- Email: [email protected]
Myelodysplasia and deficiency of uridine diphosphate–galactose 4-epimerase
The Journal of Pediatrics Volume 127, Number 4
tently elevated aminotransferase values, led to cirrhosis in this patient during a period of 5 years. The severe recurrent hypoglycemia and complete absence of PK enzyme also possibly contributed to the hepatic insult leading to cirrhosis. We thank Professor Frederick J Suchy for reviewing the manuscript, his constructive critism, and his editorial comments. REFERENCES
1. Hug G, Schubert WK, Chuck G. Phosphorylase kinase of the liver: deficiency in a girl with increased hepatic glycogen. Science 1966;153:1534-5. 2. Huijing F, Femandes J. X-chromosomal inheritance of liver glycogenosis with phosphorylase ldnase deficiency. Am J Hum Genet i969;21:275-83. 3. Schimke RN, Zakheim RM, Corder RC, Hug G. Glycogen storage disease type IX: benign glycogenosis of liver and hepatic phosphorylase kinase deficiency. J PEDIATR 1973;83: 1031-4. 4. Lemer A, Iancu TC, Bashan N, Potashnik R, Moses S. A new variant of glycogen storage disease: type IXc. Am J Dis Child 1982; 136:406-10.
Rosoff
605
5. Hug G. Glycogen storage disease. In: Berhman RE, Kleigman RM, Nelson WE, Vaughan VC lII, eds. Nelson textbook of pediatrics. 14th ed. Philadelphia: WB Saunders, 1992:370-1. 6. Van den Berg IET, Berger R. Phosphorylase b kinase deficiency in man: a review. J Inher Metab Dis 1990;13:442-51. 7. Smit GPA, Fernandes J, Leonard JV, et al. The long-term outcome of patients with glycogen storage diseases. J Inher Metab Dis 1990;13:411-8. 8. Shin YS. Diagnosis of glycogen storage disease. J Inher Metab Dis 1990;13:419-34. 9. Hers HG, Hoof FV, Barsy T. Glycogen storage diseases In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:425-51. 10. Starzl TE, Putnam CW, Porter KA, et al. Portal diversion for the treatment of glycogen disease in humans. Ann Surg 1973; 178:525-39. 11. Momoi T, Sano H, Yamanaka C, Sasaki H, Mikawa H. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am J Med Genet 1992;42:696-9. 12. Markowitz AJ, Chen YT, Muenzer J, Delbuono EA, Lucey MR. A man with type IB glycogenosis associated with cirrhosis andportalhypertension. Gastroenterology 1993; 105:1882-5.
Myelodysplasia and deficiency of uridine diphosphate-galactose 4-epimerase Philip M. Rosoff, MD a From the Depaffments of Medicine and Pediatrics (Divisions of Hematology-Oncology) and Physiology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusells
A 4-year-old girl known to have peripheral uridine diphosphate-galactose 4-epimerase deficiency was examined for bruising and thrombocytopenia. She had dysplastic peripheral blood and bone marrow changes, with a global platelet function defect. Uridine diphosphate-galactose-4-epimerase participates in a metabolic pathway that provides substrates for posttranslational glycosylation of secreted and membrane glycoproteins, including hematopoietic growth factors and their receptors; there may be a causal relationship between the two disorders. (J PEDIATR1995; 127:605-8)
Submitted for publication March 23, 1995; accepted June 6, 1995. Reprint requests: Philip M. Rosoff, MD, Department of Medicine, Division of Hematology-Oncology, New England Medical Center (Box No. 245), 750 Washington St., Boston, MA 02111.
