Klinisk og genetisk forskning på
døvblindhed-3
Tverrfaglighed- CHARGE syndrom
Eikholt 23.8-24.8.2011
Lisbeth Tranebjærg
tranebjaerg@sund.ku.dk
Døvhetssyndromer:CHARGE,
dynamik rundt diagnose, nye
metoder.Tverrfaglige tiltak
Lisbeth Tranebjærg
tranebjaerg@sund.ku.dk
Implications of a diagnosis
Diagnosis-prognosis-treatment-counselling
• Distinguish between genetic/non-genetic cause
(CRS vs CHARGE, chromosomal abnormality)
• Be tuned for early assessment of associated
medical problems (WFS1 related disease/Usher
syndrome/Alström)
• Be prepared for progressive/stable condition, and
guide choice of treatment (CI or not) and method
of communication (CHARGE/Usher)
• The parents always will ask: WHY OUR CHILD??
Rubella
• Congenit rubella syndrom har likhetstrekk
med CHARGE syndrom
Congenital Rubella syndrome (CRS)
• Created the awareness towards congenital
deafblindness in general
• Has almost disappeared as etiology
• Miscarriage, hearing impairment, cataract, heart
malformations, mental delay
• Late -manifestations: diabetes mellitus,
hypertension, neurological and psycho-social
problems, endocrine abnormalities, early
menopause, osteoporosis, progressive rubella
panencephalitis(learning disability, ataxia,
cerebral palsy, psychosis)
CRS-Dammeyer, 2010
Dammeyer J Int J Pediatr Otorhinol 2010 ;74:1067-1070
Late manifestations of congenital rubella syndrome (CRS) ?
Are they real?
• 123 congenital deafblind adult individuals
(evaluated in 2003)
• N= 35 with CRS – average age 41 years
• No evidence for more frequent occurrence of
the postulated late-manifeatations cp with a
group of 82 non-CRS cong deafblind
individuals (etiology other or unknown)
(Dammeyer J et al, 2010)
Rubella? CHARGE?
• Kvinne LC født 141258:
• Syg Tvillinge søster GC141258 døde 1993
• LC født af 18 år gl kvinne, serologisk bekræftet
rubella tidligt i svangerskabet. Afslag på ab. Prov.
(!!!)
• Jente tvillinger født med alvorlige misdannelser
• CHD7-sekventering og and MLPA analyse af
CDH7 var normale.
• Konklusion: Congenital Rubella Syndrome.
Tværfaglig udredning af syns-og høretab
Multidisciplinarity in hereditary hearing
impairment-examining the patient
Genetic
counselling
GJB2 and
other
genes
Family
history
Clinical
photos
Hearing
impairment
CT scan,
Eye exam,
Renal US
Array CGH
Geography
and ethnicity
Audiological
Bioinformatics profile
C-H-A-R-G-E Association (1979)
•
•
•
•
•
•
C: Coloboma
H: Heart malformation
A: Atresia Choanae
R: Retarded growth and development
G: Genital-urinvejsabnormiteter
E: Ear anomaly and/or hearing impairment
(Pagon et al, 1981)
This list no longer is recommended for diagnosis
Epidemiologi
Autosomal dominant syndrom- de fleste tilfælde
er sporadiske
Prævalens: Skøn: 1: 10.000- 1: 15.000
Canada: 1: ~ 8.500 levendefødte (UK: 250 pts)
Ca 8 nye børn pr år i DK (?)
Næsthyppigste årsag hos børn med døvblindhed
20% ud af 67 børn (Dammeyer J, Int J Audiol,
2010;49: 76-82)
CHARGE:fra klinisk beskrivelse til så meget
mere
• 1979/81: Hall/Pagon- Diagnostiske kriterier
• 2004: en spec pt: med chrom 8abn: CHD7
• 2005-2006: > 200 pts mutationsanalyseret
• De sjældnere dukker op: familiære tilfælde, Kallman’s syndrom
(oftest++), påvisning af de-novo mutation, sandsynliggøring af køns celle
mosaik
•
•
•
•
% af pts med påvist CHD7 mutation først meget høj (65-70%).
Raten falder når flere klinisk variable pts us.
Flere gener (type 1- type 2 etc)? Hvor mange?
Næsthyppigste ætiologi hos danske døvblinde børn (20/67)
(Dammeyer J, Int J Audiol, 2010;49: 76-82)
Clinical criteria for CHARGE syndrome
Major criteria

