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Neonatal manifestations of congenital dyserythropoietic anemia type I
manifestations of congenital poietic anemia type I [annab Tamary, MD, Dina Shaft, Msc, Peretz Reznitsky, ~ID, and Rtha Zaizov, MIJ
Congenital dyserythropoietie anemia type I is a rare inherited bone marrow disorder characterized by macrocytlc anemia with pathognomonic morphological ultrastructural features in erythroid precursors. The disease is usually not diagnosed in the neonatal period. In a retrospective study of 31 patients we found that 17 were first seen in the neonatal age with significant anemia (birth hematocAt 0.34 +_0.07); 14 of the 17 infants also had early jaundice. Six infants were small for gestational age and two had syndactyly. Although rare, congenital dyserythropoietic anemia type I should be considered in the differential diagnosis of neonatal anemia. (J Pediatr 1997;131:95-7)
Congenital dyserythropoietic anemia is a rare group of disorders characterized by ineffective erythropoiesis, pathognomonic cytopathologic fmdings of the nucleated erythroeytes in bone marrow, and secondary hemoehromatosis. 1 In 1968 Heimpel and Wendt2 classified these disorders into three types. Congenital dyserythropoiefic anemia type I is characterized by megaloblastoid erythroid hyperplasia and the presence in bone marrow of nuclear ehromafin bridges between erythroblasts. Bone marrow dectron microscopy of erythroid precursors displays spongy-appearing nuclei with extensive disruption of nuclear membranes and invaginafion of cytoplasm into the nuclear area? Type II CDA is characterized by cryFrom the Division of Pediatrics, Soroka Medical Center, Beer Sheva;the Department of PediatricHematology Oacology, SehneaOerCbildrenb Medical Centerof lsrae~ Beih~son Campus, Petab Tiqva;Saekler Faculty of MeOicine, TelAviv University, TelAviv; and Efrati ResearchInstitute for Blood Ce[[sand Cytology,Kaplan Hosfita~ Rehovot, Israel
Submitted for publicationJune 5, 1996;accepted Oct. 18, 1996. Reprint requests: H. Tamary,MD, Departmentof Pediatric HematologyOncology,Schneider Children's Medical Center of Israel, Beilinson Campus, Petah Tiqva49202, Israel. Copyright© 1997by Mosby-YearBook,Inc. 0022-3476/97/$5.00 + 0 9/21/78815
throblastic multinucleaAty and positive acidified serum test results (HEMPAS anemia), and type Ill by macrocytosis and erythroblastic multinuelearity with gigantoblasts. In type IV disease, the bone marrow morphologie findings resemble those in type II, b u t the acid serum test result is negative. Unclassified CDAs have also been reported, some manifesting as hydrops fetalis.4"8 Congenital dyserythropoietic anemia type I is an autosomal recessive macrocytic anemia. About 80 cases have been deseabed in the literature, including 20 by our group. & 9 Anemia, jaundice, or both are usually noted in infancy, childhood or adolescence, and occasionally at an older age.l, 8 Only a few cases of C D A type I have been diagnosed in early infancy 10' 11; however, in our previous study we observed that many patients with C D A were first seen in the neonatal period. 9 This article describes the clinical and laboratory manifestations of CDA type I in the neonatal period.
METHODS We retrospectively studied 51 children from seven Bedouin families in whom CDA type I was diagnosed and who were
followed at Soroka Medical Center. Twenty patients were included in our original report9; seven have been born since then, and four had newly diagnosed disease. Most of the clinical and laboratory data have been described? Results of the physical examination and laboratory studies, and the course of disease during the first month of life were reviewed. Early jaundice was defined as serum bilirubin >5 mg/dl in the first 24 hours of life. Complete blood cell count, folio acid measurement, vitamin B12, Coombs test, liver function tests, osmotic fragility, and serologic studies for determination of viral infections were performed according to standard techniques. 12 Diagnosis was b a s e d on the presence of macroeyfic anemia and typical bone marrow findings including large erythroblasts with incomplete nuclear division and a chromatin bridge connecting the nuclei of two cells. In each patient the diagnosis of CDA type I was confirmed by bone marrow electron microscopy, with findings of spongy heterochromatin, enlargement of nuclear pores, and invaglnafion of cytoplasm into the nuclear area.
