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Facial clefts and holoprosencephaly

Larry H Hollier, Jr, MD
Section Editors
Leonard E Weisman, MD
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS


Development of the face and cranium during embryogenesis is a complex and orchestrated process that involves cellular proliferation, differentiation, migration, and selective apoptosis. Facial clefts and holoprosencephaly (HPE) are conditions caused by the disruption of these normal embryonic processes.


Facial clefts are deformations of the face and/or cranium caused by relative excesses or deficits of tissue along linear anatomic planes [1,2]. Although the exact incidence of facial clefts is unknown, they are estimated to affect 1.4 to 4.9 newborns per 100,000 livebirths [1,3,4].

Embryology — More than one theory exists regarding the embryologic pathogenesis of facial clefts. Fetal craniofacial development is a complex series of events that occurs between the third and eighth weeks of gestation. During the initial stages, five facial processes (one frontal, two maxillary, two mandibular) form and subsequently fuse (by the sixth week of gestation) to form the human face. The classic theory states that facial clefting occurs when the fusion process is disrupted. However, other theories propose that the pathogenesis is related to the infarction of primordial blood vessels, amniotic bands, failure of certain developmental zones of the face to develop completely, or errors in cellular migration, penetration, and differentiation [2].

Etiology — Although the precise etiology is unknown, multiple genetic and environmental factors may be involved. The environmental risk factors implicated include antenatal exposure to radiation, viral infections, metabolic abnormalities, and teratogenic compounds [2].

Classification of clefts — Paul Tessier, the father of modern craniofacial surgery, introduced a classification system to describe the anatomic planes along which facial clefts fall [1]. The classification system numbers clefts based upon their location surrounding the orbit. Numbers 0 through 7 run inferior to the orbit (facial clefts) from medial to lateral, number 8 runs on the lateral portion of the orbit, and numbers 9 through 14 run superior to the orbit from lateral to medial (cranial clefts) (figure 1).

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Literature review current through: Nov 2017. | This topic last updated: Jun 30, 2017.
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  1. Tessier P. Anatomical classification facial, cranio-facial and latero-facial clefts. J Maxillofac Surg 1976; 4:69.
  2. Bradley JP, Hurwitz DJ, Carstens MH. Embryology, classifications, and descriptions of craniofacial clefts. In: Plastic surgery, 2nd ed, Mathes SJ, Hentz VR (Eds), Saunders Elsevier, Philadelphia 2006. Vol Vol 4, p.15.
  3. Kawamoto HK Jr. The kaleidoscopic world of rare craniofacial clefts: order out of chaos (Tessier classification). Clin Plast Surg 1976; 3:529.
  4. Kawamoto HK Jr. Rare craniofacial clefts. In: Plastic surgery, McCarthy JG (Ed), WB Saunders, Philadelphia 1990. Vol Vol 4, p.2922.
  5. Bersani TA, Cecchi LM. Resection of anterior orbital meningoencephalocele in a newborn infant. Ophthal Plast Reconstr Surg 2006; 22:391.
  6. Lewis CW, Jacob LS, Lehmann CU, SECTION ON ORAL HEALTH. The Primary Care Pediatrician and the Care of Children With Cleft Lip and/or Cleft Palate. Pediatrics 2017; 139.
  7. van der Meulen JC. Oblique facial clefts: pathology, etiology, and reconstruction. Plast Reconstr Surg 1985; 76:212.
  8. Longaker MT, Lipshutz GS, Kawamoto HK Jr. Reconstruction of Tessier no. 4 clefts revisited. Plast Reconstr Surg 1997; 99:1501.
  9. Resnick JI, Kawamoto HK Jr. Rare craniofacial clefts: Tessier no. 4 clefts. Plast Reconstr Surg 1990; 85:843.
  10. Blaas HG, Eriksson AG, Salvesen KA, et al. Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases. Ultrasound Obstet Gynecol 2002; 19:24.
  11. Nanni L, Schelper RL, Muenke MT. Molecular genetics of holoprosencephaly. Front Biosci 2000; 5:D334.
  12. Muenke M, Beachy PA. Genetics of ventral forebrain development and holoprosencephaly. Curr Opin Genet Dev 2000; 10:262.
  13. Arnold WH, Meiselbach V. 3-D reconstruction of a human fetus with combined holoprosencephaly and cyclopia. Head Face Med 2009; 5:14.
  14. Barr M Jr, Hanson JW, Currey K, et al. Holoprosencephaly in infants of diabetic mothers. J Pediatr 1983; 102:565.
  15. De Wals P, Bloch D, Calabro A, et al. Association between holoprosencephaly and exposure to topical retinoids: results of the EUROCAT Survey. Paediatr Perinat Epidemiol 1991; 5:445.
  16. Croen LA, Shaw GM, Lammer EJ. Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study. Am J Med Genet 2000; 90:320.
  17. Cohen MM Jr, Shiota K. Teratogenesis of holoprosencephaly. Am J Med Genet 2002; 109:1.
  18. Ming JE, Muenke M. Multiple hits during early embryonic development: digenic diseases and holoprosencephaly. Am J Hum Genet 2002; 71:1017.
  20. Picone O, Hirt R, Suarez B, et al. Prenatal diagnosis of a possible new middle interhemispheric variant of holoprosencephaly using sonographic and magnetic resonance imaging. Ultrasound Obstet Gynecol 2006; 28:229.
  21. Delezoide AL, Narcy F, Larroche JC. Cerebral midline developmental anomalies: spectrum and associated features. Genet Couns 1990; 1:197.
  22. Dubourg C, Bendavid C, Pasquier L, et al. Holoprosencephaly. Orphanet J Rare Dis 2007; 2:8.
  23. Hahn JS, Plawner LL. Evaluation and management of children with holoprosencephaly. Pediatr Neurol 2004; 31:79.
  24. Stashinko EE, Clegg NJ, Kammann HA, et al. A retrospective survey of perinatal risk factors of 104 living children with holoprosencephaly. Am J Med Genet A 2004; 128A:114.
  25. Plawner LL, Delgado MR, Miller VS, et al. Neuroanatomy of holoprosencephaly as predictor of function: beyond the face predicting the brain. Neurology 2002; 59:1058.
  26. Lewis AJ, Simon EM, Barkovich AJ, et al. Middle interhemispheric variant of holoprosencephaly: a distinct cliniconeuroradiologic subtype. Neurology 2002; 59:1860.
  27. Roach E, Demyer W, Conneally PM, et al. Holoprosencephaly: birth data, benetic and demographic analyses of 30 families. Birth Defects Orig Artic Ser 1975; 11:294.
  28. Leevers HJ, Roesler CP, Flax J, Benasich AA. The Carter Neurocognitive Assessment for children with severely compromised expressive language and motor skills. J Child Psychol Psychiatry 2005; 46:287.