Oculo-auriculo-vertebral spectrum. Center for Human Genetics K.U.Leuven

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1 Oculo-auriculo-vertebral spectrum Koen Devriendt Center for Human Genetics K.U.Leuven

2 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-faciale. Eye : epibulbar dermoid Ear : preauricular tags & fistules Goldenhar M. Journal de Génétique Humaine, 1952, 1:

3 Hemifacial microsomia unilateral anomalies - ear - mouth - mandibula

4 Novel names : Goldenhar syndrome Hemifacial i microsomia i Lateral facial dysplasia First arch syndrome First and second branchial arch syndrome Unilateral l craniofacial i microsomia i Oral-mandibular-auricular syndrome Unilateral l intrauterine t i facial necrosis Auriculo-branchiogenic dysplasia Otomandibular dysostosis Craniofacial microsomia Oculo-auriculo-verbebral dysplasia

5 - overlapping features - no discriminating diagnostic criteria - unknown cause => no diagnostic test suggested term : oculo-auriculo-vertebral l l spectrum

6 OCULO AURICULO VERTEBRAL SPECTRUM OCULO

7 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

9 choristomas = normal tissues that are in the wrong place = congenital, non-neoplastic = solid masses, white-yellow aspect Dermoid 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

10 Dermolipomas contain fat tissue minimal skin adnexae more commonly superotemporal quadrant & extending to lacrimal gland

14 Eyelid anomalies ptosis upper eyelid coloboma

15 Coloboma upper eyelid (+/- 20%)

16 - microphthalmia (=> intellectual disability) - Peters anomaly - retinal coloboma,

17 OCULO AURICULO VERTEBRAL SPECTRUM AURICULO

18 Auriculo : ears Variable ear anomalies in OAVS microtia - anotia unilateral - bilateral

Microtia, First Degree median longitudinal length < 2 SD Presence of all normal ear

but not all, parts of the normal ear Microtia, Third Degree presence of some auricular a

Classification of congenital deformities of the auricle. Facial Plastic Surg 5:385 388.

19 Microtia, First Degree median longitudinal length < 2 SD Presence of all normal ear components Microtia, Second Degree median longitudinal length < 2 SD presence of some, but not all, parts of the normal ear Microtia, Third Degree presence of some auricular a structures, u none conform to recognized ear components * Weerda H Classification of congenital deformities of the auricle. Facial Plastic Surg 5: * Hunter A et al Elements of morphology: standard terminology for the ear. Am J Med Genet A. 149A:40-60.

20 Auricular hillocks external ear first arch second arch First pharyngeal cleft external auditory canal Week 6

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

22 Hearing loss first arch second arch aural atresia & middle ear anomalies => Conductive hearing loss > 50% inner ear anomalies => Sensorineural hearing loss 15%

23 MICROTIA AND HEARING LOSS 115 ears of 89 patients (68 males, 21 females; mean age, 11 yr; range, 5-44 yr) y) High resolution CT scan of temporal bone hearing level l * correlated with - the formation of oval/round windows - ossicular development * did NOT correlate with - the degree of middle ear aeration, - facial nerve aberration, - severity of microtia. Ishimoto S et al. Laryngoscope Mar;117(3):461-5

26 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 malformations cause / pathogenesis the same? isolated microtia = frequently mild OAVS features Rollnick et al. Am J Med Genet ;( Tasse et al. Eur J Med Genet 2005;48:

27 Human embryo 6 weeks First arch maxillary process mandibular process Second arch K. Sulik

28 First arch Maxillary process Mandibular process failure => lateral facial cleft (Tessier N 7) incomplete => groove, dimple, pit abnormal => appendages

29 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 * rarely > ant. border of m. masseter

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

32 Groove Extending beyond the masseter muscle

33 Pits Preauricular Cheeck

34 Skin tags

35 Skin tags - variable number

36 Skin tags variable size

37 Composition : Composition : choristoma s = skin, cartilage

39 frequently bilateral unilateral: ~ epibulbar dermoid, microtia microtia : frequently unilateral

