Table of Contents

HK J Paediatr (New Series)
Vol 1. No. 1, 1996

HK J Paediatr (New Series) 1996;1:53-55

Original Article

Successful Bone Marrow Transplant for Congenital Bone Marrow Failure Syndromes

SY Ha, ACW Lee, CF Chan, RHS Liang, HL Yuen, YL Lau


Dyskeratosis congenita and Diamond-Blackfan syndrome are two rare congenital conditions both characterized by cytopenia due to marrow failure, and special somatic features. We report the successful experience of allogeneic bone marrow transplantation in two patients each with one of the conditions. Both had normal reconstitution of marrow activities and became transfusion independent after transplantation.

Keyword : Bone marrow transplantation; Diamond-Blackfan syndrome; Dyskeratosis congenita

Abstract in Chinese


Bone marrow failure may produce pancytopenia or depression of one or more of the haemopoietic cell lines in the peripheral blood. In addition to the acquired causes of bone marrow depression which are often common to both adults and children, there are a number of rare congenital or constitutional, and frequently inherited causes. Fanconi's anaemia, one of the best known conditions, is autosomal recessively inherited and characterized by aplastic anaemia, various congenital abnormalities, and chromosome fragility.1 Dyskeratosis congenita (DC) is a rare form of ectodermal dysplasia consisting of dystrophic nails, hyperpigmentation and mucosal leukoplakia, often associated with aplastic anaemia.2 DC is usually X-linked recessive in inheritance but autosomal recessive mode has been reported. Isolated red cell aplasia is referred as Diamond-Blackfan syndrome (DBS) when it occurs as a congenital form of marrow failure.' DBS is often sporadic in occurrence but familial cases have been reported. Skeletal or ocular abnormalities may occur in patients with DBS.

Definitive treatment is often not available for the majority of patients with congenital or inherited marrow failure syndromes. Blood component support is indicated when patients are symptomatic as a result of marrow failure. Steroid is however found to be useful in patients with Diamond-Blackfan syndrome if treatment is commenced at an early stage. Growth factors have also been tried in a small number of patients with DC3 and DBS4 with no consistent benefit.

The use of bone marrow transplantation (BMT) in treating DC or DBS have been described with variable results.5-7 Since the availability of bone marrow transplant services at Queen Mary Hospital in 1991, we had transplanted two paediatric patients with congenital bone marrow failure syndromes, one with dyskeratosis congenita and the other with Diamond-Blackfan syndrome. We report here our experience in transplanting them.


Case 1

The girl is the eldest of three daughters of an unconsanguinous couple. She was noted to have pallor complexion and easy bruising since the age of six years. During a hospital admission for pneumonia at the age of eight, she was found to have pancytopenia. Clinical examination revealed presence of dystrophic nails of hands (Fig.) and feet, increased skin pigmentation, and abnormal tongue mucosa which was smooth and discolored in scattered areas. Marrow examination confirmed severe hypoplastic marrow. Fanconi's screen by diepoxybutane (DEB) sensitivity test was negative. There was no obvious secondary cause to account for the aplastic anaemia. The overall picture was consistent with dyskeratosis congenita. An autosomal recessive inheritance is probable in this girl without positive family history of the same disease. She subsequently required blood transfusion at six weeks' intervals. On follow up, white cell count was consistently reduced and the neutrophil count was often below 0.5 x 109/L and platelet count below 20 x 109/L. She was given two months' trial of granulocyte/macrophage colony-stimulating factor (GM-CSF) and erythropoietin with only transient response in the leucocyte count.

The youngest sister was fully compatible in human leucocyte antigens (HLA). She had normal blood count and no features of dyskeratosis congenita. She was observed for 18 more months to confirm that she developed no signs of DC. We then decided to proceed with BMT when the donor was over 6 years of age. The ferritin level of the patient before BMT was 1,874 ng/ml.

Fig Nail dystrophy in the patient with dyskeratosis congenita.

