Molecular Genetics of Human Facial Dysostoses

Abstract

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.

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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.

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