RESULTS Of the 31 patients with C D A type I, 17 (55%) had symptoms during the neonatal period, although the diagnosis was delayed in the majority of cases. The clinical data for these 17 neonates are summarized in Table I. All had a significantly decreased hematocrit at birth (0.349 _+0.072,
95
THE JOURNAL OF PEDIATRICS JULY 1997
SHALFV ET AL.
Table L Clinical manifestations of CDA type I in the neonatal period (n = 17)
Table IL Current clinical manifestation of CDA type I in 15 of 17 original neonates
normal range 0.61 ± 0.074), with normal mean corpuscular volume for age (110 to 118 fl) and reficulocyte count (2% to 14%). Peripheral blood smears displayed numerous nucleated erythrocytes. Fourteen of the 17 patients (82%) had early jaundice. Osmotic fragility test results, glucose-6-phosphate dehydrogenase activity, folie acid level, and vitamin B12 levels were all within normal range. Results of Coombs test, acidified serum hemolysis test, and serologic tests for viral infections were negative. Fifteen of 17 neonates (88%, or 48% of the 31 with C D A type I) required 1 or more blood transfusions during the first month of life (12 required 1 transfusion, 2 required 2 transfusions, and 1 required 6 transfusions), and all of the patients needed blood transfusions within the next 3 months of life. All but two became transfusion-independent thereafter. One of the two patients requiring constant blood transfusions underwent splenectomy at the age of 4 years and the other at the age of 51/2years. Eleven infants (65%) had transient hepatosplenomegaly. Abnormal liver function was detected in three of five examined
96
neonates. Two neonates had transient left ventricular hypertrophy and one had congestive heart failure. One neonate had ventricular septal defect and one had patent ductus arteriosus. Six infants (35%) were small for gestational age. Two (12%) had syndactyly. Fifteen of the 17 original neonates were recently reevaluated. The current median age is 6 years (range 1 to 16 years); the clinical manifestations are summarized in Table II. All patients had moderate macrocytic anemia (hemoglobin 8.6 _+2.3 gm/dl, mean corpuscular volume 92 +_8 fl), and 19 (67%) required additional blood transfusions after the neonatal period (8 patients, 1 to 4 transfusions; 2 patients, monthly blood transfusions until spleneetomy at age 4 and 51/2years).
DISCUSSION Type I CDA is a rare, moderate to severe macrocytic anemia of unknown cause with pathognomonic ultrastructural findings in erythroid bone marrow precursors. We recently described the clinical and laboratory manifestations in a large
group of such patients and suggested that the electron microscopy bone marrow ~'mdings resemble those in apoptosis. 10 Although CDA type I is considered a congenital disease, most cases are diagnosed during infancy, childhood, and adolescence, and only rarely during the neonatal period. 12-14 However, in this study we found that more than half the patients had symptoms during this period and required blood transfusions. The early anemia was accompanied by jaundice, hepatosplenomegaly, and, in one patient, congestive heart failure. Most of the children improved during the first year of life. Although high mean corpuscular volume is the hallmark of C D A type I, it was not prominent in our neonatal patients with the disease. Interestingly, there are also several reports of hydrops fetalis in CDA, although not in type I.4-8 Two of our infants had syndactyly. Five cases of C D A type I associated with skeletal abnormalities have been previously reported, 1' 14 including three with abnormalities in the distal extremities, three with syndactyly, and two with lack of distal phalanges. Skeletal limb defects are also seen in other inherited marrow disorders, such as Fanconi anemia, Diamond-Blackfan anemia, and thromboeytopenia with absent radii. 8 Another manifestation of inherited bone marrow disorders, found also in CDA type 1, is small size for gestational age, which was observed in 35% of the patients in this study. However, growth does improve in most; 16 of the 20 patients in our earlier work had a normal mean height for age. 8 In summary, we found that at least half of our 31 patients with CDA type I have anemia and jaundice in the neonatal period. Therefore CDA type I should also be considered in the differential diagnosis of neonatal anemia. Skeletal llmb deformities and small size for gestational age are further indications of this rare disease.
REFERENCES 1. Heimpel H. Congenital dyserythropoiefic anemia type I: cliniea| and experiemental
THE JOURNAL OF PEDIATRICS Volume 13 I, Number I, Part I
2.
3.
4.
5.
