RESEARCH LETTER

Familial Transmission of OculoauriculovertebralSpectrum (Goldenhar Syndrome) Is Not Due toMutations in Either EYA1 or SALL1Kara Goodin,1 Sandra Prucka,1 Audie L. Woolley,2 Juergen Kohlhase,3 Richard J.H. Smith,4

John Grant,2,5 and Nathaniel H. Robin1*1Department of Genetics, University of Alabama, Birmingham, Alabama2Department of Pediatrics, University of Alabama, Birmingham, Alabama3University of Freiburg, Freiburg, Germany4Department of Otolaryngology, University of Iowa, Iowa City, Iowa5Department of Surgery, University of Alabama, Birmingham, Alabama

Received 19 December 2007; Accepted 3 November 2008

TO THE EDITOR:

Oculoauriculovertebral spectrum (OAV) is one name applied to

the constellation of findings that includes facial asymmetry, ipsi-

lateral microtia with associated preauricular skin pits and tags,

epibulbar dermoids, and extracranial malformations including

vertebral, cardiac, and renal defects. OAV is most often associated

with microtia at a minimum; however it is widely variable, with

some affected individuals presenting with mild features such as

facial asymmetry or ear anomalies alone, and others with more

significant features such as multiple skin tags, epibulbar dermoids,

or extracranial malformations [Tasse et al., 2005; Kosaki et al.,

2007]. Due to this variability, OAV demonstrates clinical overlap

with several other genetic disorders, notably Townes–Brocks (TBS)

and branchial-oto-renal (BOR) syndromes.

TBS is associated with mutations in the SALL1 gene and involves

dysmorphic features including microcephaly, hemifacial micro-

somia, epibulbar dermoids, ear malformations, macrostomia, and

extracranial malformations (including cardiac, gastrointestinal,

genitourinary, and skeletal anomalies). It can also be associated

with mental retardation and hearing loss. BOR is associated with

mutations in the EYA1 gene in addition to other genes and involves

dysmorphic features including a long narrow face, facial asym-

metry, ear malformations, palate anomalies, and branchial cleft

fistulas. Characteristic ear anomalies include preauricular pits and

overfolded helices. BOR can also be associated with renal anomalies

and hearing loss. It is important to distinguish these disorders to

permit proper medical management and genetic counseling, in-

cluding recurrence risks. TBS and BOR are each inherited in an

autosomal dominant fashion, while OAV is etiologically heteroge-

neous with a 2–3% empiric recurrence risk [Rollnick and Kaye,

1983; Gorlin, 2001].

Interestingly, autosomal dominant transmission of OAV has

been reported [Kaye et al., 1992; Stoll et al., 1998; Beck et al., 2005;

Richieri-Costa and Ribeiro, 2005; Tasse et al., 2007]. This has

prompted speculation that such cases may actually represent

variants of TBS [Johnson et al., 1996; Keegan et al., 2001] and

BOR [Rollnick and Kaye, 1985; Sensi et al., 1996] and be caused by

mutations in either the TBS or BOR genes, SALL1 and EYA1,

respectively. To test this hypothesis, we undertook screening of

SALL1 and EYA1 in three families that segregated dominant

transmission of OAV phenotype.

In the first family, the proposita was a 20-year-old college student

with a history of multiple right facial skin tags removed shortly after

birth, referred for evaluation of facial asymmetry. Her mother also

had a history of left-sided ‘‘cleft jaw,’’ skin tags, and an epibulbar

dermoid, with repair and removal at a very young age. Both the

proposita and her mother were otherwise well, with normal devel-

opment and intelligence. Growth parameters for the propositus

were within two standard deviations of the mean. Permission for

*Correspondence to:

Nathaniel H. Robin, Department of Genetics, University of Alabama at

Birmingham, Kaul 210D, 1530 3rd Ave. South, Birmingham, AL 35294-

0024. E-mail: nrobin@uab.edu

Published online 11 February 2009 in Wiley InterScience

(www.interscience.wiley.com)

DOI 10.1002/ajmg.a.32673

How to Cite this Article:Goodin K, Prucka S, Woolley AL, Kohlhase J,

Smith RJH, Grant J, Robin NH. 2009. Familial

transmission of Oculoauriculovertebral

spectrum (Goldenhar syndrome) is not due to

mutations in either EYA1 or SALL1.

Am J Med Genet Part A 149A:535–538.

� 2009 Wiley-Liss, Inc. 535

photo publication was denied. First family pedigree information is

limited by history and physical exam documentation (see Fig. 1).

