Archives of Gynecology and Obstetrics

, Volume 283, Issue 4, pp 909–916 | Cite as

Craniosynostosis: prenatal diagnosis by means of ultrasound and SSSE-MRI. Family series with report of neurodevelopmental outcome and review of the literature

  • Gabriele Tonni
  • Marco Panteghini
  • Andrea Rossi
  • Maurizia Baldi
  • Cinzia Magnani
  • Bruno Ferrari
  • Mario Lituania
Short Communication



Craniosynostosis is a condition characterized by a premature closure of one or more skull sutures and refers to a wide spectrum of cranial malformation with an estimated birth of 1:2,000–1:4,000 live births. Four receptors (FGFR 1, FGFR 2, FGFR 3, FGFR 4) involving mutation in the fibroblast growth factor have been identified.

Materials and methods

Two cases occurred in the same family and diagnosed prenatally by means of ultrasound, and antenatal and postnatal MR imaging are reported. Molecular biology regarding identification of craniosynostosis type has been analyzed. A revision of the medical literature is also provided.


The premature closure of sagittal suture is characterized by a disproportionately large occipito-frontal and short biparietal diameter (scaphocephaly). The prenatal ultrasound diagnosis of craniosynostosis in utero may be difficult and be suspected when the cephalic index, the cranial shape or the fetal face shape are abnormal. Fetal karyotype is recommended and DNA testing plays a critical role in achieving an appropriate diagnosis, when possible. The prognosis of craniosynostosis is primarily dependent on the presence of associated anomalies as craniosynostosis are correlated with three to fivefold increased risk for cognitive disabilities.


Craniosynostosis FGFR Prenatal diagnosis Ultrasound Magnetic resonance imaging Molecular biology Neurodevelopmental outcome 