SHALEV ET AL.
aspects. In: Congenital disorders of dyserythropoiesis, Ciba Foundation Symposium 37. Amsterdam: Elsevier; 1973. p. 135-50. Heimpel H, Wen& E Congenitaldyserythrepoietie anemia with karyorrhexis and multinudearity. Helv IViedActa 1968;34:103-15. Lewis SM, Frisch B. Congenital dyserythropnietie anemia: electron microscopy. In: Congenital disorders of erythropoiesis; Ciba Foundation Symposium 37. Amsterdam: Elsevier; 1973. p. 171-205. Roberts D J, Nadel A, Lage J, Rutherford CJ. An unusual variant of congenital dyserythropoietic anemia with mild maternal and lethal fetal disease. Br J Haematol 1993;84:549-51. Williams G, Lorimer S, Merry CC, Greenberg CR, Bishop AJ. A variant congenital dyserytliropoietic anemia presenting as a fatal hydrops foetalis. Br J Haematol
1990;76:438-9.
i|
I
i|
~1
6. Carter C, Darbyshire PJ, Wickramasinghe SN. A congenital dyserythropoiefic anemia variant presenting as hydrops foetalls. Br J Haematol 1989;72:289-90. 7. Kristiansen JD, Rasmussen LN, Vetner M. Congenital dyserythropoietic anemia (CDA) with intrauterine symptoms and early lethal outcome. Eur J Haematol 1990;45:113-4. 8. Alter BE Young NS. The bone marrow failure syndromes. In: Nathan D J, Oski FA, editors. Hematology of infancy and childhood, vol 1. Philadelphia: WB Saunders; 1993. p. 273-7. 9. Tamary H, Shalev H, Luria D, Shaft D, Zoldan M, Shalmon L, et al. Clinical features and studies of erythropoiesis in Israeli Bedouins with congenital dyserythropoietic anemia. Blood 1996;87:1763-70. 10. Lay HN, Pemberton P J, Hilton HB. Congenital dyserythropoietic anemia type
i
i|
Ill
i
11.
12.
13.
14.
i|
I in two brothers presenting with neonatal jaundice. Arch Dis Child 1978;53:7535. Zald M, Hassanein AA, Daoud AS, Saleh Q. Congenitaldyserythropoietic anemia in children: report of three cases from Kuwait. Ann Trop Paediatr 1989;9:16I-4. Williams W J, Beutler E, Erslev AJ, Lichtman MA. Hematology. New York: McGraw Hill; 1990. p. 1695-738. Holmberg L, Jansson L, Raasiag A, Henriksson P. Type 1 congenital dyserythropoietic anemia with myelopoietic abnormalities and hand malformations. Scand J Haematol 1978;21:72-9. Brichard B, Vermylen J, Scheiff JM, Michaux L, Ninane J, Cornu G. Two cases of congenital dyserythropoietc anemia type I associated with unusual skeletal abnormalities of the limbs. Br J Haematol 1994;86:201-2.
i|
i_
50 Years Ago in The Journal of Pediatrics The Treatment of Acute Poliomyelitis, Together With Some Suggestions on Diagnosis Stinz~on P. J Pediatr 1947;31:82-92.
q
q
Before Sahin and Salk, this article reviewed the management of acute poliomyelitis, as practiced in 1947. The importance of keeping the airway free of secretions was emphasized, and early administration of oxygen was recommended. Nutrition was recognized as an important issue, and nasogastric feeding was considered a significant advance. Some measures, such as use of respiratory stimulants and intravenously administered hypertonic glucose to reduce edema of the central nervous system, would not be used today. On the other hand, mechanical ventilation was discussed at some length but, without the availability of the pulse oximeter or arterial blood gas determinations, evaluation of respiratory failure was by clinical assessment. The author of this article was not in favor of using artificial respirators early because of concerns about aspiration (unless the patient had a tracheotomy), increased risk of atelectasis, and the possibility of psychologic dependency. The issue of residual disabilities was addressed, and it was thought that psychologic counseling could help the patient move "from an old, familiar room to a new room which must be furnished as best one can." It is interesting to reflect that, within several years, effective vaccines would be developed and that the large summer epidemics of poliomyelitis, serried ranks of iron lungs, and "ventilator rooms" would become a memory.
