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Case Reports

Indian Pediatrics 2003; 40:355-358

Diamond-Blackfan Anemia: Report of 6 Cases

Mamta Manglani
M.R. Lokeshwar
Ratna Sharma
 

From the Division of Pediatric Hematology-Oncology, Department of Pediatrics, L.T.M.M. College and General Hospital, Sion, Mumbai, India.

Correspondence to: Dr. Mamta Manglani, 51, Sea Springs, B. J. Road, Band Stand, Bandra (W), Mumbai 400 050, India.

Manuscript received: July 22, 2002; Initial review completed: September 19, 2002;
Revision accepted: December 23, 2002.

Diamond-Blackfan anemia is a rare congenital hypoplastic anemia. We report 6 children diagnosed as Diamond-Blackfan anemia at our clinic. All had severe pallor at presentation, with mild hepato-megaly and just palpable spleen in one child. Thumb anomaly was present in one of them. All of them had macrocytic or normocytic anemia with reticulo-cytopenia, and bone marrow examination revealed marked erythroid hypoplasia. All of them were treated with oral steroids with a good response.

Key words: Congenital pure red cell aplasia, Diamond-Blackfan syndrome, Oral steroids.

Diamond-Blackfan anemia (DBA) is a rare congenital hypoplastic anemia that usually presents early in infancy. Congenital anomalies, in particular of the head and upper limbs, are present in 25% of reported patients(1). DBA has also been referred to as congenital pure red cell aplasia, chronic aregenerative anemia, erythrogenesis imper-fecta and congenital hypoplastic anemia(2). The diagnosis of this disease is clinched by the finding of a normochromic, macrocytic or normocytic anemia manifesting early in life, reticulocytopenia, normocellular bone marrow with erythroid hypoplasia. To date, a total of approximately 600 patients have been reported worldwide. 354 patients have been enrolled in the Diamond Blackfan Anemia registry of North America and 229 in the DBA group of France, Germany and eight other countries(3). We report six such cases diagnosed at our clinic.

Case Report

Six children, four males and two females were seen with a history of pallor noticed between two and four months of age (Table I). Four of these patients came with the incorrect diagnosis of iron deficiency anemia (IDA). They presented to us at the age of 7,8,10 and 18 months. One child was clinically diagnosed as thalassemia major elsewhere and was seen at our clinic at 7 months of age, while the 6th child had received a transfusion at the age of two months for anemia with cardiac failure, without any investigations for the cause of anemia. This child came to us at the age of 10 months. All of them had received transfusions ranging from one to four times before being seen at our clinic. There was no history of consanguinity amongst parents and none of the patients had affected siblings. The antenatal and perinatal periods were uneventful in all of them. None of them were small for gestational age at birth.

Table I

Clinical Features and Investigative Findings in Six Patients with Diamond
Blackfan Anemia.
 
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Age at presentation (mo)
7
8
10
18
7
10
Age of 1st symptom (mo)
2
2.5
2.5
3
4
2
Gender
Male
Male
Male
Female
Female
Male
Pallor
Present
Present
Present
Present
Present
Present
Congenital anomalies
Absent
Absent
Absent
Absent
Thumb anomaly
Absent
Hepatomegaly
Yes
Yes
Yes
Yes
Yes
Yes
Splenomegaly
No
No
No
JP
No
No
Hemoglobin (g/dL)
3.0
5.4
3.8
4.4
6.0
4.8
Platelet count (lacs/c.mm)
4.34
3.5
3.68
6.3
5.54
3.5
MCV (fL)
91
98
99
88
79
94
Reticulocyte
0.5
0.6
0.3
0.5
0.8
0.4
HbF (%)
2.5
2.2
5.8
6.8
0.5
8.6
Transferrin saturation (%)
22
38
33
45
53
40
M:E ratio in bone marrow
16:1
16.5:1
20:1
19.5:1
20:1
18:1
JP: Just Palpable.

 

On examination, all had severe pallor and mild hepatomegaly. Spleen was just palpable in one patient. One of the patients had thumb anomaly. No other congenital anomalies were observed during physical examination in any of them. Other systems were normal. Investigations revealed hemoglobin ranging from 3 to 6 g/dL, with a corrected reticulocyte count of less than 1%. The peripheral smear showed macrocytic (4 patients) or normocytic (2 patients) and normochromic anemia with mild anisocytosis. The MCV at diagnosis ranged from 79 to 99 fL. Leucocyte counts were normal in all patients, however, platelet counts were high in 2 patients. All patients had elevated serum iron levels with transferrin saturation ranging between 22 and 53%. Fetal hemoglobin (HbF) was elevated in 5 of them ranging from 2.2% to 8.6%. Only one child had HbF of 0.5%. Skeletal surveys and ultrasonography of the abdomen ruled out any congenital anomalies, except in the one child (case 5) with thumb anomaly. Her X-ray showed an accessory bone in the left thumb with a normal biphalangeal configuration of the right thumb (Fig. 1). Chromosomal studies were normal in the 5 patients, in whom it could be done.

 Fig. 1. X-ray of hands (case 5) showing an accessory bone between the 2 phalangeal bones in the left thumb and normal biphalangeal configuration of the right thumb

The diagnosis was confirmed on bone marrow aspiration and trephine biopsy, which showed marked erythroid hypoplasia with elevated M:E ratio ranging from 16:1 to 20:1. Megakaryopoiesis and myelopoiesis were normal in all. All of them required one transfusion of packed red cells of 5 mL/kg body weight, following which they were given oral prednisolone in the dose of 2 mg/kg body weight/day in three to four divided doses. A good response was noted in all 6 patients with a rise in hemoglobin (6 to 9 g/dL) and reticulocyte counts (1 to 3%) within a preriod of 7 to 10 days of therapy. After the hemoglobin rose to 10 g/dL, they were shifted to alternate day low dose therapy with tapering of the doses. Three patients have been maintaining hemoglobin between 11 and 12.5 g/dL on intermittent low dose alternate day steroid therapy for a median follow-up of 4.3 years (range: 4 to 8 years). Two have sustained remission and are off steroid therapy, after initial therapy for 4 and 8 months each (follow up of 2.3 and 4 years). One patient has been lost to follow up.

