Genetic Bases of Hearing Loss: Future Treatment Implications · Luis F. Escobar, MD Medical...
Transcript of Genetic Bases of Hearing Loss: Future Treatment Implications · Luis F. Escobar, MD Medical...
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Genetic Bases of Hearing Loss: Future Treatment Implications
Luis F. Escobar, MDMedical Director
Medical Genetics & Neurodevelopmental Pediatrics of Indiana
Peyton Manning Children’s Hospital
St. Vincent Hospital and Health Services Indianapolis, Indiana
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1. Review Basic Concepts and Ideas
2. Review Gene Involvement in Hearing and Auditory organs development
3. Review some of the future forms of treatment involving hearing loss
4. Review the importance of recognizing that genetic testing does not equal to genetic evaluation
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Special Needs
Used in clinical diagnostic and functional development to describe individuals who require assistance : medical, mental, or psychological
Special needs often refers to special needs within an educational context. This is also referred to as special educational needs (SEN).
In Germany a similar term exists. Special needs children are called "besondere Kinder" ("special children").
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Special Needs
Me
Family
Friends
School
Community
Wilder Society
Genetic InheritanceEnvironmental Experience
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Establishment of a System
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Medical Special Needs in the UShttp://www.cdc.gov/nchs/data
19% of Americans are classified as a person with a special need, which equals the population of the states of FL and CA combined
41% of children with developmental difficulties have multiple special needs
17% of Americans will experience a communication disorder at some point in their life, which includes sensing, interpreting and responding (i.e. auditory processing disorder).
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Medical Genetics
Isolated hearing loss may not
be the most common form of
hearing loss in the future
20-40%
•Of Children with hearing loss have other disabilities
900
•Genetic conditions have been described to include hearing loss and other special needs
802 •Conditions have
been described to present with deafness
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Other Diagnoses Associated with Hearing LossGallaudet Research Institute, 2003
Diagnosis %
Learning difficulties 10.7
Developmental delay 9.8
Attention difficulties 6.6
Blindness and low vision 3.9
Cerebral palsy 3.5
Emotional disturbance 1.5
Other conditions 12.1
TOTAL 48.1
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Genetics: A case against perfection
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Developments
1) Molecular/genetic understanding of hereditary hearing
loss vastly enhanced over last 10 years
•Genetic testing and Genetic Evaluation is now an integral
part on the assessment of children with hearing
impairment
2) Early intervention [medical vs. surgical] now standard of
care with limitations
3) Genetic treatment may be the choice in the future
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Definition of Evolution
“Evolution is a process that results in
heritable changes in a population
spread over many generations”
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Evolution and Birth Defects
Birth defects are suppose to happen
Birth defects can be advantageous
Birth defects can be deleterious
In search of individuality
Birth defects can be silent
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Mutated miR-96 gene
14 April 2009. Chrissie Giles
15
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Stage12-4th week
of gestation
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Embryology of the ear placode
Images of the lateral view of the human embryonic head from
week 5 (stage 14) through to week 8 (stage 23)
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RNA in situ hybridization of Pds in noncochlear regions of
the mouse inner ear.
Everett L A et al. PNAS 1999;96:9727-9732
©1999 by National Academy of Sciences
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Mutations in OTOGL, Encoding the Inner Ear Protein Otogelin-like, Cause Moderate Sensorineural Hearing Loss
Kemal O. Yariz, et al. AJHG Volume 91, Issue 5, 2 November 2012, Pages 872–882
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Newborn mice lacking the Slitrk6 gene (right) have severe reductions in the numbers of nerve fiber bundles
innervating the inner ear compared to wild-type animals (left).
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The ATP-dependent chromatin remodeling enzyme CHD7 regulates
pro-neural gene expression and neurogenesis in the inner ear
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Cochlea and Kidney a genetic relationship
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Statoacustic
ganglion
Otocyst
Basal turn of
the cochlea
Tip of digits
Nasal/Oral
epithelia
Vibrissae
Amniotic
membrane
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Multi-system gene expression: 30,000 genes
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A systems Biology of early mouse inner ear organogenesis: gene
expression, patterns, networks and pathways.Samin Ahmed Sajan, PhD.