Robert W. Wilmott, MD Division of Pulmonary Medicine, Allergy, and Immunology Children's Hospital Medical Center Cincinnat£ 0H45229-3039
97
Congenital dyserythropoietie anemia type I is a rare inherited bone marrow disorder characterized by macrocytlc anemia with pathognomonic morphological ultrastructural features in erythroid precursors. The disease is usually not diagnosed in the neonatal period. In a retrospective study of 31 patients we found that 17 were first seen in the neonatal age with significant anemia (birth hematocAt 0.34 +_0.07); 14 of the 17 infants also had early jaundice. Six infants were small for gestational age and two had syndactyly. Although rare, congenital dyserythropoietic anemia type I should be considered in the differential diagnosis of neonatal anemia. (J Pediatr 1997;131:95-7)
Congenital dyserythropoietic anemia is a rare group of disorders characterized by ineffective erythropoiesis, pathognomonic cytopathologic fmdings of the nucleated erythroeytes in bone marrow, and secondary hemoehromatosis. 1 In 1968 Heimpel and Wendt2 classified these disorders into three types. Congenital dyserythropoiefic anemia type I is characterized by megaloblastoid erythroid hyperplasia and the presence in bone marrow of nuclear ehromafin bridges between erythroblasts. Bone marrow dectron microscopy of erythroid precursors displays spongy-appearing nuclei with extensive disruption of nuclear membranes and invaginafion of cytoplasm into the nuclear area? Type II CDA is characterized by cryFrom the Division of Pediatrics, Soroka Medical Center, Beer Sheva;the Department of PediatricHematology Oacology, SehneaOerCbildrenb Medical Centerof lsrae~ Beih~son Campus, Petab Tiqva;Saekler Faculty of MeOicine, TelAviv University, TelAviv; and Efrati ResearchInstitute for Blood Ce[[sand Cytology,Kaplan Hosfita~ Rehovot, Israel
Submitted for publicationJune 5, 1996;accepted Oct. 18, 1996. Reprint requests: H. Tamary,MD, Departmentof Pediatric HematologyOncology,Schneider Children's Medical Center of Israel, Beilinson Campus, Petah Tiqva49202, Israel. Copyright© 1997by Mosby-YearBook,Inc. 0022-3476/97/$5.00 + 0 9/21/78815
throblastic multinucleaAty and positive acidified serum test results (HEMPAS anemia), and type Ill by macrocytosis and erythroblastic multinuelearity with gigantoblasts. In type IV disease, the bone marrow morphologie findings resemble those in type II, b u t the acid serum test result is negative. Unclassified CDAs have also been reported, some manifesting as hydrops fetalis.4"8 Congenital dyserythropoietic anemia type I is an autosomal recessive macrocytic anemia. About 80 cases have been deseabed in the literature, including 20 by our group. & 9 Anemia, jaundice, or both are usually noted in infancy, childhood or adolescence, and occasionally at an older age.l, 8 Only a few cases of C D A type I have been diagnosed in early infancy 10' 11; however, in our previous study we observed that many patients with C D A were first seen in the neonatal period. 9 This article describes the clinical and laboratory manifestations of CDA type I in the neonatal period.
METHODS We retrospectively studied 51 children from seven Bedouin families in whom CDA type I was diagnosed and who were
followed at Soroka Medical Center. Twenty patients were included in our original report9; seven have been born since then, and four had newly diagnosed disease. Most of the clinical and laboratory data have been described? Results of the physical examination and laboratory studies, and the course of disease during the first month of life were reviewed. Early jaundice was defined as serum bilirubin >5 mg/dl in the first 24 hours of life. Complete blood cell count, folio acid measurement, vitamin B12, Coombs test, liver function tests, osmotic fragility, and serologic studies for determination of viral infections were performed according to standard techniques. 12 Diagnosis was b a s e d on the presence of macroeyfic anemia and typical bone marrow findings including large erythroblasts with incomplete nuclear division and a chromatin bridge connecting the nuclei of two cells. In each patient the diagnosis of CDA type I was confirmed by bone marrow electron microscopy, with findings of spongy heterochromatin, enlargement of nuclear pores, and invaglnafion of cytoplasm into the nuclear area.
