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Infantile Malignant Osteopetrosis
Infantile Malignant Osteopetrosis
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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.1,2 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.3 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.4 This patient’s findings are notable in that her radiographs provide a clear chronologic representation of the stages of both illness and treatment. n 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.
Munier Nour, MD, FRCPC Division of Pediatric Endocrinology Alberta Children’s Hospital University of Calgary Calgary, Alberta, Canada
Leanne M. Ward, MD, FRCPC Departments of Pediatrics and Surgery Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada
References available at www.jpeds.com
Figure. Chronological representation of the stages of illness and treatment of infantile malignant osteopetrosis as captured on knee radiographs in a six month old girl; A, at presentation; B, after treatment of rickets with calcitriol plus calcium and phosphate; C, after hematopoietic transplantation resulting in correction of the osteosclerosis; and D, subsequent skeletal remodeling with normalization of bone density. J Pediatr 2013;163:1230. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.04.031
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References 1. Gonen KA, Yazici Z, Gokalp G, Ucar AK. Infantile osteopetrosis with superimposed rickets. Pediatr Radiol 2013;43:189-95.
2. Donnelly LF, Johnson JF 3rd, Benzing G. Infantile osteopetrosis complicated by rickets. AJR Am J Roentgenol 1995;164:968-70. 3. Biega nski T, Oestreich AE, Nowak S, Rudecka M. Ebb and flow rickets in a premature infant: the Afghan turban sign. Skeletal Radiol 1999;28:651-4. 4. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis 2009;4:5.
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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.1,2 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.3 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.4 This patient’s findings are notable in that her radiographs provide a clear chronologic representation of the stages of both illness and treatment. n 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.
Munier Nour, MD, FRCPC Division of Pediatric Endocrinology Alberta Children’s Hospital University of Calgary Calgary, Alberta, Canada
Leanne M. Ward, MD, FRCPC Departments of Pediatrics and Surgery Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada
References available at www.jpeds.com
Figure. Chronological representation of the stages of illness and treatment of infantile malignant osteopetrosis as captured on knee radiographs in a six month old girl; A, at presentation; B, after treatment of rickets with calcitriol plus calcium and phosphate; C, after hematopoietic transplantation resulting in correction of the osteosclerosis; and D, subsequent skeletal remodeling with normalization of bone density. J Pediatr 2013;163:1230. 0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.04.031
1230
Vol. 163, No. 4 October 2013
References 1. Gonen KA, Yazici Z, Gokalp G, Ucar AK. Infantile osteopetrosis with superimposed rickets. Pediatr Radiol 2013;43:189-95.
2. Donnelly LF, Johnson JF 3rd, Benzing G. Infantile osteopetrosis complicated by rickets. AJR Am J Roentgenol 1995;164:968-70. 3. Biega nski T, Oestreich AE, Nowak S, Rudecka M. Ebb and flow rickets in a premature infant: the Afghan turban sign. Skeletal Radiol 1999;28:651-4. 4. Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis 2009;4:5.
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