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A family with dominant oculoauriculovertebral spectrum

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American Journal of Medical Genetics 78:345–349 (1998)
A Family With Dominant
Oculoauriculovertebral Spectrum
C. Stoll,1* B. Viville,2 A. Treisser,2 and B. Gasser3
Service de Génétique Médicale, Centre Hospitalo-Universitaire, Strasbourg, France
Maternité, Centre Hospitalo-Universitaire, Strasbourg, France
Institut d’Anatomie Pathologique, Centre Hospitalo-Universitaire, Strasbourg, France
In 1990, Gorlin et al. [Syndromes of the Head
and Neck, New York: Oxford University
Press, pp 641–649, 707–708] proposed to
lump several syndromes together, including
facioauriculovertebral syndrome, hemifacial microsomia, otomandibular dysostosis,
Goldenhar syndrome, the first branchial
arch anomalies and the first and second
branchial arches anomalies. They proposed
to use the term oculoauriculovertebral
‘‘spectrum.’’ Because there is no agreement
on minimal diagnostic criteria the phenotype overlaps many genetic and teratologic
syndromes. Most cases are sporadic, but familial instances have also been observed in
first-degree relatives. We report on a
mother and two of her children who have
the oculoauriculovertebral ‘‘spectrum.’’ The
mother had only auricular anomalies for
which she had plastic and reconstructive
surgery. Her first child, a girl, had a bilateral cleft lip and palate, a coloboma of upper
eyelid, facial asymmetry, and posteriorly
angulated ears. This child also had bilateral
vesicoureteral reflux. During the second
pregnancy fetal ultrasonographic examination performed at 18th week of gestation
showed a cleft lip and palate. At the thirtyfirst week of gestation, club feet, hypoplasia
of the left ear, hypoplasia of the left maxillary and mandibular arches, and left microphthalmia were evident. Examination of
this fetus confirmed ultrasonographic findings and demonstrated vertebral anomalies.
This familial observation confirmed variable expressivity of the oculoauriculovertebral anomaly with isolated microtia (the
mother), major malformations (the fetus),
and less serious anomalies (the first child)
and showed that this condition may be in-
*Correspondence to: Pr. C. Stoll, Service de Génétique, Médicale, Hopital de Hautepierre, Avenue Molière, 67098 Strasbourg
Cedex, France.
Received 11 August 1997; Accepted 24 February 1998
© 1998 Wiley-Liss, Inc.
herited as an autosomal or X-linked dominant condition. Am. J. Med. Genet. 78:345–
349, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: facioauriculovertebral syndrome; first branchial arch;
Goldenhar syndrome; hemifacial microsomia; oculoauriculovertebral spectrum;
otomandibular dysostosis;
second branchial arch
Gorlin et al. [1990] proposed to lump several conditions together, including facioauriculovertebral syndrome, hemifacial microtia, otomandibular dysostosis,
Goldenhar ‘‘syndrome,’’ the first branchial arch anomalies, and the first and second branchial arches anomalies. He proposed the term oculoauriculovertebral
spectrum. Because there is no agreement on minimal
diagnostic criteria, the phenotype overlaps many syndromes. Most cases are sporadic, but familial instances
have also been observed involving first-degree relatives. We report on a mother and two of her children
who had the oculoauriculovertebral syndrome.
Case 1
The proposita, a girl, was the first child of a 24-yearold mother and a 24-year-old father. She was the product of a pregnancy complicated by gestational diabetes
from 28 weeks of gestation (WG) that was treated by
diet only. At this stage of pregnancy a bilateral cleft lip
and a single umbilical artery were discovered by ultrasonographic examination. An amniocentesis was performed. Since the karyotype was normal (46,XX) the
parents decided to continue the pregnancy. The infant
was born at 39 WG. Birth weight was 2,300 g, length 44
cm, and occipitofrontal circumference (OFC) 32 cm.
The bilateral cleft-lip and single umbilical artery were
confirmed. There were no other anomalies.
At age 3 weeks results of evoked response audio-
Stoll et al.
metry were normal. Cleft lip and palate were repaired at
6 weeks, 4 1/2 months, and at 8 months. She had recurrent otitis and failure to thrive was noted. At 13
months of age weight was 6,000 g (<3rd centile), length
70 cm (3rd centile), and OFC 42 cm (3rd centile). Several episodes of fever occurred. Ureterocystography
showed bilateral ureterohydronephrosis with bilateral
lithiasis. Ureterolithotomy was performed at 14 and at
18 months. Stone analysis showed oxalic acid. Blood
oxalic acid concentration was increased at 9.8 ␮mol/
liter (N < 3). Blood creatinin and urea concentrations
were normal.