The myelodysplastic syndromes consist of a distinct category of premalignant disorders that are relatively uncommon MDS UDP
Myelodysplastic syndrome Uridine diphosphate
aScholar'of the Leukemia Society of America. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$5.00 + 0 9/22/66934
in childhood. 1,2 In adults, they most often presage the development of acute nonlymphocytic leukemia. 3 Child-
606
Rosoff
The Journal of Pediatrics October 1995
h
e
f
d
r
i¸ :
g
i¸
h
Figure. Photomicrographs of peripheral blood and bone marrow, a to e, Wright-stained specimens of peripheral blood (magnification: xl000), a, Giant "gray" platelet, b, Pelger-Hu6[ anomaly in polymorphonuclear leukocyte, c, Dysmorphic myeloid circulating progenitor cell with dysplastic nuclear chromatin staining and size, and giant primary granules, d, Transmission electron micrograph of peripheral blood platelet stained with osmium tetroxide (magnification: x25,000), e to h, Bone marrow aspirate specimens stained with Wright-Giemsa stain (magnification: xl000), e, Dysmorphic rnegakaryocyte, f, Trinucleate myeloid progenitor, g, Hematophagocytosis of a polymorphonuClear leukocyte by a myeloid progenitor, h, Hematophagocytosis of a dysplastic myeloid precursor by an enucleated megakaryocyte. CASE REPORT hood MDSs undergo malignant transformation to myeloid leukemias with a frequency similar to that in adults.I, 2 The French-American-British Working Group has classified MDS into five types according to the histologic appearance of the bone marrow. 2 These patients most often have clinical problems consistent with dysplastic or ineffective hematopoiesis, in association with a hypercellular bone marrow, a,2 However, some patients also have significant developmental and physical anomalies with a hypoplastic marrow and rapid progression to acute nonlymphocytic leukemia. 4 The cause or causes of MDS are incompletely understood, although a close association with several acquired cytogenetic abnormalities, particularly monosomy 7,2' 5 suggests that the acquisition Of discrete and accumulated genetic damage may result in a predisposition to the development of MDS. This report describes a patient known to have a form of uridine diphosphate-galactose 4-epimerase deficiency who also had an unclassifiable MDS.
A 6-year-old girl known to have UDP-galactose 4-epimerase deficiency was examined for thrombocytopenia, leukopenia, occasional anemia, and platelet dysfunction, first recognized at the age of 3 years, when she was hospitalized for pneumonia. A complete blood cell count showed leukopenia with neutropenia, a hematocrit of 0.28, and,a platelet count of 35 x 109/L (35,000/mm3). Except for scattered rales, findings of a physical examination were normal. The patient was treated with a cephalosporin and referred to a hematologist for further evaluation. Her parents reported that she had bruised easily since infancy and had occasional bouts of petechiae, although a platelet count had never been obtained. Neonatal blood screening had detected elevated levels of reducing substances. On further evaluation by the Massachusetts State Public Health Laboratories (Dr. Harvey Levy), the patient was found to have "peripheral" UDP-galactose 4-epimerase deficiency because her erythrocytes had undetectable enzymatic activity. She had no clinical manifestations of galactosemia. Her parents and an human leukocyte antigen-identical brother were in excellent health and were found to be heterozygotes with approximately 50% normal enzy-
The Journal of Pediatrics Volume 127, Number 4
