Multimodality Craniofacial Phenotyping of Congenital Facial Weakness Disorders

Konstantinia Almpani; Katelin R Devine; Denise K Liberton; Rashmi Mishra; Carol Bassim; Carol Van Ryzin; Flavia M Facio; Bryn D Webb; Brenda J Barry; Elizabeth C Engle; Ethylin Wang Jabs; Francis S Collins; Irini Manoli; Janice S Lee; Moebius Syndrome Research Consortium

doi:10.1177/10556656251344128

Multimodality Craniofacial Phenotyping of Congenital Facial Weakness Disorders

Cleft Palate Craniofac J. 2025 Jul 3:10556656251344128. doi: 10.1177/10556656251344128. Online ahead of print.

Authors

Konstantinia Almpani¹, Katelin R Devine¹, Denise K Liberton¹, Rashmi Mishra¹, Carol Bassim¹, Carol Van Ryzin², Flavia M Facio², Bryn D Webb^{3

4

5}, Brenda J Barry^{6

7

8}, Elizabeth C Engle^{6

9}, Ethylin Wang Jabs^{3

10

11}, Francis S Collins^{2

12}, Irini Manoli², Janice S Lee¹; Moebius Syndrome Research Consortium

Affiliations

¹ Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MB, USA.
² Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, Bethesda, MD, USA.
³ Department of Genetics and Genomic Sciences and Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁴ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵ Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
⁶ Department of Neurology, Boston Children's Hospital, Boston, MA, USA.
⁷ F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
⁸ Howard Hughes Medical Institute, Chevy Chase, MD, USA.
⁹ Departments of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Howard Hughes Medical Institute, Chevy Chase, Boston, MA, USA.
¹⁰ Departments of Genetic Medicine and Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹ Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
¹² Center for Precision Health Research, National Human Genome Research Institute, Bethesda, MD, USA.

PMID: 40611650
DOI: 10.1177/10556656251344128

Abstract

ObjectiveCongenital facial weakness (CFW) disorders are a heterogeneous group of rare conditions, that present at birth, with reduced facial movement, and mask-like facies. This study utilized a multimodality approach to examine the craniofacial and intraoral phenotypes among CFW disorders: Moebius syndrome (MBS), Hereditary Congenital Facial Palsy (HCFP), β-tubulin isotype 3 syndrome (CFEOM3A-TUBB3), Carey-Fineman-Ziter syndrome (CFZS), and a group of rarer disorders (Other).DesignProspective cohort study.Setting: Dental clinic.Participants: Sixty individuals (sex ratio 1:1, mean age 26.2 ± 17.5 years) with a diagnosis of CFW.Interventions: Deep clinical craniofacial and dental phenotyping, three-dimensional facial surface and cone-beam computed tomography scans, and cephalometric and geometric morphometric analyses.ResultsCFEOM3A-TUBB3, MBS, and CFZS groups had the highest prevalence of craniofacial anomalies; HCFP individuals were least affected. CFEOM3A-TUBB3 had a higher prevalence of short lower face (75%), poor oral hygiene (100%)/decay (75%), and Class II malocclusion (87.5%). Moebius syndrome was associated with lagophthalmos (90.9%), tongue fissures (72.4%), tight/small oral orifice (51.7%), and tongue fasciculations (50%). Carey-Fineman-Ziter syndrome had oblong facial shape (100%), downward lip commissures (100%), and abnormal hearing (60%). Moderate-severe decay/gingivitis correlated with restricted oral orifice, common among patients with facial animation/sling surgery. Morphologically, the CFW cohort had a relatively small craniofacial centroid size, anthropometric measurements, and distinct craniofacial shapes for each subtype.ConclusionsCongenital facial weakness can result in abnormal craniofacial development in addition to the loss of facial movement. Multimodality phenotypic characterization of CFW disorders elucidated key clinical findings and distinct craniofacial shape segregation among the different groups.

Keywords: 3D facial surface; CAPS; CBCT; Carey-Fineman-Ziter syndrome; Moebius syndrome; TUBB3; cephalometric analysis; clinical phenotyping; cone-beam computed tomography; congenital facial weakness; craniofacial anomalies prevalence score; geometric morphometric analysis; hereditary congenital facial palsy; multimodality craniofacial phenotyping; oral-dental anomalies; β-tubulin isotype 3 syndrome.