Malignant infantile osteopetrosis (MIOP) is the severe, autosomal recessive form of osteopetrosis with an estimated incidence of 1 in 250,000 births in the general population.1 Hematopoietic stem cell transplantation (HSCT), has become the standard of care for MIOP and represents the only curative treatment for the disease, although it is not indicated for certain genetic subgroups.1,2 The mortality rate associated with untreated MIOP is approximately 70% by the age of 6 years, which is mainly attributed to bone marrow failure due to insufficient hematopoiesis.3 

While the clinical presentation of MIOP is heterogeneous, patients commonly present with failure to thrive, visual impairments, hepatosplenomegaly, and skeletal changes such as macrocephaly, frontal bossing, tooth eruption defects, and bone fractures. The presence of neonatal hypocalcemia should raise suspicion of MIOP. Laboratory findings may show anemia, thrombocytopenia, and leukocytosis, and immunophenotyping of peripheral blood may demonstrate an abundance of CD34+ cells, thus mimicking acute leukemia or juvenile myelomonocytic leukemia.1

Diagnosis is typically established based on unique radiographic findings including “sclerotic bones with increased bone marrow density and the absence of bone marrow cavity,” which are pathognomonic for MIOP.1 “Classical features include vertebral midbodies sandwiched between dense bands along superior and inferior endplates (‘sandwich vertebrae’) and bone within bone appearance.” The severity of radiological findings may vary by genetic subgroup.

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MIOP diagnosis must be confirmed with molecular genetic analysis, such as whole-exome sequencing, to guide treatment planning and determine appropriateness for HSCT. For HSCT candidates, the authors suggested the following pretransplant investigations to facilitate posttransplant monitoring of symptom resolution: baseline radiological evaluation, abdominal ultrasound, neurological and neuroradiological assessment (and surgical intervention in severe cases), cardiologic evaluation, and dental, auditory, and ophthalmologic assessments.1

In searching for HSCT donors, if a matched sibling is not available, the authors considered the possibility of a matched donor in more distant relatives and then search registries for an unrelated donor if no matched related donor is identified.1 In a 2015 study of 193 patients, transplantation from a matched sibling was associated with 5- and 10-year survival rates of 62% at both time points, compared to 42% and 39%, respectively, with alternative donor transplantation.3

For further discussion regarding MIOP diagnosis and management, we conducted email interviews with review co-author Ehud Even-Or, MD, a pediatric hemato-oncologist in the department of bone marrow transplantation and cancer immunotherapy at Hadassah Medical Center in Jerusalem, Israel, as well as Paul J. Orchard, MD, a professor of pediatrics in the division of blood and marrow transplantation at the University of Minnesota in Minneapolis and co-author of the 2015 study mentioned above.

What are the main challenges in the diagnosis and management of MIOP, and how are these approached in practice?

Dr Even-Or: The main challenge with the diagnosis of MIOP is the importance of a quick, early diagnosis in order to minimize permanent neurological damage, and to preserve vision as much as possible. Therefore, it is of utmost importance for primary care physicians, especially pediatricians, to be aware of this rare disease and the wide variety of initial presenting signs—such as visual impairment and nystagmus, skeletal changes such as macrocephaly and frontal bossing, hepatosplenomegaly, and hypocalcemia—that may lead to a quick diagnosis.

Dr Orchard: The ability to establish a precise molecular diagnosis for osteopetrosis has been extremely advantageous. Identifying the genes responsible for the majority of cases has helped us better understand the biology of the disease and what forms may be amenable to intervention such as transplantation. For instance, patients with OSTM1 mutations develop aggressive neurodegeneration, which is not impacted by transplantation. In those with a RANK ligand genotype, the cause of the disease is extrinsic to the osteoclasts, and transplantation would not be expected to provide benefit.