Oculo-auriculo-vertebral spectrum

Koen Devriendt Center for Human Genetics K.U.Leuven

Goldenhar

Associations malformatives de l’oeil et de l’oreille, en particulier le syndrome dermoïde epibulbaire- appendices auriculaires - fistula auris congenita et ses relations avec la dysostose mandibulo facialeet ses relations avec la dysostose mandibulo-faciale.

•Eye : epibulbar dermoid•Ear : preauricular tags p g

& fistules

Goldenhar M. Journal de Génétique Humaine, 1952, 1: 243-282.

Hemifacial microsomia

unilateral anomaliesunilateral anomalies - ear- mouth- mouth- mandibula

Novel names :

Goldenhar syndromeH if i l i iHemifacial microsomiaLateral facial dysplasiaFi t h dFirst arch syndromeFirst and second branchial arch syndromeU il t l i f i l i iUnilateral craniofacial microsomiaOral-mandibular-auricular syndromeU il t l i t t i f i l iUnilateral intrauterine facial necrosisAuriculo-branchiogenic dysplasiaOtomandib lar d sostosisOtomandibular dysostosisCraniofacial microsomiaOculo auriculo verbebral dysplasiaOculo-auriculo-verbebral dysplasia…

- overlapping features- no discriminating diagnostic criteriaunknown cause => no diagnostic test- unknown cause => no diagnostic test

suggested term :suggested term :

l i l t b l toculo-auriculo-vertebral spectrum

OCULO – AURICULO – VERTEBRAL SPECTRUM

OCULO

Epibulbar dermoid

• located both over the cornea and sclera

• typically inferior temporal quadrant of the corneal limbus

• unilateral > 50% - bilateral 25%

• astigmatism => may result in amblyopia - follow-up and treatment

choristomas = normal tissues that are in the wrong place= congenital , non-neoplastic

lid hit ll t= solid masses, white-yellow aspect

DermoidDermoid⇒ cutaneous and subcutaneous tissue ⇒ may contain hair and other skin structures.⇒ same histology as skin tags

= more often on the same side as the skin tags

DermolipomasDermolipomas

⇒ contain fat tissue⇒ contain fat tissue⇒ minimal skin adnexae ⇒ more commonly superotemporal quadrant

& extending to lacrimal gland g g

Eyelid anomalies ptosis y

lid l bupper eyelid coloboma

C l b lidColoboma upper eyelid(+/- 20%)

- microphthalmia (=> intellectual disability)

- Peters anomaly

- retinal coloboma,

OCULO – AURICULO – VERTEBRAL SPECTRUM

AURICULOAURICULO

Auriculo : earsAuriculo : ears

Variable ear anomalies in OAVS

microtia - anotiaunilateral - bilateralunilateral bilateral

Microtia, First Degreemedian longitudinal length < 2 SD Presence of all normal ear components

Microtia, Second DegreeMicrotia, Second Degreemedian longitudinal length < 2 SD presence of some, but not all,

parts of the normal ear

Microtia, Third Degreepresence of some auricular structures, p ese ce o so e au cu a s uc u es,none conform to recognized

ear components

* Weerda H. 1988. Classification of congenital deformities of the auricle. Facial Plastic Surg 5:385–388.* Hunter A et al. 2009 Elements of morphology: standard terminology for the ear. Am J Med Genet A. 149A:40-60.

Auricular hillocks⇒ external ear⇒ external ear

first archFirst pharyngeal cleft

t l dit lsecond arch

⇒ external auditory canal

Week 6Week 6

AURAL ATRESIA

MICROTIA : often associated with AURAL ATRESIAMICROTIA : often associated with AURAL ATRESIA = abnormal development of the external auditory canal

first arch

Hearing lossfirst arch

second arch

aural atresia & middle ear anomalies => Conductive hearing loss > 50%

inner ear anomalies => Sensorineural hearing loss 15%

MICROTIA AND HEARING LOSS

115 ears of 89 patients (68 males, 21 females; mean age, 11 yr; range, 5-44 yr)( , ; g , y ; g , y )High resolution CT scan of temporal bone

h i l lhearing level * correlated with

- the formation of oval/round windows- the formation of oval/round windows - ossicular development

* did NOT correlate with - the degree of middle ear aeration,

f i l b ti- facial nerve aberration, - severity of microtia.

