Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis
Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. Case: This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO under...
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Bone Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352187220304988 |
| _version_ | 1818907086718763008 |
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| author | Tashunka Taylor-Miller Ponni Sivaprakasam Sarah F. Smithson Colin G. Steward Christine P. Burren |
| author_facet | Tashunka Taylor-Miller Ponni Sivaprakasam Sarah F. Smithson Colin G. Steward Christine P. Burren |
| author_sort | Tashunka Taylor-Miller |
| collection | DOAJ |
| description | Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. Case: This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. Management: She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. Conclusion: This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase. |
| first_indexed | 2024-12-19T21:49:32Z |
| format | Article |
| id | doaj.art-c45ef3a1ef9143d9a52d88dac1481010 |
| institution | Directory Open Access Journal |
| issn | 2352-1872 |
| language | English |
| last_indexed | 2024-12-19T21:49:32Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Bone Reports |
| spelling | doaj.art-c45ef3a1ef9143d9a52d88dac14810102022-12-21T20:04:27ZengElsevierBone Reports2352-18722021-06-0114100738Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosisTashunka Taylor-Miller0Ponni Sivaprakasam1Sarah F. Smithson2Colin G. Steward3Christine P. Burren4Department of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United KingdomPaediatric Bone Marrow Transplant Service, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United KingdomDepartment of Clinical Genetics, St Michaels Hospital, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom; Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, United KingdomBristol Medical School: Translational Health Sciences, University of Bristol, Bristol, United Kingdom; School of Cellular and Molecular Medicine, University of Bristol, Queens Road, Bristol BS8 1QU, United KingdomDepartment of Paediatric Endocrinology, Bristol Royal Hospital for Children, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, United Kingdom; Bristol Medical School: Translational Health Sciences, University of Bristol, Bristol, United Kingdom; Corresponding author at: Bristol Royal Hospital for Children, Bristol BS2 8BJ, United Kingdom.Autosomal recessive osteopetrosis (ARO) is rare, involving increased bone density due to defective osteoclast differentiation or function, with several genetic subtypes. Case: This child with compound heterozygous novel loss-of-function TNFRSF11A pathogenic variants causing osteoclast-poor ARO underwent haematopoietic stem cell transplantation (HSCT) aged 3.1 years and experienced episodic severe hypercalcaemia over 2.5 years. She initially presented aged 8 months with craniosynostosis and visual impairment and underwent surgery; no increased bone density evident on skull imaging nor variants in genes associated with craniosynostosis identified. She was subsequently referred for investigation of poor linear growth and low alkaline phosphatase. Clinical abnormalities included asymmetric pectus carinatum, thickened anterior tibia and wrists, and markedly delayed dentition. Skeletal survey revealed generalised osteosclerosis with undertubulation. Management: She received haploidentical HSCT aged 3.1 years and developed hypercalcaemia (adjusted calcium 4.09mmol/L = 16.4mg/dL) Day 18 post-HSCT, unresponsive to hyperhydration and diuretics. Denosumab achieved normocalcaemia, which required 0.6mg/kg every 6 weeks long-term. The ensuing 2.75 years feature full donor engraftment, good HSCT graft function, skeletal remodelling with 2.5 years recurrent severe hypercalcaemia and nine fragility long bone fractures. Conclusion: This case illustrates challenges of bone and calcium management in ultrarare TNFRSF11A-related OP-ARO. Craniosynostosis was an early feature, evident pre-sclerosis in osteopetrosis. Following HSCT, restoration of osteoclast activity in the context of elevated bone mass produced severe and prolonged (2.5 years) hypercalcaemia. Denosumab was effective medium-term, but required concurrent long duration (11 months) zoledronic acid to manage recurrent hypercalcaemia. Fragility fractures brought appreciable additional morbidity in the post-HSCT phase.http://www.sciencedirect.com/science/article/pii/S2352187220304988CraniosynostosisDenosumabHaematopoietic stem cell transplantationHypercalcaemiaOsteopetrosisTNFRSF11A |
| spellingShingle | Tashunka Taylor-Miller Ponni Sivaprakasam Sarah F. Smithson Colin G. Steward Christine P. Burren Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis Bone Reports Craniosynostosis Denosumab Haematopoietic stem cell transplantation Hypercalcaemia Osteopetrosis TNFRSF11A |
| title | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
| title_full | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
| title_fullStr | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
| title_full_unstemmed | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
| title_short | Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
| title_sort | challenges in long term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for tnfrsf11a osteoclast poor autosomal recessive osteopetrosis |
| topic | Craniosynostosis Denosumab Haematopoietic stem cell transplantation Hypercalcaemia Osteopetrosis TNFRSF11A |
| url | http://www.sciencedirect.com/science/article/pii/S2352187220304988 |
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