Molecular Genetics of Human Facial Dysostoses


Human facial dysostoses comprise mandibulofacial (MFDs) and acrofacial dysostoses (AFDs). Both types are characterised by similar craniofacial dysmorphisms, which are assumed to be caused by an abnormal development of the neural crest cells. Craniofacial anomalies consist of downslanting palpebral fissures, lower eyelid coloboma with or without absence of lower eyelashes medial to the defect, hypoplasia of the zygomatic complex, micrognathia and microtia often associated with hearing loss. The facial anomalies are associated with limb anomalies in the AFDs, which are preaxial, postaxial or cannot be classified into one of these groups.

The molecular basis for most of the MFDs and AFDs is unknown. For Treacher Collins syndrome (TCOF1, POLR1D and POLR1C) and MFD type Hutterite (TCOF1), the molecular basis is known which is also true for three of the AFDs, Nager syndrome (SF3B4), Miller syndrome (DHODH) and AFD type Guion‐Almeida (EFTUD2).

Key Concepts:

  • In human facial dysostoses, the development of the structures of the first and second branchial arches is disturbed.

  • Facial dysostoses can be subdivided into those with normal extremities, the mandibulofacial dysostoses (MFDs), and those with anomalies of limbs, the acrofacial dysostoses.

  • TCOF1 mutations are causal for Treacher Collins syndrome and MFD type Hutterite.

  • POLR1D and POLR1C mutations are causal for Treacher Collins syndrome.

  • SF3B4 mutations are causal for Nager syndrome.

  • EFTUD2 mutations are causal for ADGA.

  • DHODH mutations are causal for Miller syndrome.

  • EVC and EVC2 mutations are causal for Weyers syndrome.

Keywords: mandibulofacial dysostosis; acrofacial dysostosis; Nager syndrome; Miller syndrome; acrofacial dysostosis type Guion‐Almeida; spliceosome; Treacher Collins syndrome; MFD type Hutterite

Figure 1.

Overview of MFDs. TCOF1, Treacher Collins–Franceschetti syndrome 1; POLR1D, polymerase (RNA) I polypeptide D; POLR1C, polymerase (RNA) I polypeptide C.

Figure 2.

Three‐year‐old individual with TCS and characteristic facial dysmorphism with downward slanting palpebral fissures, lower eyelid coloboma, hypoplasia of zygomatic bones, large mouth, small chin and microtia. She carries the TCOF1 splice mutation c.2629–3A>G.

Figure 3.

Overview of AFDs. ID, intellectual disability; DHODH, dihydroorotate dehydrogenase (quinone); EVC2, Ellis–van Creveld syndrome 2; EFTUD2, elongation factor Tu GTP‐binding domain containing 2; SF3B4, splicing factor 3b, subunit 4.

Figure 4.

This patient with Nager syndrome carries a nonsense mutation in SF3B4 (c.574G>T, p.Glu192*). The photo shows characteristic facial features such as downward slanting palpebral fissures, micrognathia, zygomatic hypoplasia and ear dysplasia, as well as malformations of the upper extremities, that is, bilateral thumb aplasia and syndactyly. The patient required tracheostomy because of airway problems.



Bernier FP, Caluseriu O, Ng S et al. (2012) Haploinsufficiency of SF3B4, a component of the pre‐mRNA spliceosomal complex, causes Nager syndrome. American Journal of Human Genetics 90(5): 925–933.

Beygo J, Buiting K, Seland S et al. (2012) First report of a single exon deletion in TCOF1 causing Treacher Collins syndrome. Molecular Syndromology 2(2): 53–59.

Bowman M, Oldridge M, Archer C et al. (2012) Gross deletions in TCOF1 are a cause of Treacher‐Collins‐Franceschetti syndrome. European Journal of Human Genetics 20(7): 769–777.

Burn J, McKeown C, Wagget J, Bray R and Goodship J (1992) New dysmorphic syndrome with choanal atresia in siblings. Clinical Dysmorphology 1(3): 137–144.

Caluseriu O, Lowry BR, McLeod R et al. (2013) The hutterite variant of Treacher Collins syndrome: a 28‐year‐old story solved. American Journal of Medical Genetics. Part A 161A(11): 2855–2859.

Chemke J, Mogilner BM, Ben‐Itzhak I, Zurkowski L and Ophir D (1988) Autosomal recessive inheritance of Nager acrofacial dysostosis. Journal of Medical Genetics 25(4): 230–232.

Czeschik JC, Voigt C, Alanay Y et al. (2013) Clinical and mutation data in 12 patients with the clinical diagnosis of Nager syndrome. Human Genetics 132(8): 885–898.

D'Asdia MC, Torrente I, Consoli F et al. (2013) Novel and recurrent EVC and EVC2 mutations in Ellis‐van Creveld syndrome and Weyers acrofacial dyostosis. European Journal of Medical Genetics 56(2): 80–87.