At 14 months, the evoked audiometry response was
normal on the right side but abnormal on the left side
(40 dB/conductive hearing impairment).
The child was seen when she was 19 months old.
Weight was 8.3 kg (<3rd centile), length 77 cm (25th
centile), and OFC 43 cm (<3rd centile). There was no
mental retardation. Blood oxalic acid concentration
was normal at 1.2 ␮mol/liter. She had scars of cleft lip
repair, telecanthus, upslanting palpebral fissures, epicanthus, coloboma of upper lid, sparse eyelashes in the
external third of the lid and thin hair. The philtrum
and the external ears were normal (Fig. 1A,B).
Case 2
At this time the mother was pregnant again. At 18
WG a bilateral cleft lip and palate was detected by
ultrasonographic examination of the fetus. Amniocentesis was performed showing a normal karyotype
(46,XY). The parents decided to continue the pregnancy. Again the mother had gestational diabetes from
26 WG that was treated by diet only. At 31 WG ultrasonographic examination showed club feet, hypoplasia
of the left external ear and of the left facial bones, and
left microphthalmia. Because there is no upper limit
for termination of pregnancy in France, the parents
decided to terminate the pregnancy.
Examination of the fetus (Fig. 2A,B) showed right
cleft lip, left cleft lip and palate, left microphthalmia,
hypoplasia of the left external ear, asymmetric bifid
tongue, hypoplasia of the left facial bones and left club
foot. Radiographic examination confirmed hypoplasia
of left mandibular and malar bones and vertebral
anomalies (Fig. 3).
The pedigree of the family is shown in Figure 4. The
family was unremarkable except that the mother had a
hypoplastic left external ear that was repaired by plastic and reconstructive surgery when she was 16 years
old. During this pregnancy the maternal grandmother
had no diabetes.
The oculoauriculovertebral ‘‘spectrum’’ (OAVS) includes a variable combination of microtia, hemifacial
microsomia, lateral facial cleft, epibulbar dermoid and
upper eye lid coloboma [Gorlin et al., 1990]. This condition is thought to affect structures developed from
the first and second branchial arches. According to Kumar et al. [1993] the minimum criteria for diagnosis of
OAVS are the presence of at least two of the following:
otic hypoplasia, hemifacial microsomia, lateral facial
cleft, epibulbar dermoid and/or upper eye lid coloboma,
and vertebral anomalies (fusion of vertebral body or
spine, and segmentation abnormality or ‘‘butterfly’’
Case 2 fulfilled all of the OAVS criteria. His sister,
case 1, had only two of these criteria: cleft lip and upper
eyelid coloboma. Therefore she can also be considered
as having OAVS. The mother of case 1 and case 2 had
only unilateral otic hypoplasia. According to the criteria of Kumar et al. [1993] she did not have the OAVS.
However, in the OAVS extreme variability of expression is characteristic [Gorlin et al., 1990]. Evaluation of
first-degree relatives is important to exclude mild fa-
Fig. 1. A, B: The proposita at age 19 months.
Oculoauriculovertebral Spectrum
Fig. 2. A, B: Brother of the proposita.
cial manifestations of the defect [Gorlin et al., 1990].
Marked facial asymmetry is present in 20% of the cases
but some degree of asymmetry is evident in 65%
[Smakel, 1986]. A high level of variability of expression
is also characteristic of eye involvement ranging from
anophthalmia to coloboma of the upper lid as in case 1
[Gorlin et al., 1990]. Ear abnormalities ranging from
anotia to an ill-defined mass of tissue that is placed
anteriorly and inferiorly to a mildly abnormal ear are
found in over 65% of the cases [Gorlin et al., 1990].
Moreover, isolated microtia is considered a microform
of OAVS [Bennum et al., 1985]. Spina bifida, hemivertebrae, butterfly, fused, and hypoplastic vertebrae,
Klippel-Feil anomaly, scoliosis and anomalous ribs
(agenesis, bifidity, fusion, supernumerary) occur in at
least 30% of the cases [Gorlin et al., 1990]. Case 2 had
major vertebral anomalies. His sister and his mother
Fig. 3. Radiograph of proposita’s brother showing anomalies of the left
mandibular-maxillary bones and of vertebrae.
did not have skeletal anomalies. This familial observation confirmed variable expressivity of the OAVS with
isolated microtia (the mother), major malformations
(the fetus), and less serious anomalies (the first child),
and showed that familial cases can be an autosomal
dominant trait.
