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Re: Role of bone biopsy & mismatched stem cell transplantation in infantile osteopetrosis

I thank Wilson and Vellodi for their comprehensive review of autosomal recessive osteopetrosis.[1] I would, however, like to take issue with two of their recommendations for patient management.

The first concerns the authors' advice to restrict bone biopsy to children with an unclear diagnosis or aberrant clinical phenotype. By contrast, I would propose that biopsy should be performed in all children at diagnosis. This can be done with minimal trauma as a closed procedure using a sharp trephine needle. Using a combination of conventional histology and electron microscopy it is then possible to distinguish those patients with normal or increased numbers of osteoclasts (at least half of whom will have mutations of the vacuolar proton pump gene OC116[2] [3]) from other recognised subtypes (eg, those with apparent lack of osteoclasts on light microscopy or lack of a ruffled absorption border on electron microscopy). Better classification in this way is essential if we are to improve prognostication and aid the search for other causative genes.

For the same reason, DNA should be stored and blood mononuclear cells cryopreserved on all children - again this is not uniform practice at present. In the future it may be possible to avoid biopsy if in vitro studies of osteoclasts grown from patient's peripheral blood show good correlation with biopsy appearances.[4] However, these studies are only in their infancy.

Secondly, I disagree that stem cell transplantation (SCT) should be restricted to children with at least a phenotypically HLA identical donor. This advice is based on a European Bone Marrow Transplant group (EBMT) report of transplants performed between 1976 and 1994 which showed only 13% of patients to be alive and free of disease 5 years after haplotype mismatched related donor transplantation.[5] However, these procedures predated G-CSF stem cell mobilisation of donors and major technical advances in T-cell depletion, developments which have greatly widened the safety and efficacy of haploidentical SCT. I am aware of at least six children who have undergone successful haploidentical SCT during the past 4 years and are now free of osteopetrosis W Friedrich & T Klingebiel, personal communication). Although such transplants are technically difficult and conditioning chemotherapy regimens are still being improved, it is likely that cure rates will exceed 50%.

An updated EBMT report on transplantation for osteopetrosis is currently being prepared. It is clearly important that parents and medical professionals are informed of these developments.

Colin G Steward
Medical Advisor, Osteopetrosis Support Trust
Consultant Senior Lecturer in Bone Marrow Transplantation of Metabolic & Genetic Diseases
Royal Hospital for Sick Children, St. Michael's Hill
Bristol BS2 8BJ, UK

References
(1) Wilson CJ, Vellodi A. Autosomal recessive osteopetrosis: diagnosis, management and outcome. Arch Dis Child 2000;83:449-52.

(2) Frattini A, Orchard PJ, Sobacchi C, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000;25:343-6.

(3) Kornak U, Schulz A, Friedrich W, et al. Mutations in the a3 subunit of the vacuolar H+-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 2000;9:2059-63.

(4) Flanagan AM, Sarma U, Steward CG, et al. Study of the nonresorptive phenotype of osteoclast-like cells from patients with malignant osteopetrosis: a new approach to investigating pathogenesis. J Bone Min Res 2000;15:352-60.