Infantile Malignant Osteopetrosis

Abstract

A 6-month-old infant girl presented with hepatosplenomegaly, pancytopenia, diffuse osteosclerosis, and rickets (Figure, A). Hypocalcemia, hypophosphatemia, and hyperparathyroidism were noted in the absence of hypovitaminosis D. Bone marrow biopsy revealed abundant osteoclasts and depressed hematopoietic progenitors due to marrow space narrowing. Spine bone mineral density on dual energy x-ray absorptiometry showed a z-score of +8.3. Osteoclast-rich infantile malignant osteopetrosis (“marble bone disease”) was confirmed due to a compound heterozygous mutation in the TCIRG1 gene (IVS13-2A>C and C.2008C>T). Calcium, phosphate, and calcitriol therapy administered between 6 and 12 months of age normalized serum calcium and phosphate levels and treated the rickets (Figure, B). Successful hematopoietic transplantation from an unrelated cord-blood donor at 12 months of age corrected the osteosclerosis by introducing functional osteoclasts. At 14 months of age, there were 4 distinct radiographic zones at the distal femoral metaphysis, representing the different phases of her illness and treatment (Figure, C). Zone 1 was consistent with sclerotic bone formed in the perinatal period; zone 2 represented the less dense, osteopetrorickets phase; zone 3 highlighted the treated-rickets phase; and zone 4 showed the “eudense” bone formed in the presence of functional osteoclasts after transplantation. By 22 months of age, skeletal remodeling led to normalization of bone density (spine bone mineral density z-score +2.4), as demonstrated at the distal femur (Figure, D). Infantile malignant osteopetrosis is a rare, autosomal recessive disorder with an early presentation that can mimic hematologic malignancy. In the absence of functional osteoclasts, a paradoxical finding of both osteopetrosis and rickets may be present, as noted in our patient as well as in other reports.1Gonen K.A. Yazici Z. Gokalp G. Ucar A.K. Infantile osteopetrosis with superimposed rickets.Pediatr Radiol. 2013; 43: 189-195Crossref PubMed Scopus (13) Google Scholar, 2Donnelly L.F. Johnson 3rd, J.F. Benzing G. Infantile osteopetrosis complicated by rickets.AJR Am J Roentgenol. 1995; 164: 968-970Crossref PubMed Scopus (16) Google Scholar The clear demarcation of treatment zones on radiographs has not been previously reported in osteopetrosis, although a similar phenomenon has been described in relapsing rickets of prematurity.3Biegański T. Oestreich A.E. Nowak S. Rudecka M. Ebb and flow rickets in a premature infant: the Afghan turban sign.Skeletal Radiol. 1999; 28: 651-654Crossref PubMed Scopus (2) Google Scholar As demonstrated, early hematopoietic transplantation in TCIRG1-affected patients can result in a significant decline in the pathologically high bone mass and correct biochemical abnormalities.4Stark Z. Savarirayan R. Osteopetrosis.Orphanet J Rare Dis. 2009; 4: 5Crossref PubMed Scopus (277) Google Scholar This patient's findings are notable in that her radiographs provide a clear chronologic representation of the stages of both illness and treatment. Supported by a University of Ottawa Research Chair Award and by the Children's Hospital of Eastern Ontario, Departments of Pediatrics and Surgery (to L.W.). M.N. was supported by fellowships from the Canadian Pediatric Endocrine Group , Osteoporosis Canada, and the Canadian Society of Endocrinology and Metabolism . The authors would like to thank Victor Konji for his assistance in preparing the Figure for the manuscript.