia, anemia, and increased levels of hemoglobin F (14%). Hepatomegaly was noted, and liver ALT was 60 IU/L. Skeletal survey revealed multiple metaphysial dysostosis, with central excavation of the meta-
Nanneth Tiu, M.D. Gilberto E. Rodriguez, M.D.
Medical College of Virginia Virginia Commonwealth University Richmond, VA
78
0197-1859/86/$0.00 + 02.20
© 1986 Elsevier Science Publishing Co., Inc.
Clinical Immunology Newsle'aer 7:5, 1986
physial plates of the femur, proximal tibia, and ribs. Pulmonary function tests showed low forced expiratory volume (FEV) and forced vital capacity (FVC). Other investigations showing normal results were electrolytes, including Ca 2+ , PO4- , bilirubin, alkaline phosphatase, HBs Ag, stool parasitology, bacterial cultures, and thyroid function tests. Biopsy showed extensive fatty infiltration of a normal size pancreas. The acinar cells were replaced by fat. Interstitial connective tissue was increased, but the islets of Langerhans appeared low in number. Bone marrow aspiration revealed absence of myeloid precursors with erythroid hyperplasia. Pancreatic and fatsoluble vitamins improved his condition, but his growth remained retarded. He received prednisone for the management of neutropenia and multiple transfusions for anemia. He was in and out of the hospital for several episodes of pneumonia and upper respiratory infections until he developed a hemorrhagic complication of leukemia and died. Self A s s e s s m e n t 1. What is the diagnosis of this case? a. Cystic Fibrosis b. Shwachman's Syndrome c. Hereditary Pancreatitis d. Addfson's Disease e. Hypothyroidism 2. What is an almost invariable finding in this disease that may contribute to patient's susceptibility to infection? a. Defective neutrophil mobility b. Malnutrition c. Thoracic dystrophy d. Hypotonia e. Androgenic hormonal deficiency . Hemoglobin F can be moderately raised in many hematologic disorders, but the highest observations have been associated with which of the following? a. Erythroleukemia and chronic myeloid leukemia b. Monocytic leukemia c. Myeloblastic anemia
ClinicalImmunologyNewsletter7:5, 1986
d. Hypoplastic anemia e. Myeloproliferative leukemia 4. What finding in this case had not been reported before in this disease? a. Myeloproliferative leukemia b. Monocytic leukemia c. Erythroleukemia d. Myeloblastic leukemia e. Chronic myeloid leukemia 5. What is the most commonly affected site for metaphysial chondroplasia? a. Femoral head (hip) b. Knees c. Humerus d. Ribs e. Tibia and fibula 6. What is the genetic defect in this disorder ? a. Autosomal recessive b. Autosomal dominant c. Sex-linked recessive d. Sex-linked dominant
The hip is the earliest and most frequently affected site for metaphysial chondro-dysplasia. The pathogenesis is obscure; however, poorly vascularized and disoriented column cartilage have been suggested as the cause. This feature would seem to be primary to the syndrome rather than secondary to malnutrition. It has been calculated that the severity of growth retardation cannot be explained by the degree of metaphysial dysostosis. Fatty change in the liver can be secondary to malnutrition and infection, but a primary feature cannot be excluded. Thorough followup of the hematologic status in patients with SS is recommended because it may be associated with leukemia, even though this association is rare.
Comment The features of chronic pancreatic insufficiency, growth retardation, skeletal abnormality, bone marrow hypoplasia, neutropenia, anemia, and a raised level of hemoglobin F (HbF) in this patient point to Schwachman's Syndrome (SS), which is a rare multiorgan disease thought to be a genetic defect transmitted as autosomal recessive. Susceptibility to respiratory infections and systemic infection in SS may be explained by the abnormal thoracic configuration, neutropenia, and hypotonia. Recent reports demonstrate that defective neutrophil mobility is an almost invariable finding in this syndrome and may contribute to the susceptibility to infections. Patients with erythroleukemia, which has not been reported in SS, and juvenile chronic myeloid leukemia were observed to have high HbF, where levels of 30% or more may occur; but because levels of 10-20% may exist with hypoplastic anemia, one cannot ascribe any prognostic sign to the raised HbF.
