American Journal of Medical Genetics 134A:359–362 (2005)

New SyndromeAutosomal Dominant Microtia and Ocular Coloboma:New Syndrome or an Extension of theOculo-Auriculo-Vertebral Spectrum?Anita E. Beck,* Louanne Hudgins, and H. Eugene Hoyme

Department of Genetics, Stanford University School of Medicine, Stanford, California

The oculo-auriculo-vertebral (OAV) spectrum is anetiologically heterogeneous condition classicallyconsisting of microtia, hemifacial microsomia,epibulbar dermoids, and vertebral anomalies.Other eye findings described in OAV includeupper eyelid colobomas, ptosis, and varying de-grees of microphthalmia or even anophthalmia.Iris and/or retinal colobomas have rarely beenreported. We describe two familial cases of appar-ent OAV with ocular colobomas. We postulate thatiris and/or retinal colobomas associated with OAVmay represent a subgroup within the OAV spec-trum with autosomal dominant inheritance, as inthe families described herein. Since microtia canresult from aberrant migration of neural crestcells into the first and second branchial archesduring early embryonic development, and con-comitant deficient neural crest migration into thedeveloping eye can lead to ocular coloboma and oriris heterochromia, it may be that the altered geneor genes in our familial cases are involved withregulation of neural crest development.� 2005 Wiley-Liss, Inc.

KEY WORDS: oculo-auriculo-vertebral spec-trum; OAV; Goldenhar; hemifacialmicrosomia; microtia; coloboma

INTRODUCTION

The oculo-auriculo-vertebral (OAV) spectrum (OMIM#164210), also referred to as Goldenhar syndrome, hemifacialmicrosomia and facio-auriculo-vertebral spectrum [Cohenet al., 1989], is an etiologically heterogeneous condition.Characteristic findings include microtia, hemifacial micro-somia, epibulbar dermoids, and vertebral anomalies [Gorlinet al., 1963; Rollnick and Kaye, 1983; Gorlin, 2001]. However,the range of features which can be considered part of the OAVspectrum is extensive and can include cardiac anomalies, cleftlip and/or cleft palate, macrostomia, and renal or pulmonarymalformations [Cohen et al., 1989]. Even within families,variability of expression is characteristic. Isolated microtia orauricular or preauricular abnormalities have been consideredthe mildest form of the OAV spectrum [Cohen et al., 1989;

Gorlin, 2001]. OAV spectrum usually occurs sporadically inotherwise normal families.

In addition to epibulbar dermoids, other eye findings de-scribed in OAV include upper eyelid colobomas, ptosis, andvarying degrees of microphthalmia or even anophthalmia[reviewed in Cohen et al., 1989]. The association of microtiaand iris and/or retinal colobomas has rarely been reported. Wereport the finding of ocular colobomas in OAV in two families.The purpose of this report is to suggest the potential etiologyand pathogenesis of this uncommon association.

CLINICAL REPORTS

Table I summarizes the clinical and laboratory findings ofthe affected individuals in the following families.

Family 1

The femaleprobandwasbornat termtonon-consanguineousparents with a birth weight of 3,581 g (75th centile), lengthof 48.3 cm (25th centile), and head circumference of 34.0 cm(50th centile). Bilateral microtia (Fig. 1) and bilateral iriscolobomas (Fig. 2)were evident. External auditory canalswereabsent bilaterally, and there were two preauricular tags pre-sent on the right. There was no evidence of mandibular hypo-plasia or dramatic facial asymmetry.

Auditory brainstem response testing revealed bilateralconductive and mild sensorineural hearing loss. She had anormal renal ultrasound study and normal spine radiographs.An ophthalmologic exam revealed that the iris colobomasextended into the retinas bilaterally. In addition, a small leftoptic nerve coloboma was discovered. However, because therewas no involvement of the central foveal or macular regions,the prediction for visual function was positive. No iris pig-mentary anomalieswere noted. A formal cardiology evaluationfound no pathologic signs clinically to suggest a congenitalcardiac defect; therefore, no echocardiogram was performed.Chromosome analysis revealed a normal 46,XX female kary-otype (>550 band resolution).