Ishimoto S et al. Laryngoscope. 2007 Mar;117(3):461-5

microtia as the mildest manifestation ?

family members of OAVS cases more frequently• ear pits / preauricular tags (Tasse et al. 2005)

• isolated microtia (Rollnick 1983)

OAVS and isolated microtia : • same type of ear malformationssame type of ear malformations• cause / pathogenesis the same ? • isolated microtia = frequently mild OAVS featuresisolated microtia frequently mild OAVS features

Rollnick et al. Am J Med Genet. 1983 ;(233-53.Tasse et al. Eur J Med Genet 2005;48:397-411

Human embryo 6 weeks

First arch

maxillary process

mandibularmandibular process

Second arch

K. Sulik http://syllabus.med.unc.edu/courseware/embryo_images/unit-welcome/welcome_htms/contents.htm

First arch

Maxillary processMaxillary process

Mandibular process

• failure => lateral facial cleft (Tessier N° 7)• incomplete => groove, dimple, pitincomplete groove, dimple, pit• abnormal => appendages

Tessier facial cleft N° 7 (lateral cleft)

cleft between angle of mouth and ear

edges lined by vermilion.

skin – muscle defect* orbicularis and buccinator muscles orbicularis and buccinator muscles * rarely > ant. border of m. masseter

Eppley BL et al., Plast. Reconstr. Surg. 115: 101e, 2005

GrooveGrooveExtending beyond the masseter muscle

Pits – Preauricular Cheeck

Skin tags

Skin tags - variable number

Skin tags – variable size

Composition :Composition : choristoma’s = skin, cartilage

frequently bilateral unilateral: ~ epibulbar dermoid microtiaunilateral: ~ epibulbar dermoid, microtiamicrotia : frequently unilateral

OCULO – AURICULO – VERTEBRAL SPECTRUM

FACIAL ASYMMETRY

FACIAL ASYMMETRY

ki• ears, eyes, skin tags• mouth : lateral cleft

• underdevelopmentunderdevelopment - mandibula & maxilla

soft tissues- soft tissues

BONY ANOMALIES

- mandibular hypoplasia- zygomatico-orbital dysplasia :zygomatico orbital dysplasia :

disruption & hypoplasia zygomatic archdisruption & hypoplasia zygomatic arch ⇒ inferior displacement of the lateral canthus

http://www.craniofacial.net/syndromes-hemifacial-microsomia

zygomatic arch is incompletesmall maxilla

ll t l bsmall squamous temporal bone

hypoplasia & malformationhypoplasia & malformation mandibular body, ramus, & condyle

Tessier classification of facial clefts

Maxillary prominence of first arch :y p- maxilla, - zygomatic arch,

t l b- squamous temporal bone- palatine bone

Brancial arches

Gorlin Collection

other craniofacial :

- cleft lip +/- palatecleft lip / palate- cleft palate

velopharyngeal insufficiency (VPI)- velopharyngeal insufficiency (VPI) muscular hypoplasia

/ i l l (?)+/- cranial nerve palsy (?)