RESULTS Of the 31 patients with C D A type I, 17 (55%) had symptoms during the neonatal period, although the diagnosis was delayed in the majority of cases. The clinical data for these 17 neonates are summarized in Table I. All had a significantly decreased hematocrit at birth (0.349 _+0.072,
95
THE JOURNAL OF PEDIATRICS JULY 1997
SHALFV ET AL.
Table L Clinical manifestations of CDA type I in the neonatal period (n = 17)
Table IL Current clinical manifestation of CDA type I in 15 of 17 original neonates
normal range 0.61 ± 0.074), with normal mean corpuscular volume for age (110 to 118 fl) and reficulocyte count (2% to 14%). Peripheral blood smears displayed numerous nucleated erythrocytes. Fourteen of the 17 patients (82%) had early jaundice. Osmotic fragility test results, glucose-6-phosphate dehydrogenase activity, folie acid level, and vitamin B12 levels were all within normal range. Results of Coombs test, acidified serum hemolysis test, and serologic tests for viral infections were negative. Fifteen of 17 neonates (88%, or 48% of the 31 with C D A type I) required 1 or more blood transfusions during the first month of life (12 required 1 transfusion, 2 required 2 transfusions, and 1 required 6 transfusions), and all of the patients needed blood transfusions within the next 3 months of life. All but two became transfusion-independent thereafter. One of the two patients requiring constant blood transfusions underwent splenectomy at the age of 4 years and the other at the age of 51/2years. Eleven infants (65%) had transient hepatosplenomegaly. Abnormal liver function was detected in three of five examined
96
neonates. Two neonates had transient left ventricular hypertrophy and one had congestive heart failure. One neonate had ventricular septal defect and one had patent ductus arteriosus. Six infants (35%) were small for gestational age. Two (12%) had syndactyly. Fifteen of the 17 original neonates were recently reevaluated. The current median age is 6 years (range 1 to 16 years); the clinical manifestations are summarized in Table II. All patients had moderate macrocytic anemia (hemoglobin 8.6 _+2.3 gm/dl, mean corpuscular volume 92 +_8 fl), and 19 (67%) required additional blood transfusions after the neonatal period (8 patients, 1 to 4 transfusions; 2 patients, monthly blood transfusions until spleneetomy at age 4 and 51/2years).
DISCUSSION Type I CDA is a rare, moderate to severe macrocytic anemia of unknown cause with pathognomonic ultrastructural findings in erythroid bone marrow precursors. We recently described the clinical and laboratory manifestations in a large
group of such patients and suggested that the electron microscopy bone marrow ~'mdings resemble those in apoptosis. 10 Although CDA type I is considered a congenital disease, most cases are diagnosed during infancy, childhood, and adolescence, and only rarely during the neonatal period. 12-14 However, in this study we found that more than half the patients had symptoms during this period and required blood transfusions. The early anemia was accompanied by jaundice, hepatosplenomegaly, and, in one patient, congestive heart failure. Most of the children improved during the first year of life. Although high mean corpuscular volume is the hallmark of C D A type I, it was not prominent in our neonatal patients with the disease. Interestingly, there are also several reports of hydrops fetalis in CDA, although not in type I.4-8 Two of our infants had syndactyly. Five cases of C D A type I associated with skeletal abnormalities have been previously reported, 1' 14 including three with abnormalities in the distal extremities, three with syndactyly, and two with lack of distal phalanges. Skeletal limb defects are also seen in other inherited marrow disorders, such as Fanconi anemia, Diamond-Blackfan anemia, and thromboeytopenia with absent radii. 8 Another manifestation of inherited bone marrow disorders, found also in CDA type 1, is small size for gestational age, which was observed in 35% of the patients in this study. However, growth does improve in most; 16 of the 20 patients in our earlier work had a normal mean height for age. 8 In summary, we found that at least half of our 31 patients with CDA type I have anemia and jaundice in the neonatal period. Therefore CDA type I should also be considered in the differential diagnosis of neonatal anemia. Skeletal llmb deformities and small size for gestational age are further indications of this rare disease.
REFERENCES 1. Heimpel H. Congenital dyserythropoiefic anemia type I: cliniea| and experiemental
THE JOURNAL OF PEDIATRICS Volume 13 I, Number I, Part I
2.
3.
4.
5.
