Skip to main content

Advertisement

SpringerLink
Log in

Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

This is the first Egyptian study with detailed clinical and orodental evaluation of eight patients with pycnodysostosis and identification of four mutations in CTSK gene with two novel ones and a founder effect.

Introduction

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia due to mutations in the CTSK gene encoding for cathepsin K, a lysosomal cysteine protease.

Methods

We report on the clinical, orodental, radiological, and molecular findings of eight patients, from seven unrelated Egyptian families with pycnodysostosis.

Results

All patients were offspring of consanguineous parents and presented with the typical clinical picture of the disorder including short stature, delayed closure of fontanels, hypoplastic premaxilla, obtuse mandibular angle, and drum stick terminal phalanges with dysplastic nails. Their radiological findings showed increased bone density, acro-osteolysis, and open cranial sutures. Mutational analysis of CTSK gene revealed four distinct homozygous missense mutations including two novel ones, c.164A>C (p. K55T) and c.433G>A (p.V145M). The c.164A>C (p. K55T) mutation was recurrent in three unrelated patients who also shared similar haplotype, suggesting a founder effect.

Conclusion

Our findings expand the mutational spectrum of CTSK gene and emphasize the importance of full clinical examination of all body systems including thorough orodental evaluation in patients with pycnodysostosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Arman A, Bereket A, Coker A, Kiper PÖ, Güran T, Ozkan B, Atay Z, Akçay T, Haliloglu B, Boduroglu K, Alanay Y, Turan S (2014) Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features. Orphanet J Rare Dis 9:60. https://doi.org/10.1186/1750-1172-9-60

    Article  PubMed  PubMed Central  Google Scholar 

  2. Morateaux P, Lamy M (1962) Pyknodysostosis. Presse Med 70:999–1002

    Google Scholar 

  3. Muto T, Michiya H, Taira H, Murase H, Kanazawa M (1991) Pycnodysostosis. Report of a case and review of the Japanese literature, with emphasis on oral and maxillofacial findings. Oral Surg Oral Med Oral Pathol 72:449–455

    Article  PubMed  CAS  Google Scholar 

  4. Alves N, Cantín M (2014) Clinical and radiographic maxillofacial features of pycnodysostosis. Int J Clin Exp Med 7(3):492–496

    PubMed  PubMed Central  Google Scholar 

  5. 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(1):20. https://doi.org/10.1186/1750-1172-6-20

    Article  PubMed  PubMed Central  Google Scholar 

  6. Araujo TF, Ribeiro EM, Arruda AP, Moreno CA, Medeiros PF, Minillo RM, Melo DG, Kim CA, Doriqui MJ, Felix TM, Fock RA (2016) Molecular analysis of the CTSK gene in a cohort of 33 Brazilian families with pycnodysostosis from a cluster in a Brazilian Northeast region. Eur J Med Res 21(1):33

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Turan S (2014) Current research on pycnodysostosis. Intractable Rare Dis Res 3:91–93

    Article  PubMed  PubMed Central  Google Scholar 

  8. Toral-López J, Gonzalez-Huerta LM, Sosa B, Orozco S, González HP, Cuevas-Covarrubias SA (2011) Familial pycnodysostosis: identification of a novel mutation in the CTSK gene (cathepsin K). J Investig Med 59(2):277–280. https://doi.org/10.231/JIM.0b013e318202a9db

  9. Utokpat P, Panmontha W, Tongkobpetch S, Suphapeetiporn K, Shotelersuk V (2013) Novel CTSK mutation resulting in an entire exon 2 skipping in a Thai girl with pycnodysostosis. Pediatr Int 55(5):651–655. https://doi.org/10.1111/ped.12091

    Article  PubMed  CAS  Google Scholar 

  10. Huang X, Qi X, Li M, Wang O, Jiang Y, Xing X, Hu Y, Xia W (2015) A mutation in CTSKgene in an autosomal recessive pycnodysostosis family of Chinese origin. Calcif Tissue Int 96:373–378. https://doi.org/10.1007/s00223-015-9963-y

    Article  PubMed  CAS  Google Scholar 

  11. 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(12):e6367. https://doi.org/10.1097/MD.0000000000006367