Hermother exhibited unilateral right-sidedmicrotia accom-panied by ipsilateral mixed hearing loss. There was somesubtle facial asymmetry with mild hypoplasia of the rightmandible and cheek, and a mild right-sided lateral facial cleftat the corner of hermouth (macrostomia). Although themotherdid not display iris colobomas, she did have a segmental area ofheterochromia of her right iris (Fig. 3).

Family history was significant for the maternal grandfatherhaving cupped ears requiring surgical correction, and hisbrother having a preauricular tag. Further family history ofiris pigmentation abnormalities is unknown and photographsare not available for review.

Family 2

The second patient was a female born at 40 weeks gestationto non-consanguineous parents with a birth weight of 3,180 g

*Correspondence to: Anita E. Beck, M.D., Ph.D., Department ofGenetics, Stanford University School of Medicine, BeckmanCenter B203, 279 Campus Drive, Stanford, CA 94305-5323.E-mail: abeck@stanford.edu

Received 17 February 2004; Accepted 3 January 2005

DOI 10.1002/ajmg.a.30638

� 2005 Wiley-Liss, Inc.

(50th centile), length of 49.5 cm (50th–75th centile), and headcircumference of 33 cm (25th–50th centile). She was noted tohave leftmicrophthalmia, and an ophthalmologic examinationrevealed a large left inferior chorioretinal coloboma involvingher optic nerve and macula. An MRI revealed a left orbitalmass that was consistent with a colobomatous cyst. She hadunusual, prominent ears with simple helices and small lobesbilaterally. In addition, bilateral conductive hearing loss wasnoted. Over time she exhibited short stature and mild speechdelay. Evaluations included a normal renal ultrasound and anormal 46,XX female karyotype at>550band resolution. FISHfor the 22q11 deletion was performed because of the speechdelay. The results were normal, as was a subtelomeric probestudy. Spine radiographs showed 11 rib-bearing vertebrae andpartial sacralization of the last lumbar vertebrae.

Her sister had come to medical attention several years priorbecause of right microtia, right-sided facial palsy, and severeconductive hearing loss on the structurally normal left side.Therewas relative preservation of the structure of the superioraspect of the pinna on the right side, but the inferior aspectwasmarkedly abnormal. Her left ear was structurally normal.Renal ultrasound and spine radiographs were normal. Anechocardiogram showed one aberrant cardiac vessel, butotherwise normal anatomy. Chromosome analysis revealed anormal 46,XX female karyotype.

TABLE

I.ClinicalandLaboratory

Findingsin

TwoOcu

lo-A

uricu

lo-V

ertebral(O

AV)Families

Ocu

loAuricu

loVertebral

Facialasymmetry

Ren

al

Card

iac

Other

Karyotype/studies

Family1

Proband

Colob

omas:

iris

and

retinal(B

),op

tic

nerve(L)

Microtia(B

),absence

ofex

tern

alauditory

canals

(B),preauricu

lar

tags�2(R

),mixed

hea

ringloss

(B)

Normalsp

ine

radiographs

No

Normal

ultrasound

Normalex

am

Normal46,XX

(>550band)

Mother

Seg

men

taliris

heterochromia

(R)

Microtia(R

),mixed

hea

ringloss

(R)

Subtlehypop

lasia(R

),mildmacrostomia

(R)

Matern

algrandfather

Cupped

ears

(B)

Matern

algranduncle

Preauricu

lartag

Family2

Patien

tMicrophthalm

ia(L),

Chorioretinal

colobom

ainvolving

theop

ticnerveand

macu

la(L),

Colob

omatous

cyst

(L)

Prominen

t,unusu

alea

rs(B

),conductivehea

ring

loss

(B)

11rib-bea

ring

vertebrae,

partial

sacraliza

tion

last

lumbarvertebrae

No

Normal

ultrasound

Shortstature,

spee

chdelay

Normal46,XX

(>550band),normal

FIS

H22q11,normal

sub-telom

eric

probes

Sister

Microtia(R

),conductive

hea

ringloss

(L)

Normalsp

ine

radiographs

Facialpalsy(R

)Normal

ultrasound

Oneaberrant

card

iacvessel

Normal46,XX

Father

Prominen

t,unusu

alea

rs(B

),hea

ringloss

Abnormalpronation

/su

pination

arm

s(B

)

B,bilateral;R,right;L,left.