Conflict of interest



  1. 1.
    Cohen MM Jr (1993) Epidemiology of craniosynostosis. In: Craniosynostosis: diagnosis, evaluation and management, Chap. 10. Oxford University Press, New York, pp 103–111Google Scholar
  2. 2.
    Singer S, Bower C, Southall P, Goldblatt J (1999) Craniosynostosis in western Australia 1980–1994: a population-based study. Am J Med Genet 23:382–387CrossRefGoogle Scholar
  3. 3.
    Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac D, Renier D (1996) Genetic study of scaphocephaly. Am J Med Genet 62:228–285CrossRefGoogle Scholar
  4. 4.
    Bernardini L, Castori M, Capalbo A, Mokini V, Mingarelli R, Simi P, Bertuccelli A, Novelli A, Dallapiccola B (2007) Syndromic craniosynostosis due to complex chromosome 5 rearrangement and MSX2 gene triplication. Am J Med Genet A 143A:2937–2943PubMedCrossRefGoogle Scholar
  5. 5.
    Lajeunie E, Le Merrer M, Bonaïti-Pellie C, Marchac C, Renier D (1995) Genetic study of non-syndromic coronal craniosynostosis. Am J Med Gen 55:500–504CrossRefGoogle Scholar
  6. 6.
    Nyberg DA, McGahan JP, Pretorius DH, Pilu G (2003) In: Diagnostic imaging of fetal anomalies, Chap. 5. Lippincott Williams and Wilkins. Philadelphia, PA, p 147Google Scholar
  7. 7.
    Renier D, Le Merrer M, Arnaud E, Marchac D (2006) Etiologie des craniostènose. Neurochirurgie 52:228–237PubMedGoogle Scholar
  8. 8.
    Wilkie AO (1997) Craniosynostosis: genes and mechanism. Hum Mol Genet 6:1647–1656PubMedCrossRefGoogle Scholar
  9. 9.
    Mason IJ (1994) The in and out of fibroblast growth factor. Cell 78:547PubMedCrossRefGoogle Scholar
  10. 10.
    Ciurea AV, Toader C (2009) Genetics of craniosynostosis: review of the literature. J Med Life 2:5–17PubMedGoogle Scholar
  11. 11.
    Passos-Bueno MR, Sertiè AL, Richieri-Costa A, Alonso LG, Zatz M, Alonso N, Brunoni D, Ribeiro SF (1998) Description of a new mutation and characterization of FGFR1, FGFR2 and FGFR3 mutations among Brazilian patients with syndromic craniosynostosis. Am J Med Genet 78:237–241PubMedCrossRefGoogle Scholar
  12. 12.
    Meyers GA, Day D, Goldberg R, Daentl DL, Przylepa KA, Abrams LJ, Graham JM Jr, Feingold M, Moeschler JB, Rawnsley E, Scott AF, Jabs EW (1996) FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions, and a deletion due to alternative RNA splicing. Am J Hum Genet 58:491–498PubMedGoogle Scholar
  13. 13.
    Reardon W, Wilkes D, Rutland P, Pulleyn LJ, Malcom S, Dean JC, Evans RD, Jones BM, Hayward R, Hall CM, Nevin NC, Baraister M, Winter RM (1997) Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. J Med Genet 34:632–636PubMedCrossRefGoogle Scholar
  14. 14.
    Kan SH, Elanko N, Johnson D, Cornejo-Roldman L, Cook J, Reich EW, Tomkins S, Verloes A, Twigg SR, Rannan-Eliya S, McDonald-McGinn DM, Zackai EH, Wall SA, Muenke M, Wilkie AO (2002) Genomic screening of fibroblast growth factor receptor 2 reveals a wide spectrum of mutations in patients with syndromic craniosynostosis. Am J Hum Genet 70:472–486PubMedCrossRefGoogle Scholar
  15. 15.
    Vogels A, Fryns JP (2006) Pfeiffer syndrome. Orphanet J Rare Dis 1:19Google Scholar
  16. 16.
    Bernstein PS, Gross SJ, Cohen DJ, Tiller GR, Shanke AL, Bombard AT, Marion RW (1996) Prenatal diagnosis of type 2 Pfeiffer syndrome. Ultrasound Obstet Gynecol 8:425–428PubMedCrossRefGoogle Scholar
  17. 17.
    Balumeiser B, Loquet P, Wuyts W, Nöthen MM (2004) Prenatal diagnosis of Pfeiffer syndrome type 2. Prenat Diagn 24:644–646CrossRefGoogle Scholar
  18. 18.
    Hackett A, Rowe L (2006) FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report. Clin Dysmorphol 15:207–210PubMedCrossRefGoogle Scholar
  19. 19.
