Multiple Fractures and Impaired Bone Fracture Healing in a Patient with Pycnodysostosis and Hypophosphatasia
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Pycnodysostosis (PYCD) is a rare recessive inherited skeletal disease, characterized by short stature, brittle bones, and recurrent fractures, caused by variants in the Cathepsin K encoding gene that leads to impaired osteoclast-mediated bone resorption. Hypophosphatasia (HPP) is a dominant or recessive inherited condition representing a heterogeneous phenotype with dental symptoms, recurrent fractures, and musculoskeletal problems. The disease results from mutation(s) in the tissue non-specific alkaline phosphate encoding gene with reduced activity of alkaline phosphatase and secondarily defective mineralization of bone and teeth. Here, we present the first report of a patient with the coexistence of PYCD and HPP. This patient presented typical clinical findings of PYCD, including short stature, maxillary hypoplasia, and sleep apnoea. However, the burden of disease was caused by over 30 fractures, whereupon most showed delayed healing and non-union. Biochemical analysis revealed suppressed bone resorption and low bone formation capacity. We suggest that the coexistence of impaired bone resorption and mineralization may explain the severe bone phenotype with poor fracture healing.
KeywordsPycnodysostosis Hypophosphatasia CTSK Fracture Bone healing
TNSALP encoding gene
Bone-specific alkaline phosphatase
Bone mineral content
Bone mass density
Continuous positive airway pressure
Cathepsin K encoding gene
C-terminal telopeptide of type I collagen
Dual-energy X-ray absorptiometry
Bones extracellular matrix
Fibroblast growth factor 23
High-resolution peripheral quantitative computed tomography
Plasma procollagen type 1 N-terminal propeptide
Trabecular bone score
Tissue non-specific alkaline phosphatase
Tartrate-resistant acid phosphatase-5b
Volumetric bone mineral density
NH, PV, HBH, KH, and JEBJ contributed to examination and treatment of the patient. ALF contributed to supervision and genetic counselling. MD helped with the implementation of genetic analyses, and NRJ with implementation of biochemical analyses. BL provided data from HR-pQCT evaluation. All authors contributed to the interpretation of data, development, and critical revision of the manuscript, and approved the final version for submission.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Compliance with Ethical Standards
Conflict of interest
NH, PV, HBH, KH, ALF, MD, and NRJ have nothing to disclose. Jens-Erik Beck Jensen (JEBJ) was a board member in Eli Lilly, Amgen and MSD. JEBJ received funding from Eli Lilly and Amgen and consulting fees from MSD, Giliad and Amgen. Bente Langdahl (LB) received research grants from Novo Nordisk and Amgen. LB has received personal fess by acting on advisory boards and giving lectures from Amgen, UCB, Eli Lilly and TEVA.
Genetic analysis, blood sample analysis, DXA, and X-ray evaluation were performed during clinical diagnostic investigations.
The research was conducted in accordance with the ethical standards.
Informed consent was obtained from the subjects to publish their data.
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