1. Coloboma,
microphthalmia

2. Choanal atresia
or stenosis†

3. Characteristic
external ear
anomaly,
middle/inner ear
malformations,
mixed deafness
Blake* (1998)

4. Cranial nerve
dysfunction
Minor criteria

1. Cardiovascular
malformations

2. Tracheooesophageal
defects

3. Genital
hypoplasia or
delayed pubertal
development

4. Cleft lip and/or
palate

5. Developmental
delay

6. Growth
retardation

7. Characteristic
face
Inclusion rule
Typical CHARGE:
4 major or
3 major + 3 minor
Clinical criteria for CHARGE syndrome
Major criteria
Verloes (2005)

1. Ocular coloboma

2. Choanal atresia

3. Hypoplastic
semicircular canals
Minor criteria

1. Heart or
oesophagus
malformation

2. Malformation of
the middle or
external ear

3. Rhombencephalic
dysfunction
including
sensorineural
deafness

4. Hypothalamohypophyseal
dysfunction
(gonadotropin or
growth hormone
deficiency)

5. Mental
retardation
Inclusion rule
Typical CHARGE:
3 major or 2
major+2 minor
Partial CHARGE:
2 major + 1 minor
Atypical CHARGE:
2 major +0 minor or
1 major + 3 minor
Overview of features occurring in CHARGE syndrome (frequencies are shown in table 2).
Bergman J E H et al. J Med Genet 2011;48:334-342
©2011 by BMJ Publishing Group Ltd
Patient with typical CHARGE syndrome and a 22q11 deletion.
Bergman J E H et al. J Med Genet 2011;48:334-342
©2011 by BMJ Publishing Group Ltd
Kliniske karakteristika
Meta-analysis from 25 reports:254 pts with CDH7 mutations, and 125 were negative
→
Zentner GE et al. Molecular and phenotypic aspects of CHD7 mutation in
CHARGE syndrome. Am J Med Genet 2010; 152A: 674-686
Klinik- hollandske erfaringer
Feature
CHD7 mut.(n=280)
CHARGE før CHD7gen (n=124)
Ext ear anomaly
97%
96%
Cranial nerve dysf.
99%
86%
Semicircular canal
abn
94%
100%
coloboma
81%
77%
Choanal atresia
55%
61%
Cleft lip/palate
48%
18%
Feeding difficulties
82%
85%
Facial palsy
66%
36%
Inability to smell
(anosmia)
80%
Genital hypoplasia
81%
36%
Klinik-hollandske erfaringer-cont’d
Feature (cont’d)
CHD7 mut (n=280) (Cont’d) CHARGE before CHD7
(n=124)
Heart defect
76%
85%
Tracheo-oesophageal
anomaly
29%
18%
Developmental delay
Delayed motor
milestones:98%
Cognitive delay:74%
Developmental delay:100%
Growth retardation
37%
65%
Typer af mutationer
Mekanisme sandsynligvis haploinsufficiens da punkt mutationer og total
deletion af CHD7 giver samme kliniske billede.
Zentner GE et al. Molecular and phenotypic aspects of CHD7 mutation in CHARGE
syndrome. Am J Med Genet 2010; 152A: 674-686
Guideline for CHD7 analysis in patients suspected of CHARGE syndrome.
Bergman J E H et al. J Med Genet 2011;48:334-342
©2011 by BMJ Publishing Group Ltd
Atypiske CHARGE pts
CHARGE-familial case-Fam A
Diagnostic criteria:
Major:1/3
1/3
2/3
Minor:2/5
5/5
3/5
Delahaye A et al. Clin Genet 2007; 72: 112-121
CHARGE-Familiær
Fam A:
• III:2: læbe-ganespalte,
øsophagus atresi+ fistel, complex
hjertefeil, og ribbensanomalier,
lærevansker, ingen anosmi,
kortvokst
• III:3: retina colobom, ingen
hjertefeil, gik 21 mdr gl,
• II:2: asymptomatisk vestibulær
abnormiteter, retina colobomdiagnosticeret efter børnenes
diagnose, balanceproblemer som
barn, normal mentalt. (Mosaik i
kønsceller for mutationen?)
•
•
CHD7 mutation: c.2501C>T; p.S834F
(Delahaye A et al, 2007)
Familial Kallmann syndrom with CHD7 mutation
Mother healthy; no
CHD7 mutation
•
I:1
I:2
DNA
II:1
signe
winther
070549CHD7-sekn exon 31:N/N
DNA
B8134-08
III:1
lene margrethe
lohre
061072CHD7:exon 31
B7093-07
II:2
II:3
II:4
II:5
lohre
DNA
III:2
ann-elisabeth
lohre
150578CHD7:exon 31
B7099-07
III:3
CHD7 mutation:exon 31:
c.6221T>C; p.L2074P
Neuropsychology: Deficient
continous attention,
memory,in particular visual,
and reduced cognitive
flexibility.
Functions badly in work
life,extremely easily distracted
and works slowly
III:4
19-y-old woman. Affected sister
