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A double cure: Omenn syndrome and β thalassaemia successfully treated with mismatched unrelated donor transplantation

Bone Marrow Transplantation volume 47, pages 589–590 (2012)Cite this article

Omenn syndrome (OS) describes forms of SCID with additional characteristic features, including erythroderma, hepatosplenomegaly and lymphadenopathy.1 A variety of genetic defects responsible for lymphocyte or thymic development can give rise to OS, with mutations in genes responsible for V(D)J recombination during T- and B-cell development, such as the recombinase-activating genes (RAG1 and RAG2) being the best characterised.2 Here we describe an infant suffering with OS as well as β thalassaemia, who was successfully cured of both conditions by mismatched unrelated donor hematopoietic SCT following reduced intensity conditioning.

The infant was born at term after an uneventful pregnancy to consanguineous Asian parents, known to be β-thalassaemia carriers. Routine postnatal screening at 5 days of age detected 100% fetal Hb consistent with β-thalassaemia major, and this was confirmed on subsequent genetic analysis (homozygous for β thalassaemia with codon 8/9 (+G) mutation). Delayed separation of the umbilical cord stump, failure to thrive and an erythrodermatous skin rash was investigated further at the age of 2 months. Immunological investigations revealed absent B cells and although her CD3 T-cell count was raised (10.2 × 109/L), these cells were associated with an abnormal phenotype, with a predominance of activated CD4 cells, and they failed to respond to mitogenic stimulation in vitro. In association with low serum Igs (IgG 2.63 g/L, IgA <0.05 g/L, IgM 0.07 g/L) and eosinophilia, a clinical diagnosis of OS was made. Genetic analysis subsequently detected heterozygotic mutations of the recombinase-activating gene-1 (RAG1), the gene most commonly associated with OS. The patient was hypertransfused to maintain Hb above 13 g/dL, but she did not require chelation therapy and did not develop the organ-specific co-morbidities often associated with thalassaemia in older patients. A single Ag (DRB1) mismatched unrelated donor was identified following registry searches. Sub-myeloablative conditioning with treosulphan (three daily doses of 12 g/m2; total 36 g/m2), fludarabine (five daily doses of 30 mg/m2; total 150 mg/m2) was combined with alemtuzamab (five daily doses of 0.2 mg/kg; total 1 mg/kg). CY and mycophenolate mofetil were administered as prophylaxis against graft vs host disease. The PBSC harvest yielded a CD34 stem cell dose of 14.5 × 106/kg and a CD3 dose of 5.7 × 108/kg. Stable 100% donor engraftment was achieved without significant GVHD. At 6 months after transplantation, the patient developed haemolytic anaemia, requiring red cell transfusions. The detection of red cell antibodies confirmed an immune-based mechanism and additional immunosuppression with prednisolone (2 mg/kg per day) and rituximab (four weekly doses of 375 mg/m2) was required to control haemolysis. After withdrawal of immunosuppression, the patient went on to fully reconstitute her cellular immune compartment with normal lymphocyte subsets, including naive T-cell populations, good thymic output as determined by levels of T-cell receptor excision circles and diverse T-cell repertoire as characterised by T-cell receptor Vβ spectratyping. At 2 years after her transplant, she has full donor chimaerism in all lineages, is transfusion independent, off all immunosuppression and no longer receiving Ig replacement therapy.

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  1. Bone Marrow and Blood Stem Cell Transplant Unit, Great Ormond Street Hospital, London, UK

    V Wootten, N Goulden, P Veys & W Qasim

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  1. V Wootten
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Correspondence to W Qasim.

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Wootten, V., Goulden, N., Veys, P. et al. A double cure: Omenn syndrome and β thalassaemia successfully treated with mismatched unrelated donor transplantation. Bone Marrow Transplant 47, 589–590 (2012). https://doi.org/10.1038/bmt.2011.115

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