matic activity. She had also been followed since birth for a small ventricular septal defect. There was no other history of hematologic problems in her family. Several weeks later, she again had leukopenia (leukocyte count 2.7 x 109/L [2700/mm3]), with a normal differential cell count, a hematocrit of 0.28, and a platelet count of 51 x 109/L (51,000]mm3); she was thought to have bone marrow suppression as a result of a viral infection. At a follow-up visit 1 month later, her hematocrit had normalized to 0.35, but she continued to have leukopenia and thrombocytopenia. Antiplatelet and antinuclear antibodies were not detected. A bone marrow aspirate and biopsy specimen showed 90% cellularity with normal morphologic features. She was thought to have immune thrombocytopenic purpura and was treated with prednisone. Increased platelet-associated IgG or circulating antiplatelet antibodies were not detected. Because of a lack of response, administration of prednisone was stopped after 3 weeks. She was subsequently treated with intravenously administered IgG and bad minimal increases in her platelet counts. Twelve months after the initial evaluation and diagnosis, the patient was referred to the Floating Hospital Hematology Service. She had had no major bleeding episodes, but she did have moderate bruising in her extremities, petechiae, and occasional nosebleeds, which resolved with pressure after about 10 minutes. Physical examination showed both new and old bruises on the extremities, especially the lower. There were also scattered petechiae. There was no hepatosplenomegaly or lymphadenopathy. The leukocyte count was 2.4 x 109/L (2400/mm3), with a differential cell count of 47% nentrophils, 24% lymphocytes, 18% monocytes, and 3% basophils. The hemoglobin level was 115 gm/L, with a hematocrit of 0.33 and a reticulocyte count of 1%. Mean corpuscular volume was 80 ft. Of note were the strikingly large, agranular platelets on a Wrightstained specimen of peripheral blood (Figure); these cells could also be seen in peripheral blood films from the initial presentation. The patient had evidence of the Pelger-Hu~t anomaly in some hypergranulated polymorphonuclear leukocytes, as well as occasional immature and dysplastic myeloid cells; this was thought to have been acquired because neither parent had this finding and not all of her neutrophilic granulocytes were affected. 6 Bone marrow aspirate and a biopsy specimen showed normal cellularity and numbers of megakaryocytes but with dysynchrony of nuclear and cytoplasmic maturation and occasional hemocytophagia (Figure). There was no other evidence suggestive of a hemocytophagic syndrome] Myelofibrosis was not present. Immunophenotyping of the patient's marrow showed a predominant population of CD 10 (CALLA: common acute lymphoblastic leukemia antigen, a marker of early B cells) and CD19/B4 (+) B ceils (60% and 40%, respectively); the karyotype was normal. Further analysis of her platelets showed a global aggregation defect to adenosine diphosphate, epinephrine, collagen, and ristocetin. Electron microscopy of her platelets showed a slight increase in the canalicular system and decreased staining of the granules (Figure), the significance of which was unclear. Hemoglobin F levels were normal. Since evaluation she has been essentially well with no major intercurrent illnesses. She has had at least one episode of profound leukopenia (absolute neutrophil count <0.5 x 109/L [<500/mm3]) and thrombocytopenia (platelet count
Rosoff
607
< 10 x 109/L [< 10,000/pl]) and fever, which spontaneously resolved and was associated with a probable viral syndrome. DISCUSSION This patient had a complete absence of detectable UDPgalactose 4-epimerase activity in her peripheral blood erythrocytes, although she did not have any clinical evidence of galactosemia. This enzyme, encoded by a single genetic locus in mammalian cells,S catalyzes the reversible epimerization reactions converting UDP-ghicose to UDP-galactose and UDP-N-acetylglucose to UDP-N-acetylgalactactose. At the time of this writing, only eight patients have been identified with this "peripheral" type of epimerase deficiency; all of them are free of symptoms, as is our patient, or have normal peripheral blood cell counts (H. Levy: personal communication, 1994). Except for the patient described in this report, none of the other symptom-free patients, nor those with galactosemia, have had any symptoms referable to an MDS. Several reports have described patients with a homozygous epimerase deficiency and clinically severe disease9-11; as in the more common forms of galactosemia, these patients