40 OCULO AURICULO VERTEBRAL SPECTRUM FACIAL ASYMMETRY

41 FACIAL ASYMMETRY ears, eyes, skin tags mouth : lateral cleft underdevelopment - mandibula & maxilla - soft tissues

42 BONY ANOMALIES - mandibular hypoplasia - zygomatico-orbital orbital dysplasia : disruption & hypoplasia zygomatic arch disruption & hypoplasia zygomatic arch inferior displacement of the lateral canthus

44 zygomatic arch is incomplete small maxilla small squamous temporal bone hypoplasia & malformation hypoplasia & malformation mandibular body, ramus, & condyle

45 Tessier classification of facial clefts

46 Maxillary yprominence of first arch : - maxilla, - zygomatic arch, - squamous temporal bone - palatine bone Brancial arches

47 Gorlin Collection

50 other craniofacial : - cleft lip +/- palate - cleft palate - velopharyngeal insufficiency (VPI) muscular hypoplasia +/- cranial nerve palsy (?) - pharyngeal and laryngeal anomalies! feeding difficulties! speech delay

51 VERTEBRAL - C1-C2 instability -spina bifida - hemivertebrae - butterfly vertebrae - fused vertebrae - hypoplastic vertebrae - klippel-feil anomaly follow-up for scoliosis!

53 anomalies of thoracic vertebrae

54 Non-craniofacial malformations -vertebral - gastrointestinal esophageal atresia, imperforate anus - cardiac : most typically y VSD / ToFallot - trachea and lung lung lobation anomalies, TEfistula - renal - limb - radius agenesis, thumb anomalies - club foot

55 Episode of major bleeding 8 weeks gestation

57 OCULO AURICULO VERTEBRAL SPECTRUM Neurodevelopmental outcome?

58 24 infants and toddlers 58% > 2 SD below mean in at least one domain of development. NO DIFFERENCE IN DEVELOPMENTAL OUTCOME - boys versus girls - side of anomalies - severe or mild clinical manifestations WORSE OUTCOME : -abnormal muscle tone - affected bilaterally - cervical spine abnormalities Cohen MS et al. Am J Med Genet Dec 18;60(6):

59 20 participants - 12 males, 8 females - age range 8mo-17y - mean age 8y neuroimaging > 50 % : grey and white matter anomalies > 33% : enlarged ventricles Johansson M et al. Dev Med Child Neurol Apr;49(4):280-8

Autism NORMAL Borderline Mild ID Severe ID Profound ID

60 20 participants AUTISM SPECTRUM DISORDER INTELLECTUAL DISABILITY Autistic traits AUTISTIC-LIKE Autism NORMAL Borderline Mild ID Severe ID Profound ID NORMAL Johansson M et al. Dev Med Child Neurol Apr;49(4):280-8

61 Tasse C, et al. Wieczorek Dagmar Eur J Med Genet. 2005;48: Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation & severity scoring of 53 patients & proposal for a new classification. SCORING SYSTEM : - each major anomaly = 2 points microtia; hemifacial microsomia; vertebral anomaly - each associated anomaly = 1 point deafness, facial cleft, eye, dermoids, motor delay, speech delay growth delay, urogenital, brain, heart, limb defects, microcephaly

62 Three groups : number of major criteria unilateral - bilateral GROUP MINIMAL N cases MANIFESTATIONS (n=53) 1 unilateral 3 microtia 1 bilateral 6 2 unilateral 20 microtia/ preauricular tag 2 bilateral + hemifacial microsomia 14 3 unilateral microtia/ preauricular tag 3 + hemifacial microsomia 3 bilateral + vertebral anomalies 7

63 PROGNOSIS : Associated malformations increases with subgroup more major malform. = more associated malform. increases with bilateral involvement Developmental outcome inversely correlates with score and subgroup

