Osteogenic Sarcoma Associated With Diamond[ndash]Blackfan... : Journal of Pediatric Hematology/Oncology (original) (raw)
Diamond[ndash]Blackfan anemia (DBA) is a rare pure red cell aplasia, predominantly of infancy and childhood (1). Although the actuarial risk of cancer is unknown, malignancy has been reported in a number of patients with DBA. The majority of these malignancies have been hematopoietic, primarily of myeloid origin (2). However, rare solid tumors have also been identified, including two cases of osteogenic sarcoma (2,3). We now describe three additional patients with osteogenic sarcoma reported to the Diamond[ndash]Blackfan Anemia Registry of North America (DBAR) (4).
METHODS
The DBAR of North America was established in 1993 to collect demographic, laboratory, and clinical data on patients with DBA in the United States and Canada. Enrollment has been solicited through outreach to pediatric hematologists and family groups. After informed consent is obtained, patients are enrolled in the DBAR and complete a detailed questionnaire with the help of their physician. Deceased patients may be enrolled anonymously by their physician. Additional specific information is provided by a review of available medical records. Pathology reports are reviewed for cases of malignancy reported to the DBAR. Telephone interviews are periodically conducted with the patient and/or their family and their physician to clarify and update information. Patients are excluded from the data analysis if they do not meet established diagnostic criteria for DBA as described by Diamond et al. (5).
RESULTS
As of December 31, 1999, 354 patients have been enrolled in the DBAR. An analysis of the number of patients enrolled, as a function of their year of birth (Fig. 1), reveals only rare patients enrolled who were born between 1949 and 1967 (median 1.0 [plusmn] 1.4 cases/yr of birth). Between the years 1968 and 1977, 1978 and 1987, and between 1988 and 1997, there were a median of 5.0 [plusmn] 3.3, 11.0 [plusmn] 2.7, and 17.0 [plusmn] 2.4 cases per year of birth enrolled for each decade, respectively. Data from the French registry, established in 1984, reveal an incidence of DBA of 7.3 cases per million live births (3). If the incidence of DBA in France and North America are assumed to be the same, the expected number of cases per year in North America would be approximately 31. Thus, caution must currently be observed when using the DBAR, only opened to enrollment in 1993, for an actuarial analysis of events. In particular, fatal events are likely to be underreported because a posthumous enrollment is less likely to occur than that for a living patient. Therefore, no actuarial risk of osteogenic sarcoma in patients with DBA can be ascertained at this time.
Analysis of the number of patients enrolled in the DBAR as a function of the patient's year of birth.
A review of the cases of malignancy (2,3,6[ndash]20) in patients with DBA described in the literature is presented in Table 1. Five cases of osteogenic sarcoma, two from the literature (patients 8 and 9) and three (patients 24, 25, and 26) reported to the DBAR (unique patient identification number [lsqb]UPIN[rsqb] 143, 200, and 354) are presented in Table 2. Case reports for the patients with osteogenic sarcoma are provided later in this article. Three other patients with DBA with cancer (patients 27, 28, and 29); one with myelodysplastic syndrome (UPIN 100), one with colon carcinoma (UPIN 159), and one with a soft tissue sarcoma (UPIN 185), are also briefly reported (Table 3).
