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Childhood myelofibrosis and osteosclerosis without myeloid metaplasia
860
B r i e f clinical and laboratory observations
REFERENCES 1. Berdon, W. E., Baker, D. H., and James, L. S.: The ductus bump. A transient physiologic mass in chest roentgenograms of newborn infants, Am. J. Roentgenol. 95: 91, 1965. 2. Heikkinen, E. S., and Simila, S.: Aneurysm of the ductus arteriosus in infancy: Report of two surgically treated cases, J. Pediatr. Surg. 7: 392, 1972.
Childhood myelofibrosis and osteosclerosis without myeloid metaplasia Kamren Tebbi, M.D., Harold S. Zarkowsky, M.D.,* Barry A. Siegel, M.D., and William H. McAlister, M.D., St. Louis, Mo.
M Y E L O F I B R O S I S is r a r e in c h i l d h o o d a n d m a n y previous r e p o r t s fail to d i s t i n g u i s h b e t w e e n p r i m a r y myelofibrosis a n d t h e s e c o n d a r y f o r m , w h i c h is m o s t o f t e n associated w i t h a c u t e leukemia. 1 In general, prim a r y m y e l o f i b r o s i s in c h i l d r e n h a s b e e n c h a r a c t e r i z e d as a rapidly fatal c o n d i t i o n . In this report, we p r e s e n t a u n i q u e case o f p r i m a r y myelofibrosis w i t h osteosclerosis in a n l l - y e a r - o t d boy, in w h o m t h e clinical c o u r s e has e x t e n d e d o v e r a twoyear period. R a d i o n u c l i d e b o n e m a r r o w scans a n d ferr o k i n e t i c s t u d i e s w e r e p e r f o r m e d to e v a l u a t e t h e pathophysiology of the anemia. CASE REPORT C. M. was referred to St. Louis Children's Hospital in June, 1972, at 10 years of age because of anemia. During the previous 12 months his hemoglobin concentration remained at 7.5 Gin. per deciliter, despite oral iron therapy. The past a n d fa~nily histories were essentially unremarkable. The initial hemogram was: hemoglobin, 8.2 Gin. per deciliter; hematocrit, 27 per cent; white blood cell count, 4,000 per cubic millimeter, with 69 per cent lymphocytes, 4 per cent monocytes, and 27 per cent From the Edward Mallinckrodt Department of Pediatrics and the Edward Mallinckrodt Institute of R adiology, Washington University School of Medicine, and the Division o f Hematology and Oncology, St. Louis Children "sHospital Supported by NIH Grant CA 05 587-13 and NIH Training Grant GMO-1747. *Reprintrequests:St. Louis Children"sHospital, 500 S. Kingshighway,St. Louis, Mo. 63110.
The Journal o f Pediatrics June 1974
3. Heymann, M. A., and Rudolph, A. M.: Effects of congenital heart disease on fetal and neonatal circulation, Progr. Cardiovasc. Dis. 15: 115, 1972. 4. Moss, A. J., Emmanoulides, G., and Duffle, E. R.: Closure of the ductus arteriosus in the newborn infant, Pediatrics 32: 25, 1963.