64 Vascular disruption eyes Genetic factors First arch Second arch Teratogens?

65 ENVIRONMENTAL RISK FACTORS - vasoactive drugs : pseudoephedrine, p aspirin, ibuprofen (1.5-2 fold increased risk) - second trimester bleeding (OR 13.2, 95% CI ) - maternal diabetes mellitus (OR 6.0, 95% CI ) - multiple gestation (OR 9.4, 95% CI ) - 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

66 VASCULAR PATHOGENESIS Poswillo et al. (1973, 1974, 1975) phenocopy of hemifacial microsomia - mouse : ti triazene, - monkey : thalidomide craniofacial bleeding & hematoma formation in anastomoses preceding formation of stapedial artery (2nd arch) severity correlated to size & extent of hematoma

67 CHROMOSOMAL IMBALANCES many different imbalances have been reported recurrent associations : - del5p - trisomy 18 - del 18p - trisomy 22 del22q

68 Terminal deletion 5p14 Microtia Preauricular tag Epibulbar lipodermoid Mild hemifacial microsomia Choong YF et al. J AAPOS Jun;7(3): Goldenhar and cri-du-chat syndromes: a contiguous gene deletion syndrome?

69 Del22q11.22 congenital heart defect hypocalcemia cleft palate left hemifacial i microsomia i mandibular hypoplasia, microtia bilateral preauricular tags left aural atresia coloboma of the upper left eyelid, Digilio ili MC et al. Am J Med Genet A Dec;149A(12): Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2.

70 BODY ASYMMETRY => CONSIDER MOSAICISM Mosaic trisomy 22 de Ravel et al. Clin Dysmorphol Oct;10(4):263-7

71 SINGLE-GENE CAUSES 1%-2% of families : autosomal dominant inheritance rarely : autosomal recessive inheritance => empirical recurrence risk : few percent

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

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

74 Kelberman D Hum Genet Dec;109(6):

75 Linkage analysis : 10.7 cm region on chromosome 14q32 maximum multipoint lod score of 3.00

76 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.

77 MOUSE MODEL Hfm transgenic mouse microtia external auditory meatus middle ear, cranial base mandibula (asymmetry) y) maxilla pharyngeal structures temporomandibular joint palatal shelf fusion Otani H ET AL; Anat Anz. 1991;172(1): Cousley R Cleft Palate Craniofac J Jan;39(1):81-92.

78 DIFFERENTIAL DIAGNOSIS

79 Treacher-Collins syndrome zygoma & mandibular hypoplasia, microtia coloboma of the lower eyelid extracranial malformations : rare

80 6 patients with hemifacial microsomia - 4 hearing loss - 3 additional i major anomalies - 2 developmental delay. -same de novo mutation 4127 ins G (fs) in exon 24 in the TCOF1 gene Su PH, et al. Clin Genet Aug 17. [Epub ahead of print]

81 Townes-Brocks syndrome Microtia Radial hand anomalies R l li Renal anomalies Anal atresia

82 Branchio-oto-renal syndrome Wang et al.pediatrics 2001;108;e32 microtia hearing loss branchial cleft anomalies renal malformations

83 NAGER SYNDROME preaxial acrofacial dysostosis Microtia Mandibular hypoplasia Malar hypoplasia lower eyelid coloboma Preaxial hand anomalies

84 Auriculo-condylar syndrome (A.D) question mark ears prominent cheeks, small mouth abnormal temporomandibular joint mandibular condyle hypoplasia

85 Masotti C et al. Eur J Hum Genet. 2008;16:

86 Parry Romberg Progressive hemifacial i atrophy Postnatal progressive

A REPORT OF HEMIFACIAL MICROSOMIA IN A 7-YEAR OLD MALE

A REPORT OF HEMIFACIAL MICROSOMIA IN A 7-YEAR OLD MALE 1 2 3 4 Monika Koul, Warisha Akhlaq, Sajid S Shaikh, Ahsan Abdullah University Journal of Dental Sciences Case Report ABSTRACT : Hemifacial microsomia