Skip to main content
Advertisement

Main menu

  • Home
  • Content
    • Current Issue
    • Accepted Manuscripts
    • Article Preview
    • Past Issue Archive
    • Video Articles
    • AJNR Case Collection
    • Case of the Week Archive
    • Case of the Month Archive
    • Classic Case Archive
  • Special Collections
    • AJNR Awards
    • Low-Field MRI
    • Alzheimer Disease
    • ASNR Foundation Special Collection
    • Photon-Counting CT
    • View All
  • Multimedia
    • AJNR Podcasts
    • AJNR SCANtastic
    • Trainee Corner
    • MRI Safety Corner
    • Imaging Protocols
  • For Authors
    • Submit a Manuscript
    • Submit a Video Article
    • Submit an eLetter to the Editor/Response
    • Manuscript Submission Guidelines
    • Statistical Tips
    • Fast Publishing of Accepted Manuscripts
    • Graphical Abstract Preparation
    • Imaging Protocol Submission
    • Author Policies
  • About Us
    • About AJNR
    • Editorial Board
    • Editorial Board Alumni
  • More
    • Become a Reviewer/Academy of Reviewers
    • Subscribers
    • Permissions
    • Alerts
    • Feedback
    • Advertisers
    • ASNR Home

User menu

  • Alerts
  • Log in

Search

  • Advanced search
American Journal of Neuroradiology
American Journal of Neuroradiology

American Journal of Neuroradiology

ASHNR American Society of Functional Neuroradiology ASHNR American Society of Pediatric Neuroradiology ASSR
  • Alerts
  • Log in

Advanced Search

  • Home
  • Content
    • Current Issue
    • Accepted Manuscripts
    • Article Preview
    • Past Issue Archive
    • Video Articles
    • AJNR Case Collection
    • Case of the Week Archive
    • Case of the Month Archive
    • Classic Case Archive
  • Special Collections
    • AJNR Awards
    • Low-Field MRI
    • Alzheimer Disease
    • ASNR Foundation Special Collection
    • Photon-Counting CT
    • View All
  • Multimedia
    • AJNR Podcasts
    • AJNR SCANtastic
    • Trainee Corner
    • MRI Safety Corner
    • Imaging Protocols
  • For Authors
    • Submit a Manuscript
    • Submit a Video Article
    • Submit an eLetter to the Editor/Response
    • Manuscript Submission Guidelines
    • Statistical Tips
    • Fast Publishing of Accepted Manuscripts
    • Graphical Abstract Preparation
    • Imaging Protocol Submission
    • Author Policies
  • About Us
    • About AJNR
    • Editorial Board
    • Editorial Board Alumni
  • More
    • Become a Reviewer/Academy of Reviewers
    • Subscribers
    • Permissions
    • Alerts
    • Feedback
    • Advertisers
    • ASNR Home
  • Follow AJNR on Twitter
  • Visit AJNR on Facebook
  • Follow AJNR on Instagram
  • Join AJNR on LinkedIn
  • RSS Feeds

AJNR Awards, New Junior Editors, and more. Read the latest AJNR updates

Research ArticleHead and Neck Imaging

Subtle Malformation of the Cochlear Apex and Genetic Abnormalities: Beyond the “Thorny” Cochlea

F. D’Arco, A. Biswas, E. Clement, K. Rajput and A.F. Juliano
American Journal of Neuroradiology December 2022, DOI: https://doi.org/10.3174/ajnr.A7746
F. D’Arco
aFrom the Departments of Radiology (F.D., A.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for F. D’Arco
A. Biswas
aFrom the Departments of Radiology (F.D., A.B.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for A. Biswas
E. Clement
bClinical Genetics (E.C.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for E. Clement
K. Rajput
cAudiological Medicine (K.R.), Great Ormond Street Hospital for Children, National Health Service Foundation Trust, London, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for K. Rajput
A.F. Juliano
dDepartment of Radiology (A.F.J.), Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for A.F. Juliano
  • Article
  • Figures & Data
  • Info & Metrics
  • Responses
  • References
  • PDF
Loading