In the second family, the proposita was a 19-month-old female

who presented at birth with left microtia, left-sided preauricular

skin tag, left-sided epibulbar dermoid, and left-sided mandibular

underdevelopment. Her development was age appropriate, and her

physical growth was within the normal range (parameters within

two standard deviations of the mean). Her mother had left-sided

hemifacial microsomia, left-sided preauricular skin tags, and bilat-

eral epibulbar dermoids. Maternal grandmother had right-sided

microsomia and preauricular skin tags; and a maternal first cousin

had right-sided preauricular skin tags. Permission for photo pub-

lication was denied (see Fig. 2).

In the third family, the proposita was a 14-year-old female with

left-sided hemifacial microsomia with an atretic left ear canal,

hypoplastic left ear, and left preauricular cyst. She had normal

growth parameters (within two standard deviations of the mean)

and normal development but had been in special education classes

for select subjects (math and English) for several years. Her sister

had bilateral malformed ears, bilateral branchial cleft cysts, a single

kidney, and pulmonary stenosis. Her mother had mild left-sided

hemifacial microsomia, left-sided microtia, and bilateral sensori-

neural hearing loss. Permission for photo publication was denied

(see Fig. 3).

The proposita from each family underwent genetic testing for

SALL1 and EYA1. EYA1 mutation analysis was performed through

bidirectional sequencing of exons [Vervoort et al., 2002]. SALL1

mutation analysis was performed by direct sequencing of the

complete coding region and deletion analysis by quantitative Real

Time PCR as described [Kohlhase et al., 1999; Borozdin et al., 2006].

No changes were detected in either the SALL1 or EYA1 genes,

suggesting that, at least for these three families, autosomal domi-

nant OAV is genetically distinct from TBS and BOR.

Other studies have undertaken a similar analysis. Keegan et al.

[2001] investigated the relationship between OAV and TBS per-

forming mutation analysis for SALL1 on eight individuals with

overlapping findings, including facial asymmetry. A SALL1 muta-

tion was found in 50%, though imperforate a.u. was present, a

FIG. 1. Pedigree for first family.

FIG. 2. Pedigree for second family.

536 AMERICAN JOURNAL OF MEDICAL GENETICS PART A

characteristic anomaly for TBS but one uncommon in OAV.

Rollnick and Kaye [1985] first postulated that OAV may in some

cases represent a variable manifestation of BOR. Sensi et al. [1996]

reported BOR families in which affected members manifest findings

typical for OAV, including facial asymmetry.

SALL1 is the only gene thought to be associated with TBS.

Mutation detection rate is approximately 64% for individuals with

a typical TBS clinical presentation [Kohlhase et al., 1999]. Muta-

tions in EYA1 are identified in only �40% of BOR patients [Chang

et al., 2004]. However, BOR is heterogeneous with at least one other

gene known, SIX5 [OMIM #610896]. It is therefore possible that

other mutations in that other BOR gene or undetected mutations in

either SALL1 or EYA1 are involved in OAV.

Alternatively, there may be a distinct gene for familial OAV. To

date, several loci have been mapped in familial OAV: 5p terminal

deletions, 8q11 (EYA1 maps to 8q13), 11q12-13, 14q32, and

22q11.2 microdeletions [Singer et al., 1994; Graham et al., 1995;

Kelberman et al., 2001; Tasse et al., 2005]. Therefore, the need for

careful clinical delineation of this disorder as well as further

molecular investigation into OAV is further emphasized as accurate

diagnosis is important for proper medical management and genetic

counseling, including recurrence risks.

REFERENCES

Beck A, Hudgins L, Hoyme E. 2005. Autosomal dominant microtia andocular coloboma: New syndrome or an extension of the oculo-auriculo-vertebral spectrum? Am J Med Genet Part A 134A:359–362.

Borozdin W, Steinmann K, Albrecht B, Bottani A, Devriendt K, Leipoldt M,Kohlhase J. 2006. Detection of heterozygous SALL1 deletions by quanti-tative real time PCR proves the contribution of a SALL1 dosage effectin the pathogenesis of Townes-Brocks syndrome. Hum Mutat 27:211–212.

Chang E, Menezes M, Meyer N, Cucci RA, Vervoort VS, SchwaartzCE, Smith RJ. 2004. Branchio-oto-renal syndrome: The mutation spec-trum in EYA1 and its phenotypic consequences. Hum Mutat 23:582–589.

Gorlin RJ. 2001. Branchial arch and oro-acral disorders. In: Gorlin RJ,Cohen MM Jr, Levin LS, editors. Syndromes of the head and neck. 4thedition. New York: Oxford University Press. pp 790–797.

