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Skeletal ciliopathies: a pattern recognition approach

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Abstract

Ciliopathy encompasses a diverse group of autosomal recessive genetic disorders caused by mutations in genes coding for components of the primary cilia. Skeletal ciliopathy forms a subset of ciliopathies characterized by distinctive skeletal changes. Common skeletal ciliopathies include Jeune asphyxiating thoracic dysplasia, Ellis–van Creveld syndrome, Sensenbrenner syndrome, and short-rib polydactyly syndromes. These disorders share common clinical and radiological features. The clinical hallmarks comprise thoracic hypoplasia with respiratory failure, body disproportion with a normal trunk length and short limbs, and severely short digits occasionally accompanied by polydactyly. Reflecting the clinical features, the radiological hallmarks consist of a narrow thorax caused by extremely short ribs, normal or only mildly affected spine, shortening of the tubular bones, and severe brachydactyly with or without polydactyly. Other radiological clues include trident ilia/pelvis and cone-shaped epiphysis. Skeletal ciliopathies are commonly associated with extraskeletal anomalies, such as progressive renal degeneration, liver disease, retinopathy, cardiac anomalies, and cerebellar abnormalities. In this article, we discuss the radiological pattern recognition approach to skeletal ciliopathies. We also describe the clinical and genetic features of skeletal ciliopathies that the radiologists should know for them to play an appropriate role in multidisciplinary care and scientific advancement of these complicated disorders.

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References

  1. Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet. 2012;160(3):165–74.

    CAS  Google Scholar 

  2. Zhang W, Taylor SP, Ennis HA, Forlenza KN, Duran I, Li B, et al. Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies. Hum Mutat. 2018;39(1):152–66.

    PubMed  CAS  Google Scholar 

  3. Yuan X, Serra RA, Yang S. Function and regulation of primary cilia and intraflagellar transport proteins in the skeleton. Ann N Y Acad Sci. 2015;1335:78–99.

    PubMed  CAS  Google Scholar 

  4. Schmidts M. Clinical genetics and pathobiology of ciliary chondrodysplasias. J Pediatric Genet. 2014;3(2):46–944.

    Google Scholar 

  5. Hammarsjo A, Wang Z, Vaz R, Taylan F, Sedghi M, Girisha KM, et al. Novel KIAA0753 mutations extend the phenotype of skeletal ciliopathies. Sci Rep. 2017;7(1):15585.

    PubMed  PubMed Central  CAS  Google Scholar 

  6. Dagoneau N, Goulet M, Genevieve D, Sznajer Y, Martinovic J, Smithson S, et al. DYNC2H1 mutations cause asphyxiating thoracic dystrophy and short rib-polydactyly syndrome, type III. Am J Hum Genet. 2009;84(5):706–11.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, et al. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167(12):2869–92.

    CAS  Google Scholar 

  8. Spranger J. Pattern recognition in bone dysplasias. Prog Clin Biol Res. 1985;200:315–42.

    PubMed  CAS  Google Scholar 

  9. Spranger J. Bone dysplasia 'families'. Pathol Immunopathol Res. 1988;7(1–2):76–80.

    PubMed  CAS  Google Scholar 

  10. Jeune M, Beraud C, Carron R. Asphyxiating thoracic dystrophy with familial characteristics. Arch Fr Pediatr. 1955;12(8):886–91.

    PubMed  CAS  Google Scholar 

  11. Oberklaid F, Danks DM, Mayne V, Campbell P. Asphyxiating thoracic dysplasia Clinical, radiological, and pathological information on 10 patients. Arch Dis Child. 1977;52(10):758–65.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Keppler-Noreuil KM, Adam MP, Welch J, Muilenburg A, Willing MC. Clinical insights gained from eight new cases and review of reported cases with Jeune syndrome (asphyxiating thoracic dystrophy). Am J Med Genet A. 2011;155(5):1021–32.

    Google Scholar 

  13. Waters AM, Beales PL. Ciliopathies: an expanding disease spectrum. Pediatr Nephrol. 2011;26(7):1039–56.

    PubMed  PubMed Central  Google Scholar 

  14. Aurora P, Wallis CE. Jeune syndrome (asphyxiating thoracic dystrophy) associated with Hirschsprung disease. Clin Dysmorphol. 1999;8(4):259–63.