Abstract

SUMMARY: With the routine use of high-resolution heavily T2-weighted sequences to evaluate patients with hearing deficits, new, subtle phenotypes of cochlear malformations are being discovered and an increasing number of genotype-phenotype correlations are being found through a reverse phenotype approach, which can help guide geneticists. In this brief report, we present subtle malformations of the apical turn of the cochlea related to 3 genetic mutations, emphasizing the importance of a careful assessment of the cochlear apex.

ABBREVIATIONS:

BOR
branchio-oto-renal syndrome
DEGCAGS
DEvelopmental delay with Gastrointestinal, CArdiovascular, Genitourinary, and Skeletal abnormalities
IAC
internal auditory canal
SNHL
sensorineural hearing loss

With the use of high-resolution sequences in MR imaging assessment of patients with congenital sensorineural hearing loss (SNHL), newer phenotypes of cochlear malformations have been described, including several types of cochlear hypoplasias.1,2 There is increasing recognition that specific radiologic appearances of the cochlea and temporal bone may be associated with specific syndromes or genetic mutations.3⇓⇓-6 Thus, an imaging phenotype can suggest an underlying genotype, contributing to clinical and genetic work-up of the patient.

The normal cochlea has an apical turn that is smooth in contour and evenly tubular throughout its length. The apex (following the basal and middle turns) typically spans 180°–270° around the center point, resulting in a cochlea with 2.5–2.75 turns total.7

Here, we describe subtle malformations of the apical aspect of the cochlea in 5 patients with 3 different genetic abnormalities and cochleovestibular symptoms; these apical malformations were chosen among the authors by consensus. The patients were selected from the Great Ormond Street Hospital database of dysplastic cochleae. We retrospectively reviewed the database for all cases that involved an anomaly in the apical turn, yielding these 5 cases. All these cases had genetic diagnoses available. We describe possible genetic mechanisms that may cause apical turn anomalies, and emphasize the importance of not overlooking such subtle cochlear abnormalities.

CASE SERIES

TKFC-Related Disorder

A 7-year-old patient known to have a biallelic mutation in the TKFC gene (Mendelian Inheritance in Man, 618805), with congenital cataracts, microophthalmia, and developmental delay, underwent MR imaging of the brain and inner ear/internal auditory canal (IAC) for balance difficulties and hypersensitivity to loud and sudden noises without hearing loss.

MR imaging of the brain demonstrated bilateral cataracts and cerebellar atrophy. A high-resolution 3D heavily T2-weighted sequence of the IAC revealed symmetric subtle cochlear abnormality characterized by a peculiar appearance of the upper part of the cochlea with an extra half-turn beyond the apical turn, resulting in >3 turns total (Fig 1A).7 The apical turn and the extra half-turn were not pointed but were smooth and flat like a normal apical turn. The cochlear height, measured in accordance with described methods in the literature (Fig 1B), was 6 mm (above the normal range of 4.3–5.4 mm).8,9 The cochleovestibular nerves were present and normal in course and caliber. The other inner ear structures were normal as well, including preserved internal partitioning of both cochleae.

FIG 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG 1.

A, High-resolution 3D heavily T2-weighted MR images of the inner ear and IAC in a patient with a TKFC-related disorder. There is an extra turn (arrows) at the apical portion of the cochlea beyond the usual apical turn and an overall greater cochlear height. The cochlear nerves are present, the modiolus is normal in appearance, and there is normal internal partitioning. Contrast this appearance with that of the normal cochlear apical turn seen in Fig 3B, without an extra turn beyond it. B, Coronal CT image through the cochlea shows the method to measure cochlear height as defined by Shim et al:8 The maximal height of the cochlea is measured along an axis perpendicular to the oval window (white line).