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© 1986ElsevierSciencePublishingCo.. Inc.
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References 1. Aggett, P. J., N. P. C. Cavanagh, D. J Matthew, J. R. Pineott, J. Sufcliffe, and J. T. Harries (1980). Schwachman's syndrome: a review of 21 cases. Arch. Dis. Child. 55:331347. 2. Caselitz, J., G. KIoppei, G. Delling, R. Gruttner, U. Holdhoff, and M. Stern (1979). Schwachman's syndrome and leukaemia. Virchows Arch [A] 385:109-116. 3. Graham, A. R., P. D. Walson, S. H. Paplanus, and C. M. Payne (1980). Testicular fibrosis and cardiomegaly in Schwachman's syndrome. Arch. Pathol. Lab. Med. 104:242-245. 4. Hislop, W. S., P. C. Hayes, and E. J. S. Boyd (1982). Late presentation of Schwachman's syndrome. Acta Paediatr. Scand. 71:677-679. 5. Sannders, E. F., G. Gall, and M. H. Freedman (1979). Granulopoiesis in Schwachman's syndrome. Pediatrics 64:515-519. 6. Savilahti, E. and J. Rapola. (1984). Frequent myocardial lesions in Schwachman's syndrome. Acta Paediatr. Scand. 73:642-651.
0197-1859/86/$0.00+ 02.20
79
induced arthritis. Clinical and histologic studies in athymic nude and euthymic rats. Lab. Invest., 47:27-36. 11. Pearson, C. M. 1956. Development of arthritis, periarthritis, and periostitis in rats given adjuvants. Proc. Soc. Exp. Biol. Med. 91:95. 12. Pearson, C. M., B. H. Waksman, and J. T. Sharp. 1961. Studies of arthritis and other lesions induced in rats by injection of mycobacterial adjuvant. J. Exp. Med. 113:485. 13. Pearson, C. M., and F. D. Wood. 1964. Passive transfer of adjuvant arthritis by lymph node and spleen cells. J. Exp. Med. 120:547. 14. Pearson, C. M., and Y. H. Chang. 1979. Adjuvant disease: Pathology and immune reactivity. (Workshop on aetiopathogenic factors in Reiter's syndrome). Ann. Rheum. Dis. (Suppl.) 38:102- 110. 15. Rosenbaum, J. T. 1981. Why HLA-B27: An analysis based on two animal models. Ann. Intern. Med. 94:261 - 263. 16. Sehoen R. T., M. I. Greene, D. E. Trentham. 1982. Antigen-specific suppression of type II collagen-induced arthritis by collagen-coupled spleen cells. J. Immunol. 128:717. 17. Stuart, J. M., and F. J. Dixon. 1983. Serum transfer of collagen-induced arthritis in mice. J. Exp. Med. 158:378. 18. Stuart, J. M., K. Tomoda, T. J. Yoo, A. S. Townes, and A. H. Kang. 1983. Serum transfer of collageninduced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats. Arthritis Rheum. 26:1237. 19. Takagishi, N., T. Kaibara, K. Arai, et al. 1985. Serum transfer of collagen arthritis in congenitally athymic nude rats. J. Immunol. 134:3864. 20. Taurog, J. D., G. P. Sandberg, and M. L. Mahowaid. 1983. The cellular basis of adjuvant arthritis. I. Enhancement of cell-mediated passive transfer by concanavalin A and by immunosuppressive pretreatment of the recipients. Cell. Immunol. 75:271.
