Download Does UNHS Identify all Children with GJB2 (Connexin 26) Deafness?

Does UNHS Identify All
Children with GJB2
(Connexin 26) Deafness?
Presented by
Wendy D. Hanks, Ph.D.
Gallaudet University
Contributors….

Virginia W. Norris
Kathleen S. Arnos
Wendy D. Hanks

Xia Xia
Walter E. Nance
Arti Pandya
Gallaudet University
Virginia
Commonwealth
University
Washington, D.C.
Richmond, Virginia
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
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
Common Alleles by Population
•
35delG
•
167delT
235delC
R143W
•
•
Caucasian European and
American
Ashkenazi Jewish
Japanese
Africans from Ghana
Hearing Loss and GJB2

Most often stable, symmetric, congenital

Recent studies suggest 35delG
homozygotes’ loss is more severe than
heterozygotes
3 specific mutations were associated
with mild to moderate HL (M34T, V37I,
L90P)

• Range from mild to profound HL
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
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
O
40
50
X
60
40
O
X
O
X
O
X
50
60
70
70
80
80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
JH



Male born in 1996
•
• Oxygen hood for several hours
Passed ABR screen in hospital – 3 days old
HL identified at 60 months during school
screening
•

Emergency C-section for fetal distress
Mild to moderate
Compound heterozygote for 35delG and C37I
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
O
X
O
X
X
O
O
X
30
X
O
20
30
60
O 40
X X50
O60
70
70
80
80
90
90
40
50
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
O
X
40
50
X X
O
O
60
X
O
O
X
40
50
60
70
70
80
80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
40
40
50
50
60
60
O
X
70
80
X
O
O
X
O
OO
O70
80
X
90
XX
90
100
X100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
40
40
50
50
60
X60
70
X
O
80
X
O
X
O
O
X
X
X
O
80
O
90
70
90
100
O100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
RZ



Male born in 2001 at home
•
•
Passed OAE screen at hospital shortly after
birth
HL identified at 9 months following parental
concerns
•
•

Breech with umbilical cord wrapped around neck
High risk as older brother has HL
Mild bilateral SNHL
40 months revealed moderately severe loss in sound
field
RZ and brother are homozygous for 35delG
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
0
0
10
10
20
20
30
30
40
40
50
50
S
60
S
S
S
70
S
60
70
80
80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
S = Sound Field
Better Ear
Responding
-R--L-
Why only soundfield
at 40 months??
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
Why no behavioral
results???
TH




Male born in 2001 without complications
Passed hearing screen at hospital before discharge
•
Parents concerned about his hearing at 24 months
HL identified at 31 months and is progressive
•
•

Type unknown…..
Initial ABR: moderate RE and severe-profound LE
•
Absent OAEs
39 months ABR revealed profound bilateral SNHL
•
Absent OAEs
HB is homozygous for 35delG
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
250
500
1000
2000
4000
O = Right Ear
0
0
10
10
20
20
30
30
40
40
50
50
60
60
70
70
80
80
O
X
90
100
O
O
X
X
110
O
O
X
90
100
O
X
120
BC
AC
8000
X110
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
AG





Female born in 2000 without complications
•
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
•
•

Induced labor at 41 weeks gestation
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
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
O
40
50
X
60
70
O
X
O
X
40
50
O
X
80
X
O
60
70
80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
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 pediatrician’s office
HL identified at 72 months
•
•
Multiple behavioral results consistent with moderate
bilateral SNHL (Mom was “shopping”)
Absent DPOAEs
AR is homozygous for 35delG
FREQUENCY IN HERTZ (Hz)
HEARING LEVEL IN DECIBELS (dB) ANSI 1989
125
BC
AC
250
500
1000
2000
4000
8000
O = Right Ear
0
0
10
10
20
20
30
30
O
X
40
50
60
40
O
X
70
O
X
O
X
50
O
X
O60
70
80
X X80
90
90
100
100
110
110
120
120
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
-R--L-
dB EFFECTIVE MASKING LEVEL IN NON-TEST EAR
-R--L-
X = Left Ear
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
Ear
Stimulu
s
Predicted
ASSR
Threshold
Predicted
Range of
Hearing
Sensitivity
RIGHT
500 Hz
110 dBHL
85-125 dBHL
1000 Hz
125 dBHL
105-130+ dBHL
2000 Hz
125 dBHL
105-130+ dBHL
4000 Hz
NR
110-130+ dBHL
500 Hz
NR
100-130+ dBHL
1000 Hz
NR
115-130+ dBHL
2000 Hz
NR
115-130+ dBHL
4000 Hz
120 dBHL
95-130+ dBHL
LEFT
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