were found to lack hepatic expression of the protein. The patient's hematologic disease has been manifested as thrombocytopenia and leukopenia with qualitative platelet functional and morphologic defects. The latter have been described in MDS. 12, 13 A diagnosis of " g r a y platelet syndrome," which might have been consistent with the patient's global aggregation defect, was entertained initially. However, other features of myelodysplasia (including the Pelger-Hu6t anomaly) in her peripheral blood and the presence of granules detected by ultrastructural examination of her platelets ruled out this diagnosis. The Pelger-Hu6t anomaly can occur as either an autosomal, dominantly inherited abnormality of polymorphonuclear leukocytes without clinical significance, or as an acquired abnormality associated with MDS, as in this patient. 2 Although laboratory data before the initial evaluation of the patient at age 3 years are lacking, the clinical history of easy bruising and petechiae since infancy suggests that the condition is congenital. The platelet count increased slightly after intravenous administration of IgG. One could speculate that this was a result of an inhibition of splenic removal of her abnormal circulating platelets, although a precise explanation is lacking. However, there was insufficient evidence to support a diagnosis of immune thrombocytopenic purpura. In the majority of both children and adults, MDS can be classified by means of the standard criteria. 14 However, many patients remain whose disease cannot be classified with this system, as in this patient. Although the progression
608
Rosoff
to malignant transformation in many patients is rapid and inexorable, the long-term prognosis of other patients is unclear. 15 Furthermore, although this patient's bone marrow karyotype is normal, the acquisition of cytogenetic abnormalities may be progressive before the limit of detection is reached. 2 The occurrence of two such rare conditions in the same patient may be more than coincidental. This enzyme is an important participant in the biochemical pathway providing substrate "building blocks" for the posttranslational addition of carbohydrates to glycoproteins. 16 In many cases of both secreted and membrane glycoproteins, full physiologic function is retained in the absence of glycosylation. However, there are exceptions, including erythropoietin 17 and the low-density !ipoprotein receptor. 18 Thus both extracellular hormonal ligands and plasma membrane receptors may require the addition of a critical carbohydrate structure for biologic activity. The importance of glycosylation in the two examples cited here is particularly relevant to the discussion of this patient, because the experiments to demonstrate glycosylation were performed on a Chinese hamster ovary cell line lacking UDP-galactose 4-epimerase. We have not proved that this patient also lacks enzymatic activity in her other hematopoietic cells; however, it is likely that she does. If so, we may hypothesize that failure to glycosylate one or more critical hematopoietic hormones (or, more likely, their receptors) may lead to myelodysplasia. REFERENCES
1. Grier HE, Civin CL Acute and chronic myeloproliferative disorders and myelodysplasia. In: Nathan DG, Oski FA, eds. Hematology of infancy and childhood. Philadelphia: WB Sannders, 1993:1288-1318. 2. Schwartz CL, Cohen HJ. Myeloproliferative and myelodysplastic syndromes. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. 2nd ed. Philadelphia: JB Lippincott, 1993:519-35. 3. Tricot GJK. The myelodysplasfic syndromes. In: Hoffman R, Benz EJJ, Shattil SJ, Furie B, Cohen HJ; eds. Hematology: basic principles and practice. New York: Churchill Livingstone, 1991:805-17.
The Journal of Pediatrics October 1995