n e u t r o p h i l s ; platelets, 200,000 per cubic m i l l i m e t e r ; reticulocytes, 2 per cent. The erythrocyte morphology was normal except for mild hypochromia and the Presence of an occasional nucleated red blood cell. A stained smear of the buffy coat contained myelocytes and metamyelocytes. The patient received no medications or blood transfusions and has remained in excellent general health. No enlargement of liver or spleen has been noted. His hemogram has not changed, except for a decrease in hemoglobin concentration to 7.0 Gm. per deciliter. The following laboratory tests were performed and were negative or within normal limits: urinalysis, SGOT, SGPT, alkaline phosphatase, serum iron and iron-binding capacity, serum calcium, phosphorus, proteins, antinuclear antibody, hemoglobin electrophoresis (2.1 per cent fetal hemoglobin), Coombs' test, sucrose hemolysis test, osmotic red blood cell fragility, red blood cell autohemolysis, and red blood cell glucose-6-phosphate dehydrogenase. The erythrocyte sedimentation rate was 65 mm. per hour. The peripheral leukocyte chromosomal pattern was normal. Red blood cell volume, determined with 51Cr-labeled autologous red cells, was 14 ml. per kilogram (N = 25 to 33). The plasma volume (10 minute 125I-albumin space) was 49 ml. per kilogram (N = 40 to 50). Urine erythrop0ietin excretion was 180 U. per 24 hr. (control, 4.5 units). Roentgen findings. There was a diffuse osteosclerosis, especially noted in the pelvic bones, and manifested in the chest by increased homogenous opacification of all ribs and the clavicles (Fig. 1). The spine showed a diffuse mild decrease in density and some loss of definition of the trabeculae. The increased density in the extremities was uniform with minute focal denser areas of osteosclerosis in the midshaft of the femurs and radii. The epiphyses were involved. Tl~e skull showed a diffuse mild increase in density in the base. There was no interference with modeling of the bones. Bone marrow biopsy. Since all attempts to obtain a sample of bone marrow by aspiration were unsuccessful, a bone marrow biopsy of the iliac croat was performed. The bone marrow had areas of both hypo- and hypercellularity with reduced numbers of erythroid precursors. Marked diffuse fibrosis and focal collagen fiber formation were present; stainable iron was focally increased. Erythroeyte survival and ferrokinetic studies. The half-time of 51Cr-labeled erythrocytes was 22 days (N = 24-38). External
Volume 84 Number 6
Brief clinical and laboratory observations
86 1
Fig. 1. Diffuse osteosclerosis of pelvis and femurs.
organ counting over spleen, liver, and precordium demonstrated no evidence of abnormal splenic or hepatic erythrocyte sequestration. Ferrokinetic studies were performed in standard fashion 2 following the intravenous injection of 5/xCi of Fe-ferrous citrate which had been incubated with the patient's plasma. At the time of the study, the plasma iron was 123/zg per deciliter and the unbound iron-binding capacity was 228 ~g per deciliter. The plasma iron turnover rate was 33 /.tg per kilogram of body weight per hour (N = 15-25). Erythrocyte iron incorporation was 55 per cent on day 10 (N = 74-89). External counting over liver, spleen, precordium, and sacrum showed a normal pattern except for a slight rise in liver and spleen activity over the first three days. Radionuelide hone marrow imaging. After administration of 5 mCi. of 99mTc-sulfur colloid, bone marrow scan (Fig. 2) showed nonvisualization of the axial and extremity marrow except for a small amount of uptake in the calvaria. Liver and spleen were normal. A marrow scan obtained with 1.5 mCi. of indium-Ill chloride (Fig. 2) demonstrated good uptake throughout the marrow of the skull, axial skeleton, pelvis, femurs, and proximal tibias. A small amount of activity was noted in both liver and spleen. DISCUSSION T h e diagnosis of primary myelofibrosis in our patient is supported by bone m a r r o w biopsy, no e v i d e n c e o f other underlying disease, and the skeletal changes o f osteosclerosis. Osteosclerosis is seen in approximately 50 per c e n t 3' 4 o f a d u l t p a t i e n t s with p r i m a r y
Fig. 2. Representative images from the ]]]In-chloride and 99mTc-sulfur colloid bone marrow studies. The tllln images demonstrate good radio-pharmaceutical concentration in the skull, axial marrow, and peripheral marrow. There is a very poor localization of 99mTc-sulfur colloid in the axial marrow and femurs and only slight activity in the calvarium. These findings suggest a disparity between the hernatopoietic and reticuloendothelial functions of the marrow in this patient.