    van Maldegrem L (1993) Baller-gerold syndrome [Internet]. In: Pagon RA, Bird TC, Dolan CR, Stephens K (eds) GeneReviews [Internet]. University of Washington, SeattleGoogle Scholar
  20. 20.
    Johnson D (2003) A comprehensive screen of genes implicated in craniosynostosis. Ann R Coll Surg Engl 85:371–377PubMedCrossRefGoogle Scholar
  21. 21.
    Shiihara T, Kato M, Kimura T, Hayasaka K, Yamamori S, Ogata T (2004) Craniosynostosis with extra copy of MSX2 in a patient with partial 5q-trisomy. Am J Med Genet A 128A:214–216PubMedCrossRefGoogle Scholar
  22. 22.
    Wang JC, Steinraths M, Dang L, Lomax B, Eydoux P, Stockley T, Yong SL, Van Allen MI (2007) Craniosynostosis associated with distal 5q-trisomy: further evidence that extra copy of MSX2 gene leads to craniosynostosis. Am J Med Genet A 143A:2931–2936PubMedCrossRefGoogle Scholar
  23. 23.
    Kariminejad A, Kariminejad R, Tzschach A, Ullmann R, Ahmed A, Asghari-Roodsari A, Salehpour S, Afroozan F, Ropers HH, Kariminejad M (2009) Craniosynostosis in a patient with 2q37.3 deletion 5q34 duplication: association of extra copy of MSX2 with craniosynostosis. Am J Med Genet A 149A:1544–1549PubMedCrossRefGoogle Scholar
  24. 24.
    Li X, Ma L, Snead M, Hawoth I, Spakers R, Jackson C, Warman M, Mulliken J, Maxson R, Muller U, Jabs E (1993) A mutation in the homeodomain of the MSX2 gene in a family affected with craniosynostosis, Boston type. Am J Hum Genet 53:A213-onlyGoogle Scholar
  25. 25.
    Mavrogiannis LA, Taylor IB, Davies SJ, Ramos FJ, Olivares JL, Wilkie AOM (2006) Enlarged parietal foramina caused by mutations in the homeobox genes ALX4 and MSX2: from genotype to phenotype. Eur J Hum Genet 14:151–158PubMedCrossRefGoogle Scholar
  26. 26.
    Nazzaro A, Della Monica M, Lonardo F, Di Blasi A, Baffico M, Baldi M, Nazzaro G, De Placido G, Scarano G (2004) Prenatal ultrasound diagnosis of a case of Pfeiffer syndrome without cloverleaf skull and review of the literature. Prenat Diagn 24:918–922PubMedCrossRefGoogle Scholar
  27. 27.
    Romero R, Pilu G, Jeanty P (1988) In: Prenatal diagnosis of congenital anomalies, Chap. 10. Appleton and Lange, Norwalk, p 370Google Scholar
  28. 28.
    Pooh RK, Nakagawa Y, Pooh KH, Nakagawa Y, Nagamachi N (1999) Fetal craniofacial structure and intracranial morphology in a case of Apert syndrome. Ultrasound Obstet Gynecol 13:274–280PubMedCrossRefGoogle Scholar
  29. 29.
    Skidmore DL, Pai AP, Toi A, Steele L, Chitayat D (2003) Prenatal diagnosis of Apert syndrome: report of two cases. Prenat Diagn 23:1009–1013PubMedCrossRefGoogle Scholar
  30. 30.
    Kaufmann K, Baldinger S, Pratt L (1997) Ultrasound detection of Apert syndrome: a case report and literature review. Am J Perinatol 14:427–430PubMedCrossRefGoogle Scholar
  31. 31.
    Ferreira JC, Carter SM, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, Baergen RN, Gross SJ (1999) Second-trimester molecular prenatal diagnosis of syndromic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynceol 14:426–430CrossRefGoogle Scholar
  32. 32.
    Mahieu-Caputo D, Sonigo P, Amiel J, Simon I, Aubry MC, Lemerrer M, Delezoide AL, Gigarel N, Dommergues M, Dumez Y (2001) Prenatal diagnosis of sporadic Apert syndrome: a sequential diagnostic approach combining three-dimensional computed tomography and molecular biology. Fetal Diagn Ther 16:10–12PubMedCrossRefGoogle Scholar
  33. 33.
    Gorrincour G, Rypens F, Grignon A, Garel L, Bortoluzzi P, Oligny L, Lemyre E, Duperron L (2005) Prenatal diagnosis of cloverleaf skull: watch the hands. Fetal Diagn Ther 20:296–300CrossRefGoogle Scholar
  34. 34.
    Lyu KJ, Ko TM (2000) Prenatal diagnosis of Apert syndrome with widely separated cranial sutures. Prenat Diagn 20:254–256PubMedCrossRefGoogle Scholar
