Re-focusing on Agnathia-Otocephaly complex

Clinical Oral Investigations volume 25, pages1353–1362(2021)Cite this article

Abstract

Objectives

Agnathia-otocephaly complex is a rare condition characterized by mandibular hypoplasia or agnathia, ear anomalies (melotia/synotia) and microstomia with aglossia. This severe anomaly of the first branchial arch is most often lethal. The estimated incidence is less than 1 in 70.000 births, with etiologies linked to both genetic and teratogenic factors. Most of the cases are sporadic. To date, two genes have been described in humans to be involved in this condition: OTX2 and PRRX1. Nevertheless, the overall proportion of mutated cases is unknown and a significant number of patients remain without molecular diagnosis. Thus, the involvement of other genes than OTX2 and PRRX1 in the agnathia-otocephaly complex is not unlikely. Heterozygous mutations in Cnbp in mice are responsible for mandibular and eye defects mimicking the agnathia-otocephaly complex in humans and appear as a good candidate. Therefore, in this study, we aimed (i) to collect patients presenting with agnathia-otocephaly complex for screening CNBP, in parallel with OTX2 and PRRX1, to check its possible implication in the human phenotype and (ii) to compare our results with the literature data to estimate the proportion of mutated cases after genetic testing.

Materials and methods

In this work, we describe 10 patients suffering from the agnathia-otocephaly complex. All of them benefited from array-CGH and Sanger sequencing of OTX2, PRRX1 and CNBP. A complete review of the literature was made using the Pubmed database to collect all the patients described with a phenotype of agnathia-otocephaly complex during the 20 last years (1998–2019) in order (i) to study etiology (genetic causes, iatrogenic causes…) and (ii), when genetic testing was performed, to study which genes were tested and by which type of technologies.

Results

In our 10 patients’ cohort, no point mutation in the three tested genes was detected by Sanger sequencing, while array-CGH has allowed identifying a 107-kb deletion encompassing OTX2 responsible for the agnathia-otocephaly complex phenotype in 1 of them. In 4 of the 70 cases described in the literature, a toxic cause was identified and 22 out the 66 remaining cases benefited from genetic testing. Among those 22 patients, 6 were carrying mutation or deletion in the OTX2 gene and 4 in the PRRX1 gene. Thus, when compiling results from our cohort and the literature, a total of 32 patients benefited from genetic testing, with only 34% (11/32) of patients having a mutation in one of the two known genes, OTX2 or PRRX1.

Conclusions

From our work and the literature review, only mutations in OTX2 and PRRX1 have been found to date in patients, explaining around one third of the etiologies after genetic testing. Thus, agnathia-otocephaly complex remains unexplained in the majority of the patients, which indicates that other factors might be involved. Although involved in first branchial arch defects, no mutation in the CNBP gene was found in this study. This suggests that mutations in CNBP might not be involved in such phenotype in humans or that, unlike in mice, a compensatory effect might exist in humans. Nevertheless, given that agnathia-otocephaly complex is a rare phenotype, more patients have to be screened for CNBP mutations before we definitively conclude about its potential implication. Therefore, this work presents the current state of knowledge on agnathia-otocephaly complex and underlines the need to expand further the understanding of the genetic bases of this disorder, which remains largely unknown.

Clinical relevance

We made here an update and focus on the clinical and genetic aspects of agnathia-otocephaly complex as well as a more general review of craniofacial development.

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Acknowledgments

We are extremely indebted to the patients and their families for their participation in this study.