Anacusis dxt, anosmia, coloboma n.
Opt. dxt, ptosis sin,
very delayed growth and puberty,
lack of growth hormone. H:164 cm,
Bilat vesico-uret reflux,
Pregnant x2→ Spont ab.
• Father: anacusis sin, dupl ureter sin,
died of AMI 40-y-old, coarctatio
aortae. H:179 cm- not available for
genetic test.
• Sister:anacusis sin, anosmia, no
coloboma,bilat vesico-uret reflux,
delayed puberty,no deficiency of
growth hormone. H:165 cm
• MRI: missing the olfactory sulcus
Levy CM & Knudtzon J.Clin Genet 1993; 43:51-53
Kallmann syndrome: lack of spontaneous puberty+ anosmia- many causes
CHARGE syndrome- old pt
• 56-year old cong.deaf-blind female- protected living conditions• An older brother died perinatally with similar malformations
• Clinically: HA from age 17 years: conductive/sensorineural HI,right ear
deaf
• Eyes: left blind, glasses from age 42 years, incipient cataract,scars in
retina, no colobomas
• Never mentruated,hyperthyroidism,adipose
• Broadbased gait, poor balance
• Heart malformation
• Unilateral facial paresis
• Emotionally fragile
• Peculiar behaviour
• CHD7-sequencing: c.7252C>T: p.R2418X/N
• CT scan of temporal bones: Mondini dysplasia, complete agenesis of
semicircular canals,small orbital coloboma
Atypical CHARGE- late diagnosis
• MH 090801, 1. child- born to Turkish consanguineous parents
• In 2002: severe HI diagnosed- sign language
• Agenesis of acoustic nerve unilaterally, bilat agenesis of semicircular
canals
• CI operation had to be refused
• No coloboma, or choanal atresia
• Major problems with coordination of vision due to paresis of the
abducens nerve
• Hardly any feeding problems, good olfactory sense
• Short stature (6,5 år gl: 103 cm)
• Aud afd, neuropaediatrician, dept for growth and reproduction,eye
dept: none raised the CHARGE suspicion
• CHARGE diagnosis obtained by deafblind coordinator and geneticist
in 2007
CHARGE adfærd fænotype
(udkast-T.Hartshorne)
• Lav normal cognitiv funktion
• Meget målrettet, persisterende, og humoristisk
sans
• Socialt interesseret, men umoden
• Repetitiv adfærd, øges under stress
• Søger meget intenst sansestimuli
• Under stress og sanseoverstimulation: svært at
udøve selvregulerinmg og mister let konntrollen
• Svært at skifte opmærksomhed og overgå til nye
aktiviteter; bliver let fraværende i egne tanker
Naturhistorien for CHARGE
• Mange patienter og mutationer beskrevet:
man kan begynde at ane et billede for en del
af symptomerne: ex.vækst/pubertet,
hjertemisdannelser, adfærd
Pubertet/vækst
Pubertet/vækst: ”the R and the G”
• Forskellige faser med forskelligt normal
biologisk mønster i spædbarn-barndom og
ved pubertet
• Jeremy Kirk’s opsummering fra SENSE kan
anbefales
• Anbefaling: opfølgning af en pædiatrisk
endokrinolog
Pubertet
Lugtesans/pubertet
•
•
•
•
Study on smell and puberty in CHARGE syndrome
Smell deficiency and delayed or absent puberty often occur in CHARGE syndrome,
but few studies have looked if these features are associated in adolescents with
CHARGE syndrome. Therefore, we studied smell and pubertal development in 35
individuals with CHARGE syndrome from the Netherlands. In this study, we
included 19 boys and 16 girls aged 10 years or older who all had a mutation in the
CHD7-gene.
We performed a smell test (the University of Pennsylvania Smell Identification Test,
see the picture below) in all persons without mental retardation, bilateral choanal
atresia and/or severe feeding difficulties (26/35).
Also, we re-analyzed MRI brain scans (whenever available) for abnormalities of the
olfactory bulbs (the area in the brain involved in olfaction). Pubertal development
was evaluated by a paediatric endocrinologist who did a physical exam and
measured hormone levels in blood.
Pubertet/lugtesans
• How often does a smell deficit occur in CHARGE syndrome?