University of Washington, May 2008
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An inner ear gene expression database.Chen ZY, Corey DP Assoc Res Otolaryngol. 2002 Jun;3(2):140-8.
Neurology Service, Massachusetts General Hospital, Boston 02114, USA.
Microarray technology
Mouse cochleas were examined at two developmental
stages (P2 and P32) using GeneChip oligonucleotide
arrays
> 10,000 genes were found to be expressed in the cochlea
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Gene Function and Hearing
Developmental Time
Gene Expression
Gene Expression Transformation
Gene Regulation
Genetic susceptibility
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Identifying Infants with Hearing Loss
Undetected hearing loss can delay speech and language development
All states and U.S. territories also have established Early Hearing Detection and Intervention (EHDI) programs
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Infant
Hearing Loss
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Hearing Loss
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Case 5 - CATSHL� Camptodactyly
� Tall Stature
� Congenital bone abnormalities
� Congenital hearing loss –
diagnosed as isolated non-
syndromic at birth (moderate
bilateral SNHL)
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Toydemir, et al. A Novel Mutation in FGFR3
Causes Camptodactyly, Tall Stature, and Hearing
Loss (CATSHL) Syndrome, AJHG 2006; 79, 5
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Mutation in FGFR3 (1862G→A): CATSHL syndrome
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RB
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RB
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CATSHL syndrome
Mutation in the FGFR3 gene
Chromosome 4
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ENT Medical Work UPABR testing - moderate CHL right and normal hearing left
CT scan of temporal bones
- bilateral dysplasia of bony labyrinths
- normal cochleae, IACs, vestibular acqueducts,
and ossicles
- Possible anomaly of right facial nerve
Testing for Pendred Syndrome - Insurance company rejected
testing unless recommended by Medical Genetics
Referral to Genetics
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Medical Genetics Findings
1. Cervical fusion – fusion of C1-
C2, retrolisthesis of C3 on C4,
C6 and C7 fusion
2. Facial asymmetry
3. Speech/language delay
4. Hand and arm anomalies
5. DX: Klippel Feil Syndrome
6. No Genetic testing needed
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Klippel-Fiel Syndrome Most Common Associated Abnormalities
Anomaly Percentage of Patients
Congenital scoliosis > 50 %
Rib abnormalities (excluding cervical ribs) 33%
Deafness 30%
Genitourinary abnormalities 25-35%
Sprengel’s deformity 20-30%
Synkinesia 15-20%
Cervical Ribs 12-15%
Cardiovascular abnormalities 4-29%
Tracy, M.R, Dormans, J.P., and Kusumi, P. Klippel-Fiel Syndrome, Clinical Orthopaedics and Related Research, 2004.
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Hearing Loss
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Clinical Application
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Genetic Testing vs. Genetic Evaluation
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Iris Colobomas
Cat-Eye syndrome
Preauricular tags/pits
Stenotic ear canals
22q deletion
Mixed Hearing loss
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Robin Sequence
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Micrognathia
Cleft palate
Apnea
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Stickler Syndrome
-Micrognathia
-Hypermobility
-Mixed hearing
loss
-Mutation in
Collagen gene
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Clefting
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Cleft lip/palate
Van Der Wood syndrome
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Genetic Testing:
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Genetic Evaluation:
Dysmorphology Exam
Team agrees on Isolated hearing loss
1. Otochip
2. Clinical Follow up
3. Metabolic testing
Hearing loss + recognizable syndrome
1. Targeted gene testing
2. Clinical Follow up
3. Management of
comorbidity
Hearing loss + other findings but not
recognizable syndrome
1. Microarray analysis
2. Karyotype
3. Exome Sequencing
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