- pharyngeal and laryngeal anomalies

! feeding difficulties! speech delay! speech delay

VERTEBRALVERTEBRAL

- C1-C2 instability- spina bifidap- hemivertebrae- butterfly vertebrae- butterfly vertebrae- fused vertebrae

h l ti t b- hypoplastic vertebrae- klippel-feil anomaly

follow-up for scoliosis !p

anomalies of thoracic vertebrae

Non-craniofacial malformationsNon-craniofacial malformations

t b l- vertebral- gastrointestinal

esophageal atresia, imperforate anus- cardiac : most typically VSD / ToFallot yp y- trachea and lung

lung lobation anomalies TEfistulalung lobation anomalies, TEfistula- renal

li b- limb - radius agenesis, thumb anomalies- club foot

Episode of major bleeding 8 weeks gestation

OCULO – AURICULO – VERTEBRAL SPECTRUMSPECTRUM

NeurodevelopmentalNeurodevelopmental outcome ?

24 infants and toddlers

58% > 2 SD below mean in at least one domain of development.

NO DIFFERENCE IN DEVELOPMENTAL OUTCOME - boys versus girls- boys versus girls - side of anomalies - severe or mild clinical manifestations

WORSE OUTCOME : b l l t- abnormal muscle tone

- affected bilaterally - cervical spine abnormalitiescervical spine abnormalities

Cohen MS et al. Am J Med Genet. 1995 Dec 18;60(6):535-40.

20 participants12 l 8 f l- 12 males, 8 females

- age range 8mo-17y - mean age 8y

neuroimagingneuroimaging

> 50 % : grey and white matter anomaliesg y> 33% : enlarged ventricles

Johansson M et al. Dev Med Child Neurol. 2007 Apr;49(4):280-8

AUTISM SPECTRUM INTELLECTUAL

20 participants

AUTISM SPECTRUMDISORDER

INTELLECTUAL DISABILITY

1

52

4

2

1

23

Autistic traitsAUTISTIC-LIKEA ti

BorderlineMild IDSevere IDAutism

NORMAL

Severe IDProfound IDNORMAL

Johansson M et al. Dev Med Child Neurol. 2007 Apr;49(4):280-8

Tasse C, et al. Wieczorek DagmarEur J Med Genet. 2005;48:397-411.

Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation &severity scoring of 53 patients & proposal for a new classification.

SCORING SYSTEM :

- each major anomaly = 2 pointsmicrotia; hemifacial microsomia; vertebral anomaly

- each associated anomaly = 1 pointdeafness, facial cleft, eye, dermoids,motor delay, speech delay growth delay,

it l b i h t li b d f t i h lurogenital, brain, heart, limb defects, microcephaly

Three groups : number of major criteriaunilateral - bilateral

GROUP MINIMAL N° cases

unilateral bilateral

MANIFESTATIONS (n=53)

1 unilateral 31 unilateral 3microtia

1 bilateral 6

2 unilateral 20i ti / i l tmicrotia/ preauricular tag

2 bilateral + hemifacial microsomia 14

3 unilateral microtia/ preauricular tag 3+ hemifacial microsomia

3 bilateral + vertebral anomalies 7

PROGNOSIS :PROGNOSIS :

Associated malformationsAssociated malformations

• increases with subgroupincreases with subgroupmore major malform. = more associated malform.

• increases with bilateral involvement

Developmental outcomep

inversely correlates with score and subgroupy g p

Vascular disruption

Genetic factorsdisruption factors

eyes

First arch

Second arch

?Teratogens ?

ENVIRONMENTAL RISK FACTORS

- vasoactive drugs : pseudoephedrine, aspirin, ibuprofen g p p p p(1.5- 2 fold increased risk)

- second trimester bleeding (OR 13.2, 95% CI 2.3 - 76)g- maternal diabetes mellitus (OR 6.0, 95% CI 2.5 - 14)- multiple gestation (OR 9.4, 95% CI 4.3 - 21)g- maternal use of assisted reproductive technology - lower family income- very low maternal body-mass index- Native American or Hispanic ethnicity

(cfr isolated microtia)

REVIEWED IN http://www.ncbi.nlm.nih.gov/books/NBK5199/

VASCULAR PATHOGENESIS

Poswillo et al. (1973, 1974, 1975)

phenocopy of hemifacial microsomiat i- mouse : triazene,

- monkey : thalidomide

⇒ craniofacial bleeding & hematoma formationi t di f tiin anastomoses preceding formation of stapedial artery (2nd arch)