• Smell testing showed absent sense of smell in 21/26 (81%)
individuals and normal or slightly decreased sense of smell in 5/26
(19%) individuals. History taking was not reliable for determining
sense of smell.
• MRI brain scans were available in 10 persons, but could be
analysed for olfactory bulb abnormalities in only three persons.
These three persons all had abnormal olfactory bulbs.
• How often do individuals with CHARGE syndrome have delayed or
absent puberty?
• 23 Individuals were old enough to distinguish between delayed or
normal puberty. In 17 persons puberty was delayed or absent
(74%), whereas 6 persons had experienced normal puberty (26%).
Pubertet/lugtesans
•
•
•
•
•
•
•
•
•
Was there a correlation between sense of smell and pubertal development?
From 15 individuals complete data on both smell and puberty were available: 11 persons had
both a smell deficit and delayed puberty and 4 persons had normal sense of smell in
combination with normal pubertal development. Seven boys were too young to know if they
would enter puberty at a normal age, but they all had cryptorchidism or a micropenis, which
is suggestive for delayed puberty. These seven boys had no sense of smell. Therefore, a
total of 22 persons showed concordance between smell and (suspected) pubertal
development. We conclude that smell and pubertal development are 100% correlated in this
study.
•
•
•
•
•
•
•
•
Can a smell test predict whether spontaneous puberty will occur?
Because of the correlation between sense of smell and pubertal development, a smell test
can probably predict whether spontaneous puberty will occur. When a patient with CHARGE
syndrome is unable to smell, he/she will probably need hormone replacement therapy to
enter puberty. We recommend timely start of hormone replacement therapy in children with
CHARGE syndrome who have no sense of smell to make sure they enter puberty
simultaneously with their peers. This will reduce social problems and risk of osteoporosis
(brittle bone disease).
Fraværende lugtesans som prædiktor
af udebleven spontan pubertet?
• 35 personer m. CHD7
mutation
• Komplette data på 15
pts:11 havde komplet
anosmi og HH
• 4 hypo/normo osmi +
spontan pubertet
• Konklusion:Opstart af
hormonel induktion af
pubertet på aldersadækvat tidspunkt
Bergman JEH et al; J Pediatrics 2011;158:474-479
Klinisk 0pfølgning-del1
Evaluation
Ophthalmology
Tests
Treatment/advice
Be aware of
Full ophthalmological
examination including
funduscopy
Tinted spectacles for
photophobia (iris coloboma)
Artificial tears in case of facial
palsy
Retinal detachment (in case of
retinal coloboma)
Correction of refraction errors
Klinisk 0pfølgning-del2-ENT-part 1
Evaluation
ENT, audiology,
occupational/speech therapy,
gastroenterology
Tests
Multidisciplinary
evaluation:
Assess patency of
choanae (CT scan or
nasal endoscopy)
Evaluation for cleft
palate and tracheooesophageal
anomalies
Audiometry (BAER),
tympanometry
Temporal bone CT
scan (pathology of
middle ear, inner ear,
cranial nerves,
semicircular canals,
aberrant course of
blood vessels or
cranial nerves)
Treatment/advice
Surgical
correction of
choanal atresia
Hearing aids,
ventilation tubes
Sign language
and speech
training
GORD: Nissen
fundoplication,
antispasmodics
Be aware of
Respiratory
aspiration
(recurrent
pneumonias)
Aberrant course of
blood vessels or
cranial nerves when
surgery for cochlear
implants
Klinisk 0pfølgning-del3-ENT-part 2
Evaluation
ENT, audiology,
occupational/speec
h therapy,
gastroenterology
Tests
Cranial nerve
function tests
Swallowing studies,
pH monitoring,
reflux scan in case
of
feeding/swallowing
difficulties
University of
Pennsylvania Smell
Identification Test
Treatment/advice
Be aware of
Gastrostomy/trache Obstructive sleep
otomy in case of
apnoea
severe swallowing
problems
Surgery of tracheooesophageal