4. Kobrinsky NL, Nesbit ME Jr, Ramsay NKC, Arthur DC, Krivit W, Brunning RD. Hematopoietic dysplasia and marrow hypocellularity in children: a preleukemic condition. J PEDIATR 1982;100:907-13. 5. Luna-Fineman S, Shannon KM, Lange BJ. Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 1995;85:1985-99. 6. Stockman JAI, Ezekowitz A. Hematologic manifestations of systemic diseases. In: Nathan DG, Oski FA, eds. Hematology of infancy and childhood. Philadelphia: WB Sannders, 1993: 1834-85. 7. Ladisch S, Jaffe ES. The histiocytoses. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology~ Philadelphia: JB Lippincott, 1993:617-31. 8. Piller F, Hanlon MH, Hill RL. Co-purification and characterization of UDP-glucose 4-epimerase and UDP-N-acetylglueosamine 4-epimerase from porcine submaxillary glands. J Biol Chem 1983;258:10774-8. 9. Holton JB, Gillett MG, MacFaul R, Young R. Galactosemia: a new severe variant due to uridine disphosphate galactose-4epimerase deficiency. Arch Dis Child 1981;56:885-7. 10. Garibaldi L, Superti-Furga A, Borrone C. Galactosemia caused by generalized uridine disphosphate galactose-4-epimerase deficiency. J PEDIATR1986;109:1074-5. 11. Sardharwalla IB, Waraith JE, Bridge C, Fowler B, Roberts SA. A patient with severe type of epimerase deficiency galactosemia. J Inherit Metah Dis 1988;1 l(suppl 2):249-51. 12. Cowan DH, Graham RCJ, Baunach D. The platelet defect in leukemia. J Clin Invest 1975;56:188-200. 13. Stuart JJ, Lewis JC. Platelet aggregation and electron microscopic studies ofplatelets in preleukemia. Arch Pathol Lab Med 1982;106:458-61. 14. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189-99. 15. Rosoff PM. Congenital bone marrow failure with myelodysplasia in siblings. Am J Pediatr Hematol/Onc 1995;17:56-60. 16. Darnell J, Lodish H, Baltimore D. Molecular cell biology. 2nd ed. New York: Scientific American Press/WH Freeman, 1990. 17. Wasley LC, Timony G, Murtha P, et al. The importance of Nand Oqinked oligosaccharides for the biosynthesis and in vitro and in vivo biologic activities of erythropoietin. Blood 1991 ;77:2642-32. 18. Kingsley DM, Kozarsky KF, Hobbie L, Krieger M. Reversible defects in O-linked glycosylation and LDL receptor expression in a UDP-gal/UPD-galNac 4-epimerase deficient mutant. Cell 1986;44:749-59.
tently elevated aminotransferase values, led to cirrhosis in this patient during a period of 5 years. The severe recurrent hypoglycemia and complete absence of PK enzyme also possibly contributed to the hepatic insult leading to cirrhosis. We thank Professor Frederick J Suchy for reviewing the manuscript, his constructive critism, and his editorial comments. REFERENCES
1. Hug G, Schubert WK, Chuck G. Phosphorylase kinase of the liver: deficiency in a girl with increased hepatic glycogen. Science 1966;153:1534-5. 2. Huijing F, Femandes J. X-chromosomal inheritance of liver glycogenosis with phosphorylase ldnase deficiency. Am J Hum Genet i969;21:275-83. 3. Schimke RN, Zakheim RM, Corder RC, Hug G. Glycogen storage disease type IX: benign glycogenosis of liver and hepatic phosphorylase kinase deficiency. J PEDIATR 1973;83: 1031-4. 4. Lemer A, Iancu TC, Bashan N, Potashnik R, Moses S. A new variant of glycogen storage disease: type IXc. Am J Dis Child 1982; 136:406-10.
Rosoff
605
5. Hug G. Glycogen storage disease. In: Berhman RE, Kleigman RM, Nelson WE, Vaughan VC lII, eds. Nelson textbook of pediatrics. 14th ed. Philadelphia: WB Saunders, 1992:370-1. 6. Van den Berg IET, Berger R. Phosphorylase b kinase deficiency in man: a review. J Inher Metab Dis 1990;13:442-51. 7. Smit GPA, Fernandes J, Leonard JV, et al. The long-term outcome of patients with glycogen storage diseases. J Inher Metab Dis 1990;13:411-8. 8. Shin YS. Diagnosis of glycogen storage disease. J Inher Metab Dis 1990;13:419-34. 9. Hers HG, Hoof FV, Barsy T. Glycogen storage diseases In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989:425-51. 10. Starzl TE, Putnam CW, Porter KA, et al. Portal diversion for the treatment of glycogen disease in humans. Ann Surg 1973; 178:525-39. 11. Momoi T, Sano H, Yamanaka C, Sasaki H, Mikawa H. Glycogen storage disease type III with muscle involvement: reappraisal of phenotypic variability and prognosis. Am J Med Genet 1992;42:696-9. 12. Markowitz AJ, Chen YT, Muenzer J, Delbuono EA, Lucey MR. A man with type IB glycogenosis associated with cirrhosis andportalhypertension. Gastroenterology 1993; 105:1882-5.