Case 2

Patient was a girl who was noted to be pale soon after birth and was subsequently transfusion-dependent. The diagnosis of Diamond-Blackfan syndrome was made when marrow aspiration showed pure erythroblastopenia. There was no other somatic abnormalities. The subsequent management consisted of regular blood transfusion at six to eight weeks' interval. A course of steroid was tried but she only responded to high-dose prednisolone treatment at 4 mg/kg/day, which was not sustained once the dose was tapered. Consequently she became grossly Cushingoid with stunted growth. She was therefore put back on regular transfusion. A trial of intravenous immunoglobulin infusion did not produce any improvement, nor did a six-week course of cyclosporin A treatment.

Indeed, the latter treatment had to be stopped when she developed gastroenteritis due to Plesiomonas shigelloides.

Her elder sister was fully HLA compatible. At the time of transplantation, the patient had caught up in growth with no obvious signs of iron toxicity. Her serum ferritin level was 1,358 ng/ml. No significant hepatosplenomegaly was detected, but the liver biopsy prior to BMT showed obvious evidence of haemosiderosis. Portal tract fibrosis was absent.

The Transplant

For both patients, cyclophosphamide and antilymphocyte globulin were employed for conditioning. For Case 2 busulfan was given in addition. The same regimen of graft-versus-host (GvHD) prophylaxis were used. In addition to being HLA matched, both transplants were also ABO matched. The details of the transplants were listed in Table.

Both achieved durable engraftment. Case 1 was transfusion independent since Day 28 post-BMT and last platelet transfusion was on Day 16. Bone marrow examination on Day 97 was normal. Blood count checked 12 months post-BMT revealed Hb 14.1 g/dl, WBC 4.2 x 109/L, Neutrophil 1.5x 109/L, Platelet 119 x 109/L. Case 2 engrafted more slowly and granulocyte colony-stimulating factor (G-CSF) had to be employed on Day 28 to Day 31 for augmentation. She received the last blood and platelet transfusions on Day 18 and Day 35 respectively. Marrow examination on Day 21 revealed abundance of erythroblasts. Blood count checked 18 months post-BMT revealed Hb 13.2 g/dl, WBC 9.3 x 109/L, normal differential count, Platelet 261 x 109/L.

Table Details of Bone Marrow Transplant
  Case 1 Case 2
Diagnosis dyskeratosis congenita Diamond-Blackfan syndrome
Sex/age F/9 yr F/4 yr
Conditioning regimen cyclophosphamide 200 mg/Kg
ATG 120 mg/Kg
busulphan 20 mg/Kg
cyclophosphamide 200 mg/Kg
ATG 90 mg/Kg
GCHD prophylaxis cyclosporin A methotrexate cyclosporin A methotrexate
donor/age younger sister/6 yr elder sister/6 yr
Donor's marrow    
MNC* dose x 108/L 4.08 4.93
CFU-GM** x 104/Kg 3.67 8.83
neutrophil >500 x 109/L post BMT D25 D29
platelet > 20 x 109/L post BMT D17 D35
Outcome normal Hb, WBC, mild thrombocytopenia transfusion independent
Follow up 12 months 18 months
* MNC: mononuclear cell
** CFU-GM: colony forming unit-granulocyte/macrophage

Case 1 had no GvHD. Case 2 had mild acute GvHD in form of mild skin rash (grade II) which subsided gradually with cyclosporin treatment. The gut and liver were not involved. She developed diarrhea on first day of transplant and fever on D3 which did not respond to vancomycin, ceftazidime and amikacin treatment. Subsequent blood culture yielded Listeria monocytogenes which responded to intravenous ampicillin. This infectious complication has already been reported.8 During the last follow up, both patients were well with no significant complications or chronic GvHD as a result of the transplant.