    PubMed  CAS  Google Scholar 

  15. Tuz K, Bachmann-Gagescu R, O'Day DR, Hua K, Isabella CR, Phelps IG, et al. Mutations in CSPP1 cause primary cilia abnormalities and Joubert syndrome with or without Jeune asphyxiating thoracic dystrophy. Am J Hum Genet. 2014;94(1):62–72.

    PubMed  PubMed Central  CAS  Google Scholar 

  16. Shaheen R, Shamseldin HE, Loucks CM, Seidahmed MZ, Ansari S, Ibrahim Khalil M, et al. Mutations in CSPP1, encoding a core centrosomal protein, cause a range of ciliopathy phenotypes in humans. Am J Hum Genet. 2014;94(1):73–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Pirnar T, Neuhauser EB. Asphyxiating thoracic dystrophy of the newborn. Am J Roentgenol Radium Ther Nucl Med. 1966;98(2):358–64.

    PubMed  CAS  Google Scholar 

  18. Leonard O, Langer J. Thoracic–pelvic–phalangeal dystrophy. Radiology. 1968;91(3):447–56.

    Google Scholar 

  19. Shaheen R, Schmidts M, Faqeih E, Hashem A, Lausch E, Holder I, et al. A founder CEP120 mutation in Jeune asphyxiating thoracic dystrophy expands the role of centriolar proteins in skeletal ciliopathies. Hum Mol Genet. 2015;24(5):1410–9.

    PubMed  CAS  Google Scholar 

  20. Cavalcanti DP, Huber C, Sang KH, Baujat G, Collins F, Delezoide AL, et al. Mutation in IFT80 in a fetus with the phenotype of Verma-Naumoff provides molecular evidence for Jeune-Verma-Naumoff dysplasia spectrum. J Med Genet. 2011;48(2):88–92.

    PubMed  CAS  Google Scholar 

  21. Halbritter J, Bizet AA, Schmidts M, Porath JD, Braun DA, Gee HY, et al. Defects in the IFT-B component IFT172 cause Jeune and Mainzer-Saldino syndromes in humans. Am J Hum Genet. 2013;93(5):915–25.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Ellis RW, van Creveld S. A syndrome characterized by ectodermal dysplasia, polydactyly, chondro-dysplasia and congenital morbus cordis: report of three cases. Arch Dis Child. 1940;15(82):65–84.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. Weller SD. Chondro-ectodermal dysplasia (Ellis-Van Creveld syndrome). Proc R Soc Med. 1951;44(8):731–2.

    PubMed  CAS  Google Scholar 

  24. McKusick VA, Egeland JA, Eldridge R, Krusen DE. Dwarfism in the amish I. The Ellis-Van creveld syndrome. Bull Johns Hopkins Hosp. 1964;115:306–36.

  25. da Silva EO, Janovitz D, de Albuquerque SC. Ellis-van creveld syndrome: report of 15 cases in an inbred kindred. J Med Genet. 1980;17(5):349–56.

    PubMed  PubMed Central  Google Scholar 

  26. Ruiz-Perez VL, Ide SE, Strom TM, Lorenz B, Wilson D, Woods K, et al. Mutations in a new gene in Ellis-van creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000;24(3):283–6.

    PubMed  CAS  Google Scholar 

  27. Galdzicka M, Patnala S, Hirshman MG, Cai JF, Nitowsky H, Egeland JA, et al. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab. 2002;77(4):291–5.

    PubMed  CAS  Google Scholar 

  28. Tompson SW, Ruiz-Perez VL, Blair HJ, Barton S, Navarro V, Robson JL, et al. Sequencing EVC and EVC2 identifies mutations in two-thirds of Ellis-van Creveld syndrome patients. Hum Genet. 2007;120(5):663–70.

    PubMed  CAS  Google Scholar 

  29. Caparros-Martin JA, De Luca A, Cartault F, Aglan M, Temtamy S, Otaify GA, et al. Specific variants in WDR35 cause a distinctive form of Ellis-van Creveld syndrome by disrupting the recruitment of the EvC complex and SMO into the cilium. Hum Mol Genet. 2015;24(14):4126–37.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Sensenbrenner JA, Dorst JP, Owens RP. New syndrome of skeletal, dental and hair anomalies. Birth Defects Orig Artic Ser. 1975;11(2):372–9.

    PubMed  CAS  Google Scholar 

  31. Levin LS, Perrin JC, Ose L, Dorst JP, Miller JD, McKusick VA. A heritable syndrome of craniosynostosis, short thin hair, dental abnormalities, and short limbs: cranioectodermal dysplasia. J Pediatr. 1977;90(1):55–61.