Fig. 1. Right and left microtia in Proband 1. Two right preauricular tagshad spontaneously detached prior to this photo. [Color figure can be viewedin the online issue, which is available at www.interscience.wiley.com.]

Fig. 2. Proband 1 iris coloboma (bilateral, right shown). [Color figure canbe viewed in the online issue, which is available at www.interscience.wiley.com.]

360 Beck et al.

Themother was noted to have unilateral ptosis secondary toeye trauma. The father was described as having unusual ears(similar to Patient 2) with congenital hearing loss. In addition,he was reported to have difficulty with pronation and supina-tion of his arms bilaterally. The couple had one spontaneousabortion and one unaffected daughter as well. No familyhistory of iris pigmentary anomalies was described. Photo-graphs of additional family members are not available forreview.

DISCUSSION

The most common eye findings reported in OAV are epi-bulbar dermoids, upper eyelid colobomas, ptosis, and varyingdegrees of microphthalmia or anophthalmia [reviewed inCohen et al., 1989]. While iris or retinal colobomas are in-frequent, there are at least nine previously reported cases inseven reports.

In 1904, a child was reported with bilateral preauriculartags, bilateral upper eyelid colobomas, two dermoids on theright, right macrostomia, and a left coloboma of the iris andchoroid [Harman, 1904]. Although this report preceded thedescription of OAV, the findings described in this child areconsistent with that diagnosis.

After Goldenhar’s delineation of this syndrome in 1952,an occasional case of ocular coloboma associated with OAVappeared in the literature [Goldenhar, 1952]. Limaye [1972]described the case of a young man with left hemifacial micro-somia and preauricular appendages bilaterally. The patientexhibited left microphthalmia with a large epibulbar dermoid.His right eye showed a small epibulbar dermoid as well as acoloboma of the iris and choroid.

Baum and Feingold [1973] described the ocular findings of13 cases of OAV, 2 of which were found to have ocularcolobomas. They reported on a 2-year-old whose right eyeshowed an eyelid coloboma, a lipodermoid tumor,microcornea,and a fundus coloboma. This child also had left cryptophthal-mos.Another case in the samearticlewasdescribedashavingaright iris coloboma in addition to a right upper eyelid coloboma,a right bilobed dermolipoma, and a left lipodermoid.

In 1983, pedigree data were presented on 97 probands withhemifacial microsomia or a variant, 44 of whom had a familyhistory of the same or similar anomalies [Rollnick and Kaye,1983]. Of these probands, one was described as having a left-sided coloboma of the optic disc accompanied by moderatemicrotia andmildhypoplasia of themandible. In addition,mildmicrotia was observed on the right. A paternal aunt of this boyhad a malformation of the helix by report.

Margolis et al. [1984] reported on two additional cases. A14-year-old male was described with left-sided findings in-

cluding facial hypoplasia, microtia with preauricular tags, anupper eyelid notch, microphthalmia, and an iris coloboma.Another case presented in this same article involved a 3-year-old boy with left-sided facial hypoplasia, microtia, and hypo-plasia of the lung. The child also displayed colobomatousmicrophthalmia on the right.

Mansour et al. [1985] examined 57 consecutive patientswithOAVspectrumfindings. One of these patientswas described ashaving a choroidal coloboma.

In a study by Rollnick et al. [1987] in which phenotypiccharacteristics of 294 patients with OAV were detailed, 18%had an eye defect other than epibulbar dermoids or lipoder-moids.Malformations included iris and optic nerve colobomas,although the details or exact number of patients with thisfinding were not given.

