Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice

Austin S Lam; Carrie C Liu; Gail H Deutsch; Joshua Rivera; Jonathan A Perkins; Greg Holmes; Ethylin W Jabs; Michael L Cunningham; John P Dahl

doi:10.1002/lary.29060

Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice

Laryngoscope. 2021 Apr;131(4):E1349-E1356. doi: 10.1002/lary.29060. Epub 2020 Sep 4.

Authors

Austin S Lam^{1

2

3}, Carrie C Liu^{1

2

4}, Gail H Deutsch^{5

6}, Joshua Rivera^{7

8}, Jonathan A Perkins^{1

2

9}, Greg Holmes⁷, Ethylin W Jabs⁷, Michael L Cunningham^{3

9

10}, John P Dahl^{1

2

9}

Affiliations

¹ Department of Otolaryngology - Head & Neck Surgery, University of Washington School of Medicine, Seattle, Washington, U.S.A.
² Division of Pediatric Otolaryngology - Head & Neck Surgery, Seattle Children's Hospital, Seattle, Washington, U.S.A.
³ Seattle Children's Research Institute, Center for Developmental Biology and Regenerative Medicine, Seattle, Washington, U.S.A.
⁴ Current address: Divisions of Otolaryngology - Head and Neck Surgery, and Pediatric Surgery, Department of Surgery, University of Calgary, Calgary, Alberta, Canada.
⁵ Department of Pathology, University of Washington School of Medicine, Seattle, Washington, U.S.A.
⁶ Department of Pathology, Seattle Children's Hospital, Seattle, Washington, U.S.A.
⁷ Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York City, New York, U.S.A.
⁸ Current address: Center for Personalized Cancer Therapy, University of Massachusetts, Boston, Massachusetts, U.S.A.
⁹ Craniofacial Center, Seattle Children's Hospital, Seattle, Washington, U.S.A.
¹⁰ Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, U.S.A.

Abstract

Objectives: To characterize tracheal cartilage morphology in mouse models of fibroblast growth factor receptor (Fgfr2)-related craniosynostosis syndromes. To establish relationships between specific Fgfr2 mutations and tracheal cartilaginous sleeve (TCS) phenotypes in these mouse models.

Methods: Postnatal day 0 knock-in mouse lines with disease-specific genetic variations in the Fgfr2 gene (Fgfr2^C342Y/C342Y , Fgfr2^C342Y/+ , Fgfr2^+/Y394C , Fgfr2^+/S252W , and Fgfr2^+/P253R ) as well as line-specific controls were utilized. Tracheal cartilage morphology as measured by gross analyses, microcomputed tomography (μCT), and histopathology were compared using Chi-squared and single-factor analysis of variance statistical tests.

Results: A greater proportion of rings per trachea were abnormal in Fgfr2^C342Y/+ tracheas (63%) than Fgfr2^+/S252W (17%), Fgfr2^+/P253R (17%), Fgfr2^+/Y394C (12%), and controls (10%) (P < .001 for each vs. Fgfr2^C342Y/+ ). TCS segments were found only in Fgfr2^C342Y/C342Y (100%) and Fgfr2^C342Y/+ (72%) tracheas. Cricoid and first-tracheal ring fusion was noted in all Fgfr2^C342Y/C342Y and 94% of Fgfr2^C342Y/+ samples. The Fgfr2^C342Y/C342Y and Fgfr2^C342Y/+ groups were found to have greater areas and volumes of cartilage than other lines on gross analysis and μCT. Histologic analyses confirmed TCS among the Fgfr2^C342Y/C342Y and Fgfr2^C342Y/+ groups, without appreciable differences in cartilage morphology, cell size, or density; no histologic differences were observed among other Fgfr2 lines compared to controls.

Conclusion: This study found TCS phenotypes only in the Fgfr2^C342Y mouse lines. These lines also had increased tracheal cartilage compared to other mutant lines and controls. These data support further study of the Fgfr2 mouse lines and the investigation of other Fgfr2 variants to better understand their role in tracheal development and TCS formation.

Level of evidence: NA Laryngoscope, 131:E1349-E1356, 2021.

Keywords: Apert syndrome; Beare-Stevenson syndrome; Crouzon syndrome; FGFR2; craniosynostosis; tracheal anomalies; tracheal cartilaginous sleeve.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Acanthosis Nigricans / genetics
Acrocephalosyndactylia / genetics
Animals
Cartilage / pathology
Craniofacial Dysostosis / genetics
Craniosynostoses / genetics
Disease Models, Animal
Ear / abnormalities
Genetic Association Studies / methods*
Humans
Mice
Mutation
Phenotype
Receptor, Fibroblast Growth Factor, Type 2 / genetics*
Scalp Dermatoses / genetics
Skin Abnormalities / genetics
Trachea / abnormalities*
Trachea / embryology
Trachea / pathology
Tracheal Diseases / diagnosis
Tracheal Diseases / genetics*
Tracheal Diseases / pathology
X-Ray Microtomography / methods

Genotype-Phenotype Correlation of Tracheal Cartilaginous Sleeves and Fgfr2 Mutations in Mice

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