myelofibrosis, but has n e v e r been reported in a child to our knowledge. Myeloid metaplasia and splenomegaly are prominent features of myelofibrosis in adult patients.4Spleno megaly may develop prior to m a j o r marrow fibrosis and can even be present during a stage of marrow byperplasia.4The normal-sized spleen in our patient is a m o s t unusual finding. T h e r e is no reported experience with the use of both 11qn-chloride and 99mTc-sulfur colloid in the evaluation of patients with myelofibrosis. Nonvisualization of the bone marrow, after injections o f 99mTc-sulfur colloid, reflects dysfunction of the phagocytic reticuloendothelial bone marrow. Since bone m a r r o w scans with sulfur col-
862
Brief clinical and laboratory observations
loids do n o t assess hematopoietic bone marrow, other radionuclides, such as llqn-chloride, have been developed. The validity of r a i n as an agent for scanning hematopoietic bone marrow is still debatable. Although m l n binds t o transferrin in vitro, s studies in animals showed that i n d i u m was not incorporated into hemoglobin 6, 7 and n o r m a l accumulation occurred in bone marrow after irradiation i n j u r y ? However, clinical studies have d e m o n strated the usefulness of r a i n as an agent for b o n e marrow s c a n n i n g . D e c r e a s e d to a b s e n t r a i n u p t a k e with n o r m a l 99mTc-sulfur colloid uptake in bone marrow was observed in patients,with pure red blood cell aplasia 9 and leukemia w i t h a n e m i a ] The disparity between l l q n and 99mTc uptake in our patierit suggests abnormal phagocytic function of the reticuloendothelial marrow with preservation of hematopoietic activity. This interpretation of the i n d i u m scan is supported by the finding of an increased p l a s m a iron turnover. Our patient has few clinical features in c o m m o n with either myelofibrosis in childhood or the adult form of the disease. Perhaps his disease process is different from that of myelofibrosis with myeloid metaplasia. We are grateful to Dr. Esmail D. Zanjani, Mount Sinai School of Medicine, for performing the erythropoietin assay.
The Journal of Pediatrics June 1974
REFERENCES 1. Say, B., and Berkel, I.: Idiopathic myelofibrosis in an infant, J. PEDIATR.64: 580, 1964. 2. Weinstein, I. M.: Disorders of hematopoiesis, the reticuloendothial system, and the spleen, in Blahd, W. H., editor: Nuclear medicine, New York, 1971, McGraw-Hill Book Company, Inc. 3. Pettigrew, J. D., and Ward, H. P.: Correlation of radiologic, histologic and clinical findings in agnogenic myeloid metaplasia, Radiology 93: 541, 1969. 4. Wintrobe, M. M.: Clinical hematology, ed. 6, Philadelphia, 1967, Lea & Febiger, Publishers, p. 770. 5. Lilien, D. L., Berger, H. G., Anderson, D. P., and Bennett, L. R.: rain-chloride: a new agent for bone marrow imaging, J. Nucl. Med. 14: 184, 1973. 6. Beamish, M. R., and Brown, E. B.: A comparison of the in vitro and in vivo behavior of 59Fel141n-and 59Fe-chloride in the rat, J. Clin. Invest. 52: 7a, 1973 (abst.). 7. Farrer, P. A., Saha, G. B., and Katz, M.: Further observations on the use of mln-transferrin for the visualization of bone marrow in man, J. Nucl. Med. 14: 394, 1973 (abst.). 8. McIntyre, P. A., Larson, S. M., Scheffel, U., et al.: Comparison of metabolism of iron-transferrin and indiumtransferrin by erythropoietic marrow, J. Nucl. Med. 14: 425, 1973 (abst.). 9. Staub, R. T., and Gaston, E.: rain-chloride distribution and kinetics in hematologic disease, J. Nucl. Med. 14: 456, 1973 (abst.).
Cervical cord compression in diastrophic dwarfism IrwinJ. Kash, M.D.,* Pittsburgh, Pa., ShashikantM. Sane, M.D., Minneapolis, Minn., Frederick J. Samaha, M.D., Pittsburgh, Pa., and Jakob Briner, M.D., Switzerland
D IASTROPH1C DWARFISM was first described in 1960 by L a m y and Maroteaux. 1 Since then, m o r e than 30 cases have been reported. The typical features include dwarfism, abnormal spinal curvature, micromelia, distinctive h a n d deformities, clubfeet, multiple joint contractures and/or subluxations, cleft or high-arched palate, and swelling of the external ears? "4 Despite the occurrence of kyphosis a n d subluxation of cervical verFrom the Departments of Pediatrics, Pathology, and Radiology, University of Pittsburgh School of Medicine. *Reprint address: Children's Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh,Pa. 15213.
Fig. 1. Lateral view of the cervical spine showing marked dorsal kyphosis with small sized vertebral bodies of C 3, C 4, and C 5.
