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Multiple Fractures and Impaired Bone Fracture Healing in a Patient with Pycnodysostosis and Hypophosphatasia

  • Nicola HeppEmail author
  • Anja Lisbeth Frederiksen
  • Morten Dunø
  • Niklas Rye Jørgensen
  • Bente Langdahl
  • Poul Vedtofte
  • Hanne B. Hove
  • Klaus Hindsø
  • Jens-Erik Beck Jensen
Case Reports
  • 32 Downloads

Abstract

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.

Keywords

Pycnodysostosis Hypophosphatasia CTSK Fracture Bone healing 

Abbreviations

ALP

Alkaline phosphatase

ALPL

TNSALP encoding gene

BALP

Bone-specific alkaline phosphatase

BMC

Bone mineral content

BMD

Bone mass density

CPAP

Continuous positive airway pressure

CT

Computed tomography

CTSK

Cathepsin K

CTSK

Cathepsin K encoding gene

CTX

C-terminal telopeptide of type I collagen

DXA

Dual-energy X-ray absorptiometry

ECM

Bones extracellular matrix

FGF23

Fibroblast growth factor 23

HPP

Hypophosphatasia

HR-pQCT

High-resolution peripheral quantitative computed tomography

nr

Normal range

OB

Osteoblasts

OC

Osteoclasts

PEA

Phosphoethanolamine

Pi

Inorganic phosphate

PINP

Plasma procollagen type 1 N-terminal propeptide

PLP

Pyridoxal-5′-phosphate

PPi

Inorganic pyrophosphate

PTH

Parathyroid hormone

rd

Reference data

TBS

Trabecular bone score

TNSALP

Tissue non-specific alkaline phosphatase

TRAP-5b

Tartrate-resistant acid phosphatase-5b

vBMD

Volumetric bone mineral density

Notes

Author Contributions

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.

Funding

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.

Ethical Approval

Genetic analysis, blood sample analysis, DXA, and X-ray evaluation were performed during clinical diagnostic investigations.

Human Rights

The research was conducted in accordance with the ethical standards.

Informed Consent

Informed consent was obtained from the subjects to publish their data.

Supplementary material

223_2019_605_MOESM1_ESM.doc (1.3 mb)
Supplementary material 1 (DOC 1295 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Nicola Hepp
    • 1
    Email author
  • Anja Lisbeth Frederiksen
    • 2
    • 3
  • Morten Dunø
    • 4
  • Niklas Rye Jørgensen
    • 5
    • 6
  • Bente Langdahl
    • 7
  • Poul Vedtofte
    • 8
  • Hanne B. Hove
    • 9
  • Klaus Hindsø
    • 10
  • Jens-Erik Beck Jensen
    • 1
    • 11
  1. 1.Department of EndocrinologyHvidovre University Hospital CopenhagenHvidovreDenmark
  2. 2.Department of Clinical GeneticsOdense University HospitalOdense CDenmark
  3. 3.Department of Clinical Research, Faculty of HealthUniversity of Southern DenmarkOdense CDenmark
  4. 4.Department of Clinical GeneticsUniversity Hospital Copenhagen RigshospitaletCopenhagenDenmark
  5. 5.Department of Clinical BiochemistryRigshospitaletGlostrupDenmark
  6. 6.OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical ResearchUniversity of Southern DenmarkOdense CDenmark
  7. 7.Department of Endocrinology and Internal MedicineAarhus University HospitalAarhus NDenmark
  8. 8.Department of Oral and Maxillofacial SurgeryUniversity Hospital Copenhagen RigshospitaletCopenhagenDenmark
  9. 9.Center for Rare Diseases, Department of PediatricsUniversity Hospital CopenhagenCopenhagenDenmark
  10. 10.Paediatric Section, Department of Orthopedic SurgeryUniversity Hospital Copenhagen RigshospitaletCopenhagenDenmark
  11. 11.Department of Clinical MedicineUniversity of CopenhagenCopenhagenDenmark

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