  35. 35.
    Delahaye S, Bernard JP, Rénier D, Ville Y (2003) Prenatal ultrasound diagnosis of fetal craniosynostosis. Ultrasound Obstet Gynecol 21:347–353PubMedCrossRefGoogle Scholar
  36. 36.
    Benacerraf BR, Spiro R, Mitchell AG (2000) Using three dimensional ultrasound to detect craniosynostosis in a fetus with Pfeiffer syndrome. Ultrasound Obstet Gynecol 16:391–394PubMedCrossRefGoogle Scholar
  37. 37.
    David AL, Turnbull C, Scott R, Freeman J, Bilardo CM, van Maarle M, Chitty LS (2007) Diagnosis of Apert syndrome in the second-trimester using 2D and 3D ultrasound. Prenat Diagn 27:629–632PubMedCrossRefGoogle Scholar
  38. 38.
    Pretorius DH, Gattu S, Ek Ji, Hollenbach K, Newton R, Hull A, Carmona S, D’Agostino D, Nelson TR (2006) Preexamination and postexamination assessment of parental–fetal bonding in patients undergoing 3-/4-dimensional obstetrics ultrasonography. J Ultrasound Med 25:1411–1421PubMedGoogle Scholar
  39. 39.
    Ji EK, Pretorius DH, Newton R, Uyan K, Hull AD, Hollenbach K, Nelson TR (2005) Effects of ultrasound on maternal–fetal bonding: a comparison of two- and three-dimensional imaging. Ultrasound Obstet Gynecol 25:473–477PubMedCrossRefGoogle Scholar
  40. 40.
    Esser T, Rogalla P, Bamberg C, Kalache KD (2005) Application of the three-dimensional maximum mode in prenatal diagnosis of Apert syndrome. Am J Obstet Gynecol 193:1743–1745PubMedCrossRefGoogle Scholar
  41. 41.
    Boog G, Le Vaillant C, Winer N, David A, Quere MP, Nomballais MF (1999) Contribution of tridimensional sonography and magnetic resonance imaging to prenatal diagnosis of Apert syndrome at mid-trimester. Fetal Diagn Ther 14:20–23PubMedCrossRefGoogle Scholar
  42. 42.
    Chaoui R, Levaillant JM, Benoit B, Faro C, Wegrzyn P, Nicolaides KH (2005) Three-dimensional sonographic description of abnormal metopic suture in second- and third-trimester fetuses. Ultrasound Obstet Gynecol 26:761–764PubMedCrossRefGoogle Scholar
  43. 43.
    Faro C, Chaoui R, Wegrzyn P, Levaillant JM, Benoit B, Nicolaides KH (2006) Metopic suture in fetuses with Apert syndrome at 22–27 weeks of gestation. Ultrasound Obstet Gynecol 27:28–33PubMedCrossRefGoogle Scholar
  44. 44.
    Ferreira JC, Carter SM, Bernstein PS, Jabs EW, Glickstein JS, Marion RW, Baergen RN, Gross SJ (1999) Second trimester molecular prenatal diagnosis of sporadic Apert syndrome following suspicious ultrasound findings. Ultrasound Obstet Gynecol 14:426–430PubMedCrossRefGoogle Scholar
  45. 45.
    Bernard JP, Levaillant JM (2006) Diagnostic prenatal de craniosténose. Neurochirurgie 52:246–258PubMedGoogle Scholar
  46. 46.
    Fjørtoft MI, Sevely A, Boetto S, Kessler S, Sarramon MF, Rolland M (2007) Prenatal diagnosis of craniosynostosis: value of MR imaging. Neuroradiology 49:515–521PubMedCrossRefGoogle Scholar
  47. 47.
    Itoh S, Nojima M, Yoshida K (2006) Usefulness of magnetic resonance imaging for accurate diagnosis of Pfeiffer syndrome type II in utero. Fetal Diagn Ther 21:168–171PubMedCrossRefGoogle Scholar
  48. 48.
    Weber B, Schwabegger AH, Vodopiutz J, Janecke AR, Forstner R, Steiner H (2010) Prenatal diagnosis of Apert syndrome with cloverleaf skull deformity using ultrasound, fetal magnetic resonance imaging and genetic analysis. Fetal Diagn Ther 27:51–56PubMedCrossRefGoogle Scholar
  49. 49.
    Miller E, Ben-Sira L, Constantini S, Beni-Adani L (2006) Impact of prenatal magnetic resonance imaging on postnatal neurosurgical treatment. J Neurosurg 105:203–209PubMedGoogle Scholar
  50. 50.
    Rogers GF, Proctor MR, Mulliken JB (2002) Unilateral fusion of the frontosphenoidal suture: a rare cause of synoptic frontal plagiocephaly. Plast Reconstr Surg 110:1011–1021PubMedCrossRefGoogle Scholar
