1. Does UNHS Identify All Children with GJB2 (Connexin 26) Deafness? Presented by Wendy D. Hanks, Ph.D. Gallaudet University

2. Contributors…. Virginia W. Norris Kathleen S. Arnos Wendy D. Hanks Gallaudet University Washington, D.C. Xia Xia Walter E. Nance Arti Pandya Virginia Commonwealth University Richmond, Virginia

3. Etiology of Deafness 40-50% Environmental CMV Prematurity Prenatal Rubella Infection Meningitis 60% Genetic 400 types 100 genes for syndromic and nonsyndromic hearing loss have been mapped and cloned

4. GJB2 or Connexin 26 Most common cause of recessive deafness in many populations Accounts for 50 to 80% of all cases of profound nonsyndromic recessive deafness Explains 10 to 37% of simplex cases (only one affected family member) More than 100 pathogenic mutations reported

5. Common Alleles by Population 35delGCaucasian European and American 167delTAshkenazi Jewish 235delCJapanese R143WAfricans from Ghana

6. Hearing Loss and GJB2 Most often stable, symmetric, congenital Range from mild to profound HL Recent studies suggest 35delG homozygotes loss is more severe than heterozygotes 3 specific mutations were associated with mild to moderate HL (M34T, V37I, L90P)

7. Therefore…. UNHS should detect children with GJB2 deafness … UNLESS…. Loss is very mild Loss is progressive Screening not properly performed Here we present 11 cases of exceptions

8. SM Male born in 2001 Uncomplicated full-term pregnancy Passed OAE screen in hospital Mother began suspecting HL at 8-9 months HL identified at 24 months Mild to moderate Progressive, now moderate to moderately-severe Compound heterozygote for 35delG and delE120

9. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O OOO X XXX O = Right Ear X = Left Ear

10. JH Male born in 1996 Emergency C-section for fetal distress Oxygen hood for several hours Passed ABR screen in hospital – 3 days old HL identified at 60 months during school screening Mild to moderate Compound heterozygote for 35delG and C37I

11. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 OOO OO O O XX X X X X X O = Right Ear X = Left Ear

12. AB Female born in 1999 without complications Older brother with profound SNHL Born before NBHS in that state HL identified at 9.5 months Failed OAE screen in hospital – documented fluid Passed ABR screen (40 dB) at 7 weeks HL identified at 48 months during school screening Mild to moderate Both AB and her brother are homozygous for 35delG

13. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O O O O O X X X X X O = Right Ear X = Left Ear

14. BS Female born in 2001 without complications Passed OAE screen in hospital – 2 days old Parents concerned starting at 12 months HL identified at 21 months by ABR Severe in Left; Severe to Profound in Right 41 months progressed to bilateral severe to profound Homozygous for 35delG

15. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O O O OOO OXXX XXX X O = Right Ear X = Left Ear

16. TK Male born in 1994 High risk as father has severe SNHL Passed ABR screen in hospital – 1 day old Results were asymmetrical Conductive pathology suspected No follow-up recommended! HL identified at 18 months by ABR Moderately severe to severe SNHL Homozygous for 35delG

17. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O O O O O O O XX X X X X X O = Right Ear X = Left Ear

18. RZ Male born in 2001 at home Breech with umbilical cord wrapped around neck High risk as older brother has HL Passed OAE screen at hospital shortly after birth HL identified at 9 months following parental concerns Mild bilateral SNHL 40 months revealed moderately severe loss in sound field RZ and brother are homozygous for 35delG

19. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 S SS S S S = Sound Field Better Ear Responding Why only soundfield at 40 months??

20. HB Female born in 2002 without complications Passed OAE screen at hospital before discharge Mother concerned about her hearing at 8 months HL identified at 17 months by ABR Suggested moderately severe to profound bilateral SNHL 20 month ABR revealed profound bilateral SNHL Absent OAEs HB is homozygous for 35delG

21. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O = Right Ear X = Left Ear Why no behavioral results???

22. TH Male born in 2001 without complications Passed hearing screen at hospital before discharge Type unknown….. Parents concerned about his hearing at 24 months HL identified at 31 months and is progressive Initial ABR: moderate RE and severe-profound LE Absent OAEs 39 months ABR revealed profound bilateral SNHL Absent OAEs HB is homozygous for 35delG

23. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O O O O O O X X X XXX O = Right Ear X = Left Ear

24. AG Female born in 2000 without complications Induced labor at 41 weeks gestation Passed hearing screen at hospital before discharge Type unknown….. Parents reported she developed speech and talked for 2 years Mother concerned about her hearing at 29 months HL identified at 33 months ABR suggested: Mild to moderately-severe RE Moderate to severe high frequency LE 35 months and 47 months: Behavioral testing: Stable results HB is heterozygous for 35delG and 312del14

25. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 OOO O O X X X X X O = Right Ear X = Left Ear

26. AR Female born in 2000 without complications Passed hearing screen at hospital before discharge Type unknown….. Passed 2 hearing screenings in kindergarten but failed at pediatricians office HL identified at 72 months Multiple behavioral results consistent with moderate bilateral SNHL (Mom was shopping) Absent DPOAEs AR is homozygous for 35delG

27. 0 10 20 30 40 50 60 70 90 80 110 120 100 0 10 20 30 40 50 60 70 90 80 110 120 100 1252505001000200040008000 FREQUENCY IN HERTZ (Hz) -R--L- BC AC dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR HEARING LEVEL IN DECIBELS (dB) ANSI 1989 O O OO OX X XX X O = Right Ear X = Left Ear O XX

28. ER Male born in 2003 without complications Referred hearing screen at hospital before discharge Type unknown….. Passed DPOAE screening at 12 weeks HL identified at 11 months Behavioral SF awareness at mid and high frequencies at the severe level ABR and ASSR at 13 months revealed severe to profound AR is heterozygous for 35delG and 167delT

29. EarStimulu s Predicted ASSR Threshold Predicted Range of Hearing Sensitivity RIGHT500 Hz110 dBHL85-125 dBHL 1000 Hz125 dBHL105-130+ dBHL 2000 Hz125 dBHL105-130+ dBHL 4000 HzNR110-130+ dBHL LEFT500 HzNR100-130+ dBHL 1000 HzNR115-130+ dBHL 2000 HzNR115-130+ dBHL 4000 Hz120 dBHL95-130+ dBHL

30. Conclusions… Record all parameters of your screening program and follow established guidelines! Continue surveillance of ALL children with known risk factors Refer children with nonsyndromic hearing loss for genetic testing even if they PASSED their newborn hearing screening This study shows 3.8% were nonpenetrant at birth Includes cases 1-9 only