Journal of Assisted Reproduction and Genetics

, Volume 26, Issue 8, pp 455–460 | Cite as

Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: a 9-year experience

Prenatal diagnosis in FGFR3 gene
  • M. J. Trujillo-Tiebas
  • M. Fenollar-Cortés
  • I. Lorda-Sánchez
  • J. Díaz-Recasens
  • A. Carrillo Redondo
  • C. Ramos-Corrales
  • C. Ayuso
GENETICS

Abstract

Purpose

Prenatal diagnosis with ultrasound findings compatible with skeletal dysplasia due to FGFR3 mutations over a 9 year period in pregnancies and abortuses.

Methods

54 samples were studied. Aneuploidy studies were carried out on all samples. By sequencing analysis, we determined mutations for achondroplasia (ACH), hypochondroplasia (HCH), and type I and type II tanathophoric dysplasia (TD).

Results

2 chorionic villi samples had a G380R mutation due to a mother with ACH; 4 amniotic fluid samples with TDs in which the foetuses had micromelia plus hypoplastic thoraces; 5 samples from abortuses with TDs. Neither ACH nor HCH occurred in sporadic cases.

Conclusions

Molecular studies in ongoing pregnancies are indicated in cases with an affected parent, a family history with positive molecular studies (maternal anxiety), and when the US finding demonstrates micromelia with a hypoplastic thorax. A protocol for tissues of abortuses should include an X-ray, pathologic anatomy, and genetic studies.

Keywords

FGFR3 gene Prenatal diagnosis Skeletal dysplasias Ultrasound finding 

Notes

Acknowledgements

This group is founded by the Centro de Investigaciones Biomédicas en Red de Enfermedades Raras (CIBERER) [ISCIII, Madrid, Spain]. We would like to thank to the Fundación Ramón Areces and INERGEN (FIS PIC03/05; FIS PI05/0263) for its support.