Malignancy in patients with Diamond[ndash]Blackfan anemia reported in the literature
Osteogenic sarcoma in five patients with Diamond[ndash]Blackfan anemia
Other malignancies in patients with Diamond[ndash]Blackfan anemia from the DBAR
CASE REPORTS
Unique Patient Identification Number 143
Patient 143 had severe anemia at birth (Hb 7.2 g/dL). He was the product of a full-term, normal pregnancy, labor, and delivery, born to a 35-year-old primigravida mother. There is no family history of hematologic disease. His maternal grandmother had bone cancer of unspecified type as an adult, the paternal grandfather had gastric carcinoma, and the paternal grandmother had breast carcinoma. A bone marrow aspirate showed marked erythroid hypoplasia (myeloid-erythroid ratio [lsqb]M[colon]E[rsqb] [equals] 13.8[colon]1) with intact maturation of all other cell lines. A diagnosis of DBA was made at age 4-weeks-old. These congenital anomalies, in addition to short stature, were documented over the course of time[colon] ventricular septal defect, inguinal and umbilical hernias, anterior pituitary hypoplasia and an anomaly of the medial aspect of the left carpals, and a small navicula. The patient initially responded to corticosteroids; however, pseudotumor cerebri developed and corticosteroids were discontinued. The patient was thereafter maintained on chronic red cell transfusions and deferoxamine chelation. He remained in acceptable iron balance (ferritin [sim]1,500 [mgr]g/L). A trial of IL-3 was unsuccessful. At 14-years-old, the patient was treated for growth hormone deficiency with recombinant human growth hormone and testosterone. Hypothyroidism was treated with thyroxine. At 22-years-old, the patient had pain in the upper left region of his hard palate. A biopsy revealed high-grade osteogenic sarcoma, chondroblastic type, for which a radical left maxillectomy was performed with positive margins in the mandible, coronoid process, vertical pterygoid plate, and hard palate. The patient underwent postoperative external beam radiation therapy. A local recurrence in the left orbital area was discovered shortly after the completion of radiation therapy. He received chemotherapy with cisplatin and doxorubicin. The chemotherapy was complicated by severe neutropenia. He died from sepsis 3 weeks after the initiation of chemotherapy.
Unique Patient Identification Number 200
Patient 200 was delivered to a primigravida mother via emergency cesarean section at 38 weeks gestation because of hydrops fetalis. The hematocrit was 14[percnt] at birth. There is no family history of hematologic or oncologic disease. An aunt and a cousin both have hypothyroidism and receive replacement therapy. A bone marrow aspirate showed the absence of erythroid precursors with intact maturation of all other cell lines. A diagnosis of DBA was made. In addition to short stature and hypothyroidism, the patient had a bifid right fourth rib. There was no response to either prednisone or dexamethasone. Chronic red cell transfusions were instituted. He remained in good iron balance (ferritin [sim]1,000 [mgr]g/L) before stem cell transplantation. At 1.5-years-old, the patient underwent a successful cord blood transplantation from a serologically human leukocyte antigen-mismatched unrelated donor. The preparatory regimen consisted of busulfan, cyclophosphamide, and total body irradiation (750 cGy in a single fraction). Graft-versus-host disease prophylaxis included cyclosporine A and methylprednisolone. After transplantation, graft-versus-host disease of the gut was diagnosed. There was no skin or liver graft-versus-host disease. One year after transplantation, the patient was administered thyroxine for hypothyroidism and growth hormone for short stature. At 4-years-old, the patient had pain in the left distal femur and high-grade osteogenic sarcoma was diagnosed. Initial treatment was with high-dose methotrexate. Because of the extensive nature of the tumor and a pathologic fracture at the tumor site, an above-knee amputation was performed with negative margins. Adjuvant chemotherapy consisted of high-dose methotrexate, cisplatin, and doxorubicin. Despite dose modifications, complications from chemotherapy included severe mucositis with resulting esophageal stricture, candidiasis, and episodes of fever and neutropenia. The chemotherapy was discontinued early. Multiple bilateral pulmonary, pericardial, and metastatic brain lesions were found, 1 year after the initiation of chemotherapy, from which the patient died.