21. Taurog, J. D., G. P. Sandberg, and M. L. Mahowald. 1983. The cellular basis of adjuvant arthritis. II. Characterization of the cells mediating passive transfer. Cell. Immunol. 80:198. 22. Taurog, J. D., S. S. Kerwar, R. A. McReynolds, G. P. Sandberg, S. L. Leary, and M. L. Mahowald. 1985. Synergy between adjuvant arthritis and collagen-induced arthritis in rats. J. Exp. Med. (in press). 23. Terato, K., K. A. Hasty, M. A. Cremer, J. M. Stuart, A. S. Townes, A. H. Kang. 1985. Collagen-induced arthritis in mice. Localization of an arthritogenic determinant to a fragment of the type II collagen molecule. J. Exp. Med. 162:637. 24. Trentham, D. E. 1982. Collagen arthritis as a relevant model for rheumatoid arthritis. Evidence pro and con. Arthritis Rheum. 25:911. 25. Trentham, D. E., A. S. Townes, and A. H. Kang. 1977. Autoimmunity to type 11 collagen: an experimental model of arthritis. J. Exp. Med. 146:857. 26. van Eden, W., J. Holoshitz, Z. Nero, A. Frenkel, A. Kiajam, I. R. Cohen. 1985. Arthritis induced by a T-lymphocyte clone that responds to Mycobacterium tuberculosis and to cartilage proteoglycans. Proc. Nat. Acad. Sci. USA. 82:5117. 27. Waksman, B. H., and C. Wennersten. 1963. Passive transfer of adjuvant arthritis in rats with living lymphoid cells of sensitized donors. Int. Arch. Allergy Appl. Immunol. 23:129. 28. Wooley, P. H., H. S. Luthra, J. M. Stuart, and C. S. David. 1981. Type II collagen-induced arthritis in mice. 1. Major histocompatibility complex (I region) linkage and antibody correlates. J. Exp. Med. 154:688. 29. Wooley, P. H., H. S. Luthra, S. K. Singh, H. R. Huse, J. M. Stuart, C. S. David. 1984. Passive transfer of arthritis to mice by injection of human anti-type II collagen antibody. Mayo Clin. Proc. 59:737.
Case Report and Self Assessment
An 8-year-old boy, belonging to the third percentile in height, weight, and occipito-frontal circumference, had been born full term, with a birth weight of 3.27 kg, by normal vaginal delivery. H e ' d had hypotonia during the neonatal period. No other siblings were affected. At 2 months old, he had shown failure to thrive, pneu-
monia, diarrhea, and steatorrhea. Markedly reduced activities of trypsin, amylase, and lipase were noted, in addition to neutropenia, anemia, and increased levels of hemoglobin F (14%). Hepatomegaly was noted, and liver ALT was 60 IU/L. Skeletal survey revealed multiple metaphysial dysostosis, with central excavation of the meta-
Nanneth Tiu, M.D. Gilberto E. Rodriguez, M.D.
Medical College of Virginia Virginia Commonwealth University Richmond, VA
78
0197-1859/86/$0.00 + 02.20
© 1986 Elsevier Science Publishing Co., Inc.