⇒ severity correlated to size & extent of hematoma

CHROMOSOMAL IMBALANCESCHROMOSOMAL IMBALANCES

• many different imbalances have been reported

• recurrent associations :• recurrent associations :

- del5pdel5p- trisomy 18 - del 18p- trisomy 22 – del22q

Terminal deletion 5p14

MicrotiaPreauricular tagEpibulbar lipodermoidEpibulbar lipodermoidMild hemifacial microsomia

Choong YF et al. J AAPOS. 2003 Jun;7(3):226-7.Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?

Del22q11 2Del22q11.2

congenital heart defecthypocalcemiacleft palatecleft palate

l ft h if i l i ileft hemifacial microsomiamandibular hypoplasia, microtiabilateral preauricular tags left aural atresiacoloboma of the upper left eyelid,

Di ili MC t l A J M d G t A 2009 D 149A(12) 2860 4

y

Digilio MC et al. Am J Med Genet A. 2009 Dec;149A(12):2860-4.Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2.

• BODY ASYMMETRY => CONSIDER MOSAICISM

Mosaic trisomy 22

de Ravel et al. Clin Dysmorphol. 2001 Oct;10(4):263-7

SINGLE-GENE CAUSES

1%-2% of families : autosomal dominant inheritance

rarely : autosomal recessive inheritance

=> empirical recurrence risk : few percent

Vendramini-Pittoli , Clinical Dysmorphology 2009, 18:67–77

Tohoku J et al. Exp Med. 2010;222(4):311-8.

Kelberman D Hum Genet. 2001 Dec;109(6):638-45.

Linkage analysis : 10.7 cM region on chromosome 14q32maximum multipoint lod score of 3.00

familial simplex bilateral involvement 71% 46%hearing loss 26% 87%aural atresia 41% 79%

Tasse C et al. Afamily with autosomal dominant oculo-auriculo-vertebral spectrum.Clin Dysmorphol. 2007;16:1–7.

MOUSE MODEL Hfm transgenic mouseg

microtia external auditory meatus middle ear, cranial basemandibula (asymmetry) ( y y)maxillapharyngeal structurestemporomandibular joint palatal shelf fusion

Otani H ET AL; Anat Anz. 1991;172(1):1-9.Ota ; at 99 ; ( ) 9

Cousley R Cleft Palate Craniofac J. 2002 Jan;39(1):81-92.

DIFFERENTIAL DIAGNOSISDIFFERENTIAL DIAGNOSIS

Treacher-Collins syndrome

zygoma & mandibular hypoplasiazygoma & mandibular hypoplasia, microtia

coloboma of the lower eyelid extracranial malformations : rare

6 patients with “hemifacial microsomia”- 4 hearing loss

3 ddi i l j li- 3 additional major anomalies- 2 developmental delay.

-same de novo mutation 4127 ins G (fs) in exon 24 in the TCOF1 geneg

Su PH, et al. Clin Genet. 2011 Aug 17. [Epub ahead of print]

Townes-Brocks syndrome

Microtia

Radial hand anomalies

R l liRenal anomaliesAnal atresia

Branchio-oto-renal syndrome Wang et al.Pediatrics 2001;108;e32

microtiahearing lossbranchial cleft anomaliesbranchial cleft anomalies

renal malformations

NAGER SYNDROMEpreaxial acrofacial dysostosis

MicrotiaMandibular hypoplasiaMalar hypoplasialower eyelid coloboma

Preaxial hand anomalies

Auriculo-condylar syndrome (A.D)

question mark earsprominent cheeks, small mouthabnormal temporomandibular jointmandibular condyle hypoplasia

Masotti C et al. Eur J Hum Genet. 2008;16:145-52.

P R bParry Romberg

P i h if i l t hProgressive hemifacial atrophy

Postnatalprogressive