Get access

A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia

Authors

  • Reinhard Ramsebner MD,

    1. Department of Otorhinolaryngology, the Division of Molecular Pharmacokinetics and Imaging, Biochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    2. Department of Clinical Pharmacology, Division of Molecular Pharmacokinetics and ImagingBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Martin Ludwig MD,

    1. the Center of Anatomy and Cell BiologyBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Thomas Parzefall MD,

    1. the Center of Anatomy and Cell BiologyBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Trevor Lucas PhD,

    1. the Center of Anatomy and Cell BiologyBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Wolf-Dieter Baumgartner MD,

    1. Department of Clinical Pharmacology, Division of Molecular Pharmacokinetics and ImagingBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Olaf Bodamer MD, PhD,

    1. the Department of Nuclear and Developmental Biology, Vienna Medical University; the Vienna Medical University Children's Hospital, Biochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Filiz Basak Cengiz MD,

    1. the Department of Pediatrics, Division of Clinical Molecular Pathology and Genetics, Ankara University School of Medicine, Ankara, Turkey
    Search for more papers by this author
  • Christian Schoefer PhD,

    1. the Center of Anatomy and Cell BiologyBiochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    Search for more papers by this author
  • Mustafa Tekin MD,

    1. the Department of Pediatrics, Division of Clinical Molecular Pathology and Genetics, Ankara University School of Medicine, Ankara, Turkey
    2. Dr. John T. Macdonald Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, U.S.A.
    Search for more papers by this author
  • Klemens Frei MD

    Corresponding author
    1. Department of Otorhinolaryngology, the Division of Molecular Pharmacokinetics and Imaging, Biochemical Genetics and National Neonatal Screening Laboratories, Vienna, Austria
    • Department of Otorhinolaryngology, Medical University of Vienna, AKH-8J, Waehringer Gürtel 18-20, A-1090, Vienna, Austria
    Search for more papers by this author

  • This project was supported by the MedEl Corporation, Innsbruck and IhrOhr, Vienna, Austria.

Abstract

Objectives/Hypothesis:

Analysis of association between genotype and phenotype.

Study Design:

Prospective genetic study in a family.

Methods:

Auditory investigations, computer tomography, and genetic sequencing of the fibroblast growth factor 3 (FGF3) gene were performed on a Somali family presenting with autosomal recessive, hearing impairment, microdontia, and outer ear morphologies ranging from normal auricle development to microtia assessed as type 1 Weerda dysplasia in affected individuals.

Results:

Computed tomography imaging identified differential inter- and intraindividual malformations of the inner ear including labyrinth aplasia, development of a common cavity to the presence of a cochlear with 1.5 windings (Mondini malformation) in affected individuals, symptoms similar to those described as labyrinth aplasia, microtia, and microdontia (LAMM) syndrome, caused by mutations in FGF3. Genetic sequencing revealed the presence of a novel p.R95W missense mutation in FGF3 segregating with pathology. The p.R95W mutation substitutes a positively charged arginine for a polar tryptophan in the highly conserved RYLAM consensus of the β6 sheet of FGF3 that interacts with FGFR2.

Conclusions:

These findings describe, for the first time, variable inner ear malformations and outer ear dysplasia in the presence of constant microdontia, associated with homozygous inheritance of the p.R95W mutation in FGF3, mirroring phenotypes observed in mouse models ablating FGF3/FGFR2 signaling. Laryngoscope, 2010

Ancillary