Unique Patient Identification Number 354
Patient 354 was a 2,870-g product of a full-term, normal pregnancy, labor, and delivery to a 22-year-old primigravida mother. Her initial complete blood count revealed a hemoglobin of 6.9 g/dL, mean corpuscular volume of 112.5 fL, and a reticulocyte count of 0.2[percnt]. There is no family history of hematologic or oncologic disease with the exception of an episode of transfusion-requiring anemia at 22 years of age in a now-85-year-old great-grandmother. A bone marrow aspirate showed marked erythroid hypoplasia (M[colon]E [equals] 5.6[colon]1) with maturational arrest. Other cell lines were intact. A diagnosis of DBA was made. The only documented congenital abnormalities were umbilical and right inguinal hernias. She responded initially to prednisone (3[ndash]4 mg/kg per day) but could not be weaned to less than 1 to 2 mg/kg per day. She was unresponsive to cyclosporine A (initiated at age 9 months). At 14-months-old, rickets was diagnosed, attributed to steroids and exclusive breast-feeding. Corticosteroids were discontinued at 22-months-old because of her cushingoid appearance. Other complications of therapy included non-A/non-B hepatitis at age 27 months (later found to be positive for hepatitis C). By 4-years-old, she had significant iron overload (ferritin 5, 160 [mgr]g/L) and nightly subcutaneous infusions of deferoxamine were started. Serum ferritin levels fluctuated between 2,000 and 4,000 [mgr]g/L. A trial of oxymetholone and prednisone was unsuccessful at 3.5-years-old, as was another trial of corticosteroids at age 9-years-old. At 13-years-old, the patient had a 4-week history of pain, swelling, and decreased range of motion of her right knee with inability to bear weight. A biopsy showed a high-grade osteogenic sarcoma of the right proximal tibia. Chest computed tomography scan revealed approximately 10 small (1-cm) pulmonary nodules bilaterally. Chemotherapy was initiated consisting of doxorubicin with dexrazoxane, cisplatin, high-dose methotrexate, ifosfamide, and etoposide. Induction treatment proceeded without significant delays. At limb-salvage surgery, performed 3 months after diagnosis, 100[percnt] necrosis of the primary tumor was noted. Postoperatively, chemotherapy with methotrexate, doxorubicin (with dexrazoxane), and cisplatin was reinstituted. Delayed platelet recovery resulted in significant treatment delays. Four months after limb-sparing surgery and one cycle of chemotherapy (two doses of methotrexate, one course of cisplatin/doxorubicin), a computed tomography scan revealed an increase in the size of the pulmonary nodules. Thrombocytopenia limited timely administration of additional chemotherapy. The pulmonary lesions continued to progress. No further chemotherapy was administered and the patient died 3 months later from metastatic disease.
DISCUSSION
The association of acute nonlymphocytic leukemia and myelodysplastic syndrome with DBA has been reported in 10 patients (Table 1). Indeed, as DBA is now recognized to result from an intrinsic hematopoietic progenitor defect (21), the association with myeloid malignancy is not unexpected. However, in 1996, Aquino and Buchanan (2) reported, in a 5-year-old, the first case of osteogenic sarcoma in a patient with DBA and suggested that the association of these two rare conditions was likely more than a chance occurrence. The presence of osteogenic sarcoma in a second patient in the literature (3) and in three additional patients reported to the DBAR, with one presenting in the first decade of life, appears to confirm the existence of such an association. Whereas two of the five patients were younger than 10-years-old at the time of the diagnosis of osteogenic sarcoma and one died at age 10 years, 11 months (age at diagnosis not reported), the median ages for patients with DBA with acute nonlymphocytic leukemia and myelodysplastic syndrome and for those with all malignancies reported in the literature are each 22 years (range 1 yr, 2 mos[ndash]43 yrs), respectively (Table 1). Therefore, if the analysis of patients enrolled versus year of birth (Fig. 1) is examined, assuming that posthumous enrollments are less likely, it is probable that the DBAR is not sufficiently mature to capture the majority of malignancies occurring in patients after the first decade of life. The presence of three additional cases of osteogenic sarcoma, one in a patient younger than 10-years-old, suggests that the prevalence of osteogenic sarcoma in older patients with DBA could be underestimated, but that the onset of osteogenic sarcoma in, or near, the first decade of life may be a particular feature of the syndrome (2). The immaturity of the database may also explain the identification of only three other malignancies in patients reported to the DBAR.
A number of the published case reports (Table 1) cite iron overload, androgen use, immunosuppression secondary to corticosteroid treatment, and, in one patient, cyclophosphamide administration as factors contributing to malignancy in DBA patients. Two patients (UPIN 143 and 354) did receive androgen therapy before the development of osteogenic sarcoma and one of these (UPIN 354) was positive for hepatitis C. Another patient (UPIN 200) had osteogenic sarcoma develop during the aftermath of a hematopoietic stem cell transplantation with a preparatory regimen containing busulfan, cyclophosphamide, and total body irradiation. Thus, although there is a clear association of hepatocellular carcinoma with hepatic hemosiderosis, hepatitis C, and androgen therapy, there is no evidence, as mentioned by van Dijken and Verwijs (14), to suggest an otherwise increased incidence of nonhematopoietic cancer in patients with iron overload (22). These malignancies do not appear to be a consequence of relatively low-dose corticosteroid or androgen therapy. Osteogenic sarcoma has not been reported as a stem cell transplant-related complication in patients with severe aplastic anemia (23[ndash]25). However, neither total body irradiation nor androgen therapy can be ruled out as contributing factors in patients with a genetic predisposition to malignancy. In addition, the hypothetical risk for recombinant human growth hormone (26) used to treat short stature in patients with DBA (UPIN 143 and 200) now needs to be carefully considered in view of the predisposition to osteogenic sarcoma in these patients.