Presumed DEGCAGS Syndrome (ZNF699 Gene)

A 7-month-old boy with a homozygous variant of unknown significance in the ZNF699 gene (presumed diagnosis of DEvelopmental delay with Gastrointestinal, CArdiovascular, Genitourinary, and Skeletal abnormalities [DEGCAGS] syndrome [Mendelian Inheritance in Man, 619488]) presented with bilateral profound SNHL. He also had developmental delay, atrial septal defect, dysmorphic features, and congenital clavicle deformity.

MR imaging of the IAC was performed to investigate the hearing loss. It demonstrated bilateral abnormality of the apical turn of the cochlea, very similar to the “thorny” cochlea described by Pao et al,10 in relation to SIX1 mutation in branchio-oto-renal syndrome (BOR). The cochlear apex was irregular, with a short, stumplike shape (Fig 2). There was mild hypoplasia of the cochlear nerve on the left, but otherwise the inner ear structures were normal bilaterally. The cochlear height was 5.8 and 5.7 mm on the right and left, respectively.

FIG 2.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG 2.

High-resolution 3D heavily T2-weighted MR images of the inner ear and IAC in a patient with a ZNF699 gene mutation. The uppermost turn of the cochlear apex following the middle turn has a short and stumpy shape (arrows).

SIX1-Related BOR

Searching our institutional archive for genetic malformations, we found, among patients with a genetic diagnosis of BOR syndrome, 3 patients with confirmed SIX1 mutation. Five of these 6 cochleae showed a characteristic “thorny” apical turn, with a small, pointed protuberant appearance (Fig 3). These patients presented with SNHL and other clinical abnormalities expected in BOR due to a SIX1 genetic mutation (ie, otic and branchial defects consistently seen, renal defects variably seen, and less prevalent than among individuals with BOR related to an EYA1 genetic mutation).11 Two of them were previously included in the study by Pao et al.10

FIG 3.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIG 3.

High-resolution 3D heavily T2-weighted MR image of a typical SIX1-BOR protuberant “thorny” tip of the cochlea (arrow in A) in comparison with a healthy control in whom the apical turn is uniform and relatively flat and tubular (arrow in B).

DISCUSSION

All patients included in this case series presented with labyrinthine symptoms (4 with SNHL and 1 with balance difficulties and sound hypersensitivity) and very subtle malformations of the cochlear apical turn, which were overlooked by the reporting radiologists in 3 of the 5 cases.

The genetics of inner ear development are not completely understood, but we know that, at some point during embryologic development, genes polarize toward the cochlear (ventral) or vestibulocanalicular (dorsal) components of the otic capsule.12 It is also clear, from radiologic studies of cochleae fitting the description of the so-called cochlear hypoplasia type 4 anomaly, that the basal turn of the cochlea may be relatively preserved while the middle and apical turns are more affected.13 Indeed, this is the case in the “unwound” cochlea in patients with BOR14,15 and in the extreme hypoplastic cochlea in patients with Walker-Warburg syndrome.4

In patients with BOR, both EYA1 and SIX1 are expressed in the ventral (cochlear) part of the developing otic vesicle, but the expression of SIX1 is dependent on that of EYA1, and its expression is more prominent in the cochlear apex in murine models.10,16 This accounts for the different phenotypes seen among patients with BOR with mutations in the EYA1 versus the SIX1 gene, with only the apex being malformed in those with SIX1 mutations.

Although the role of the TKFC gene in ear development has not been reported, patients with this mutation may have progressive low-frequency hearing impairment.17 This specific type of hearing loss may be explained by morphologic abnormalities in the cochlear apex, which allows hearing of low pitches. In fact, the role of the shape of the apical cochlea has been correlated, in a comparative study among different species, with low-frequency hearing limits.18 Our case of TKFC-related disorder represents an example of clinicoradiologic correlation that can shed light on previously unknown functions of specific genes in ear development, including rare genetic mutations that lead to multisystemic abnormalities.