  51. 51.
    de Ribaupierre S, Czorny A, Pittet B, Jacques B, Rilliet B (2007) Frontosphenoidal synostosis; a rare cause of unilateral anterior plagiocephaly. Childs Nerv Syst 23:1431–1438PubMedCrossRefGoogle Scholar
  52. 52.
    Mathijssen JM, van der Meulen JJ, van Adrichem LN, Vaandrager JM, van der Hulst RR, Lequin MH, Vermeij-Keers C (2008) The frontosphenoidal suture: fetal development and phenotype of its synostosis. Pediatr Radiol 38:431–437PubMedCrossRefGoogle Scholar
  53. 53.
    Marucci DD, Jones BM, Dunaway DJ, Hayward RD (2009) Unilateral isolated frontosphenoidal craniosynostosis causing frontal plagiocephaly. J Plat Reconstr Aesthet Surg 62:e255–e258CrossRefGoogle Scholar
  54. 54.
    Plooij JM, Verhamme Y, Bergè SJ, van Lindert EJ, Bortstlap-Engels VM, Bortslap WA (2009) Unilateral craniosynostosis of the frontosphenoidal suture: a case report and a review of literature. J Craniomaxillofac Surg 37:162–166PubMedGoogle Scholar
  55. 55.
    Weber B, Schwabegger AH, Oberaigner W, Rumer-Moser A, Steiner H (2010) Incidence of perinatal complications in children with premature craniosynostosis. J Perinat Med 38:319–325PubMedCrossRefGoogle Scholar
  56. 56.
    Renier D, Arnaud E, Marchac D (2006) Craniosténose: resultats fonctionnels et morphologiques post-opératoires. Neurochirurgie 52:302–310PubMedGoogle Scholar
  57. 57.
    Cohen MM (2005) Editorial: perspectives on craniosynostosis. Am J Med Genet 136A:313–326PubMedCrossRefGoogle Scholar
  58. 58.
    Cinalli G, Spennato P, Sainte-Rose C, Arnaud E, Aliberti F, Brunelle F, Cianciulli E, Renier D (2005) Chiari malformation in craniosynostosis. Childs Nerv Systm 10:889–901CrossRefGoogle Scholar
  59. 59.
    Collmann H, Sörensen N, Krauss J (2005) Hydrocephalus in craniosynostosis: a review. Child Nerv Syst 21:902–912CrossRefGoogle Scholar
  60. 60.
    Williams JK, Ellenbogen RG, Gruss JS (1999) State of the art in craniofacial surgery: nonsyndromic craniosynostosis. Cleft Palate Craniofac J 36:471–485PubMedCrossRefGoogle Scholar
  61. 61.
    Marentette LJ, Kim JY (2001) Correction of nonsyndromal craniosynostosis. Facial Plast Surg Clin North Am 9:93–99PubMedGoogle Scholar
  62. 62.
    Panchal J, Uttchin V (2003) Management of craniosynostosis. Plast Reconstr Surg 111:2032–2048PubMedCrossRefGoogle Scholar
  63. 63.
    Persing JA (2008) MOC-PS(SM) CME article: management considerations in the treatment of craniosynopstosis. Plast Reconstr Surg 121:1–11PubMedCrossRefGoogle Scholar
  64. 64.
    Wan DC, Kwan MD, Lorenz HP, Longaker MT (2008) Current treatment of craniosynostosis and future therapeutic directions. Front Oral Biol 12:209–230PubMedCrossRefGoogle Scholar
  65. 65.
    Speltz ML, Kapp-Simon KA, Cummingham M, Marsh J, Dawson G (2004) Single-suture craniosynostosis: a review of neurobehavioral research and theory. J Pediatr Psychol 29:651–668PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Gabriele Tonni
    • 1
  • Marco Panteghini
    • 1
  • Andrea Rossi
    • 2
  • Maurizia Baldi
    • 3
  • Cinzia Magnani
    • 4
  • Bruno Ferrari
    • 5
  • Mario Lituania
    • 6
  1. 1.Division of Obstetrics and Gynecology, Prenatal Diagnostic Center, Guastalla Civil HospitalAUSL Reggio EmiliaGuastalla (Reggio Emilia)Italy
  2. 2.Neuroradiology ServiceGaslini Pediatric HospitalGenoaItaly
  3. 3.Molecular Biology ServiceGalliera HospitalGenoaItaly
  4. 4.Neonatal Intensive Care UnitUniversity of ParmaParmaItaly
  5. 5.Department of Obstetrics and GynecologyUniversity of ParmaParmaItaly
  6. 6.Prenatal Diagnostic Service, Department of Obstetrics and GynecologyGalliera HospitalGenoaItaly

Personalised recommendations