Myelodysplasia and deficiency of uridine diphosphate-galactose 4-epimerase Philip M. Rosoff, MD a From the Depaffments of Medicine and Pediatrics (Divisions of Hematology-Oncology) and Physiology, New England Medical Center and Tufts University School of Medicine, Boston, Massachusells
A 4-year-old girl known to have peripheral uridine diphosphate-galactose 4-epimerase deficiency was examined for bruising and thrombocytopenia. She had dysplastic peripheral blood and bone marrow changes, with a global platelet function defect. Uridine diphosphate-galactose-4-epimerase participates in a metabolic pathway that provides substrates for posttranslational glycosylation of secreted and membrane glycoproteins, including hematopoietic growth factors and their receptors; there may be a causal relationship between the two disorders. (J PEDIATR1995; 127:605-8)
Submitted for publication March 23, 1995; accepted June 6, 1995. Reprint requests: Philip M. Rosoff, MD, Department of Medicine, Division of Hematology-Oncology, New England Medical Center (Box No. 245), 750 Washington St., Boston, MA 02111.
The myelodysplastic syndromes consist of a distinct category of premalignant disorders that are relatively uncommon MDS UDP
Myelodysplastic syndrome Uridine diphosphate
aScholar'of the Leukemia Society of America. Copyright © 1995 by Mosby-Year Book, Inc. 0022-3476/95/$5.00 + 0 9/22/66934
in childhood. 1,2 In adults, they most often presage the development of acute nonlymphocytic leukemia. 3 Child-
606
Rosoff
The Journal of Pediatrics October 1995
h
e
f
d
r
i¸ :
g
i¸
h
Figure. Photomicrographs of peripheral blood and bone marrow, a to e, Wright-stained specimens of peripheral blood (magnification: xl000), a, Giant "gray" platelet, b, Pelger-Hu6[ anomaly in polymorphonuclear leukocyte, c, Dysmorphic myeloid circulating progenitor cell with dysplastic nuclear chromatin staining and size, and giant primary granules, d, Transmission electron micrograph of peripheral blood platelet stained with osmium tetroxide (magnification: x25,000), e to h, Bone marrow aspirate specimens stained with Wright-Giemsa stain (magnification: xl000), e, Dysmorphic rnegakaryocyte, f, Trinucleate myeloid progenitor, g, Hematophagocytosis of a polymorphonuClear leukocyte by a myeloid progenitor, h, Hematophagocytosis of a dysplastic myeloid precursor by an enucleated megakaryocyte. CASE REPORT hood MDSs undergo malignant transformation to myeloid leukemias with a frequency similar to that in adults.I, 2 The French-American-British Working Group has classified MDS into five types according to the histologic appearance of the bone marrow. 2 These patients most often have clinical problems consistent with dysplastic or ineffective hematopoiesis, in association with a hypercellular bone marrow, a,2 However, some patients also have significant developmental and physical anomalies with a hypoplastic marrow and rapid progression to acute nonlymphocytic leukemia. 4 The cause or causes of MDS are incompletely understood, although a close association with several acquired cytogenetic abnormalities, particularly monosomy 7,2' 5 suggests that the acquisition Of discrete and accumulated genetic damage may result in a predisposition to the development of MDS. This report describes a patient known to have a form of uridine diphosphate-galactose 4-epimerase deficiency who also had an unclassifiable MDS.
