Klinisk og genetisk forskning på døvblindhed-3

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Transcript Klinisk og genetisk forskning på døvblindhed-3

Klinisk og genetisk forskning på døvblindhed-3 Tverrfaglighed- CHARGE syndrom Eikholt 23.8-24.8.2011 Lisbeth Tranebjærg [email protected]

Døvhetssyndromer:CHARGE, dynamik rundt diagnose, nye metoder.Tverrfaglige tiltak Lisbeth Tranebjærg [email protected]

Implications of a diagnosis


• • • • 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??


• 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 Family history Clinical photos CT scan, Eye exam, Renal US Array CGH GJB2 and other genes Hearing impairment 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


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

Blake * (1998)    

Major criteria

1. Coloboma, microphthalmia 2. Choanal atresia or stenosis †   

Minor criteria

1. Cardiovascular malformations 2. Tracheo oesophageal defects 3. Genital hypoplasia or delayed pubertal development 3. Characteristic external ear anomaly, middle/inner ear malformations, mixed deafness 4. Cranial nerve dysfunction    4. Cleft lip and/or palate 5. Developmental delay  6. Growth retardation 7. Characteristic face

Inclusion rule

Typical CHARGE: 4 major


3 major + 3 minor

Clinical criteria for CHARGE syndrome

Verloes (2005) 

Major criteria

  1. Ocular coloboma  2. Choanal atresia 3. Hypoplastic semicircular canals   

Minor criteria Inclusion rule

1. Heart or oesophagus malformation 2. Malformation of the middle or external ear 3. Rhombencephalic dysfunction including sensorineural deafness

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 4. Hypothalamo hypophyseal dysfunction (gonadotropin or growth hormone deficiency)  5. Mental retardation

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


Ext ear anomaly Cranial nerve dysf.

Semicircular canal abn coloboma Choanal atresia Cleft lip/palate Feeding difficulties Facial palsy Inability to smell (anosmia) Genital hypoplasia

CHD7 mut.(n=280)

97% 99% 94% 81% 55% 48% 82% 66% 80% 81%

CHARGE før CHD7 gen (n=124)

96% 86% 100% 77% 61% 18% 85% 36% 36%

Klinik-hollandske erfaringer-cont’d

Feature (cont’d)

Heart defect Tracheo-oesophageal anomaly Developmental delay Growth retardation

CHD7 mut (n=280) (Cont’d) CHARGE before CHD7 (n=124)

76% 85% 29% 18% Delayed motor milestones:98% Cognitive delay:74% 37% Developmental delay:100% 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.

©2011 by BMJ Publishing Group Ltd

Bergman J E H et al. J Med Genet 2011;48:334-342

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


• • •

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 colobom diagnosticeret 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 DNA II:1 signe winther 070549 CHD7-sekn exon 31:N/N B8134-08 DNA III:1 lene margrethe lohre 061072 CHD7:exon 31 B7093-07 I:1 II:2 lohre DNA III:2 ann-elisabeth lohre 150578 CHD7:exon 31 B7099-07 II:3 III:3 I:2 II:4 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 II:5 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: ”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



• • • •

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.


• • • • •

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%).


• • • • • • • • • • • • • • • • •

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 alders adækvat tidspunkt

Bergman JEH et al; J Pediatrics 2011;158:474-479



Klinisk 0pfølgning-del1


Full ophthalmological examination including funduscopy


Tinted spectacles for photophobia (iris coloboma) Artificial tears in case of facial palsy Correction of refraction errors

Be aware of

Retinal detachment (in case of retinal coloboma)

Klinisk 0pfølgning-del2-ENT-part 1

Evaluation Tests Treatment/advice Be aware of

ENT, audiology, occupational/speech therapy, gastroenterology Multidisciplinary evaluation: Assess patency of choanae (CT scan or nasal endoscopy) Evaluation for cleft palate and tracheo oesophageal 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) Surgical correction of choanal atresia Hearing aids, ventilation tubes Sign language and speech training GORD: Nissen fundoplication, antispasmodics Respiratory aspiration (recurrent pneumonias) Aberrant course of blood vessels or cranial nerves when surgery for cochlear implants

Klinisk 0pfølgning-del3-ENT-part 2


ENT, audiology, occupational/speec h therapy, gastroenterology


Cranial nerve function tests Swallowing studies, pH monitoring, reflux scan in case of feeding/swallowing difficulties University of Pennsylvania Smell Identification Test


Gastrostomy/trache otomy in case of severe swallowing problems Surgery of tracheo oesophageal abnormalities Advice concerning anosmia

Be aware of

Obstructive sleep apnoea


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Paediatrics/endocri nology

Treatment/advice Be aware of

Renal ultrasound, voiding cysto urethrogram 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 weeks) and follow Early treatment of bladder infections (especially in case of unilateral renal agenesis or vesico urethral reflux) Growth hormone treatment if growth hormone deficiency is present Orchidopexy when indicated Gonadotropin treatment in case of hypogonadotropic hypogonadism

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Cardiology Anaesthesiology


Cardiac evaluation including ultrasound Extensive preoperative assessment


Cardiac surgery and/or antibiotic prophylaxis

Be aware of

Combine surgical procedures whenever possible Longer surveillance after surgery Postoperative complications (due to aspiration/cranial nerve dysfunction) Problems with intubation



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Tests Treatment/advice Be aware of

Cerebral MRI scan (including visualisation of olfactory bulbs, and inner ear if no temporal bone CT scan has been performed) EEG (only when clinically seizures are observed) Anticonvulsants if overt epilepsy seen

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Behaviour, developmental and educational services


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


Integrated individualised therapy with special attention for optimising communication

Be aware of


Physiotherapy Genetics

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Assessment of balance problems, motor delay, visiospatial coordination, and hypotonia CHD7 analysis (when no CHD7 mutation or deletion is found, perform array CGH)


Therapy for hypotonia and devices to overcome balance impairment Genetic counselling, options for prenatal diagnosis

Be aware of

Intra-familial variability in CHARGE syndrome

Differentialdiagnoser til CHARGE

• Hvad så??


• • • • 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?


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 CHARGE for Beginners Coming of Age (pdf 94kb) (pdf 77kb) Hormones in CHARGE syndrome Moments of togetherness Parenting children with CHARGE Sensory processing (pdf 574kb) Sources of challenging behaviour (pdf 91kb) (pdf 74kb) (pdf 336kb) (pdf 144kb) Puberty and smell in CHARGE syndrome (pdf 50kb) Successful teaching strategies The challenge of mealtimes The genetics of CHARGE The heart in CHARGE (pdf 218kb) (pdf 183kb) (pdf 547kb) (pdf 133kb) (pdf 279kb)

Resources for professionals

Hormones in CHARGE syndrome The genetics of CHARGE The impact of relationships (pdf 74kb) (pdf 26kb) (pdf 1060kb) An overview of CHARGE syndrome (pdf 91kb) Sources of challenging behaviour Successful teching strategies The challenges of mealtimes (pdf 177kb) (pdf 183kb) (pdf 549kb)