Bone marrow transplantation has found indications in a diverse varieties of neoplastic and non-neoplastic conditions. For acquired aplastic anaemia, there is consensus that allogeneic BMT is the treatment of choice for severe or very severe cases although the use of immunosuppressive agents with antilymphocyte globulin, cyclosporin and growth factor have provided more encouraging results recently.9

For congenital marrow failure, the role of BMT is less well defined probably due to rarity of the disease and also unknown pathogenesis. It has been shown that the haemopoietic stem cells were defective in dyskeratosis congenita.10 It appears logical that immunosuppressive agents will not be useful as in acquired aplastic anemia. Diamond-Blackfan is less rarely seen than DC. Steroid works in a significant proportion of patients although its mechanism of its effectiveness is still uncertain. The use of BMT has been reported with success in a proportion of affected patients.6,8

For our two patients the haematological indications for BMT were evident. The patient with DC had blood picture similar to that of severe aplastic anemia. The patient with DBS were transfusion dependent and suffered from significant steroid side effects. The considerations against BMT in Case 1 are perhaps the possible carcinogenic effects from the use of cytotoxics for conditioning in a patient who already has had a predisposition to development of malignancy and the unpredictable long term outcome of the underlying condition. For both cases the possibility of BMT related mortality and morbidity needed to be considered.

Different conditioning regimens have been used and there are at the moment no consensus as to what is the best. In Case 1 we have used a standard regimen frequently employed for patient with severe aplastic anaemia. In Case 2 we used a regimen similar to the one we are using for patients with thalassemia major. In our experience, the use of antilymphocyte globulin, which aimed at depleting the recipient's lymphocytes, appears to be an essential component for reducing the chance of graft rejection and securing engraftment. There were no major complications associated with the BMT procedure in our two patients.

In conclusion, bone marrow transplantation is a feasible option for curing the aplastic anaemia associated with the two congenital marrow failure syndromes namely dyskeratosis congenita and Diamond-Blackfan syndrome. The regimens we employed in the two patients were effective and safe.


1. Alter BP, Young NS. The bone marrow failure syndromes. In: Nathan DG & Oski FA. Haematology of Infancy and Childhood, 4nd edn, W.B. Saunders, Philadephia 1993;216-316.

2. Brachtman RA, Alter BP. Dyskeratosis congenita clinical and genetic heterogeneity. Report of a new case and review of the literature. Am I Pediatr Hematol Oncol 1992;14:297-304.

3. Pritchard SL, Junker AK. Positive response to granulocytecolony-stimulating factor in dyskeratosis congenita before matched unrelated bone marrow transplantation. Am I Pediatr Hematol Oncol 1994;16:186-7.

4. Gillio AP, Faulkner LB, O'Reilly RJ, et al. Treatment of Diamond-Blackfan Anemia with recombinant human interleukin3. Blood 1993;82:744-51.

5. Gluckman E, Esperou H, Devergie A, Traineau R, Leverger G, Schaison G. Pediatric bone marrow transplantation for leukemia and aplastic anemia. Report of 222 cases transplanted in a single centre. Nouv Rev Fr Hematol 1989;31:111-4.

6. Phillips RJ, M Judge, Webb D, Harper JI. Dyskeratosis congenita delay in diagnosis and successful treatment of pancytopenia in bone marrow transplantation. Br I Dermatol 1992;127:278-80.

7. Mugishima H, Gale RP, Bortin MM, et al. Bone marrow transplantation for Diamond-Blackfan anemia. Bone Marrow Transplant 1995;15:55-8.

8. Lee ACW, Ha SY, Yuen KY, Lau YL. Listeria septicaemia complicating bone marrow transplantation for Diamond-Blackfan syndrome. Pediatr Hematol Oncol 1995;12:295-9.

9. Bacigalupo A, Broccia G, Glaukman E, et al. Antilymphocyte globulin, cyclosporin, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia (SAA) A pilot study of the EBMT SAA Working Party. Blood 1995;85:1343-53.

10. Marsh JCW, Will AJ, Testa NG, et al. "Stem cell' origin of the hematopoietic defect in dyskeratosis congenita. Blood 1992;79:3138-44.


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