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Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants

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Abstract

Osteogenesis imperfecta type XI (OI-XI) and Bruck syndrome type I (BS1) are two rare disorders caused by biallelic variants in the FKBP10, characterized by early-onset bone fractures and progressive skeletal deformities. The patients with OI-XI, also co-segregated with autosomal-recessive epidermolysis bullosa simplex caused by KRT14 variant, have been reported. In this study, the follow-up clinical features of the patients with OI-XI and BS1 phenotypes due to biallelic FKBP10 variants are compared. The aim of this study is to investigate the follow-up findings of OI-XI and BS1 phenotypes in patients with the FKBP10 variants. A total of 19 children, ten males and nine females, from 16 unrelated families were included in the study. FKBP10 variants were investigated by next-generation sequencing (NGS) based panel gene test or Sanger sequencing. Seventeen patients were followed between 1.5 and 16.8 years, and the last follow-up age was between 2 and 24.6 years (median 10.7 years). They received intravenous bisphosphonate infusions once every 3 months in follow-up period. We identified four different biallelic FKBP10 variants, two of which are novel (c.890_897dup TGATGGAC, p.Gly300Ter and c.1256 + 1G > A) in 16 families. Five of these patients also had findings of epidermolysis bullosa simplex, and the same biallelic c.612T > A (p.Tyr204Ter) variant in KRT14, as well as FKBP10, were identified. Twelve patients were diagnosed with OI-XI; whereas, seven were diagnosed with BS1. The BS1 phenotype was late-onset and the annual fracture number was lower. After bisphosphonate treatment, bone mineral densitometry Z score at L1–L4 increased (p = 0.005) and the number of annual fractures decreased (p = 0.036) in patients with OI-XI. However, no significant effect of bisphosphonate treatment was found on these values in BS1 patients. Despite the treatment, the rate of scoliosis and long bone deformity had increased in both groups at the last examination; and, only two patients could take a few steps with the aid of a walker, while others were not ambulatory, and they used wheelchairs for mobility. We identified two novel variants in FKBP10. Families originating from the same geographic region and having the same variant suggest founder effects. Although the number of fractures decreased with bisphosphonate treatment, none of our patients were able to walk during the follow-up. This study is valuable in terms of showing the follow-up findings of patients with FKBP10 variants for the first time.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank all patients and their families for participating in this study.

Funding

This study was funded by TUBITAK with the project number 17S278.

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Authors and Affiliations

  1. Department of Pediatric Genetics, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Aylin Yüksel Ülker, Dilek Uludağ Alkaya, Leyla Elkanova & Beyhan Tüysüz

  2. Department of Orthopedics and Traumatology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey

    Ali Şeker

  3. Department of Orthopedics and Traumatology, Baltalimani Bone Diseases Training and Research Center, Health Sciences University, Istanbul, Turkey

    Evren Akpınar

  4. Department of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara, Turkey

    Nurten Ayşe Akarsu

  5. Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Zehra Oya Uyguner

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  1. Aylin Yüksel Ülker
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Contributions

Conception and design of the study: AYÜ, BT; acquisition of data: AYÜ, DUA, LE, AŞ, EA, NAA, BT; analysis and interpretation of data: AYÜ, DUA, ZOU, NAA, BT; drafting the manuscript: AYÜ, DUA, BT; writing-original draft: AYÜ, DUA, BT; supervision: BT; final approval: all authors.

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Correspondence to Beyhan Tüysüz.

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Conflict of interest

Aylin Yüksel Ülker, Dilek Uludağ Alkaya, Leyla Elkanova, Ali Şeker, Evren Akpınar, Nurten Ayşe Akarsu, Zehra Oya Uyguner, and Beyhan Tüysüz declared that they have no conflict of interest.

Human and Animal Rights

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Istanbul University-Cerrahpasa, Cerrahpasa Medical Faculty Ethics Committee, no: 83045809-604.01.02) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Yüksel Ülker, A., Uludağ Alkaya, D., Elkanova, L. et al. Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants. Calcif Tissue Int 109, 633–644 (2021). https://doi.org/10.1007/s00223-021-00879-4

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