    PubMed  CAS  Google Scholar 

  32. Zaffanello M, Diomedi-Camassei F, Melzi ML, Torre G, Callea F, Emma F. Sensenbrenner syndrome: a new member of the hepatorenal fibrocystic family. Am J Med Genet A. 2006;140(21):2336–400.

    PubMed  Google Scholar 

  33. Amar MJ, Sutphen R, Kousseff BG. Expanded phenotype of cranioectodermal dysplasia (Sensenbrenner syndrome). Am J Med Genet. 1997;70(4):349–52.

    PubMed  CAS  Google Scholar 

  34. Bacino CA, Dhar SU, Brunetti-Pierri N, Lee B, Bonnen PE. WDR35 mutation in siblings with Sensenbrenner syndrome: a ciliopathy with variable phenotype. Am J Med Genet A. 2012;158(11):2917–24.

    CAS  Google Scholar 

  35. Miyazaki O, Nishimura G, Kagami M, Ogata T. Radiological evaluation of dysmorphic thorax of paternal uniparental disomy 14. Pediatr Radiol. 2011;41(8):1013–9.

    PubMed  Google Scholar 

  36. Moosa S, Obregon MG, Altmuller J, Thiele H, Nurnberg P, Fano V, et al. Novel IFT122 mutations in three Argentinian patients with cranioectodermal dysplasia: expanding the mutational spectrum. Am J Med Genet A. 2016;170(5):1295–301.

    CAS  Google Scholar 

  37. Silveira KC, Moreno CA, Cavalcanti DP. Beemer-Langer syndrome is a ciliopathy due to biallelic mutations in IFT122. Am J Med Genet A. 2017;173(5):1186–9.

    PubMed  CAS  Google Scholar 

  38. Saldino RM, Noonan CD. Severe thoracic dystrophy with striking micromelia, abnormal osseous development, including the spine, and multiple visceral anomalies. Am J Roentgenol Radium Ther Nucl Med. 1972;114(2):257–63.

    PubMed  CAS  Google Scholar 

  39. Verma IC, Bhargava S, Agarwal S. An autosomal recessive form of lethal chondrodystrophy with severe thoracic narrowing, rhizoacromelic type of micromelia, polydacytly and genital anomalies. Birth Defects Orig Artic Ser. 1975;11(6):167–74.

    PubMed  CAS  Google Scholar 

  40. Naumoff P, Young LW, Mazer J, Amortegui AJ. Short rib-polydactyly syndrome type 3. Radiology. 1977;122(2):443–7.

    PubMed  CAS  Google Scholar 

  41. Huber C, Wu S, Kim AS, Sigaudy S, Sarukhanov A, Serre V, et al. WDR34 mutations that cause short-rib polydactyly syndrome type III/severe asphyxiating thoracic dysplasia reveal a role for the NF-kappaB pathway in cilia. Am J Hum Genet. 2013;93(5):926–31.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. McInerney-Leo AM, Schmidts M, Cortes CR, Leo PJ, Gener B, Courtney AD, et al. Short-rib polydactyly and Jeune syndromes are caused by mutations in WDR60. Am J Hum Genet. 2013;93(3):515–23.

    PubMed  PubMed Central  CAS  Google Scholar 

  43. Spranger JW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone dysplasias. 3rd ed. New York: Oxford University Press; 2012.

    Google Scholar 

  44. Majewski F, Pfeiffer RA, Lenz W, Müller R, Feil G, Seiler R. Polysyndaktylie, verkürzte Gliedmaßen und Genitalfehlbildungen: Kennzeichen eines selbständigen Syndroms? Z Kinderheilkd. 1971;111(2):118–38.

    PubMed  CAS  Google Scholar 

  45. Baraitser M, Burn J, Fixsen J. A female infant with features of Mohr and Majewski syndromes: variable expression, a genetic compound, or a distinct entity? J Med Genet. 1983;20(1):65–7.

    PubMed  PubMed Central  CAS  Google Scholar 

  46. Burn J, Dezateux C, Hall CM, Baraitser M. Orofaciodigital syndrome with mesomelic limb shortening. J Med Genet. 1984;21(3):189–92.

