What are some of the challenges and key considerations in pre- and posttransplant management of MIOP?

Dr Even-Or: The main challenge in pretransplant management is the promptness required in locating the optimal donor and in organizing the transplant. There are many unique challenges in the post-[stem cell transplantation] management of these patients. Late or failed engraftment is a major concern in these transplants due to the damaged bone marrow niches. Another challenge is respiratory support of these patients during the immediate posttransplant period. MIOP patients often present with upper respiratory blockage due to their abnormal skeletal growth, causing choanal stenosis or obstruction. Moreover, these patients have a tendency to develop pulmonary hypertension, which may present as respiratory failure or deterioration. Therefore, posttransplant issues such as mucositis, volume overload, infections, and aspirations, which may cause respiratory deterioration, may be aggravated in these patients.

Dr Orchard: Outside of establishing the cause of osteopetrosis, patients may have disease-related issues such as severe hypocalcemia, blindness, fractures, thrombocytopenia, and anemia. Many have significant organomegaly, and fractures are sometimes present. Historically the peritransplant mortality has been high, with veno-occlusive disease, graft failure, and pulmonary hypertension as complicating factors. In addition, hypercalcemia can occur with engraftment, which can be severe and difficult to control.

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What are remaining needs in this area in terms of research or otherwise?

Dr Even-Or: The field of stem cell transplantation is rapidly developing, and alternative modalities for transplants in patients with no matched donors are constantly improving, such as new modalities for haploidentical stem cell transplants. However, stem cell transplantation is still a very difficult and dangerous treatment with many possible complications such as graft-vs-host disease, and more advanced therapies for this disease are needed. Gene therapy is a promising future therapeutic modality for curing this single gene disease, and preclinical research is ongoing.

Dr Orchard: An early diagnosis can be extremely helpful in managing these patients and improving outcomes. Optimizing transplant regimens and supportive care can also be very important. Finally, there is interest in gene therapy approaches that may be safer than allogeneic transplantation, but [these are] in early stages. 

Are there any additional points that you would like to emphasize to clinicians?

Dr Even-Or: As this is a genetic disease, prevention is the best treatment. Genetic counseling for MIOP families is very important, and awareness of proper prenatal diagnostic measures is of paramount importance.   


  1. Even-Or E, Stepensky P. How we approach malignant infantile osteopetrosis. Pediatr Blood Cancer. Published online December 12, 2020. doi:10.1002/pbc.28841
  2. Stepensky P, Grisariu S, Avni B, et al. Stem cell transplantation for osteopetrosis in patients beyond the age of 5 yearsBlood Adv. 2019;3(6):862-868. doi:10.1182/bloodadvances.2018025890
  3. Orchard PJ, Fasth AL, Le Rademacher J, et al. Hematopoietic stem cell transplantation for infantile osteopetrosis. Blood. 2015;126(2):270-276. doi:10.1182/blood-2015-01-625541