Clinical Immunology Newsle'aer 7:5, 1986
physial plates of the femur, proximal tibia, and ribs. Pulmonary function tests showed low forced expiratory volume (FEV) and forced vital capacity (FVC). Other investigations showing normal results were electrolytes, including Ca 2+ , PO4- , bilirubin, alkaline phosphatase, HBs Ag, stool parasitology, bacterial cultures, and thyroid function tests. Biopsy showed extensive fatty infiltration of a normal size pancreas. The acinar cells were replaced by fat. Interstitial connective tissue was increased, but the islets of Langerhans appeared low in number. Bone marrow aspiration revealed absence of myeloid precursors with erythroid hyperplasia. Pancreatic and fatsoluble vitamins improved his condition, but his growth remained retarded. He received prednisone for the management of neutropenia and multiple transfusions for anemia. He was in and out of the hospital for several episodes of pneumonia and upper respiratory infections until he developed a hemorrhagic complication of leukemia and died. Self A s s e s s m e n t 1. What is the diagnosis of this case? a. Cystic Fibrosis b. Shwachman's Syndrome c. Hereditary Pancreatitis d. Addfson's Disease e. Hypothyroidism 2. What is an almost invariable finding in this disease that may contribute to patient's susceptibility to infection? a. Defective neutrophil mobility b. Malnutrition c. Thoracic dystrophy d. Hypotonia e. Androgenic hormonal deficiency . Hemoglobin F can be moderately raised in many hematologic disorders, but the highest observations have been associated with which of the following? a. Erythroleukemia and chronic myeloid leukemia b. Monocytic leukemia c. Myeloblastic anemia
ClinicalImmunologyNewsletter7:5, 1986
d. Hypoplastic anemia e. Myeloproliferative leukemia 4. What finding in this case had not been reported before in this disease? a. Myeloproliferative leukemia b. Monocytic leukemia c. Erythroleukemia d. Myeloblastic leukemia e. Chronic myeloid leukemia 5. What is the most commonly affected site for metaphysial chondroplasia? a. Femoral head (hip) b. Knees c. Humerus d. Ribs e. Tibia and fibula 6. What is the genetic defect in this disorder ? a. Autosomal recessive b. Autosomal dominant c. Sex-linked recessive d. Sex-linked dominant
The hip is the earliest and most frequently affected site for metaphysial chondro-dysplasia. The pathogenesis is obscure; however, poorly vascularized and disoriented column cartilage have been suggested as the cause. This feature would seem to be primary to the syndrome rather than secondary to malnutrition. It has been calculated that the severity of growth retardation cannot be explained by the degree of metaphysial dysostosis. Fatty change in the liver can be secondary to malnutrition and infection, but a primary feature cannot be excluded. Thorough followup of the hematologic status in patients with SS is recommended because it may be associated with leukemia, even though this association is rare.
Comment The features of chronic pancreatic insufficiency, growth retardation, skeletal abnormality, bone marrow hypoplasia, neutropenia, anemia, and a raised level of hemoglobin F (HbF) in this patient point to Schwachman's Syndrome (SS), which is a rare multiorgan disease thought to be a genetic defect transmitted as autosomal recessive. Susceptibility to respiratory infections and systemic infection in SS may be explained by the abnormal thoracic configuration, neutropenia, and hypotonia. Recent reports demonstrate that defective neutrophil mobility is an almost invariable finding in this syndrome and may contribute to the susceptibility to infections. Patients with erythroleukemia, which has not been reported in SS, and juvenile chronic myeloid leukemia were observed to have high HbF, where levels of 30% or more may occur; but because levels of 10-20% may exist with hypoplastic anemia, one cannot ascribe any prognostic sign to the raised HbF.
B(9
© 1986ElsevierSciencePublishingCo.. Inc.
Answers: e(f
o(~,
~(£
~(Z
q(I
References 1. Aggett, P. J., N. P. C. Cavanagh, D. J Matthew, J. R. Pineott, J. Sufcliffe, and J. T. Harries (1980). Schwachman's syndrome: a review of 21 cases. Arch. Dis. Child. 55:331347. 2. Caselitz, J., G. KIoppei, G. Delling, R. Gruttner, U. Holdhoff, and M. Stern (1979). Schwachman's syndrome and leukaemia. Virchows Arch [A] 385:109-116. 3. Graham, A. R., P. D. Walson, S. H. Paplanus, and C. M. Payne (1980). Testicular fibrosis and cardiomegaly in Schwachman's syndrome. Arch. Pathol. Lab. Med. 104:242-245. 4. Hislop, W. S., P. C. Hayes, and E. J. S. Boyd (1982). Late presentation of Schwachman's syndrome. Acta Paediatr. Scand. 71:677-679. 5. Sannders, E. F., G. Gall, and M. H. Freedman (1979). Granulopoiesis in Schwachman's syndrome. Pediatrics 64:515-519. 6. Savilahti, E. and J. Rapola. (1984). Frequent myocardial lesions in Schwachman's syndrome. Acta Paediatr. Scand. 73:642-651.
0197-1859/86/$0.00+ 02.20
79