An increased risk for osteogenic sarcoma has been reported in three genetic disorders[colon] hereditary retinoblastoma (27), Li[ndash]Fraumeni syndrome (28), and Rothmund[ndash]Thomson syndrome (29). Diamond[ndash]Blackfan anemia should be added to this list.
Cells from patients with Rothmund[ndash]Thomson syndrome, a disorder characterized by skeletal and cutaneous abnormalities and premature aging, show genomic instability, perhaps leading to the observed malignant predisposition (30). In contrast, hereditary retinoblastoma and Li[ndash]Fraumeni syndromes occur as a consequence of germline mutations of the tumor suppressor genes RB1 (13q14) (31) and p53 (17p13) (32), respectively. When tumors from patients with osteogenic sarcoma were examined for genomic loss of constitutional heterozygosity, the chromosomal arms with the most frequent loss of constitutional heterozygosity (greater than 60[percnt] of tumors) were 13q/RB1 (67.6[percnt]) and 17p/p53 (71.4[percnt]), as well as 3q (75[percnt]) and 18q (63.6[percnt]) (33). Therefore, a multihit cause, with loss of constitutional heterozygosity in osteogenic sarcoma at these loci, is consistent with the predisposition to osteogenic sarcoma in patients with germline mutations in RB1 and p53. It is thus likely that both 3q and 18q are also loci for novel tumor suppressor genes (33).
Two DBA genes, DBA1 and DBA2, have been localized by linkage analysis to 19q13.2(34) and 8p23.2[ndash]23.1(35) in approximately 25[percnt] and 40[percnt] of DBA families, respectively. DBA1 has been cloned and codes for a ribosomal protein of unclear function, RPS 19 (36). The percentage of tumors from patients with osteogenic sarcoma found to have loss of constitutional heterozygosity at 8p (10[percnt]) is low (33). Thus, the lack of linkage of a tumor suppressor gene to 8p is probable. However, linkage to 19q (33[percnt] of tumors with loss of constitutional heterozygosity) is possible and this locus must be evaluated.
Recently, Kruzelock et al. described a subchromosomal region of 3q that contains a putative tumor suppressor gene (37). They proposed Cornelia deLange syndrome (38), not associated with osteogenic sarcoma but associated with marked skeletal dysmorphology and already mapped to this region, as possibly linked to the 3q tumor suppressor locus (37). Linkage of this locus at 3q26.2[ndash]3q26.3 to DBA should be considered.
An increased risk for cancer in patients with DBA appears to be a relatively rare but significant feature of the syndrome. Twenty-nine patients with DBA are now known to have had a malignancy develop, in particular, acute nonlymphocytic leukemia and myelodysplastic syndrome (11 cases) and osteogenic sarcoma (five cases). The cases of osteogenic sarcoma have occurred at an uncharacteristically young age in three of the five cases reported. Two of three patients from the DBAR and one of the two patients reported in the literature (2) had subtle orthopedic anomalies and short stature. Two of the three patients had hypothyroidism. In one patient, there was a history of familial hypothyroidism. An unusually large percentage, three of five patients, had metastatic disease develop. Although these cases of osteogenic sarcoma, as well as the two previously reported, appear to have occurred in patients with sporadic cases of DBA a detailed evaluation of each kindred for [ldquo]silent phenotypes[rdquo] (subtle anemia, macrocytosis, increased fetal hemoglobin, and increased erythrocyte adenosine deaminase activity) could not be performed. The response of DBA to corticosteroids in these patients was varied, with two of five responding initially to treatment. These findings emphasize the need for a careful genotypic analysis of DBA patients with cancer and their families. As additional DBA genes are identified, it is probable that the risk of cancer for specific DBA genotypes and factors modifying that risk will be defined. Also, insights into new [ldquo]cancer genes[rdquo] will no doubt unfold as this enigmatic disorder, first described more than 60 years ago (38), is investigated at the molecular level.
REFERENCES
1. Lipton JM, Alter BP. Diamond Blackfan anemia. In[colon] Feig SA, Freedman MH, eds. Clinical Disorders and Experimental Models of Erythropoietic Failure Boca Raton, FL[colon] CRC Press Inc., 1993[colon]39[ndash]67.