    PubMed  PubMed Central  CAS  Google Scholar 

  47. El Hokayem J, Huber C, Couve A, Aziza J, Baujat G, Bouvier R, et al. NEK1 and DYNC2H1 are both involved in short rib polydactyly Majewski type but not in Beemer Langer cases. J Med Genet. 2012;49(4):227–33.

    PubMed  Google Scholar 

  48. Thomas S, Legendre M, Saunier S, Bessieres B, Alby C, Bonniere M, et al. TCTN3 mutations cause Mohr–Majewski syndrome. Am J Hum Genet. 2012;91(2):372–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  49. Beemer FA, Langer LO Jr, Klep-de Pater JM, Hemmes AM, Bylsma JB, Pauli RM, et al. A new short rib syndrome: report of two cases. Am J Med Genet. 1983;14(1):115–23.

    PubMed  CAS  Google Scholar 

  50. Bizaoui V, Huber C, Kohaut E, Roume J, Bonniere M, Attie-Bitach T, et al. Mutations in IFT80 cause SRPS type IV Report of two families and review. Am J Med Genet A. 2019;179(4):639–44.

    PubMed  Google Scholar 

  51. Mainzer F, Saldino RM, Ozonoff MB, Minagi H. Familial nephropathy associated with retinitis pigmentosa, cerebellar ataxia and skeletal abnormalities. Am J Med. 1970;49(4):556–62.

    PubMed  CAS  Google Scholar 

  52. Giedion A. Phalangeal cone shaped epiphysis of the hands (PhCSEH) and chronic renal disease—the conorenal syndromes. Pediatr Radiol. 1979;8(1):32–8.

    PubMed  CAS  Google Scholar 

  53. Ehara S, Kim OH, Maisawa S, Takasago Y, Nishimura G. Axial spondylometaphyseal dysplasia. Eur J Pediatr. 1997;156(8):627–30.

    PubMed  CAS  Google Scholar 

  54. Wang Z, Horemuzova E, Iida A, Guo L, Liu Y, Matsumoto N, et al. Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations. J Hum Genet. 2017;62(4):503–6.

    PubMed  CAS  Google Scholar 

  55. Oud MM, Lamers IJ, Arts HH. Ciliopathies: genetics in pediatric medicine. J Pediatr Genet. 2017;6(1):18–29.

    PubMed  CAS  Google Scholar 

  56. Ehlen HW, Buelens LA, Vortkamp A. Hedgehog signaling in skeletal development. Birth Defects Res Part C Embryo Today Rev. 2006;78(3):267–79.

    CAS  Google Scholar 

  57. Kunova Bosakova M, Varecha M, Hampl M, Duran I, Nita A, Buchtova M, et al. Regulation of ciliary function by fibroblast growth factor signaling identifies FGFR3-related disorders achondroplasia and thanatophoric dysplasia as ciliopathies. Hum Mol Genet. 2018;27(6):1093–105.

    PubMed  PubMed Central  Google Scholar 

  58. Martin L, Kaci N, Estibals V, Goudin N, Garfa-Traore M, Benoist-Lasselin C, et al. Constitutively-active FGFR3 disrupts primary cilium length and IFT20 trafficking in various chondrocyte models of achondroplasia. Hum Mol Genet. 2018;27(1):1–13.

    PubMed  CAS  Google Scholar 

  59. Wang C, Yuan X, Yang S. IFT80 is essential for chondrocyte differentiation by regulating Hedgehog and Wnt signaling pathways. Exp Cell Res. 2013;319(5):623–32.

    PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

Part of this article was originally presented at the 104th annual meeting of the Radiological Society of North America (RSNA) in Chicago, 2018. It received a Certification of Merit for an education exhibit.

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Authors and Affiliations

  1. Department of Radiology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA

    Atsuhiko Handa

  2. Department of Radiology, Karolinska University Hospital, Stockholm, Sweden

    Ulrika Voss

  3. Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet and Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

    Anna Hammarsjö & Giedre Grigelioniene

  4. Center for Intractable Diseases, Saitama University Hospital, Saitama, Japan

    Gen Nishimura

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  1. Atsuhiko Handa
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  2. Ulrika Voss
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  5. Gen Nishimura
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Correspondence to Atsuhiko Handa.

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Handa, A., Voss, U., Hammarsjö, A. et al. Skeletal ciliopathies: a pattern recognition approach. Jpn J Radiol 38, 193–206 (2020). https://doi.org/10.1007/s11604-020-00920-w

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