Osteopetrosis (C) is an inherited connective tissue disease resulting in abnormally dense bones prone to fracture. Mutations in more than a dozen known genes result in dysfunctional osteoclasts and accumulation of old bone normally resorbed. In severe cases, malfunctioning endochondral bone replaces the marrow space, resulting in inadequate hematopoiesis. Resultant pancytopenia can lead to opportunistic infection and death in childhood. Compensatory hepatosplenomegaly ensues as a result of extramedullary hematopoiesis. Cranial nerve deficits can manifest as blood cell production in concert with ongoing hypertrophy enlarges bony structures of the skull. The continued production of abnormal endochondral bone also results in brittleness predisposing to fracture, which occurs even in patients with less severe forms and normal life expectancy.   

A diagnosis of osteopetrosis is based on a thorough clinical evaluation, detailed medical history, X-ray imaging, and bone mineral density measurements.  Genetic testing can identify the mutation in 90% of cases. In our patient, genetic testing revealed 2 heterozygous PLEKHM1 mutations (exon 4 and exon 7).  PLEKHM1 gene is important to endosomal and lysosomal vesicular function.  Defects within the PLEKHM1 gene result in defective osteoclastic ruffled border formation and consequential inadequate bone resorption. This patient’s lack of hematologic deficiencies and survival into adulthood portend an improved long-term prognosis.