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SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta

Background: Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. Most mutations occur in COL1A1 and COL1A2 genes. Rarely, mutations in BMP1 have been reported in association with OI type XIII. Disease severity is generally more severe when the mutati...

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Autores principales: Choksi, Ishani, Carpenter, Thomas O, Robinson, Cemre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209160/
http://dx.doi.org/10.1210/jendso/bvaa046.2020
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author Choksi, Ishani
Carpenter, Thomas O
Robinson, Cemre
author_facet Choksi, Ishani
Carpenter, Thomas O
Robinson, Cemre
author_sort Choksi, Ishani
collection PubMed
description Background: Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. Most mutations occur in COL1A1 and COL1A2 genes. Rarely, mutations in BMP1 have been reported in association with OI type XIII. Disease severity is generally more severe when the mutation affects both gene products encoded by BMP1 that serve as procollagenases: bone morphogenic protein 1 and mammalian tolloid (mTLD) [1]. Clinical Case: A 7-year-old Hispanic boy, with speech and gross motor delays, sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6 years, he developed severe back pain after a minor fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3 were identified radiographically, with progressive vertebral height loss in the ensuing 9 months. Fatigue was reported after walking >10 min, with difficulty running and climbing stairs. There was no family history of musculoskeletal disorders. Stature was consistently between 10-15(th)% for age. Subtle facial dysmorphism included micrognathia and small chin, with patchy blue-gray sclerae, and normal dentition. The lumbar spine was tender to percussion. Gait was slow and antalgic with external rotation of the right hip. Laboratory evaluation revealed normal serum calcium, iPTH, magnesium, phosphate, 25-hydroxyvitamin D and alkaline phosphatase for age. P1NP was slightly high (193 µg/L, 30-110 µg/L) and CTX was slightly low (554 pg/mL, n: 574-1849 pg/mL), the latter being atypical for OI. Total hip BMD (adjusted for height Z-score) was normal (Z-score = 1.76) and adjusted femoral neck BMD was high (Z-score = 2.67). VCFs precluded assessment of lumbar spine BMD. Genomic analysis revealed a homozygous missense mutation in exon 4 of BMP1 resulting in an amino acid substitution (c. C505T; p.Arg169Cys) in both the bone morphogenetic protein 1 and mTLD gene products of BMP1. The mutation is predicted to be damaging to both proteins, and associated with this rare form of OI. Conclusion: We report a novel homozygous mutation in BMP1 identified in a child with autosomal recessive OI. Unlike most forms of OI, patients with type XIII often have normal or increased BMD [1], making a correlation between BMD and fracture risk difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and concern for further increasing BMD complicate management. A high resolution peripheral quantitative CT scan to assess bone microarchitecture and quality may aid in the decision of BP therapy. As evidence is limited on the effectiveness of BP in this rare form of OI, it is important to consider each case individually. 1. Sangsin, A., et al., Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report. BMC Med Genet, 2017. 18(1): p. 25.
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spelling pubmed-72091602020-05-13 SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta Choksi, Ishani Carpenter, Thomas O Robinson, Cemre J Endocr Soc Pediatric Endocrinology Background: Osteogenesis imperfecta (OI) is characterized by bone fragility and increased fracture susceptibility. Most mutations occur in COL1A1 and COL1A2 genes. Rarely, mutations in BMP1 have been reported in association with OI type XIII. Disease severity is generally more severe when the mutation affects both gene products encoded by BMP1 that serve as procollagenases: bone morphogenic protein 1 and mammalian tolloid (mTLD) [1]. Clinical Case: A 7-year-old Hispanic boy, with speech and gross motor delays, sustained five bilateral tibial fractures with minimal trauma since age 2.5 years. At age 6 years, he developed severe back pain after a minor fall. Diffuse spinal osteopenia and multiple vertebral compression fractures (VCF) at T9, L1, L3 were identified radiographically, with progressive vertebral height loss in the ensuing 9 months. Fatigue was reported after walking >10 min, with difficulty running and climbing stairs. There was no family history of musculoskeletal disorders. Stature was consistently between 10-15(th)% for age. Subtle facial dysmorphism included micrognathia and small chin, with patchy blue-gray sclerae, and normal dentition. The lumbar spine was tender to percussion. Gait was slow and antalgic with external rotation of the right hip. Laboratory evaluation revealed normal serum calcium, iPTH, magnesium, phosphate, 25-hydroxyvitamin D and alkaline phosphatase for age. P1NP was slightly high (193 µg/L, 30-110 µg/L) and CTX was slightly low (554 pg/mL, n: 574-1849 pg/mL), the latter being atypical for OI. Total hip BMD (adjusted for height Z-score) was normal (Z-score = 1.76) and adjusted femoral neck BMD was high (Z-score = 2.67). VCFs precluded assessment of lumbar spine BMD. Genomic analysis revealed a homozygous missense mutation in exon 4 of BMP1 resulting in an amino acid substitution (c. C505T; p.Arg169Cys) in both the bone morphogenetic protein 1 and mTLD gene products of BMP1. The mutation is predicted to be damaging to both proteins, and associated with this rare form of OI. Conclusion: We report a novel homozygous mutation in BMP1 identified in a child with autosomal recessive OI. Unlike most forms of OI, patients with type XIII often have normal or increased BMD [1], making a correlation between BMD and fracture risk difficult. While bisphosphonates (BP) may help reduce recurrent fractures and provide symptomatic relief, the broad phenotypic spectrum and concern for further increasing BMD complicate management. A high resolution peripheral quantitative CT scan to assess bone microarchitecture and quality may aid in the decision of BP therapy. As evidence is limited on the effectiveness of BP in this rare form of OI, it is important to consider each case individually. 1. Sangsin, A., et al., Two novel compound heterozygous BMP1 mutations in a patient with osteogenesis imperfecta: a case report. BMC Med Genet, 2017. 18(1): p. 25. Oxford University Press 2020-05-08 /pmc/articles/PMC7209160/ http://dx.doi.org/10.1210/jendso/bvaa046.2020 Text en © Endocrine Society 2020. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Pediatric Endocrinology
Choksi, Ishani
Carpenter, Thomas O
Robinson, Cemre
SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title_full SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title_fullStr SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title_full_unstemmed SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title_short SUN-LB19 Novel Homozygous Mutation in BMP1 Causing Osteogenesis Imperfecta
title_sort sun-lb19 novel homozygous mutation in bmp1 causing osteogenesis imperfecta
topic Pediatric Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209160/
http://dx.doi.org/10.1210/jendso/bvaa046.2020
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