References

  1. 1.
    Spranger J. Bone dysplasia families. Pathol Immunpathol Res. 1988;7:76–80.CrossRefGoogle Scholar
  2. 2.
    Keegan K, Johnson DE, Williams LT, Hayman MJ. Isolation of an additional member of the fibroblast growth factor receptor family, FGFR3. Proc Acad Sci USA. 1991;88:1095–1099.CrossRefGoogle Scholar
  3. 3.
    Keegan K, Rooke L, Hayman M, Spurr NK. The fibroblast growth factor receptor 3 gene (FGFR3) is assigned to human chromosome 4. Cytogenet Cell Genet. 1993;62:172–175. 12.CrossRefPubMedGoogle Scholar
  4. 4.
    Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasia, Muenke craniosynostosis and Crouzon syndrome with acanthosis nigricans. Endocr Rev. 2000;21:23–39.CrossRefPubMedGoogle Scholar
  5. 5.
    Orioli IM, Castila EE, Barbosa-Neto JG. The birth prevalence rates for the skeletal dysplasias. J Med Genet. 1986;23:328–332.CrossRefPubMedGoogle Scholar
  6. 6.
    Martínez-Frías ML, Cereijo A, Bermejo E, López M, Sánchez M, Golnalo C. Epidemiological aspects fo Mendelian syndromes in a Spanish population sample: I. autosomal dominant malformation syndromes. Am J Med Genet. 1991;38:622–625.CrossRefPubMedGoogle Scholar
  7. 7.
    Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, et al. Thanatophoric dysplasia (types I and II) caused by distint mutations in fibroblast growth factor receptor 3. Nat Genet. 1995;9:321–328.CrossRefPubMedGoogle Scholar
  8. 8.
    Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, et al. A novel skeletal dysplasia with developmental delay and acanthosis nigricans is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3 gene. Am J Hum Genet. 1999;64:722–731.CrossRefPubMedGoogle Scholar
  9. 9.
    Stoll C, Dott B, Roth MP, Alembik Y. Birth prevalence rates of skeletal dysplasias. Clin Genet. 1989;35:88–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Rolf C, Nieschlag E. Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109:68–74.CrossRefPubMedGoogle Scholar
  11. 11.
    Wyrobeck AJ, Eskenazi B, Young S, Arnheim N, Tieman-Boege I, Jabs EW, et al. Advancing age has different effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies sperm. Proc Natl Aca Sci USA. 2006;103:9601–9606.CrossRefGoogle Scholar
  12. 12.
    Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, et al. Mutations in the gene encoding fibroblast receptor growth factor receptor-3 in achondroplasia. Nature. 1994;371:252–254.CrossRefPubMedGoogle Scholar
  13. 13.
    Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmenbrane domain of FGFR3 cause the most common genetic form of dawrfism, achondroplasia. Cell. 1994;78:335–342.CrossRefPubMedGoogle Scholar
  14. 14.
    Climent C, Lorda I, Urioste M, Gairi JM, Rodriguez JI, Rubio V. Acondroplasia: estudio molecular de 28 pacientes. Med Clin. 1998;110:492–494.Google Scholar
  15. 15.
    Bellus GA, McIntosh I, Smith EA, Aylsworth AS, Kaitila I, Horton WA, et al. A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nat Genet. 1995;10:357–359.CrossRefPubMedGoogle Scholar
  16. 16.
    Rousseau F, Bonaventure J, Legeai-Mallet L, Schmidt H, Weissenbach J, Maroteaux P, et al. Clinical and genetic heterogeneity of hypochondroplasia. J Med Genet. 1996;33:749–752.CrossRefPubMedGoogle Scholar
  17. 17.
    Parrilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor S. Antenatal detection of skeletal dysplasias. J Ultrasound Med. 2003;22:255–258.Google Scholar
  18. 18.
    Adinolfi M, Pertl B, Sherlock J. Rapid detection of aneuploidies by microsatellite and the quantitative fluorescent polymerase chain reaction. Prenat Diagn. 1997;17:1299–1311.CrossRefPubMedGoogle Scholar
  19. 19.
    Wapner RJ, Sorokin Y, Thom EA, Jonhson F, Dudley DJ, Spong CT, et al. Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol. 2006;195:633–642.CrossRefPubMedGoogle Scholar
  20. 20.
    Trujillo-Tiebas MJ, Riveiro R, Queipo A, Vallespin E, Cantalapiedra D, Lorda-Sánchez I, et al. Gene Symbol: FGFR3. Hum Genet. 2004;115(4):348.Google Scholar
  21. 21.
    Karadimas C, Sifakis S, Valsamopoulos P, Makatsoris C, Velissariou V, Nasioulas G, et al. Prenatal diagnosis of hypochondroplasia: report of two cases. Am J Med Genet Part A. 2006;140:998–1003.PubMedGoogle Scholar
  22. 22.
    Gooding HC, Boehm K, Thompson RE, Hadley D, Francomano CA, Bowles BB. Issues sorrounding prenatal testing for achondroplasia. Prenat Diagn. 2002;22:933–940.CrossRefPubMedGoogle Scholar
  23. 23.
    Camera G, Dodero D, De Pascale S. Prenatal diagnosis of thanatophoric dysplasia at 24 weeks. Am J Med Genet. 1984;18:39–43.CrossRefPubMedGoogle Scholar
  24. 24.
    Elejalde BR, Elejalde MM. Thanatophoric dysplasia: fetal manifestations and prenatal diagnosis. Am J Med Genet. 1985;22:669–683.CrossRefPubMedGoogle Scholar
  25. 25.
    Chen Ch-P, Chern S-R, Shih J-Ch, Wayseen W, Yeh L-F, Chang T-Y, et al. Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia. Prenat Diagn. 2001;21:89–95.CrossRefPubMedGoogle Scholar
  26. 26.
    Todros T, Massarenti I, Gaglioti P, Biolcati G, De Felice C. Fetal short femur length in the second trimester and the outcome of pregnancy. BJOG. 2004;111:83–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Modaff P, Horton VK, Pauli RM. Errors in the prenatal diagnosis of children with achondroplasia. Prenat Diagn. 1996;16:525–530.CrossRefPubMedGoogle Scholar
  28. 28.
    Kataoka S, Sawai H, Yamada H, Kanazawa N, Koyama K, Nishimura G, et al. Radiographic and genetic diagnosis of sporadic hypochondroplasia early in the neonatal period. Prenat Diagn. 2004;24:45–49.CrossRefPubMedGoogle Scholar
  29. 29.
    Ramalho C, Matias A, Brandão O, Montenegro N. Critical evaluation of elective termination of pregnancy in a tertiary fetal medicine center during 43 months: correlation of prenatal diagnosis findings and postmortem examination. Prenat Diagn. 2006;26:1084–1088.CrossRefPubMedGoogle Scholar
  30. 30.
    Aslan H, Yldirim G, Ongut C, Ceylan Y. Termination of pregnancy for fetal anomaly. Int J Gynaecol Obstet. 2007;99:221–224.CrossRefPubMedGoogle Scholar
  31. 31.
    Guillem P, Fabre B, Cans C, Robert-Gnansia E, Jouk PS. Trends in elective termination of pregnancy between 1989 and 2000 in French county (the Isère). Prenat Diagn. 2003;23:877–883.CrossRefPubMedGoogle Scholar
  32. 32.
    Vaknin Z, Ben-Ami I, Reish O, Herman A, Maymon R. Fetal abnormalities leading to termination of singleton pregnancy: the 7-year experience of a single medical center. Prenat Diagn. 2006;26:938–943.CrossRefPubMedGoogle Scholar
  33. 33.
    Orioli IM, Castilla EE, Scarano G, Mastroiacovo P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am J Med Genet. 1995;50:209–217.CrossRefGoogle Scholar
  34. 34.
    Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, et al. Mutation in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998;63:711–716.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • M. J. Trujillo-Tiebas
    • 1
  • M. Fenollar-Cortés
    • 2
    • 3
  • I. Lorda-Sánchez
    • 1
  • J. Díaz-Recasens
    • 4
  • A. Carrillo Redondo
    • 1
  • C. Ramos-Corrales
    • 1
  • C. Ayuso
    • 1
  1. 1.Department of GeneticsFundación Jiménez Díaz (CIBERER)MadridSpain
  2. 2.Departamento de GenéticaServicio de Análisis Clínicos, Hospital Clínicos San Carlos, C/ Prof Martín Lagos s/nMadridSpain
  3. 3.Predoctoral fellow in Fundación Jiménez DíazMadridSpain
  4. 4.Department of GynecologyFundación Jiménez DíazMadridSpain

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