10/26/2016 CMV and Connexin 26 Frontiers of Research and Therapy - PDF document

10/26/2016 CMV and Connexin 26 Frontiers of Research and Therapy for Congenital Hearing Loss Dylan K. Chan, MD, PhD, FAAP Assistant Professor Pediatric Otolaryngology-Head and Neck Surgery Director, Children’s Communication Center University of California, San Francisco dylan.chan@ucsf.edu UCSF Audiology Update XII November 4, 2016 CMV and Cx26 Hearing Loss Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research CMV and Cx26 Hearing Loss Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research 1

10/26/2016 Childhood hearing loss Definition Permanent Childhood Hearing Impairment (PCHI) Childhood hearing loss Definition Permanent Childhood Hearing Impairment (PCHI) Mild to profound Bilateral or unilateral All frequencies or some frequencies Stable or progressive Sensorineural or conductive All are eligible by law for services to prevent developmental delay Childhood hearing loss Prevalence How common is PCHI? 2

10/26/2016 Childhood hearing loss Prevalence Prevalence depends on your exact definition: From newborn/school/pediatrician screening 1:500 newborns (> 40 dB HL) 1:300 by age 9 (> 40 dB HL) From NHANES survey 1:100 by age 19 (> 25 dB HL, bilateral) 1:5 by age 19 (> 15 dB HL, any kind, laterality, or frequency) Shargorodsky, 2010 Mild/unilateral hearing loss Impact Children with mild or unilateral hearing loss have impaired school performance, behavior, and psychosocial well-being Mild/moderate hearing loss Bess 1998 1200 students, 5.5% with mild SNHL Worse on general education, educational risk, behavior, physical/emotional/social function Unilateral hearing loss Lieu 2010/2012 74 children, case-control study Children with UHL had significantly worse speech and language with persistent delays in academic and behavioral performance after 6 years Childhood hearing loss Economic impact Economic cost to the public for an untreated child with hearing loss: • $652 million: total cost in the US for education for DHH children ($11,006/ child) • $115,600: lifetime direct educational costs for 1 DHH child • $420,000: additional direct educational costs (if untreated) • $1,000,000: total lifetime (educational costs + lost productivity) • $2.1 billion: economic cost to the public for a one-year cohort of DHH children • $10 billion: cost if untreated • Estimated lifetime costs for all 380,000 children born in one year with asthma • $7 billion Johnson, 1993 Corso, 2009 http://www.cdc.gov/ncbddd/hearingloss/data.html 3

10/26/2016 Early Intervention Timing matters Yoshinaga-Itano, 1998 Newborn Hearing Screening 1-3-6 Goal Diagnosis, medical treatment, and early intervention initiated by 6 months Birth AABR or DPOAE- based screen REFER By 1 month Outpatient screen/rescreen REFER By 3 months Diagnostic audiology evaluation (ABR) Confirmed By 6 months hearing Early intervention services initiated loss Otolaryngology evaluation Ongoing audiology management CMV and Cx26 Hearing Loss Background – Congenital hearing loss Prevalence and impact Diagnostic testing CMV-associated SNHL Overview Diagnostic testing Treatment Current management Cx26-associated SNHL Clinical overview Research 4

10/26/2016 Congenital SNHL Diagnostic workup All children with congenital SNHL 50% acquired 50% genetic 33% syndromic 67% non-syndromic CMV TORCH infections 50% 50% Non-GJB2 GJB2 Pendred’s Usher’s Congenital SNHL Why test? Knowledge Why can’t my child hear? Prognosis Is the hearing going to get worse? Exclusion of other causes What else is wrong with my child? Family counseling What does this mean for my other kids? hearing.siemens.com Intervention What can we do about it? Congenital SNHL Diagnostic workup History Physical Exam Diagnostic Tests 5