abnormalities
Advice concerning
anosmia
Klinisk 0pfølgning-del 4
Evaluation
Paediatrics/endocri
nology
Tests
Treatment/advice
Renal ultrasound,
voiding cystourethrogram in case
of urinary infections
Immunological
studies in case of
recurrent infections
or suspected
hypocalcaemia
Follow-up of
growth and
development
(growth hormone
stimulation test if
indicated)
Monitor
cryptorchidism
Gonadotropin
levels (age 6–8
Be aware of
Early treatment of
bladder infections
(especially in case
of unilateral renal
agenesis or vesicourethral reflux)
Growth hormone
treatment if growth
hormone deficiency
is present
Orchidopexy when
indicated
Gonadotropin
treatment in case of
hypogonadotropic
Klinisk 0pfølgning-del 5
Evaluation
Cardiology
Anaesthesiology
Tests
Cardiac evaluation
including
ultrasound
Extensive
preoperative
assessment
Treatment/advice
Be aware of
Cardiac surgery
and/or antibiotic
prophylaxis
Combine surgical
procedures
whenever possible
Longer surveillance
after surgery
Postoperative
complications (due
to aspiration/cranial
nerve dysfunction)
Problems with
intubation
Klinisk 0pfølgning-del 6
Evaluation
Neurology
Tests
Treatment/advice
Be aware of
Cerebral MRI scan
(including
visualisation of
olfactory bulbs, and
inner ear if no
Anticonvulsants if
temporal bone CT
overt epilepsy seen
scan has been
performed)
EEG (only when
clinically seizures
are observed)
Klinisk 0pfølgning-del 7
Evaluation
Behaviour,
developmental and
educational
services
Tests
Extensive
multidisciplinary
evaluation of
developmental and
sensory
impairments and
behavioural
problems
Use formal tests in
order to screen for
autism spectrum,
obsessive
compulsive
disorders and ADHD
Perform IQ tests
regularly
Treatment/advice
Integrated
individualised
therapy with special
attention for
optimising
communication
Be aware of
Klinisk 0pfølgning-del 8
Evaluation
Tests
Treatment/advice
Be aware of
Physiotherapy
Assessment of
balance problems,
motor delay,
visiospatial
coordination, and
hypotonia
Therapy for
hypotonia and
devices to
overcome balance
impairment
Genetics
CHD7 analysis
(when no CHD7
mutation or
deletion is found,
perform array CGH)
Genetic
Intra-familial
counselling, options
variability in
for prenatal
CHARGE syndrome
diagnosis
Differentialdiagnoser til CHARGE
• Hvad så??
CHARGE??
• KR 211298:
• Bilat Choanal atresi, ve.sid iris colobom, VSD +
DAP, corpus callosum agenesi,ADHD, Tourette
lign verbale udsagn, agenesi af permente
tænder, dysmorf, kranienervedysfunktion?
(smil), ikke CT scannet for semicirkulære
kanaler, ingen HN, ingen genital hypoplasi.
• CHD7-sekv: N, MLPA:N ,
• Kromosomanalyse: normal, array CGH Normal
KR 211298
CHARGE?- mutation i ukendt gen?
Kromosomsyndrom?
Nyttige informationskilder
• http://www.servicestyrelsen.dk/dovblindfodt
• Artikler, indtryk fra SENSe konferencen marts 2011 mm
• Præsentationer fra CHARGE samlingen 11.3-13.3 2011 i UK:
www.sense.org.uk
• http://www.chargesyndrome.org.uk
•
Præsentationer fra CHARGE konf, UK
marts 2011
•
•
•
•
Resources for families
An overview of CHARGE syndrome (pdf 91kb)
CHARGE for Beginners (pdf 94kb)
Coming of Age (pdf 77kb)
Hormones in CHARGE syndrome (pdf 74kb)
Moments of togetherness (pdf 336kb)
Parenting children with CHARGE (pdf 144kb)
Puberty and smell in CHARGE syndrome (pdf 50kb)
Sensory processing (pdf 574kb)
Sources of challenging behaviour (pdf 218kb)
Successful teaching strategies (pdf 183kb)
The challenge of mealtimes (pdf 547kb)
The genetics of CHARGE (pdf 133kb)
The heart in CHARGE (pdf 279kb)
Resources for professionals
Hormones in CHARGE syndrome (pdf 74kb)
The genetics of CHARGE (pdf 26kb)
The impact of relationships (pdf 1060kb)
An overview of CHARGE syndrome (pdf 91kb)
Sources of challenging behaviour (pdf 177kb)
Successful teching strategies (pdf 183kb)
The challenges of mealtimes (pdf 549kb)