B r i e f clinical and laboratory observations
REFERENCES 1. Berdon, W. E., Baker, D. H., and James, L. S.: The ductus bump. A transient physiologic mass in chest roentgenograms of newborn infants, Am. J. Roentgenol. 95: 91, 1965. 2. Heikkinen, E. S., and Simila, S.: Aneurysm of the ductus arteriosus in infancy: Report of two surgically treated cases, J. Pediatr. Surg. 7: 392, 1972.
Childhood myelofibrosis and osteosclerosis without myeloid metaplasia Kamren Tebbi, M.D., Harold S. Zarkowsky, M.D.,* Barry A. Siegel, M.D., and William H. McAlister, M.D., St. Louis, Mo.
M Y E L O F I B R O S I S is r a r e in c h i l d h o o d a n d m a n y previous r e p o r t s fail to d i s t i n g u i s h b e t w e e n p r i m a r y myelofibrosis a n d t h e s e c o n d a r y f o r m , w h i c h is m o s t o f t e n associated w i t h a c u t e leukemia. 1 In general, prim a r y m y e l o f i b r o s i s in c h i l d r e n h a s b e e n c h a r a c t e r i z e d as a rapidly fatal c o n d i t i o n . In this report, we p r e s e n t a u n i q u e case o f p r i m a r y myelofibrosis w i t h osteosclerosis in a n l l - y e a r - o t d boy, in w h o m t h e clinical c o u r s e has e x t e n d e d o v e r a twoyear period. R a d i o n u c l i d e b o n e m a r r o w scans a n d ferr o k i n e t i c s t u d i e s w e r e p e r f o r m e d to e v a l u a t e t h e pathophysiology of the anemia. CASE REPORT C. M. was referred to St. Louis Children's Hospital in June, 1972, at 10 years of age because of anemia. During the previous 12 months his hemoglobin concentration remained at 7.5 Gin. per deciliter, despite oral iron therapy. The past a n d fa~nily histories were essentially unremarkable. The initial hemogram was: hemoglobin, 8.2 Gin. per deciliter; hematocrit, 27 per cent; white blood cell count, 4,000 per cubic millimeter, with 69 per cent lymphocytes, 4 per cent monocytes, and 27 per cent From the Edward Mallinckrodt Department of Pediatrics and the Edward Mallinckrodt Institute of R adiology, Washington University School of Medicine, and the Division o f Hematology and Oncology, St. Louis Children "sHospital Supported by NIH Grant CA 05 587-13 and NIH Training Grant GMO-1747. *Reprintrequests:St. Louis Children"sHospital, 500 S. Kingshighway,St. Louis, Mo. 63110.
The Journal o f Pediatrics June 1974
3. Heymann, M. A., and Rudolph, A. M.: Effects of congenital heart disease on fetal and neonatal circulation, Progr. Cardiovasc. Dis. 15: 115, 1972. 4. Moss, A. J., Emmanoulides, G., and Duffle, E. R.: Closure of the ductus arteriosus in the newborn infant, Pediatrics 32: 25, 1963.