The range of ear malformations observed in Family 1 (frompreauricular tags to bilateral microtia) is typical of patientswith OAV. In addition, however, the child in this family wasfound to have bilateral iris and unilateral retinal colobomas.In previous reports of ocular colobomas associated withOAV, another eye malformation was almost always present(eyelid coloboma, epibulbar dermoid or lipodermoid, or micro-phthalmia). To our knowledge, this is the first report of OAVwith bilateral ocular colobomas without additional ocularmalformations. Although it has been suggested that retinalcolobomas may not be intrinsic to OAV, but may be second-ary manifestations of microphthalmia [Mansour et al.,1985], Patient 1 in the present study suggests that this maynot be the case. This patient clearly has bilateral iris andretinal colobomas without evidence of additional ocularmalformations.

Interestingly, although the mother in Family 1 did not havean ocular coloboma, she was noted to have a region of irisheterochromia ipsilateral to her microtia. An associationbetween iris heterochromia and iris colobomas has previouslybeen reported [Morrison et al., 2000]. This study examined57 children in Scotland with iris colobomas. In 13 of thesecases (17.3%), there was noticeable iris heterochromia. Theauthors specifically commented that in their unilateral cases,the darker area of heterochromia occurred on the side of thecoloboma. The brown hyperpigmented area of heterochromiain the otherwise blue irises of the mother of Patient 1 is on heraffected right side.

In Family 2, the patient had unilateral microphthalmiaassociated with a retinal coloboma as well as bilateralprominent, unusual ears with bilateral conductive hearingloss. The finding of ocular coloboma associated with micro-phthalmia in OAV is more typical of those cases describedin the literature. This family also appeared to be a caseof autosomal dominant OAV as both the sister and thefather also have manifestations of OAV. Her sister hadunilateral microtia, hearing loss, and facial nerve palsy andthe patient’s father had similar unusual ears with hearingloss.

Markedhemifacialmicrosomiawasnot seen inanymembersof these two families. It has been noted that patients withbilateral microtia are less likely to exhibit mandibularhypoplasia [Kaye et al., 1989]. In our personal experience,familial cases of OAV are less likely to have mandibular hypo-plasia than sporadic cases. Therefore, we feel that the lack ofdramatic hemifacial microsomia does not preclude the diag-nosis of OAV in these two families.

Although there is a separate condition of ‘‘microtia withmeatal atresia and conductive deafness’’ (OMIM#251800) thatcan be inherited in an autosomal dominant or autosomalrecessive fashion [Gupta and Patton, 1995], those patients donot have eye abnormalities as part of the clinical picture.Therefore, we feel that these two families are part of the OAVspectrum.

Fig. 3. Iris heterochromia (upper, lateral quadrent of right eye).[Color figure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

Autosomal Dominant Microtia and Coloboma 361

Most cases of OAV are sporadic, and indeed there is thoughtto be etiologic heterogeneity in this condition. Althoughthere is ample evidence that teratogen exposure or vasculardisruption, for example, can lead to this phenotype [Poswillo,1973], in a subgroup of cases, OAV is clearly inherited in anautosomal dominant fashion as was demonstrated in our twofamilies. Because of this genetic component, the empiric recur-rence risk for OAV is usually quoted to be about 2%–3%[Rollnick and Kaye, 1983; Gorlin et al., 2001].

Microtia can result from aberrant migration of neural crestcells into the first and second branchial arches duringembryonic weeks 4 and 5. Concomitantly, abnormal neuralcrest migration into the developing eye at 5–7weeks gestationcan lead to abnormal closure of the optic fissure thus creatingan ocular coloboma [Pagon, 1981; Morrison et al., 2000] or irisheterochromia [Morrison et al., 2000]. Therefore, it is temptingto postulate that the altered gene or genes in our familial casesare involved with regulation of neural crest development.Further investigation of these families should include evalua-tion of such candidate genes.

In conclusion, iris and/or retinal colobomas are a rare butdescribed ocularmalformation seenwithin theOAV spectrum.From our two families presented here along with those re-ported on in the literature, we postulate that patients with irisand/or retinal colobomas associatedwithmicrotia are a specificsubgroup within the OAV spectrum. However, another diag-nostic possibility would include a newmalformation syndromewith features that overlap with OAV. In the families hereinpresented, the OAV phenotype was inherited in an autosomaldominant fashion. Therefore, genetic counseling of similarlyaffectedpatients and families should include thepossibility of a50% recurrence risk.

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