    Article  Google Scholar 

  12. Donnarumma M, Regis S, Tappino B, Rosano C, Assereto S, Corsolini F, Di Rocco M, Filocamo M (2007) Molecular analysis and characterization of nine novel CTSK mutations in twelve patients affected by pycnodysostosis. Hum Mutat 28:524–533. https://doi.org/10.1002/humu.9490

    Article  PubMed  Google Scholar 

  13. Gelb B, Shi G, Chapman H, Desnick R (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238

    Article  PubMed  CAS  Google Scholar 

  14. Osimani S, Husson I, Passemard S, Elmaleh M, Perrin L, Quelin C, Marey I, Delalande O, Filocamo M, Verloes A (2010) Craniosynostosis: a rare complication of pycnodysostosis. Eur J Med Genet 53:89–92. https://doi.org/10.1016/j.ejmg.2009.12.001

    Article  PubMed  Google Scholar 

  15. Bertola D, Amaral C, Kim C, Albano L, Aguena M, Passos-Bueno MR (2010) Craniosynostosis in pycnodysostosis: broadening the spectrum of the cranial flat bone abnormalities. Am J Med Genet A 152A:2599–2603. https://doi.org/10.1002/ajmg.a.33609

    Article  PubMed  Google Scholar 

  16. Rothenbühler A, Piquard C, Gueorguieva I, Lahlou N, Linglart A, Bougnères P (2010) Near normalization of adult height and body proportions by growth hormone in pycnodysostosis. J Clin Endocrinol Metab 95:2827–2831. https://doi.org/10.1210/jc.2009-2531

    Article  PubMed  CAS  Google Scholar 

  17. Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB (2006) Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21(6):865–875. https://doi.org/10.1359/jbmr.060313

    Article  PubMed  CAS  Google Scholar 

  18. Yates CJ, Bartlett MJ, Ebeling PR (2011) An atypical subtrochanteric femoral fracture from pycnodysostosis: a lesson from nature. J Bone Miner Res 26(6):1377–1379. https://doi.org/10.1002/jbmr.308

    Article  PubMed  Google Scholar 

  19. Hashem J, Krochak R, Culbertson MD, Mileto C, Goodman H (2015) Atypical femur fractures in a patient with pycnodysostosis: a case report. Osteoporos Int 26(8):2209–2212. https://doi.org/10.1007/s00198-015-3191-1

    Article  PubMed  CAS  Google Scholar 

  20. Chen W, Yang S, Abe Y, Li M, Wang Y, Shao J, Li E, Li YP (2007) Novel pycnodysostosis mouse model uncovers cathepsin K function as a potential regulator of osteoclast apoptosis and senescence. Hum Mol Genet 16:410–423. https://doi.org/10.1093/hmg/ddl474

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gowen M, Lazner F, Dodds R, Kapadia R, Feild J, Tavaria M, Bertoncello I, Drake F, Zavarselk S, Tellis I, Hertzog P (1999) Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 14:1654–1663. https://doi.org/10.1359/jbmr.1999.14.10.1654

    Article  PubMed  CAS  Google Scholar 

  22. Kiviranta R, Morko J, Alatalo SL, NicAmhlaoibh R, Risteli J, Laitala-Leinonen T, Vuorio E (2005) Impaired bone resorption in cathepsin K-deficient mice is partially compensated for by enhanced osteoclastogenesis and increased expression of other proteases via an increased RANKL/OPG ratio. Bone 36:159–172. https://doi.org/10.1016/j.bone.2004.09.020

    Article  PubMed  CAS  Google Scholar 

  23. Capan E, Turan S, Kilicoglu H (2015) Clinical and cephalometric analysis of three cases with pycnodysostosis: case reports. J Istanbul Univ Fac Dent 49:51–55. https://doi.org/10.17096/jiufd.70673

    Article  Google Scholar 

  24. Wen X, Yi LZ, Liu F, Wei JH, Xue Y (2016) The role of cathepsin K in oral and maxillofacial disorders. Oral Dis 22(2):109–115. https://doi.org/10.1111/odi.12378.