DEGCAGS syndrome is due to an autosomal recessive mutation in the ZNF699 gene and is characterized by neurodevelopmental delay, abnormal facial features, growth delay, syndactyly/polydactyly, and anemia/pancytopenia.19 This gene encodes for a nuclear zinc-finger protein with a possible function in nucleic acid binding.20 Little is known about the role of this gene, but patients described with this syndrome have SNHL as a constant symptom.19 It is, therefore, likely that the cause of the SNHL is related to a specific role of this gene in the development of the apical part of the cochlea. Again, the reverse phenotyping approach in this case can help define as yet suboptimally understood gene functions.

CONCLUSIONS

Subtle abnormalities of the inner ears, particularly those involving the apical part of the cochlea, can be easily overlooked, even with the use of optimal 3D high-resolution heavily-T2-weighted sequences on a 3T MR imaging scanner. We described 5 patients with 3 genetic abnormalities, all characterized by labyrinthine symptoms and malformation of the apical aspect of the cochlea and otherwise normal inner ear anatomy. These findings correlate with clinical symptoms of hearing impairment and shed light on the role of rare genetic abnormalities in inner ear development. A diligent search for these at-times subtle findings must be conducted, especially in cases of MR imaging of the IAC with seemingly negative findings in symptomatic patients.

This report adds to the growing evidence of genotype-phenotype correlation between syndromic and/or congenital deafness and anomaly of the cochlear apex in children.

Footnotes

  • Disclosure forms provided by the authors are available with the full text and PDF of this article at www.ajnr.org.

