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


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.


Pycnodysostosis Hypophosphatasia CTSK Fracture Bone healing 



Alkaline phosphatase


TNSALP encoding gene


Bone-specific alkaline phosphatase


Bone mineral content


Bone mass density


Continuous positive airway pressure


Computed tomography


Cathepsin K


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


Normal range








Inorganic phosphate


Plasma procollagen type 1 N-terminal propeptide




Inorganic pyrophosphate


Parathyroid hormone


Reference data


Trabecular bone score


Tissue non-specific alkaline phosphatase


Tartrate-resistant acid phosphatase-5b


Volumetric bone mineral density


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.


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)


  1. 1.
    Maroteaux P, Lamy M (1962) Pyknodysostosis. Presse Med 70:999–1002Google Scholar
  2. 2.
    Rodrigues C, Gomes FA, Arruda JA, Silva L, da Fonte Alvares P, Sobral AP, Silveira M (2017) Clinical and radiographic features of pycnodysostosis: a case report. J Clin Exp Dent 9:e1276–e1281CrossRefGoogle Scholar
  3. 3.
    Gelb BD, Edelson JG, Desnick RJ (1995) Linkage of pycnodysostosis to chromosome 1q21 by homozygosity mapping. Nat Genet 10:235–237CrossRefGoogle Scholar
  4. 4.
    Dhameliya MD, Dinkar AD, Khorate M, Raut Dessai SS (2017) Pycnodysostosis: clinicoradiographic report of a rare case. Contemp Clin Dent 8:134–138CrossRefGoogle Scholar
  5. 5.
    Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis A lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238CrossRefGoogle Scholar
  6. 6.
    Ketterer S, Gomez-Auli A, Hillebrand LE, Petrera A, Ketscher A, Reinheckel T (2017) Inherited diseases caused by mutations in cathepsin protease genes. FEBS J 284:1437–1454CrossRefGoogle Scholar
  7. 7.
    Ortegosa MV, Bertola DR, Aguena M, Passos-Bueno MR, Kim CA, de Faria ME (2014) Challenges in the orthodontic treatment of a patient with pycnodysostosis. Cleft Palate Craniofac J 51:735–739CrossRefGoogle Scholar
  8. 8.
    Mujawar Q, Naganoor R, Patil H, Thobbi AN, Ukkali S, Malagi N (2009) Pycnodysostosis with unusual findings: a case report. Cases J 2:6544CrossRefGoogle Scholar
  9. 9.
    Otaify GA, Abdel-Hamid MS, Mehrez MI, Aboul-Ezz E, Zaki MS, Aglan MS, Temtamy SA (2018) Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect. Osteoporos Int 29:1833–1841CrossRefGoogle Scholar
  10. 10.
    Orimo H (2010) The mechanism of mineralization and the role of alkaline phosphatase in health and disease. J Nippon Med Sch 77:4–12CrossRefGoogle Scholar
  11. 11.
    Weiss MJ, Cole DE, Ray K, Whyte MP, Lafferty MA, Mulivor RA, Harris H (1988) A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia. Proc Natl Acad Sci USA 85:7666–7669CrossRefGoogle Scholar
  12. 12.
    Schmidt T, Mussawy H, Rolvien T, Hawellek T, Hubert J, Ruther W, Amling M, Barvencik F (2017) Clinical, radiographic and biochemical characteristics of adult hypophosphatasia. Osteoporos Int 28:2653–2662CrossRefGoogle Scholar
  13. 13.
    Hofmann C, Girschick HJ, Mentrup B, Graser S, Seefried L, Liese J, Jakob F (2013) Clinical aspects of hypophosphatasia: an update. Clin Rev Bone Miner Metab 11:60–70CrossRefGoogle Scholar
  14. 14.
    Millan JL, Whyte MP (2016) Alkaline phosphatase and hypophosphatasia. Calcif Tissue Int 98:398–416CrossRefGoogle Scholar
  15. 15.
    Riancho-Zarrabeitia L, Garcia-Unzueta M, Tenorio JA, Gomez-Gerique JA, Ruiz Perez VL, Heath KE, Lapunzina P, Riancho JA (2016) Clinical, biochemical and genetic spectrum of low alkaline phosphatase levels in adults. Eur J Intern Med 29:40–45CrossRefGoogle Scholar
  16. 16.
    Rajan AR, Singh V, Bhave AA, Joshi CS (2015) Pycnodysostosis: a rare cause of short stature. Med J Armed Forces India 71:393–395CrossRefGoogle Scholar
  17. 17.