A 6-year-old girl known to have UDP-galactose 4-epimerase deficiency was examined for thrombocytopenia, leukopenia, occasional anemia, and platelet dysfunction, first recognized at the age of 3 years, when she was hospitalized for pneumonia. A complete blood cell count showed leukopenia with neutropenia, a hematocrit of 0.28, and,a platelet count of 35 x 109/L (35,000/mm3). Except for scattered rales, findings of a physical examination were normal. The patient was treated with a cephalosporin and referred to a hematologist for further evaluation. Her parents reported that she had bruised easily since infancy and had occasional bouts of petechiae, although a platelet count had never been obtained. Neonatal blood screening had detected elevated levels of reducing substances. On further evaluation by the Massachusetts State Public Health Laboratories (Dr. Harvey Levy), the patient was found to have "peripheral" UDP-galactose 4-epimerase deficiency because her erythrocytes had undetectable enzymatic activity. She had no clinical manifestations of galactosemia. Her parents and an human leukocyte antigen-identical brother were in excellent health and were found to be heterozygotes with approximately 50% normal enzy-
The Journal of Pediatrics Volume 127, Number 4
matic activity. She had also been followed since birth for a small ventricular septal defect. There was no other history of hematologic problems in her family. Several weeks later, she again had leukopenia (leukocyte count 2.7 x 109/L [2700/mm3]), with a normal differential cell count, a hematocrit of 0.28, and a platelet count of 51 x 109/L (51,000]mm3); she was thought to have bone marrow suppression as a result of a viral infection. At a follow-up visit 1 month later, her hematocrit had normalized to 0.35, but she continued to have leukopenia and thrombocytopenia. Antiplatelet and antinuclear antibodies were not detected. A bone marrow aspirate and biopsy specimen showed 90% cellularity with normal morphologic features. She was thought to have immune thrombocytopenic purpura and was treated with prednisone. Increased platelet-associated IgG or circulating antiplatelet antibodies were not detected. Because of a lack of response, administration of prednisone was stopped after 3 weeks. She was subsequently treated with intravenously administered IgG and bad minimal increases in her platelet counts. Twelve months after the initial evaluation and diagnosis, the patient was referred to the Floating Hospital Hematology Service. She had had no major bleeding episodes, but she did have moderate bruising in her extremities, petechiae, and occasional nosebleeds, which resolved with pressure after about 10 minutes. Physical examination showed both new and old bruises on the extremities, especially the lower. There were also scattered petechiae. There was no hepatosplenomegaly or lymphadenopathy. The leukocyte count was 2.4 x 109/L (2400/mm3), with a differential cell count of 47% nentrophils, 24% lymphocytes, 18% monocytes, and 3% basophils. The hemoglobin level was 115 gm/L, with a hematocrit of 0.33 and a reticulocyte count of 1%. Mean corpuscular volume was 80 ft. Of note were the strikingly large, agranular platelets on a Wrightstained specimen of peripheral blood (Figure); these cells could also be seen in peripheral blood films from the initial presentation. The patient had evidence of the Pelger-Hu~t anomaly in some hypergranulated polymorphonuclear leukocytes, as well as occasional immature and dysplastic myeloid cells; this was thought to have been acquired because neither parent had this finding and not all of her neutrophilic granulocytes were affected. 6 Bone marrow aspirate and a biopsy specimen showed normal cellularity and numbers of megakaryocytes but with dysynchrony of nuclear and cytoplasmic maturation and occasional hemocytophagia (Figure). There was no other evidence suggestive of a hemocytophagic syndrome] Myelofibrosis was not present. Immunophenotyping of the patient's marrow showed a predominant population of CD 10 (CALLA: common acute lymphoblastic leukemia antigen, a marker of early B cells) and CD19/B4 (+) B ceils (60% and 40%, respectively); the karyotype was normal. Further analysis of her platelets showed a global aggregation defect to adenosine diphosphate, epinephrine, collagen, and ristocetin. Electron microscopy of her platelets showed a slight increase in the canalicular system and decreased staining of the granules (Figure), the significance of which was unclear. Hemoglobin F levels were normal. Since evaluation she has been essentially well with no major intercurrent illnesses. She has had at least one episode of profound leukopenia (absolute neutrophil count <0.5 x 109/L [<500/mm3]) and thrombocytopenia (platelet count
Rosoff
607
