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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750151/ https://www.ncbi.nlm.nih.gov/pubmed/33364264 http://dx.doi.org/10.1016/j.bonr.2020.100738 |
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author | Taylor-Miller, Tashunka Sivaprakasam, Ponni Smithson, Sarah F. Steward, Colin G. Burren, Christine P. |
author_facet | Taylor-Miller, Tashunka Sivaprakasam, Ponni Smithson, Sarah F. Steward, Colin G. Burren, Christine P. |
author_sort | Taylor-Miller, Tashunka |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7750151 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-77501512020-12-23 Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis Taylor-Miller, Tashunka Sivaprakasam, Ponni Smithson, Sarah F. Steward, Colin G. Burren, Christine P. Bone Rep Case Report 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. Elsevier 2020-12-02 /pmc/articles/PMC7750151/ /pubmed/33364264 http://dx.doi.org/10.1016/j.bonr.2020.100738 Text en © 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Case Report Taylor-Miller, Tashunka Sivaprakasam, Ponni Smithson, Sarah F. Steward, Colin G. Burren, Christine P. Challenges in long-term control of hypercalcaemia with denosumab after haematopoietic stem cell transplantation for TNFRSF11A osteoclast-poor autosomal recessive osteopetrosis |
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 | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750151/ https://www.ncbi.nlm.nih.gov/pubmed/33364264 http://dx.doi.org/10.1016/j.bonr.2020.100738 |
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