    Article  PubMed  CAS  Google Scholar 

  25. Zhou J, Zhao Y, Xia C, Jiang L (2012) Periodontitis with hypercementosis: report of a case and discussion of possible aetiologic factors. Aust Dent J 57:511–514. https://doi.org/10.1111/j.1834-7819.2012.01725.x

    Article  PubMed  CAS  Google Scholar 

  26. Xue Y, Wang L, Xia D, Li Q, Gao S, Dong M, Cai T, Shi S, He L, Hu K, Mao T, Duan X (2015) Dental abnormalities caused by novel compound heterozygous CTSK mutations. J Dent Res 94:674–681. https://doi.org/10.1177/0022034515573964

    Article  PubMed  CAS  Google Scholar 

  27. Valdes-Flores M, Hidalgo-Bravo A, Casas-Avila L, Chima-Galan C, Hazan-Lasri EJ, Pineda-Gomez E, Lopez-Estrada D, Zenteno JC (2014) Molecular and clinical analysis in a series of patients with pyknodysostosis reveals some uncommon phenotypic findings. Int J Clin Exp Med 7:3915–3923

    PubMed  PubMed Central  Google Scholar 

  28. Alves Pereira D, Berini Aytes L, Gay Escoda C (2008) Pycnodysostosis. A report of 3 clinical cases. Med Oral Patol Oral Cir Bucal 13:E633–E635

    PubMed  Google Scholar 

  29. Mujawar Q, Naganoor R, Patil H, Thobbi AN, Ukkali S, Malagi N (2009) Pycnodysostosis with unusual findings: a case report. Cases J 2:6544–6547. https://doi.org/10.4076/1757-1626-2-6544

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tolar J, Teitelbaum SL, Orchard PJ (2004) Osteopetrosis. N Engl J Med 351:2839–2849. https://doi.org/10.1056/NEJMra040952

    Article  PubMed  Google Scholar 

  31. Ketterer S, Gomez-Auli A, Hillebrand LE, Petrera A, Ketscher A, Reinheckel T (2016) Inherited diseases caused by mutations in cathepsin protease genes. FEBS J 284:1437–1454. https://doi.org/10.1111/febs.13980

    Article  CAS  Google Scholar 

  32. Berenguer A, Freitas AP, Ferreira G, Nunes JL (2012) A child with bone fractures and dysmorphic features: remember of pycnodysostosis and craniosynostosis. BMJ Case Rep 2012:bcr2012006930. https://doi.org/10.1136/bcr-2012-006930

    Article  PubMed  PubMed Central  Google Scholar 

  33. Caracas HP, Figueiredo PS, Mestrinho HD, Acevedo AC, Leite AF (2012) Pycnodysostosis with craniosynostosis: case report of the craniofacial and oral features. Clin Dysmorphol 21:19–21. https://doi.org/10.1097/MCD.0b013e32834c7da7

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all patients and their families for participation in the study. This work was supported by STDF project no. 5253.

Author information

Authors and Affiliations

  1. Clinical Genetics Department, Human Genetics and Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt

    G. A. Otaify, M. S. Zaki, M. S. Aglan & S. A. Temtamy

  2. Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt

    M. S. Abdel-Hamid

  3. Orodental Genetics Department, Human Genetics and Genome Research Division, Center of Excellence for Human Genetics, National Research Centre, Cairo, Egypt

    M. I. Mehrez

  4. Dental Basic Science Department, Dental and Oral Research Division, National Research Centre, Cairo, Egypt

    E. Aboul-Ezz

Authors
  1. G. A. Otaify
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. S. Abdel-Hamid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. I. Mehrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E. Aboul-Ezz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. S. Zaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. S. Aglan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. A. Temtamy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. A. Otaify.

Ethics declarations

Conflicts of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Otaify, G.A., Abdel-Hamid, M.S., Mehrez, M.I. et al. Genetic study of eight Egyptian patients with pycnodysostosis: identification of novel CTSK mutations and founder effect. Osteoporos Int 29, 1833–1841 (2018). https://doi.org/10.1007/s00198-018-4555-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-018-4555-0

Keywords

Search

Navigation