Dauwerse JG, Dixon J, Seland S et al. (2011) Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. Nature Genetics 43(1): 20–22.

Dixon J, Hovanes K, Shiang R and Dixon MJ (1997) Sequence analysis, identification of evolutionary conserved motifs and expression analysis of murine tcof1 provide further evidence for a potential function for the gene and its human homologue, TCOF1. Human Molecular Genetics 6(5): 727–737.

Dixon J, Jones NC, Sandell LL et al. (2006) Tcof1/Treacle is required for neural crest cell formation and proliferation deficiencies that cause craniofacial abnormalities. Proceedings of the National Academy of Sciences of the USA 103(36): 13403–13408.

Donnai D, Hughes HE and Winter RM (1987) Postaxial acrofacial dysostosis (Miller) syndrome. Journal of Medical Genetics 24(7): 422–425.

Fabrizio P, Laggerbauer B, Lauber J, Lane WS and Lührmann R (1997) An evolutionarily conserved U5 snRNP‐specific protein is a GTP‐binding factor closely related to the ribosomal translocase EF‐2. The EMBO Journal 16(13): 4092–4106.

Fang J, Uchiumi T, Yagi M et al. (2013) Dihydro‐orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction. Bioscience Reports 33(2). doi:10.1042/BSR20120097.

Friedman RA, Wood E, Pransky SM et al. (1996) Nager acrofacial dysostosis: management of a difficult airway. Internal Journal of Pediatric Otorhinolaryngology 35(1): 69–72.

Genée E (1969) An extensive form of mandibulo‐facial dysostosis. Journal de Génétique Humaine 17(1): 45–52.

Gordon CT, Petit F, Oufadem M et al. (2012) EFTUD2 haploinsufficiency leads to syndromic oesophageal atresia. Journal of Medical Genetics 49(12): 737–746.

Groeper K, Johnson JO, Braddock SR and Tobias JD (2002) Anaesthetic implications of Nager syndrome. Paediatric Anaesthesia 12(4): 365–368.

Guion‐Almeida ML, Zechi‐Ceide RM, Vendramini S and Tabith Júnior A (2006) A new syndrome with growth and mental retardation, mandibulofacial dysostosis, microcephaly, and cleft palate. Clinical Dysmorphology 15(3): 171–174.

Hedera P, Toriello HV and Petty EM (2002) Novel autosomal dominant mandibulofacial dysostosis with ptosis: clinical description and exclusion of TCOF1. Journal of Medical Genetics 39(7): 484–488.

Herrmann BW, Karzon R and Molter DW (2005) Otologic and audiologic features of Nager acrofacial dysostosis. International Journal of Pediatric Otorhinolaryngology 69(8): 1053–1059.

Howard TD, Guttmacher AE, McKinnon W et al. (1997) Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis‐van Creveld syndrome locus. American Journal of Human Genetics 61(6): 1405–1412.

Kinoshita F, Kondoh T, Komori K et al. (2011) Miller syndrome with novel dihydroorotate dehydrogenase gene mutations. Pediatrics International 53(4): 587–591.

Lines MA, Huang L, Schwartzentruber J et al. (2012) Haploinsufficiency of a spliceosomal GTPase encoded by EFTUD2 causes mandibulofacial dysostosis with microcephaly. American Journal of Human Genetics 90(2): 369–377.

Lowry RB, Morgan K, Holmes TM, Metcalf PJ and Stauffer GF (1985) Mandibulofacial dysostosis in Hutterite sibs: a possible recessive trait. American Journal of Medical Genetics 22(3): 501–512.

Luquetti DV, Hing AV, Rieder MJ et al. (2013) ‘Mandibulofacial dysostosis with microcephaly’ caused by EFTUD2 mutations: expanding the phenotype. American Journal of Medical Genetics. Part A 161(1): 108–113.

Marcano A and Richieri‐Costa A (1998) A newly recognized autosomal dominant mandibulofacial dysostosis (Bauru type): report on a Brazilian family. Brazilian Journal of Dysmorphology and Speech‐Hearing Disorders 1: 37–41.

Mégarbané A, Chouery E, Rassi S and Delague V (2005) A new autosomal recessive oto‐facial syndrome with midline malformations. American Journal of Medical Genetics. Part A 132(4): 398–401.

Miller M, Fineman R and Smith DW (1979) Postaxial acrofacial dysostosis syndrome. Journal of Pediatrics 95(6): 970–975.

Nager F and de Reynier J (1948) Das Gehörorgan bei den angeborenen Kopfmissbildungen. Practica Oto‐Rhino‐Laryngologica 10(suppl. 2): 1–128.

Ng SB, Buckingham KJ, Lee C et al. (2009) Exome sequencing identifies the cause of a mendelian disorder. Nature Genetics 42(1): 30–35.

