First Report of Bilateral External Auditory Canal Cochlin Aggregates (“Cochlinomas”) with Multifocal Amyloid-Like Deposits, Associated with Sensorineural Hearing Loss and a Novel Genetic Variant in COCH Encoding Cochlin
- 51 Downloads
Pathogenic variants in COCH, encoding cochlin, cause DFNA9 deafness disorder with characteristic histopathologic findings of cochlin deposits in the inner and middle ears. Here, we present the first case of deafness associated with bilateral external auditory canal (EAC) cochlin deposits, previously unreported evidence suggestive of cochlin-derived amyloid formation, and a novel COCH variant. A 54-year-old woman presented with progressive sensorineural hearing loss and bilateral EAC narrowing by subcutaneous thickening. Excision and histologic evaluation of tissue from both EACs showed paucicellular eosinophilic aggregates containing multiple Congo red-positive foci with yellow and green birefringence under crossed polarization light microscopy. Mass spectrometry performed on both the Congo red-positive and Congo red-negative areas identified cochlin as the most abundant protein, as well as a low abundance of universal amyloid signature peptides only in the Congo red-positive areas. Peptides indicative of a canonical amyloid type were not detected. Electron microscopy showed haphazard, branched microfibrils (3–7 nm in diameter) consistent with cochlin, as well as swirling fibrils (10–24 nm in diameter) reminiscent of amyloid fibrils. Cochlin immunohistochemical staining showed positivity throughout the aggregates. Sequencing of the entire COCH gene coding region from the patient’s blood revealed a novel variant resulting in a non-conservative amino acid substitution of isoleucine to phenylalanine (c.1621A>T, p.I541F) in the vWFA2 domain at the protein’s C-terminus. Our findings reveal a new pathologic manifestation of cochlin, raise the possibility of previously undescribed cochlin-derived amyloid formation, and highlight the importance of thoroughly investigating all aggregative tissue findings in the practice of diagnostic pathology.
KeywordsCongo red External ear canal stenosis Cochlin Amyloid Liquid chromatography tandem mass spectrometry Deafness
We acknowledge Mayo Clinic Clinical Tissue Proteomics Laboratory for performing mass spectrometry experiments.
C. C. Morton is supported by NIDCD R01DC015052 and the University of Manchester NIHR Biomedical Research Centre.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Ikezono T, Omori A, Ichinose S, Pawankar R, Watanabe A, Yagi T. Identification of the protein product of the Coch gene (hereditary deafness gene) as the major component of bovine inner ear protein. Biochem Biophys Acta. 2001;1535(3):258–65.Google Scholar
- 7.Robertson NG, Skvorak AB, Yin Y, Weremowicz S, Johnson KR, Kovatch KA, et al. Mapping and characterization of a novel cochlear gene in human and in mouse: a positional candidate gene for a deafness disorder, DFNA9. Genomics. 1997;46(3):345–54. https://doi.org/10.1006/geno.1997.5067.CrossRefGoogle Scholar
- 12.Bae SH, Robertson NG, Cho HJ, Morton CC, Jung DJ, Baek JI, et al. Identification of pathogenic mechanisms of COCH mutations, abolished cochlin secretion, and intracellular aggregate formation: genotype-phenotype correlations in DFNA9 deafness and vestibular disorder. Hum Mutat. 2014;35(12):1506–13. https://doi.org/10.1002/humu.22701.CrossRefGoogle Scholar
- 13.Cho HJ, Park HJ, Trexler M, Venselaar H, Lee KY, Robertson NG, et al. A novel COCH mutation associated with autosomal dominant nonsyndromic hearing loss disrupts the structural stability of the vWFA2 domain. J Mol Med. 2012;90(11):1321–31. https://doi.org/10.1007/s00109-012-0911-2.CrossRefGoogle Scholar
- 22.Street VA, Kallman JC, Robertson NG, Kuo SF, Morton CC, Phillips JO. A novel DFNA9 mutation in the vWFA2 domain of COCH alters a conserved cysteine residue and intrachain disulfide bond formation resulting in progressive hearing loss and site-specific vestibular and central oculomotor dysfunction. Am J Med Genet Part A. 2005;139A(2):86–95. https://doi.org/10.1002/ajmg.a.30980.CrossRefGoogle Scholar