Author information

Affiliations

  1. Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, Toulouse, France

    C. Dubucs, N. Chassaing, M. Aubert-Mucca, P. Calvas & Julie Plaisancié

  2. Département d’Anatomie et de Cytologie Pathologiques, Institut Universitaire du cancer de Toulouse, Toulouse, France

    C. Dubucs & J. Aziza

  3. INSERM U1056, Université Toulouse III, Toulouse, France

    N. Chassaing, P. Calvas & Julie Plaisancié

  4. Department of Lab. Med. & Pathology (5B4.09), University of Alberta, Edmonton, AB, Canada

    C. Sergi

  5. Unité d’Embryofœtopathologie, Service d’Histologie Embryologie Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris (APHP), Paris, France

    T. Attié-Bitach

  6. Institut Imagine, INSERM U1163, Université Paris Descartes, Sorbonne Paris Cite, Paris, France

    T. Attié-Bitach

  7. Service de Génétique Médicale, CRMR, CHU de Bordeaux, Bordeaux, France

    D. Lacombe

  8. INSERM U1211, Université de Bordeaux, 33076, Bordeaux, France

    D. Lacombe

  9. UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France

    C. Thauvin-Robinet

  10. Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU-TRANSLAD, CHU Dijon, Dijon, Bourgogne, France

    C. Thauvin-Robinet

  11. Centre de Référence maladies rares “Anomalies du Développement et syndromes malformatifs,” Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France

    C. Thauvin-Robinet

  12. Service de Génétique Clinique, Centre Hospitalier Régional Universitaire de Tours, Tours, France

    S. Arpin

  13. Department of Medical Genetics, Reference Center for Developmental Abnormalities and Constitutional Bone Diseases, CHRU, Montpellier, France

    M. J. Perez

  14. Centre de Génétique Humaine, Centre Hospitalier Universitaire, Université de Franche-Comté, Besançon, France

    C. Cabrol

  15. Department of Materials Engineering, Ming Chi University of Technology, New Taipei City, Taiwan

    C. P. Chen

  16. Department de Biochimie et Génétique, Centre Hospitalier Universitaire, Angers, France

    E. Colin

  17. UMR CNRS 6214-INSERM 1083 and PREMMI, Université d’Angers, Angers, France

    E. Colin

  18. Unit of Fetal Pathology, AP-HP Antoine Béclère Hospital, Clamart, France

    J. Martinovic

Authors
  1. C. Dubucs
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  2. N. Chassaing
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  3. C. Sergi
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  4. M. Aubert-Mucca
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  5. T. Attié-Bitach
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  6. D. Lacombe
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  7. C. Thauvin-Robinet
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  8. S. Arpin
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  9. M. J. Perez
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  10. C. Cabrol
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  11. C. P. Chen
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  12. J. Aziza
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  13. E. Colin
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  14. J. Martinovic
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  15. P. Calvas
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  16. Julie Plaisancié
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Contributions

Charlotte Dubucs collected and analyzed data and wrote the first draft of the manuscript. Julie Plaisancié conceived of and supervised the study and revised the manuscript. Marion Aubert-Mucca performed molecular analyses and analyzed data. Patrick Calvas and Nicolas Chassaing supervised the study and participated in the preparation of the manuscript. Consolato Sergi, Tania Attié-Bitach, Didier Lacombe, Christel Thauvin-Robinet Stéphanie Arpin, Marie Josée Perez, Christelle Cabrol, Chih-Ping Chen, Jacqueline Aziza, Estelle Colin, and Jelena Martinovic made the diagnosis of AGOTC and send patients’ DNA for molecular analyses. All authors read and approved the final version.

Corresponding author

Correspondence to Julie Plaisancié.

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Conflict of interest

The authors declare that they have no conflict of interest.

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According to the French rules and regulations, the current study was approved by the ad hoc French Ethics Committee Comité de Protection des Personnes (CPP) Sud-Ouest et Outre-Mer II (# DC-2008-463).

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Dubucs, C., Chassaing, N., Sergi, C. et al. Re-focusing on Agnathia-Otocephaly complex. Clin Oral Invest 25, 1353–1362 (2021). https://doi.org/10.1007/s00784-020-03443-w

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Keywords

  • Agnathia-otocephaly complex
  • OTX2
  • PRRX1
  • CNBP
  • Treacher–Collins syndrome
  • Craniofacial development