Severe neuronopathic autosomal recessive osteopetrosis due to homozygous deletions affecting OSTM1

• We describe patients with autosomal recessive osteopetrosis due to microdeletions affecting the OSTM1 gene.
• We confirm that OSTM1-related autosomal recessive osteopetrosis shows severe neurological involvement and early lethality.
• OSTM1 microdeletions are a relatively frequent cause of neuronopathic autosomal recessive osteopetrosis.
• A comprehensive mutation analysis should comprise testing for OSTM1 microdeletions.

Autosomal recessive osteopetrosis (ARO, MIM 259700) is a genetically heterogeneous rare skeletal disorder characterized by failure of osteoclast resorption leading to pathologically increased bone density, bone marrow failure, and fractures. In the neuronopathic form neurological complications are especially severe and progressive. An early identification of the underlying genetic defect is imperative for assessment of prognosis and treatment by hematopoietic stem cell transplantation. Here we describe for the first time homozygous microdeletions of different sizes affecting the OSTM1 gene in two unrelated consanguineous families with children suffering from neuronopathic infantile malignant osteopetrosis. Patients showed an exceptionally severe phenotype with variable CNS malformations, seizures, blindness, and deafness. Multi-organ failure due to sepsis led to early death between six weeks and five months of age in spite of intensive care treatment. Analysis of the breakpoints revealed different mechanisms underlying both rearrangements. Microdeletions seem to represent a considerable portion of OSTM1 mutations and should therefore be included in a sufficient diagnostic screening.