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Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis

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Abstract

Summary

Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ.

Introduction

Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis.

Methods

A cohort comprising 56 subjects (aged 19–60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL).

Results

We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood.

Conclusions

Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.

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Authors and Affiliations

  1. Department of Rheumatology, Hospital Clínic, University of Barcelona, Villarroel 170, 08036, Barcelona, Spain

    Pilar Peris, Ana Monegal & Nuria Guañabens

  2. Folkhälsan Institute of Genetics, University of Helsinki, P.O. Box 63, FIN-00014, Helsinki, Finland

    Riikka E. Mäkitie

  3. Department of Immunology, Hospital Clínic, University of Barcelona, Barcelona, Spain

    Eva González-Roca

  4. Department of Molecular Biology, CORE Laboratory, Hospital Clínic, University of Barcelona, Barcelona, Spain

    Eva González-Roca

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  1. Pilar Peris
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  2. Ana Monegal
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  3. Riikka E. Mäkitie
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  4. Nuria Guañabens
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  5. Eva González-Roca
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Correspondence to Pilar Peris.

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Peris, P., Monegal, A., Mäkitie, R.E. et al. Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis. Osteoporos Int 34, 405–411 (2023). https://doi.org/10.1007/s00198-022-06609-2

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  • DOI: https://doi.org/10.1007/s00198-022-06609-2

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