Graham JM, Hixon H, Bacino CA, Daack-Hirsch S, Semina E, Murray JC.1995. Autosomal dominant transmission of a Goldenhar-like syndromewith linkage to the branchial-oto-renal syndrome. Pediatr Res 37:83A.

Johnson J, Poskanzer L, Sherman S. 1996. Three-generation family withresemblance to Townes-Brocks syndrome and Goldenhar/oculoauricu-lovertebral spectrum. Am J Med Genet 61:134–139.

FIG. 3. Pedigree for third family.

GOODIN ET AL. 537

Kaye CI, Martin AO, Rollnick BR, Nagatoshi K, Israel J, Hermanoff M,Tropea B, Richtsmeier JT, Morton NE. 1992. Oculoauriculovertebralanomaly: Segregation analysis. Am J Med Genet 43:913–917.

Keegan CE, Mulliken JB, Wu BL, Korf BR. 2001. Townes-Brocks syndromeversus expanded spectrum hemifacial microsomia: Review of eightpatients and further evidence of a ‘‘hot spot’’ for mutation in the SALL1gene. Genet Med 3:310–313.

Kelberman D, Tyson J, Chandler DC, McInerney AM, Slee J, Albert D,Aymat A, Botma M, Calvert M, Goldblatt J, Haan EA, Laing NG, Lim J,Malcolm S, Singer SL, Winter RM, Bitner-Glindzicz M. 2001. Hemifacialmicrosomia: Progress in understanding the genetic basis of a complexmalformation syndrome. Hum Genet 109:638–645.

Kohlhase J, Taschner PE, Burfeind P, Pasche B, Newman B, Blanck C,Breuning MH, ten Kate LP, Maaswinkel-Mooy P, Mitulla B, Seidel J,Kirkpatrick SJ, Pauli RM, Wargowski DS, Devriendt K, Proesmans W,Gabrielli O, Coppa GV, Wesby-van Swaay E, Trembath RC, Schinzel AA,Reardon W, Seemanova E, Engel W. 1999. Molecular analysis of SALL1mutations in Townes-Brocks syndrome. Am J Hum Genet 64:435–445.

Kosaki R, Fujimaru R, Samejima H, Yamada H, Izumi K, Iijima K, Kosaki K.2007. Wide phenotypic variations within a family with SALL1 mutations.Am J Med Genet Part A 143A:1087–1090.

Richieri-Costa A, Ribeiro LA. 2005. Macrostomia, preauricular tags, andexternal ophthalmoplegia: A new autosomal dominant syndrome withinthe oculoauriculovertebral spectrum? Cleft Palate Craniofac J 43:429–434.

Rollnick BR, Kaye CI. 1983. Hemifacial microsomia and variants: Pedigreedata. Am J Med Genet 15:233–253.

Rollnick BR, Kaye CI. 1985. Hemifacial microsomia and the branchio-oto-renal syndrome. J Craniofac Genet Dev Biol Suppl 1:287–295.

Sensi A, Cocchi G, Martini A, Garani G, Trevisi P, Calzolari E. 1996.Branchio-oto (BO) syndrome and oculo-auriculo-vertebral phenotype:Overlapping clinical findings in a child from a BO family. Clin Genet49:300–302.

Singer SL, Haan E, Slee J, Goldblatt J. 1994. Familial hemifacial microsomiadue to autosomal dominant inheritance. Case reports. Aust Dent J39:287–291.

Stoll C, Viville B, Treisser A, Gasser B. 1998. A family with dominantoculoauriculovertebral spectrum. Am J Med Genet 78:345–349.

Tasse C, Bohringer S, Fischer S, Ludecke HJ, Albrecht B, Horn D, Janecke A,Kling R, Konig R, Lorenz B, Majewski F, Maeyens E, Meinecke P, MitullaB, Mohr C, Preischl M, Umstadt H, Kohlhase J, Gillessen-Kaesbach G,Wieczorek D. 2005. Oculo-auriculo-vertebral spectrum (OAVS): Clini-cal evaluation and severity scoring of 53 patients and proposal for a newclassification. Eur J Med Genet 48:397–411.

Tasse C, Majewski F, Bohringer S, Fischer S, Ludecke H-J, Gillessen-Kaesbach G, Wieczorek D. 2007. A family with autosomal dominantoculo-auriculo-vertebral spectrum. Clin Dysmorphol 16:1–7.

Vervoort V, Smith R, O’Brien J, Schroer R, Abbott A, Stevenson RE,Schwartz CE. 2002. Genomic rearrangements of EYA1 account for a largefraction of families with BOR syndrome. Eur J Hum Genet 10:757–766.

538 AMERICAN JOURNAL OF MEDICAL GENETICS PART A