2. Aquino VM, Buchanan GR. Osteogenic sarcoma in a child with transfusion-dependent Diamond-Blackfan anemia. J Pediatr Hematol Oncol 1996; 18[colon]230[ndash]2.
3. Willig T-N, Niemeyer CM, Leblanc T, et al. Identification of new prognosis factors from the clinical and epidemiologic analysis of a registry of 229 Diamond-Blackfan anemia patients. Pediatr Res 1999; 46[colon]553[ndash]61.
4. Vlachos A, Alter B, Buchanan G, et al. The Diamond Blackfan Anemia Registry (DBAR)[colon] Preliminary data [lsqb]abstract[rsqb]. Blood 1993; 82[colon]339a.
5. Diamond LK, Wang WC, Alter BP. Congenital hypoplastic anemia. Adv Pediatr 1976; 22[colon]349[ndash]78.
6. Steinherz PG, Canale VC, Miller DR. Hepatocellular carcinoma, transfusion induced hemochromatosis and congenital hypoplastic anemia (Diamond-Blackfan syndrome). Am J Med 1976; 60[colon]1032[ndash]4.
7. Seip M. Malignant tumors in two patients with Diamond-Blackfan anemia treated with corticosteroids and androgens. Pediatr Hematol Oncol 1994; 11[colon]423[ndash]6.
8. Janov A, Leong T, Nathan DG, et al. Diamond Blackfan anemia. Natural history and sequelae of treatment. Medicine (Baltimore) 1996; 75[colon]77[ndash]87.
9. Greinix HT, Storb R, Sanders JE, et al. Long-term survival and cure after marrow transplantation for congenital hypoplastic anaemia (Diamond[ndash]Blackfan syndrome). Br J Haematol 1993; 84[colon]515[ndash]20.
10. Turcotte R, Bard C, Marton D, et al. Malignant fibrous histiocytoma in a patient with Blackfan-Diamond anemia. Can Assoc Radiol J 1994; 45[colon]402[ndash]4.
11. D'Oelsnitz ML, Vincent L, DeSwarte M, et al. A propos d'un cas de leucemie apres guerison d'une maladie de Blackfan-Diamond. Arch Fr Pediatr 1975; 32[colon]582.
12. Hayashi AK, Kang YS, Smith BM. Non-Hodgkin's lymphoma in a patient with Diamond-Blackfan anemia. Am J Radiol 1998; 73[colon]117[ndash]8.
13. Frappaz, D, Richard O, Perrot S, et al. Maladie de Blackfan Diamond et malignite[colon] relations de cause a effet? P[eacute]diatrie 1992; 47[colon]535[ndash]40.
14. van Dikjen PJ, Verwijs W. Diamond-Blackfan anemia and malignancy. A case report and a review of the literature. Cancer 1995; 76[colon]517[ndash]20.
15. Krishnan EU, Wegner K, Garg SK. Congenital hypoplastic anemia terminating in acute promyelocytic leukemia. Pediatrics 1978; 61[colon]898[ndash]901.
16. Wasser JS, Yolken R, Miller DR, et al. Congenital hypoplastic anemia (Diamond-Blackfan syndrome) terminating in acute myelogenous leukemia. Blood 1978; 51[colon]991[ndash]5.
17. Basso G, Cocito MG, Refubbi L, et al. Congenital hypoplastic anemia developed in acute megakaryoblastic leukemia. Helv Paediatr Acta 1981; 36[colon]267[ndash]70.
18. Glader BE, Flam MS, Dahl GV, et al. Hematologic malignancies in Diamond-Blackfan anemia [lsqb]abstract[rsqb]. Pediatr Res 1990; 27[colon]142A.
19. Mori PG, Haupt R, Fugazza G, et al. Pentasomy 21 in leukemia complicating Diamond Blackfan anemia. Cancer Genet Cytogenet 1992; 63[colon]70[ndash]2.
20. Alter BP, Young NS. The bone marrow failure syndromes. In[colon] Nathan DG, Oski FA, eds. Hematology of Infancy and Childhood. 4th ed. Philadelphia[colon] W.B. Saunders, 1991[colon]263[ndash]70.
