1. Genetics of hearing loss Chapter 146/147
Bobby Tajudeen

2. 1 child in every 1000 born will have congenital hearing impairment
At least 50% of congenital hearing impairment has a genetic origin

3. Classification Causality Clinical Presentation
Genetic (hereditary)
Nonsyndromic (hearing loss only symptom)
Environmental (nonhereditary)
Syndromic (hearing loss and other symptoms)
Multifactorial
Anatomic Defect – CHL/SNHL/Mixed
Time of onset
Congenital (at birth)
Severity
Acquired (late-onset)
Age of onset
Frequency loss
Prelingual (before speech development)
Ears affected
Prognosis – stable vs. progressive
Postlingual (after speech development)

4. Genetics AD AS

5. X-Linked
Mitochondrial

6. Most common type of genetic hearing loss is transmitted in what fashion?AD
X-linked
Mitochondrial

8. Autosomal Recessive Nonsyndromic Hearing Loss
Usually prelingual and severe to profound across all frequencies
Connexin 26 mutation most common
GJB2 gene – integral for gap junction formation and mechanosensry transduction

10. Autosomal Dominant Nonsyndromic Hearing Loss
Onset generally postlingual, progressive, and milder with characteristic audioprofiles
DFNA2 – high frequency hearing loss
DFNA8/12/13 – midfrequency hearing loss
DFNA6/14/38 – low frequency hearing loss

11. X-linked Nonsyndromic Hearing loss
Accounts for less than 2% of nonsyndromic hearing loss
DFN3 most common – mutation in POU3F4
Congenital stapes fixation
Widening of lateral IAC
Dilation of vestibule
Mixed HL
Stapedectomy  gusher

12. Mitochondrial Nonsyndromic Hearing Loss
1555 A-to-G mtDNA mutation best characterized
Associated with aminoglycoside ototoxicity
Mild high frequency loss that progresses
Presbycusis may have mitochondrial basis due to mtDNA mutation accumulation

13. Syndromic Hearing loss
Less common than nonsyndromic forms
Cosegregate with other features

14. What is the structure?

15. A patient with Pendreds is most likely to to benefit from:
Synthroid
Thyroidectomy
Amplification
Steroid Burst

16. Pendred Syndrome Most common form of hereditary syndromic SNHL
Autosomal recessive
Affected individuals also have goiter
Congenital severe-profound HL, bilateral
Mutation in SLC26A4 gene
Pendrin anion transporter involved in chloride and iodine transport
Goiter in 2nd decade, usually euthyroid
Perchlorate discharge test
Radiographs always show temporal bone anomaly either dilated vestibular aqueducts or Mondini dysplasia

17. A patient with hearing loss is diagnosed with Jervell-Lange Nielsen syndrome. Why did his brother die at a young age?
Neurologic disease
Cardiac disease
Renal disease
Thyroid disease

18. Jervell and Lange-Nielsen Syndrome
Autosomal recessive
Characterized by congenital deafness, prolonged Q-T, syncopal attacks
KVLQT1 and KCNE1 genes important for potassium channels expressed in heart and inner ear
Congenital, bilateral, severe to profound SNHL
Prolonged QT can leads to ventricuar arrhythmias, syncopal attacks, and death
Beta blockers reduce mortality from 71% to 6%

19. A patient has progressive hearing loss and blurry vision
A patient has progressive hearing loss and blurry vision. Ophthalmologic evaluation reveals interstitial keratitis. What syndrome does the patient have?
Usher’s
Cogan’s
Waardenburg syndrome
Jervell-Lange Neilson syndrome

20. Two brothers developed congenital deaf-blindness with vestibular dysfunction. Which type of Ushers syndrome do they most likely have?
Type 1
Type 2
Type 3
Type 4

21. Usher syndromes Autosomal recessive
SNHL, retinitis pigmentosa, and often vestibular dysfunction
Cause of 50% of deaf-blindness
Three variants:
Type 1 – severe to profound congenital HL, vestibular dysfunction, retinitis pigmentosa develops in childhood
Type 2 – mod to severe HL, no vestibular dysfunction, retinal degeneration in 3rd-4th decade
Type 3 – progressive hearing loss, variable vestibular dysfunction, variable onset of retinitis pigmentosa

22. Which form of Waardenburg syndrome is not associated with dystopia canthorum?
Type 1
Type 2
Type 3
Type 4

23. Which form of Waardenburg syndrome is associated with Hirschsprung disease?
Type 1
Type 2
Type 3
Type 4

24. Waardenburg syndrome Autosomal dominant (except type 4)
SNHL, pigmentary abnormalities (heterochromic iridis, white forelock, patchy skin depigmentation), craniofacial abnormalities (dystopia canthorum, synophrys, broad nasal root)
Four types
Type 1 – presence of dystopia canthorum
Type 2 – no dystopia canthorum
Type 3 – skeletal abnormalities
Type 4 – associated with Hirschsprung disease

25. A patient is diagnosed with Alport syndrome
A patient is diagnosed with Alport syndrome. How are they likely to present?
Congenital hearing loss that is progressive
Congenital hearing loss that is stable
Adolescent onset hearing loss that is progressive
Adolescent onset hearing loss that is stable

26. Alport Syndrome X-linked syndrome of Type IV collagen
Hematuric nephritis, hearing impairment, ocular changes
Diagnostic criteria: three of following
Positive family history of hematuria
Progressive high-tone SNHL
Typical eye lesion (anterior lenticonus or macular flecks)
Histologic changes of glomerular basement membrane of the kidney
Hearing loss is symmetric, high-frequency that can be detected in late childhood and progresses to involve all frequencies
Ultimately progress to end-stage renal disease

27. What type of hearing loss does this patient likely to have?
SNHL
Progressive SNHL
Mixed hearing loss
Mild “cookie bite” SNHL

28. Treacher Collins Autosomal dominant Otologic symptoms findings
Abnormalities of craniofacial development
Auricular deformities
Atresia/stenosis of EAC
Maldevelopment of the mandible and maxilla
Malformed ossicles (CHL)
Preauricular fistulas
Abnormal canthi placement
Malformed ossicles
Downsloping palpebral fissures
Bony plate replacement of TM
Ocular colobomas
Widened aqueduct
Choanal atresia
Abberrant facial nerve
Mondini malformation
Typically normal intelligence