Nur BG, Bernier FP, Oztekin O et al. (2013) Possible autosomal recessive inheritance in an infant with acrofacial dysostosis similar to Nager syndrome. American Journal of Medical Genetics, Part A 161(9): 2311–2315.

Petit P, Moerman P and Fryns JP (2013) Nager acrofacial dysostosis and preaxial polydactyly: a further example with lethal outcome. Genetic Counselling (Geneva, Switzerland) 4(2): 135–137.

Rainger J, Bengani H, Campbell L et al. (2012) Miller (Genee‐Wiedemann) syndrome represents a clinically and biochemically distinct subgroup of postaxial acrofacial dysostosis associated with partial deficiency of DHODH. Human Molecular Genetics 21(18): 3969–3983.

Ruiz‐Perez VL, Ide SE, Strom TM et al. (2000) Mutations in a new gene in Ellis–van Creveld syndrome and Weyers acrodental dysostosis. Nature Genetics 24(3): 283–286.

Ruiz‐Perez VL and Goodship JA (2009) Ellis‐van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia‐mediated diminished response to hedgehog ligands. American Journal of Medical Genetics Part C, Seminars in Medical Genetics 151C(4): 341–351.

Teber OA, Gillessen‐Kaesbach G, Fischer S et al. (2004) Genotyping in 46 patients with tentative diagnosis of Treacher Collins syndrome revealed unexpected phenotypic variation. European Journal of Human Genetics 12(11): 879–890.

The Treacher Collins Syndrome Collaborative Group (1996) Positional cloning of a gene involved in the pathogenesis of Treacher Collins syndrome. The Treacher Collins Syndrome Collaborative Group. Nature Genetics 12(2): 130–136.

Toriello HV, Higgins JV, Abrahamson J, Waterman DF and Moore WD (1985) X‐linked syndrome of branchial arch and other defects. American Journal of Medical Genetics 21(1): 137–142.

Trainor PA, Dixon J and Dixon MJ (2009) Treacher Collins syndrome: etiology, pathology and prevention. European Journal of Human Genetics 17(3): 275–283.

Verloes A and Lesenfants S (1997) A new form of mandibulofacial dysostosis with macroblepharon and macrostomia. Clinical Dysmorphology 6(1): 21–24.

Vincent M, Collet C, Verloes A et al. (2014) Large deletions encompassing the TCOF1 and CAMK2A genes are responsible for Treacher Collins syndrome with intellectual disability. European Journal of Human Genetics 22(1): 52–56.

Voigt C, Mégarbané A, Neveling K et al. (2013) Oto‐facial syndrome and esophageal atresia, intellectual disability and zygomatic anomalies – expanding the phenotypes associated with EFTUD2 mutations. Orphanet Journal of Rare Diseases 8: 110.

Watanabe H, Shionyu M, Kimura T, Kimata K and Watanabe H (2007) Splicing factor 3b subunit 4 binds BMPR‐IA and inhibits osteochondral cell differentiation. The Journal of Biological Chemistry 282(28): 20728–20738.

Weyers H (1952) A correlated abnormality of the mandible and extremities (dysostosis acrofacialis). Fortschritte auf dem Gebiete der Röntgenstrahlen 77(5): 562–567.

Wieczorek D (2013) Human facial dysostoses. Clinical Genetics 83(6): 499–510.

Wieczorek D, Gener B, González MJM et al. (2009) Microcephaly, microtia, preauricular tags, choanal atresia and developmental delay in three unrelated patients: a mandibulofacial dysostosis distinct from Treacher Collins syndrome. American Journal of Medical Genetics Part A 149A(5): 837–843.

Wiedemann HR (1973) Malformation‐retardation syndrome with bilateral absence of the 5th rays in both hands and feets, cleft palate, malformed ears and eyelids, radioulnar synostosis (author's transl). Klinische Pädiatrie 185(3): 181–186.

Zhang Y, Dai Y, Liu Y and Ren J (2010) Mandibulofacial dysostosis, microtia, and limb anomalies in a newborn: a new form of acrofacial dysostosis syndrome? Clinical Genetics 78(6): 570–574.

Further Reading

Epstein CJ, Erickson RP and Wynshaw‐Boris A (eds) (2008) Inborn Errors of Development. Oxford Monographs on Medical Genetics, 2nd edn. New York, NY, USA: Oxford University Press.

Hennekam R, Allanson J and Krantz I (eds) (2010) Gorlin's Syndromes of the Head and Neck. Oxford Monographs on Medical Genetics, 5th edn. New York, NY, USA: Oxford University Press.

Jones K (ed.) (2005) Smith's Recognizable Patterns of Human Malformation, 6th edn. Philadelphia, PA, USA: Saunders WB.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Czeschik, Johanna Christina, and Wieczorek, Dagmar(Jun 2014) Molecular Genetics of Human Facial Dysostoses. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025451]