The pathogenesis of OAVS is unknown. Its frequent
occurrence on one side of the face led to suggestion of
interference with vascular supply and focal hemorrhage in the developing first and second branchial arch
region [Poswillo, 1975]. Others have suggested impaired interaction of cranial neural crest cells with
branchial arch mesenchyme to be a factor in the causation of OAVS [Lammer et al., 1985]. The wide spectrum of anomalies including asplenia, pulmonary and
renal malformations, and other miscellaneous defects
in OAVS are difficult to explain on the basis of a localized disorder of blood flow or neural crest cell migration. The more generalized malformation in these instances suggests a disorder of blastogenesis.
Malformations presumed to be defects of early blastogenesis often occur with increased frequency in
monozygotic twinning (MZ) [Opitz, 1993]. Monozygotic
twins in OAVS have been frequently reported and a
total of 30 MZ twins and one set of triplets have been
collected in two distinct reviews [Boles et al., 1987;
Ryan et al., 1988]. Three other probable MZ twins have
been reported [Rodriguez et al., 1993]. Concordance for
Fig. 4.
Pedigree of the family.
Stoll et al.
the Goldenhar anomaly in certain MZ twins is ∼13%
[Zelante et al., 1997].
Diabetic embryopathy has among its clinical manifestations all the anomalies described in this family
[Sadler et al., 1995]. However, the teratogenicity of gestational (class A1 and class A2) diabetes mellitus remains under scrutiny [Kousseff, 1994]. However, clinical observations imply that gestational diabetes mellitus leads to a variety of malformations including
craniofacial anomalies [Kousseff, 1994]. In these cases
the mother had a gestational diabetes that appeared
late in pregnancy, at 28 and 26 WG, respectively. In
case 2 at 18 WG there was no diabetes. Moreover, the
maternal grandmother had no gestational diabetes
when she was pregnant with the mother of case 1 and
case 2. Therefore, gestational diabetes may be excluded
as a cause in this family.
It seems likely that several pathogenetic mechanisms are responsible for OAVS. Moreover, focal disturbed chondrogenesis of both the skull base and the
axial skeleton was shown recently in a case of OAVS
[Goret-Nicaise et al., 1997].
Most cases are sporadic but familial instances may
also be observed. Affected individuals in successive
generations have been observed [Cohen, 1971; Grabb,
1965; Herrmann and Opitz, 1969; Moeschler and Clarren, 1982; Regenbogen et al., 1982; Robinow et al.,
1986; Rollnick and Kaye, 1985; Saraux et al., 1963;
Setzer et al., 1981; Summitt, 1969; Taysi et al., 1983;
Thomas, 1980]. Affected sibs with normal parents have
also been reported [Grabb, 1965; Kirke, 1970; Krause,
1970; Saraux and Besnainou, 1965]. Consanguinity
was noted in a single sporadic instance [Pashayan et
al., 1970]. Although autosomal dominant and autosomal recessive inheritance have been suggested to explain the rare familial occurrence, heterogeneity is a
more likely explanation for most cases [Gorlin et al.,
1990]. Overall, it would be compatible with a low empiric recurrence risk of 2–3% [Grabb, 1965; Rollnick et
al., 1987]. However, some families [Herrmann and
Opitz, 1969; Regenbogen, et al., 1982; Summitt, 1969;
Gorlin et al., 1990] including the present family suggest that the disorder has an autosomal dominant
form. These families, which probably represent only
about 1–2% of the cases [Gorlin et al., 1990], have to be
taken into consideration for genetic counseling.
Specific expression of a particular class of homeobox
genes, Msx, appears to be critical for the differentiation
of first branchial arch ectoderm-mesenchyme leading
to various craniofacial structures [Takahashi et al.,
1992]. The Msx genes are also strongly expressed in
cephalic neural crest cells prior to migration of the cells
that contribute extensively to craniofacial development
[Hill et al., 1989; Lyons et al., 1992; Robert et al., 1989].
Manipulation of Msx genes in mice has resulted in major abnormalities of first branchial arch derivatives
[Forest-Potts and Sadler, 1997; Satokata and Maas,
1994]. Thus, homeobox genes, especially of the MSX
class, are candidate genes for OAVS, particularly in
familial cases [Sutphen et al., 1995]. This hypothesis
encompasses previous partial pathogenetic explanations for OAVS, including neurocristopathy and developmental field defects, and represents a unifying con-
cept regarding the wide spectrum of involvement in
OAVS. Mutations resulting in partial loss of function of
these genes could explain incomplete penetrance and
clinical variability occurring in individuals with differing genetic backgrounds.
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