10/26/2016 History Syndromic hearing loss Associations with syndromic SNHL apparent from personal or family history Visual impairment Usher’s Branchial cleft anomalies Branchio-oto-renal Thyroid dysfunction/goiter Pendred’s Sudden death/arrhythmia Jervell Lange-Nielsen Renal/urinary complaints Alport’s, branchio-oto-renal Pigmentation disorders Waardenburg Unsure?? Refer to genetics Physical Exam Syndromic hearing loss Associations with syndromic SNHL apparent from physical exam www.thyroidmanager.org adhb.govt.nz Goiter Branchial cleft anomalies/preauricular pits Pendred’s Branchio-oto-renal www.motownsports.com www.chargesyndrome.o rg Craniofacial abnormalities Pigmentation abnormalities Multiple Waardenburg’s History Non-syndromic hearing loss Causes of non-syndromic SNHL apparent from history Infectious Toxoplasmosis, syphilis, rubella, CMV, HSV, meningitis Ototoxic drugs Gentamicin, cisplatin Genetic Family history, consanguinity Hyperbilirubinemia Jaundice Trauma EVA-related sudden hearing loss 6

10/26/2016 Idiopathic Non-syndromic SNHL Core diagnostic tests 1) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) Urine PCR (active infection) 2) Newborn blood spot PCR (congenital infection) Idiopathic Non-syndromic SNHL Core diagnostic tests 1) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) Urine PCR (active infection) 2) Newborn blood spot PCR (congenital infection) Imaging Impact How does information gleaned from imaging affect patient management? Cochlear nerve hypoplasia cochlear implant candidacy Temporal-bone abnormalities surgical planning EVA recommendations regarding head Yan et al., 2013 trauma 7

10/26/2016 EVA Head trauma Alemi, 2015 2015 Meta-analysis of EVA, head trauma, and progressive hearing loss - EVA is associated with 40% risk of long-term progressive SNHL - There is no association between head trauma and risk for long-term progression of hearing loss in people with EVA - I do NOT recommend special precautions for head trauma relating to EVA Imaging Recommendations 1) Cochlear implant candidates MRI with or without CT 2) All others MRI or CT after discussion with parents (age, cost, anxiety) 3) No special precautions for head trauma relating to EVA Idiopathic Non-syndromic SNHL Core diagnostic tests 1) Imaging 1) CT 2) MRI 2) Genetic testing 1) Connexin 26/30 2) Complete hearing loss gene array testing 3) CMV testing 1) Urine PCR (active infection) 2) Newborn blood spot PCR (congenital infection) 8

10/26/2016 Genetic Testing Impact Any cause identified genetic counseling/family planning Syndromic association identified careful screening for associated phenotype Specific mutations increased risk of progressive hearing loss, ototoxicity Future therapeutic options gene therapy Genetic testing Available tests Test Location #genes Turnaround Cost/insurance Indication tested time GJB2/GJB6 Multiple 2 1-3 wks $300 / yes Non- (Connexin (Quest) syndromic 26/30) SNHL Pendred’s/ Stanford, 1-3 4 wks $1100 / yes SNHL + EVA SLC26A4 Cincinnati, or thyroid Boston dysfunction Usher’s panel Cincinnati, 9 8-12 wks $2500 / yes SNHL + Boston visual dysfunction OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss Exome Referral to All Varies Varies / no Any sequencing genetics congenital hearing loss Genetic testing Available tests Test Location #genes Turnaround Cost/insurance Indication tested time GJB2/GJB6 Multiple 2 1-3 wks $300 / yes Non- (Connexin (Quest) syndromic 26/30) SNHL Pendred’s/ Stanford, 1-3 4 wks $1100 / yes SNHL + EVA SLC26A4 Cincinnati, or thyroid Boston dysfunction Usher’s panel Cincinnati, 9 8-12 wks $2500 / yes SNHL + Boston visual dysfunction OtoScope Iowa 133 3 months $1500 / no Any congenital hearing loss Exome Referral to All Varies Varies / no Any sequencing genetics congenital hearing loss 9