References

  1. 1.↵
    1. Sennaroglu L
    . Histopathology of inner ear malformations: do we have enough evidence to explain pathophysiology? Cochlear Implants Int 2016;17:3–20 doi:10.1179/1754762815Y.0000000016 pmid:26158591
    CrossRefPubMed
  2. 2.↵
    1. Quirk B,
    2. Youssef A,
    3. Ganau M, et al
    . Radiological diagnosis of the inner ear malformations in children with sensorineural hearing loss. BJR Open 2019;1:20180050 doi:10.1259/bjro.20180050 pmid:33178934
    CrossRefPubMed
  3. 3.↵
    1. Siddiqui A,
    2. D’Amico A,
    3. Colafati GS, et al
    . Hypothalamic malformations in patients with X-linked deafness and incomplete partition type 3. Neuroradiology 2019;61:949–52 doi:10.1007/s00234-019-02230-z pmid:31177298
    CrossRefPubMed
  4. 4.↵
    1. Talenti G,
    2. Robson C,
    3. Severino MS, et al
    . Characteristic cochlear hypoplasia in patients with Walker-Warburg syndrome: a radiologic study of the inner ear in α-dystroglycan-related muscular disorders. AJNR Am J Neuroradiol 2021;42:167–72 doi:10.3174/ajnr.A6858 pmid:33122211
    Abstract/FREE Full Text
  5. 5.↵
    1. D’Arco F,
    2. Sanverdi E,
    3. O’Brien WT, et al
    . The link between inner ear malformations and the rest of the body: what we know so far about genetic, imaging and histology. Neuroradiology 2020;62:539–44 doi:10.1007/s00234-020-02382-3 pmid:32125475
    CrossRefPubMed
  6. 6.↵
    1. D’Arco F,
    2. Youssef A,
    3. Ioannidou E, et al
    . Temporal bone and intracranial abnormalities in syndromic causes of hearing loss: an updated guide. Eur J Radiol 2020;123:108803 doi:10.1016/j.ejrad.2019.108803 pmid:31891841
    CrossRefPubMed
  7. 7.↵
    1. Biedron S,
    2. Westhofen M,
    3. Ilgner J
    . On the number of turns in human cochleae. Otol Neurotol 2009;30:414–17 doi:10.1097/MAO.0b013e3181977b8d pmid:19225438
    CrossRefPubMed
  8. 8.↵
    1. Shim HJ,
    2. Shin JE,
    3. Chung JW, et al
    . Inner ear anomalies in cochlear implantees: importance of radiologic measurements in the classification. Otol Neurotol 2006;27:831–37 doi:10.1097/01.mao.0000227902.47483.ef pmid:16936569
    CrossRefPubMed
  9. 9.↵
    1. D’Arco F,
    2. Talenti G,
    3. Lakshmanan R, et al
    . Do measurements of inner ear structures help in the diagnosis of inner ear malformations? A review of literature. Otol Neurotol 2017;38:e384–92 doi:10.1097/MAO.0000000000001604 pmid:29065090
    CrossRefPubMed
  10. 10.↵
    1. Pao J,
    2. D’Arco F,
    3. Clement E, et al
    . Re-examining the cochlea in branchio-oto-renal syndrome: genotype-phenotype correlation. AJNR Am J Neuroradiol 2022;43:309–14 doi:10.3174/ajnr.A7396 pmid:35058298
    Abstract/FREE Full Text
  11. 11.↵
    1. Ruf RG,
    2. Xu PX,
    3. Silvius D, et al
    . SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes. Proc Natl Acad Sci U S A 2004;101:8090–95 doi:10.1073/pnas.0308475101 pmid:15141091
    Abstract/FREE Full Text
  12. 12.↵
    1. Chatterjee S,
    2. Kraus P,
    3. Lufkin T
    . A symphony of inner ear developmental control genes. BMC Genet 2010;11:68 doi:10.1186/1471-2156-11-68 pmid:20637105
    CrossRefPubMed
  13. 13.↵
    1. Talenti G,
    2. Manara R,
    3. Brotto D, et al
    . High-resolution 3 T magnetic resonance findings in cochlear hypoplasias and incomplete partition anomalies: a pictorial essay. Br J Radiol 2018;91:20180120 doi:10.1259/bjr.20180120 pmid:29688748
    CrossRefPubMed
  14. 14.↵
    1. Hsu A,
    2. Desai N,
    3. Paldino MJ
    . The unwound cochlea: a specific imaging marker of branchio-oto-renal syndrome. AJNR Am J Neuroradiol 2018;39:2345–49 doi:10.3174/ajnr.A5856 pmid:30385470
    Abstract/FREE Full Text
  15. 15.↵
    1. Robson CD
    . Congenital hearing impairment. Pediatr Radiol 2006;36:309–24 doi:10.1007/s00247-005-0042-9 pmid:16465539
    CrossRefPubMed
  16. 16.↵
    1. Zheng W,
    2. Huang L,
    3. Wei ZB, et al
    . The role of Six1 in mammalian auditory system development. Development 2003;130:3989–4000 doi:10.1242/dev.00628 pmid:12874121
    Abstract/FREE Full Text
  17. 17.↵
    1. Wortmann SB,
    2. Meunier B,
    3. Mestek-Boukhibar L, et al
    . Bi-allelic variants in TKFC encoding triokinase/FMN cyclase are associated with cataracts and multisystem disease. Am J Hum Genet 2020;106:256–63 doi:10.1016/j.ajhg.2020.01.005 pmid:32004446
    CrossRefPubMed
  18. 18.↵
    1. Manoussaki D,
    2. Chadwick RS,
    3. Ketten DR, et al
    . The influence of cochlear shape on low-frequency hearing. Proc Natl Acad Sci U S A 2008;105:6162–66 doi:10.1073/pnas.0710037105 pmid:18413615
    Abstract/FREE Full Text
  19. 19.↵
    1. Bertoli-Avella AM,
    2. Kandaswamy KK,
    3. Khan S, et al
    . Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders. Genet Med 2021;23:1551–68 doi:10.1038/s41436-021-01159-0 pmid:33875846
    CrossRefPubMed
  20. 20.↵
    1. Scholz H,
    2. Franz M,
    3. Heberlein U
    . The hangover gene defines a stress pathway required for ethanol tolerance development. Nature 2005;436:845–47 doi:10.1038/nature03864 pmid:16094367
    CrossRefPubMed
  • Received August 11, 2022.
  • Accepted after revision November 15, 2022.
  • © 2023 by American Journal of Neuroradiology
PreviousNext
Back to top
Advertisement
Print
Download PDF
Email Article