21. Perdahl EB, Naprstek BL, Wallace WC, et al. Erythroid failure in Diamond-Blackfan anemia is characterized by apoptosis. Blood 1994; 83[colon]645[ndash]50.
22. Zurlo MG, DeStefano P, Borgna[ndash]Pignatti C, et al. Survival and causes of death in thalassemia major. Lancet 1989; 2[colon]27[ndash]30.
23. Socie G, Henry-Amar M, Cosset JM, et al. Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia. Blood 1991; 78[colon]277[ndash]9.
24. Witherspoon RP, Storb R, Pepe M, et al. Cumulative incidence of secondary solid malignant tumors in aplastic anemia patients given marrow grafts after conditioning with chemotherapy alone. Blood 1992; 79[colon]289[ndash]92.
25. Socie G, Henry-Amar M, Bacigalupo A, et al. Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med 1993; 329[colon]1152[ndash]7.
26. Scheven BA, Hamilton NJ, Fakkeldij TM, et al. Effects of recombinant human insulin-like growth factor I and II (IGF-I/-II) and growth hormone (GH) on the growth of normal adult human osteoblast-like cells and human osteogenic sarcoma cells. Growth Regul 1991; 1[colon]160[ndash]7.
27. Hansen MF, Koutos A, Gallie BL, et al. Osteosarcoma and retinoblastoma[colon] a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci USA 1985; 82[colon]6216[ndash]20.
28. Toguchida J, Yamaguchi T, Ritchie B, et al. Mutation spectrum of the p53 gene in bone and soft tissue sarcoma. Cancer Res 1992; 52[colon]6194[ndash]9.
29. Cumin I, Cohen JY, David A, et al. Rothmund-Thomson syndrome and osteosarcoma. Med Pediatr Oncol 1996; 26[colon]414[ndash]6.
30. Kerr B, Ashcroft GS, Scott D, et al. Rothmund-Thomson syndrome[colon] two case reports show heterogeneous cutaneous abnormalities, an association with genetically programmed aging changes, and increased chromosomal radiosensitivity. J Med Genet 1996; 33[colon]928[ndash]34.
31. Friend SH, Horowitz JM, Gerber MR, et al. Deletions of DNA sequences in retinoblastoma and mesenchymal tumors[colon] organization of the sequence and its encoded protein. Proc Natl Acad Sci USA 1987; 84[colon]9059[ndash]63.
32. McIntyre JF, Smith-Sorensen B, Friend SH, et al. Germline mutations of the p53 tumor suppression gene in children with osteosarcoma J Clin Oncol 1994; 12[colon]925[ndash]30.
33. Yamaguchi T, Toguchida J, Yamamuro T, et al. Allelotype analysis in osteosarcoma[colon] frequent allele loss on 3q, 13q, 17p and 18q. Cancer Res 1992; 52[colon]2419[ndash]23.
34. Gustavsson P, Willig T-N, van Haeringen A, et al. Diamond-Blackfan anemia[colon] genetic homogenecity for a gene on chromosome 19q13 restricted to 1.8 Mb. Nat Genet 1997; 16[colon]368[ndash]71.
35. Gazda H, Lipton JM, Niemeyer CM, et al. Evidence for linkage of familial Diamond Blackfan anemia to chromosome 8p23.2[ndash]23.1 and non-19q non-8p disease [lsqb]abstract[rsqb]. Blood 1999; 94[colon]673a.
36. Draptchinskaia N, Gustavsson P, Anderson B, et al. The ribosomal protein S19 gene is mutated in Diamond-Blackfan anemia. Nat Genet 1999; 21[colon]169[ndash]75.
37. Kruzelock RP, Murphy EC, Strong LC, et al. Localization of a novel tumor suppressor loci on human chromosome 3q important in osteosarcoma tumorigenesis. Cancer Res 1997; 57[colon]106[ndash]9.
38. Ireland M, English C, Cross I, et al. A de novo translocation t(3;17) (q26.3;q23.1) in a child with Cornelia deLange syndrome. J Med Genet 1991; 28[colon]639[ndash]40.
39. Diamond LK, Blackfan KD. Hypoplastic anemia. Am J Dis Child 1938; 56;464[ndash]7.
Keywords:
Diamond-Blackfan anemia; Malignancy; Osteogenic sarcoma
© 2001 Lippincott Williams & Wilkins, Inc.