< 10 x 109/L [< 10,000/pl]) and fever, which spontaneously resolved and was associated with a probable viral syndrome. DISCUSSION This patient had a complete absence of detectable UDPgalactose 4-epimerase activity in her peripheral blood erythrocytes, although she did not have any clinical evidence of galactosemia. This enzyme, encoded by a single genetic locus in mammalian cells,S catalyzes the reversible epimerization reactions converting UDP-ghicose to UDP-galactose and UDP-N-acetylglucose to UDP-N-acetylgalactactose. At the time of this writing, only eight patients have been identified with this "peripheral" type of epimerase deficiency; all of them are free of symptoms, as is our patient, or have normal peripheral blood cell counts (H. Levy: personal communication, 1994). Except for the patient described in this report, none of the other symptom-free patients, nor those with galactosemia, have had any symptoms referable to an MDS. Several reports have described patients with a homozygous epimerase deficiency and clinically severe disease9-11; as in the more common forms of galactosemia, these patients were found to lack hepatic expression of the protein. The patient's hematologic disease has been manifested as thrombocytopenia and leukopenia with qualitative platelet functional and morphologic defects. The latter have been described in MDS. 12, 13 A diagnosis of " g r a y platelet syndrome," which might have been consistent with the patient's global aggregation defect, was entertained initially. However, other features of myelodysplasia (including the Pelger-Hu6t anomaly) in her peripheral blood and the presence of granules detected by ultrastructural examination of her platelets ruled out this diagnosis. The Pelger-Hu6t anomaly can occur as either an autosomal, dominantly inherited abnormality of polymorphonuclear leukocytes without clinical significance, or as an acquired abnormality associated with MDS, as in this patient. 2 Although laboratory data before the initial evaluation of the patient at age 3 years are lacking, the clinical history of easy bruising and petechiae since infancy suggests that the condition is congenital. The platelet count increased slightly after intravenous administration of IgG. One could speculate that this was a result of an inhibition of splenic removal of her abnormal circulating platelets, although a precise explanation is lacking. However, there was insufficient evidence to support a diagnosis of immune thrombocytopenic purpura. In the majority of both children and adults, MDS can be classified by means of the standard criteria. 14 However, many patients remain whose disease cannot be classified with this system, as in this patient. Although the progression
608
Rosoff
to malignant transformation in many patients is rapid and inexorable, the long-term prognosis of other patients is unclear. 15 Furthermore, although this patient's bone marrow karyotype is normal, the acquisition of cytogenetic abnormalities may be progressive before the limit of detection is reached. 2 The occurrence of two such rare conditions in the same patient may be more than coincidental. This enzyme is an important participant in the biochemical pathway providing substrate "building blocks" for the posttranslational addition of carbohydrates to glycoproteins. 16 In many cases of both secreted and membrane glycoproteins, full physiologic function is retained in the absence of glycosylation. However, there are exceptions, including erythropoietin 17 and the low-density !ipoprotein receptor. 18 Thus both extracellular hormonal ligands and plasma membrane receptors may require the addition of a critical carbohydrate structure for biologic activity. The importance of glycosylation in the two examples cited here is particularly relevant to the discussion of this patient, because the experiments to demonstrate glycosylation were performed on a Chinese hamster ovary cell line lacking UDP-galactose 4-epimerase. We have not proved that this patient also lacks enzymatic activity in her other hematopoietic cells; however, it is likely that she does. If so, we may hypothesize that failure to glycosylate one or more critical hematopoietic hormones (or, more likely, their receptors) may lead to myelodysplasia. REFERENCES
1. Grier HE, Civin CL Acute and chronic myeloproliferative disorders and myelodysplasia. In: Nathan DG, Oski FA, eds. Hematology of infancy and childhood. Philadelphia: WB Sannders, 1993:1288-1318. 2. Schwartz CL, Cohen HJ. Myeloproliferative and myelodysplastic syndromes. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. 2nd ed. Philadelphia: JB Lippincott, 1993:519-35. 3. Tricot GJK. The myelodysplasfic syndromes. In: Hoffman R, Benz EJJ, Shattil SJ, Furie B, Cohen HJ; eds. Hematology: basic principles and practice. New York: Churchill Livingstone, 1991:805-17.
The Journal of Pediatrics October 1995
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