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 1 Service de Génétique Médicale, Centre Hospitalo-Universitaire, Strasbourg, France Maternité, Centre Hospitalo-Universitaire, Strasbourg, France 3 Institut d’Anatomie Pathologique, Centre Hospitalo-Universitaire, Strasbourg, France 2 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 anomaly INTRODUCTION Gorlin et al.  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. CLINICAL REPORTS 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- 346 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. DISCUSSION 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.  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’’ vertebra). 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.  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 347 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. 348 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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