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


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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7


  1. 1.

    Robertson NG, Cremers CW, Huygen PL, Ikezono T, Krastins B, Kremer H, et al. Cochlin immunostaining of inner ear pathologic deposits and proteomic analysis in DFNA9 deafness and vestibular dysfunction. Hum Mol Genet. 2006;15(7):1071–85.

    CAS  Article  Google Scholar 

  2. 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.

    CAS  Google Scholar 

  3. 3.

    Robertson NG, O’Malley JT, Ong CA, Giersch AB, Shen J, Stankovic KM, et al. Cochlin in normal middle ear and abnormal middle ear deposits in DFNA9 and Coch (G88E/G88E) mice. J Assoc Res Otolaryngol. 2014;15(6):961–74.

    Article  Google Scholar 

  4. 4.

    Robertson NG, Lu L, Heller S, Merchant SN, Eavey RD, McKenna M, et al. Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction. Nat Genet. 1998;20(3):299–303.

    CAS  Article  Google Scholar 

  5. 5.

    Khetarpal U, Schuknecht HF, Gacek RR, Holmes LB. Autosomal dominant sensorineural hearing loss. Pedigrees, audiologic findings, and temporal bone findings in two kindreds. Arch Otolaryngol-Head Neck Surg. 1991;117(9):1032–42.

    CAS  Article  Google Scholar 

  6. 6.

    McCall AA, Linthicum FH Jr, O’Malley JT, Adams JC, Merchant SN, Bassim MK, et al. Extralabyrinthine manifestations of DFNA9. J Assoc Res Otolaryngol. 2011;12(2):141–9.

    Article  Google Scholar 

  7. 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.

    CAS  Article  Google Scholar 

  8. 8.

    Picciani R, Desai K, Guduric-Fuchs J, Cogliati T, Morton CC, Bhattacharya SK. Cochlin in the eye: functional implications. Prog Retin Eye Res. 2007;26(5):453–69.

    CAS  Article  Google Scholar 

  9. 9.

    Py BF, Gonzalez SF, Long K, Kim MS, Kim YA, Zhu H, et al. Cochlin produced by follicular dendritic cells promotes antibacterial innate immunity. Immunity. 2013;38(5):1063–72.

    CAS  Article  Google Scholar 

  10. 10.

    Nystrom A, Bornert O, Kuhl T, Gretzmeier C, Thriene K, Dengjel J, et al. Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa. Proc Natl Acad Sci USA. 2018;115(4):E705-e14.

    CAS  Article  Google Scholar 

  11. 11.

    Jung J, Yoo JE, Choe YH, Park SC, Lee HJ, Lee HJ, et al. Cleaved cochlin sequesters Pseudomonas aeruginosa and activates innate immunity in the inner ear. Cell Host Microbe. 2019;25(4):513-25.e6.

    CAS  Article  Google Scholar 

  12. 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.

    CAS  Article  Google Scholar 

  13. 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.

    CAS  Article  Google Scholar 

  14. 14.

    Vrana JA, Gamez JD, Madden BJ, Theis JD, Bergen HR 3rd, Dogan A. Classification of amyloidosis by laser microdissection and mass spectrometry-based proteomic analysis in clinical biopsy specimens. Blood. 2009;114(24):4957–9.

    CAS  Article  Google Scholar 

  15. 15.

    Baudhuin LM, Lagerstedt SA, Klee EW, Fadra N, Oglesbee D, Ferber MJ. Confirming variants in next-generation sequencing panel testing by sanger sequencing. J Mol Diagn. 2015;17(4):456–61.

    CAS  Article  Google Scholar 

  16. 16.

    Khetarpal U. DFNA9 is a progressive audiovestibular dysfunction with a microfibrillar deposit in the inner ear. The Laryngoscope. 2000;110(8):1379–84.

    CAS  Article  Google Scholar 

  17. 17.

    Abuawad YG, Uchiyama J, Kakizaki P, Valente NYS. Primary cutaneous amyloidosis of the auricular concha—case report. An Bras Dermatol. 2017;92(3):433–4.

    Article  Google Scholar 

  18. 18.

    Alexander MP, Dasari S, Vrana JA, Riopel J, Valeri AM, Markowitz GS, et al. Congophilic fibrillary glomerulonephritis: a case series. Am J Kidney Dis. 2018;72(3):325–36.

    Article  Google Scholar 

  19. 19.

    Yakupova EI, Bobyleva LG, Vikhlyantsev IM, Bobylev AG. Congo red and amyloids: history and relationship. Biosci Rep. 2019.

    Article  Google Scholar 

  20. 20.

    Howie AJ, Brewer DB. Optical properties of amyloid stained by Congo red: history and mechanisms. Micron. 2009;40(3):285–301.

    CAS  Article  Google Scholar 

  21. 21.

    Rocken C, Sletten K. Amyloid in surgical pathology. Virchows Arch. 2003;443(1):3–16.

    CAS  Article  Google Scholar 

  22. 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.

    CAS  Article  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Fang Zhou.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Basu, A., Boczek, N.J., Robertson, N.G. et al. 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. Head and Neck Pathol 14, 808–816 (2020).

Download citation


  • Congo red
  • External ear canal stenosis
  • Cochlin
  • Amyloid
  • Liquid chromatography tandem mass spectrometry
  • Deafness