SHALEV ET AL.
aspects. In: Congenital disorders of dyserythropoiesis, Ciba Foundation Symposium 37. Amsterdam: Elsevier; 1973. p. 135-50. Heimpel H, Wen& E Congenitaldyserythrepoietie anemia with karyorrhexis and multinudearity. Helv IViedActa 1968;34:103-15. Lewis SM, Frisch B. Congenital dyserythropnietie anemia: electron microscopy. In: Congenital disorders of erythropoiesis; Ciba Foundation Symposium 37. Amsterdam: Elsevier; 1973. p. 171-205. Roberts D J, Nadel A, Lage J, Rutherford CJ. An unusual variant of congenital dyserythropoietic anemia with mild maternal and lethal fetal disease. Br J Haematol 1993;84:549-51. Williams G, Lorimer S, Merry CC, Greenberg CR, Bishop AJ. A variant congenital dyserytliropoietic anemia presenting as a fatal hydrops foetalis. Br J Haematol
1990;76:438-9.
i|
I
i|
~1
6. Carter C, Darbyshire PJ, Wickramasinghe SN. A congenital dyserythropoiefic anemia variant presenting as hydrops foetalls. Br J Haematol 1989;72:289-90. 7. Kristiansen JD, Rasmussen LN, Vetner M. Congenital dyserythropoietic anemia (CDA) with intrauterine symptoms and early lethal outcome. Eur J Haematol 1990;45:113-4. 8. Alter BE Young NS. The bone marrow failure syndromes. In: Nathan D J, Oski FA, editors. Hematology of infancy and childhood, vol 1. Philadelphia: WB Saunders; 1993. p. 273-7. 9. Tamary H, Shalev H, Luria D, Shaft D, Zoldan M, Shalmon L, et al. Clinical features and studies of erythropoiesis in Israeli Bedouins with congenital dyserythropoietic anemia. Blood 1996;87:1763-70. 10. Lay HN, Pemberton P J, Hilton HB. Congenital dyserythropoietic anemia type
i
i|
Ill
i
11.
12.
13.
14.
i|
I in two brothers presenting with neonatal jaundice. Arch Dis Child 1978;53:7535. Zald M, Hassanein AA, Daoud AS, Saleh Q. Congenitaldyserythropoietic anemia in children: report of three cases from Kuwait. Ann Trop Paediatr 1989;9:16I-4. Williams W J, Beutler E, Erslev AJ, Lichtman MA. Hematology. New York: McGraw Hill; 1990. p. 1695-738. Holmberg L, Jansson L, Raasiag A, Henriksson P. Type 1 congenital dyserythropoietic anemia with myelopoietic abnormalities and hand malformations. Scand J Haematol 1978;21:72-9. Brichard B, Vermylen J, Scheiff JM, Michaux L, Ninane J, Cornu G. Two cases of congenital dyserythropoietc anemia type I associated with unusual skeletal abnormalities of the limbs. Br J Haematol 1994;86:201-2.
i|
i_
50 Years Ago in The Journal of Pediatrics The Treatment of Acute Poliomyelitis, Together With Some Suggestions on Diagnosis Stinz~on P. J Pediatr 1947;31:82-92.
q
q
Before Sahin and Salk, this article reviewed the management of acute poliomyelitis, as practiced in 1947. The importance of keeping the airway free of secretions was emphasized, and early administration of oxygen was recommended. Nutrition was recognized as an important issue, and nasogastric feeding was considered a significant advance. Some measures, such as use of respiratory stimulants and intravenously administered hypertonic glucose to reduce edema of the central nervous system, would not be used today. On the other hand, mechanical ventilation was discussed at some length but, without the availability of the pulse oximeter or arterial blood gas determinations, evaluation of respiratory failure was by clinical assessment. The author of this article was not in favor of using artificial respirators early because of concerns about aspiration (unless the patient had a tracheotomy), increased risk of atelectasis, and the possibility of psychologic dependency. The issue of residual disabilities was addressed, and it was thought that psychologic counseling could help the patient move "from an old, familiar room to a new room which must be furnished as best one can." It is interesting to reflect that, within several years, effective vaccines would be developed and that the large summer epidemics of poliomyelitis, serried ranks of iron lungs, and "ventilator rooms" would become a memory.
Robert W. Wilmott, MD Division of Pulmonary Medicine, Allergy, and Immunology Children's Hospital Medical Center Cincinnat£ 0H45229-3039
97