Discussion

Congenital pure red cell aplasia was first described by Josephs in 1936 and two years later in 1938, Diamond and Blackfan reported four such cases(2). DBA is usually seen in infancy, although cases have been detected as late as at 6 years of age. The male to female ratio 1.2:1.

Approximately 1/4th to 1/3rd of patients have congenital anomalies involving the upper limbs and the head, and the urogenital or cardiovascular systems. However, the link between these malformations and defective erythropoiesis is unclear and a defect in a molecule acting on both early embryonic development and hematopoiesis has been proposed(4). Most cases are sporadic with inheritance observed in about 10% of patients, with a dominant or, more rarely, recessive pattern. One locus on chromosome 19q13.2 encoding ribosomal protein S19 accounts for a quarter of patients with either the dominant or the sporadic form(1,4). Another locus in association with DBA has been detected on chromosome 8p(5). Families not linked with either of these loci have also been described(4,5).

The basic defect is hypothesized to be a decrease in number or function of erythroid precursors, both the CFU-E and BFU-E(4). A high level of erythropoietin in the serum suggests progenitor insensitivity to erythro-poietin(6). Additionally, immunologic cellular factors have also been considered responsible for the pathogenesis in DBA(7). However, anecdotal studies refute this finding(8).

The closest differential diagnosis of this syndrome is TEC (transient erythro-blastopenia of childhood). However, the mean age of diagnosis of TEC is 26 and 28 months in males and females respectively, whereas that for DBA is 5.2 and 6.6 months(2). MCV is generally normal in TEC and increased in DBA, and a history of preceding viral illness with no congenital anomalies characterize TEC(2). HbF is generally normal at diagnosis in TEC, whereas it is high in DBA. Besides, TEC recovers spontaneously within 1 to 2 months of onset, irrespective of treatment(2).

Red cell transfusions were the only available modality of treatment in the earlier times. Though, it still remains an important form of therapy for those who are refractory to other medications, several newer phar-macologic agents have been found effica-cious. Apart from the conventional oral prednisone (overall response rates of 60% to 70%) and high-dose intravenous methyl-prednisolone, various drugs have been tried with limited success(2). These include androgens, danazol, 6-mercaptopurine, cyclo-phosphamide, antilymphocyte globulin, vincristine etc.(2). Cyclosporine has been tried with conflicting results in different studies(9). Allogeneic stem cell transplanta-tion with HLA-identical related donor has shown promising results, though anecdotal reports of failure have been reported(10). Prenatal diagnosis has been constrained by the fact that DBA is inherited only in 10% of cases.

Acknowledgement

The authors wish to thank Dr. M.E. Yeolekar, Dean, LTMG Hospital and College, Sion, Mumbai for permitting the publication of this manuscript. We also wish to acknowledge the support received from our Head of the Department, Dr. Madhuri Kulkarni during the preparation of this manuscript.

Contributors: MM diagnosed and managed these patients. She prepared the manuscript and finalized the draft. MRL guided in patient care and revised the draft. RS helped in diagnosis and management of these children and assisted in modifying the draft.

Funding: None.

Competing interests: None stated.

REFERENCES

1. Willig TN, Gazda H, Sieff CA. Diamond-Blackfan anemia. Curr Opin Hematol 2000; 7: 85-94.

2. Alter BP, Young NS. The Bone Marrow Failure Syndromes. In: Nathan and Oski’s Hematology of Infancy and Childhood. Eds. Nathan DG, Orkin SH, 5th edn. 1998; pp 238-335.

3. Vlachos A, Klein GW, Lipton JM. The Diamond Blackfan Anemia Registry: tool for investigating the epidemiology and biology of Diamond Blackfan anemia. J Pediatr Hematol Oncol 2001; 23: 377-382.

4. Dianzani I, Garelli E, Ramenghi U. Diamond-Blackfan Anemia: an overview. Pediatr Drugs 2000; 2: 345-355.

5. Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM, Tchernia G et al. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. Blood 2001; 97: 2145-2150.

6. Tsai PH, Arkin S, Lipton JM. An intrinsic progenitor defect in Diamond-Blackfan anemia. Br J Haematol 1989; 73: 112-120.

7. Sawada K, Koyanagawa Y, Sakurama S. Nakagawa S, Konno T. Diamond-Blackfan syndrome: a possible role of cellular factors for erythropoietic suppression. Scand J Hematol 1985; 35: 158-165.

8. Freedman MH, Saunders EF. Diamond-Blackfan syndrome: evidence against cell-mediated erythropoietic suppression. Blood 1978; 51: 1125-1128.

9. Alesandri AJ, Rogers PC, Wadsworth LD, Davis JH. Diamond-Blackfan anemia and cyclosporine therapy revisited. J Pediatr Hematol Oncol 2000; 22: 176-179.

10. Vlachos A, Federman N, Reyes-Haley C, Abramson J, Lipton JM. Hematopoietic stem cell transplantation for Diamond-Blackfan anemia: a report from the Diamond Blackfan Anemia Registry. Bone Marrow Transplant 2001; 27: 381-386.

 

 

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