n e u t r o p h i l s ; platelets, 200,000 per cubic m i l l i m e t e r ; reticulocytes, 2 per cent. The erythrocyte morphology was normal except for mild hypochromia and the Presence of an occasional nucleated red blood cell. A stained smear of the buffy coat contained myelocytes and metamyelocytes. The patient received no medications or blood transfusions and has remained in excellent general health. No enlargement of liver or spleen has been noted. His hemogram has not changed, except for a decrease in hemoglobin concentration to 7.0 Gm. per deciliter. The following laboratory tests were performed and were negative or within normal limits: urinalysis, SGOT, SGPT, alkaline phosphatase, serum iron and iron-binding capacity, serum calcium, phosphorus, proteins, antinuclear antibody, hemoglobin electrophoresis (2.1 per cent fetal hemoglobin), Coombs' test, sucrose hemolysis test, osmotic red blood cell fragility, red blood cell autohemolysis, and red blood cell glucose-6-phosphate dehydrogenase. The erythrocyte sedimentation rate was 65 mm. per hour. The peripheral leukocyte chromosomal pattern was normal. Red blood cell volume, determined with 51Cr-labeled autologous red cells, was 14 ml. per kilogram (N = 25 to 33). The plasma volume (10 minute 125I-albumin space) was 49 ml. per kilogram (N = 40 to 50). Urine erythrop0ietin excretion was 180 U. per 24 hr. (control, 4.5 units). Roentgen findings. There was a diffuse osteosclerosis, especially noted in the pelvic bones, and manifested in the chest by increased homogenous opacification of all ribs and the clavicles (Fig. 1). The spine showed a diffuse mild decrease in density and some loss of definition of the trabeculae. The increased density in the extremities was uniform with minute focal denser areas of osteosclerosis in the midshaft of the femurs and radii. The epiphyses were involved. Tl~e skull showed a diffuse mild increase in density in the base. There was no interference with modeling of the bones. Bone marrow biopsy. Since all attempts to obtain a sample of bone marrow by aspiration were unsuccessful, a bone marrow biopsy of the iliac croat was performed. The bone marrow had areas of both hypo- and hypercellularity with reduced numbers of erythroid precursors. Marked diffuse fibrosis and focal collagen fiber formation were present; stainable iron was focally increased. Erythroeyte survival and ferrokinetic studies. The half-time of 51Cr-labeled erythrocytes was 22 days (N = 24-38). External
Volume 84 Number 6
Brief clinical and laboratory observations
86 1
Fig. 1. Diffuse osteosclerosis of pelvis and femurs.
organ counting over spleen, liver, and precordium demonstrated no evidence of abnormal splenic or hepatic erythrocyte sequestration. Ferrokinetic studies were performed in standard fashion 2 following the intravenous injection of 5/xCi of Fe-ferrous citrate which had been incubated with the patient's plasma. At the time of the study, the plasma iron was 123/zg per deciliter and the unbound iron-binding capacity was 228 ~g per deciliter. The plasma iron turnover rate was 33 /.tg per kilogram of body weight per hour (N = 15-25). Erythrocyte iron incorporation was 55 per cent on day 10 (N = 74-89). External counting over liver, spleen, precordium, and sacrum showed a normal pattern except for a slight rise in liver and spleen activity over the first three days. Radionuelide hone marrow imaging. After administration of 5 mCi. of 99mTc-sulfur colloid, bone marrow scan (Fig. 2) showed nonvisualization of the axial and extremity marrow except for a small amount of uptake in the calvaria. Liver and spleen were normal. A marrow scan obtained with 1.5 mCi. of indium-Ill chloride (Fig. 2) demonstrated good uptake throughout the marrow of the skull, axial skeleton, pelvis, femurs, and proximal tibias. A small amount of activity was noted in both liver and spleen. DISCUSSION T h e diagnosis of primary myelofibrosis in our patient is supported by bone m a r r o w biopsy, no e v i d e n c e o f other underlying disease, and the skeletal changes o f osteosclerosis. Osteosclerosis is seen in approximately 50 per c e n t 3' 4 o f a d u l t p a t i e n t s with p r i m a r y
Fig. 2. Representative images from the ]]]In-chloride and 99mTc-sulfur colloid bone marrow studies. The tllln images demonstrate good radio-pharmaceutical concentration in the skull, axial marrow, and peripheral marrow. There is a very poor localization of 99mTc-sulfur colloid in the axial marrow and femurs and only slight activity in the calvarium. These findings suggest a disparity between the hernatopoietic and reticuloendothelial functions of the marrow in this patient.