Thank you for your interest in spreading the word on American Journal of Neuroradiology.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Subtle Malformation of the Cochlear Apex and Genetic Abnormalities: Beyond the “Thorny” Cochlea
(Your Name) has sent you a message from American Journal of Neuroradiology
(Your Name) thought you would like to see the American Journal of Neuroradiology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Cite this article
F. D’Arco, A. Biswas, E. Clement, K. Rajput, A.F. Juliano
Subtle Malformation of the Cochlear Apex and Genetic Abnormalities: Beyond the “Thorny” Cochlea
American Journal of Neuroradiology Dec 2022, DOI: 10.3174/ajnr.A7746

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
0 Responses
Respond to this article
Share
Bookmark this article
Subtle Malformation of the Cochlear Apex and Genetic Abnormalities: Beyond the “Thorny” Cochlea
F. D’Arco, A. Biswas, E. Clement, K. Rajput, A.F. Juliano
American Journal of Neuroradiology Dec 2022, DOI: 10.3174/ajnr.A7746
del.icio.us logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One
Purchase

Jump to section

  • Article
    • Abstract
    • ABBREVIATIONS:
    • CASE SERIES
    • DISCUSSION
    • CONCLUSIONS
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • Responses
  • References
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Crossref (1)
  • Google Scholar

This article has been cited by the following articles in journals that are participating in Crossref Cited-by Linking.

  • Syndromic Hearing Loss in Children
    Martin Lewis, Caroline D. Robson, Felice D‘Arco
    Neuroimaging Clinics of North America 2023 33 4

More in this TOC Section

  • ASL Sensitivity for Head and Neck Paraganglioma
  • Post SRS Peritumoral Hyperintense Signal of VSs
  • Temporal Evolution of Vestibular schwannoma
Show more Head and Neck Imaging

Similar Articles

Advertisement

Indexed Content

  • Current Issue
  • Accepted Manuscripts
  • Article Preview
  • Past Issues
  • Editorials
  • Editor's Choice
  • Fellows' Journal Club
  • Letters to the Editor
  • Video Articles

Cases

  • Case Collection
  • Archive - Case of the Week
  • Archive - Case of the Month
  • Archive - Classic Case

More from AJNR

  • Trainee Corner
  • Imaging Protocols
  • MRI Safety Corner
  • Book Reviews

Multimedia

  • AJNR Podcasts
  • AJNR Scantastics

Resources

  • Turnaround Time
  • Submit a Manuscript
  • Submit a Video Article
  • Submit an eLetter to the Editor/Response
  • Manuscript Submission Guidelines
  • Statistical Tips
  • Fast Publishing of Accepted Manuscripts
  • Graphical Abstract Preparation
  • Imaging Protocol Submission
  • Evidence-Based Medicine Level Guide
  • Publishing Checklists
  • Author Policies
  • Become a Reviewer/Academy of Reviewers
  • News and Updates

About Us

  • About AJNR
  • Editorial Board
  • Editorial Board Alumni
  • Alerts
  • Permissions
  • Not an AJNR Subscriber? Join Now
  • Advertise with Us
  • Librarian Resources
  • Feedback
  • Terms and Conditions
  • AJNR Editorial Board Alumni

American Society of Neuroradiology

  • Not an ASNR Member? Join Now

© 2025 by the American Society of Neuroradiology All rights, including for text and data mining, AI training, and similar technologies, are reserved.
Print ISSN: 0195-6108 Online ISSN: 1936-959X

Powered by HighWire