    Song HK, Sohn YB, Choi YJ, Chung YS, Jang JH (2017) A case report of pycnodysostosis with atypical femur fracture diagnosed by next-generation sequencing of candidate genes. Medicine (Baltimore) 96:e6367CrossRefGoogle Scholar
  18. 18.
    Xue Y, Cai T, Shi S, Wang W, Zhang Y, Mao T, Duan X (2011) Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011. Orphanet J Rare Dis 6:20CrossRefGoogle Scholar
  19. 19.
    Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA (2000) Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet 8:431–436CrossRefGoogle Scholar
  20. 20.
    Hansen S, Shanbhogue V, Folkestad L, Nielsen MM, Brixen K (2014) Bone microarchitecture and estimated strength in 499 adult Danish women and men: a cross-sectional, population-based high-resolution peripheral quantitative computed tomographic study on peak bone structure. Calcif Tissue Int 94:269–281CrossRefGoogle Scholar
  21. 21.
    Rabelo FD, do Prado CH, Rabelo FL, Martins L (2010) Reconsiderations regarding time of fracture healing in pycnodysostosis. Rev Bras Ortop 45:606–611CrossRefGoogle Scholar
  22. 22.
    Rovira Marti P, Ullot Font R (2016) Orthopaedic disorders of pycnodysostosis: a report of five clinical cases. Int Orthop 40:2221–2231CrossRefGoogle Scholar
  23. 23.
    Leung HW, Wong CW, Shen WY (2008) Intramedullary nailing for adult hypophosphatasia: a case report. J Orthop Surg (Hong Kong) 16:385–388CrossRefGoogle Scholar
  24. 24.
    Marsell R, Einhorn TA (2011) The biology of fracture healing. Injury 42:551–555CrossRefGoogle Scholar
  25. 25.
    Morcos MW, Al-Jallad H, Li J, Farquharson C, Millan JL, Hamdy RC, Murshed M (2018) PHOSPHO1 is essential for normal bone fracture healing: an animal study. Bone Joint Res 7:397–405CrossRefGoogle Scholar
  26. 26.
    Hosking DJ (1978) Changes in serum alkaline phosphatase after femoral fractures. J Bone Joint Surg Br 60:61–65CrossRefGoogle Scholar
  27. 27.
    Knoch HG (1990) Die Ultraschallwirkung auf das Kallusgewebe. In: Knoch HG (ed) Knochenbruchheilung mit Ultraschall. Springer-Verlag, Berlin, pp 71–72CrossRefGoogle Scholar
  28. 28.
    Komnenou A, Karayannopoulou M, Polizopoulou ZS, Constantinidis TC, Dessiris A (2005) Correlation of serum alkaline phosphatase activity with the healing process of long bone fractures in dogs. Vet Clin Pathol 34:35–38CrossRefGoogle Scholar
  29. 29.
    Novinec M, Lenarcic B (2013) Cathepsin K: a unique collagenolytic cysteine peptidase. Biol Chem 394:1163–1179CrossRefGoogle Scholar
  30. 30.
    Lopez-Delgado L, Riancho-Zarrabeitia L, Garcia-Unzueta MT, Tenori JA, Garcia-Hoyos M, Lapunzina P, Valero C, Riancho JA (2018) Abnormal bone turnover in individuals with low serum alkaline phosphatase. Osteoporos Int 29:2147–2150CrossRefGoogle Scholar
  31. 31.
    Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032–1045CrossRefGoogle Scholar
  32. 32.
    Kelly T (1990) Bone mineral reference databases for american men and women. J Bone Miner Res 5:249Google Scholar
  33. 33.
    Kanis JA, Adachi JD, Cooper C, Clark P, Cummings SR, Diaz-Curiel M, Harvey N, Hiligsmann M, Papaioannou A, Pierroz DD, Silverman SL, Szulc P (2013) Standardising the descriptive epidemiology of osteoporosis: recommendations from the Epidemiology and Quality of Life Working Group of IOF. Osteoporos Int 24:2763–2764CrossRefGoogle Scholar
  34. 34.
    Burghardt AJ, Link TM, Majumdar S (2011) High-resolution computed tomography for clinical imaging of bone microarchitecture. Clin Orthop Relat Res 469:2179–2193CrossRefGoogle Scholar
  35. 35.
    HansenS Brixen K, Gravholt CH (2012) Compromised trabecular microarchitecture and lower finite element estimates of radius and tibia bone strength in adults with turner syndrome: a cross-sectional study using high-resolution-pQCT. J Bone Miner Res 27:1794–1803CrossRefGoogle Scholar

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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