myelofibrosis, but has n e v e r been reported in a child to our knowledge. Myeloid metaplasia and splenomegaly are prominent features of myelofibrosis in adult patients.4Spleno megaly may develop prior to m a j o r marrow fibrosis and can even be present during a stage of marrow byperplasia.4The normal-sized spleen in our patient is a m o s t unusual finding. T h e r e is no reported experience with the use of both 11qn-chloride and 99mTc-sulfur colloid in the evaluation of patients with myelofibrosis. Nonvisualization of the bone marrow, after injections o f 99mTc-sulfur colloid, reflects dysfunction of the phagocytic reticuloendothelial bone marrow. Since bone m a r r o w scans with sulfur col-
862
Brief clinical and laboratory observations
loids do n o t assess hematopoietic bone marrow, other radionuclides, such as llqn-chloride, have been developed. The validity of r a i n as an agent for scanning hematopoietic bone marrow is still debatable. Although m l n binds t o transferrin in vitro, s studies in animals showed that i n d i u m was not incorporated into hemoglobin 6, 7 and n o r m a l accumulation occurred in bone marrow after irradiation i n j u r y ? However, clinical studies have d e m o n strated the usefulness of r a i n as an agent for b o n e marrow s c a n n i n g . D e c r e a s e d to a b s e n t r a i n u p t a k e with n o r m a l 99mTc-sulfur colloid uptake in bone marrow was observed in patients,with pure red blood cell aplasia 9 and leukemia w i t h a n e m i a ] The disparity between l l q n and 99mTc uptake in our patierit suggests abnormal phagocytic function of the reticuloendothelial marrow with preservation of hematopoietic activity. This interpretation of the i n d i u m scan is supported by the finding of an increased p l a s m a iron turnover. Our patient has few clinical features in c o m m o n with either myelofibrosis in childhood or the adult form of the disease. Perhaps his disease process is different from that of myelofibrosis with myeloid metaplasia. We are grateful to Dr. Esmail D. Zanjani, Mount Sinai School of Medicine, for performing the erythropoietin assay.
The Journal of Pediatrics June 1974
REFERENCES 1. Say, B., and Berkel, I.: Idiopathic myelofibrosis in an infant, J. PEDIATR.64: 580, 1964. 2. Weinstein, I. M.: Disorders of hematopoiesis, the reticuloendothial system, and the spleen, in Blahd, W. H., editor: Nuclear medicine, New York, 1971, McGraw-Hill Book Company, Inc. 3. Pettigrew, J. D., and Ward, H. P.: Correlation of radiologic, histologic and clinical findings in agnogenic myeloid metaplasia, Radiology 93: 541, 1969. 4. Wintrobe, M. M.: Clinical hematology, ed. 6, Philadelphia, 1967, Lea & Febiger, Publishers, p. 770. 5. Lilien, D. L., Berger, H. G., Anderson, D. P., and Bennett, L. R.: rain-chloride: a new agent for bone marrow imaging, J. Nucl. Med. 14: 184, 1973. 6. Beamish, M. R., and Brown, E. B.: A comparison of the in vitro and in vivo behavior of 59Fel141n-and 59Fe-chloride in the rat, J. Clin. Invest. 52: 7a, 1973 (abst.). 7. Farrer, P. A., Saha, G. B., and Katz, M.: Further observations on the use of mln-transferrin for the visualization of bone marrow in man, J. Nucl. Med. 14: 394, 1973 (abst.). 8. McIntyre, P. A., Larson, S. M., Scheffel, U., et al.: Comparison of metabolism of iron-transferrin and indiumtransferrin by erythropoietic marrow, J. Nucl. Med. 14: 425, 1973 (abst.). 9. Staub, R. T., and Gaston, E.: rain-chloride distribution and kinetics in hematologic disease, J. Nucl. Med. 14: 456, 1973 (abst.).
Cervical cord compression in diastrophic dwarfism IrwinJ. Kash, M.D.,* Pittsburgh, Pa., ShashikantM. Sane, M.D., Minneapolis, Minn., Frederick J. Samaha, M.D., Pittsburgh, Pa., and Jakob Briner, M.D., Switzerland
D IASTROPH1C DWARFISM was first described in 1960 by L a m y and Maroteaux. 1 Since then, m o r e than 30 cases have been reported. The typical features include dwarfism, abnormal spinal curvature, micromelia, distinctive h a n d deformities, clubfeet, multiple joint contractures and/or subluxations, cleft or high-arched palate, and swelling of the external ears? "4 Despite the occurrence of kyphosis a n d subluxation of cervical verFrom the Departments of Pediatrics, Pathology, and Radiology, University of Pittsburgh School of Medicine. *Reprint address: Children's Hospital of Pittsburgh, 125 DeSoto St., Pittsburgh,Pa. 15213.
Fig. 1. Lateral view of the cervical spine showing marked dorsal kyphosis with small sized vertebral bodies of C 3, C 4, and C 5.