Antenatal presentation of the oculo-auriculo-vertebral spectrum (OAVS)

We describe a fetus with abnormal ultrasound (US) imaging at 20 weeks showing hydrocephalus and radial aplasia. Post-mortem examination followed pregnancy termination and confirmed the diagnosis of oculo-auriculo-vertebral spectrum (OAVS). To delineate the pattern of prenatal features in OAVS, we reviewed 20 published fetuses showing abnormal US and/or magnetic resonance imaging. Gestational age at diagnosis ranged from 14 to 34-35 weeks. Cephalic abnormalities were found in only 52.4% (i.e., micro/anophthalmia, ear anomalies, hemifacial microsomia, and facial cleft). CNS defects occurred in 47.6% (i.e., hydrocephalus, occipital encephalocele, cerebellar hemisphere/vermis hypoplasia, and lipoma of the corpus callosum), together with abnormal amniotic fluid volume (AFV), either poly- or oligohydramnios. Nineteen percent had congenital heart disease, mainly atrioventricular septal defect. Hydroureteronephrosis, radial aplasia, lung, and kidney agenesis were additional findings. Recurrent patterns of anomalies included multiple asymmetric facial lesions (i.e., hemifacial microsomia, ipsilateral micro/anophthalmia, malformed ear) and CNS (particularly hydrocephalus) plus AFV abnormalities. In addition, prognosis of prenatally detected OAVS patients resulted more severe than generally observed in this condition.     

Overlap between VACTERL and hemifacial microsomia illustrating a spectrum of malformations seen in axial mesodermal dysplasia complex (AMDC)

We describe a male infant born to consanguineous healthy parents with multiple congenital anomalies of the skeleton and internal organs. His phenotype displays an overlap between VACTERL and hemifacial microsomia (oculo-auriculo-vertebral spectrum/OAV). In addition, striking asymmetry of the malformations further supports the classification as part of the "axial mesodermal dysplasia complex" (AMDC) which is supposed to arise from disturbed mesodermal cell migration during early blastogenesis. The present case was instructive to review the continuous spectrum of AMDC related anomalies.     

Two neighboring microdeletions of 5q13.2 in a child with oculo-auriculo-vertebral spectrum

We describe a patient with multiple congenital anomalies, including hemifacial microsomia, asymmetric macrostomia, dysplastic mandible, multiple preauricular tags, atresia of the external auricular canal, and vertebral anomalies, which coincide with oculo-auriculo-vertebral spectrum. G-banding (～850 band level) showed a normal 46, XY karyotype. A genome-wide screen for copy number variations (CNVs) using single nucleotide polymorphism (SNP) arrays revealed a 1 Mb and a 167 kb deletion both on chromosome 5q13.2, which were absent in the parents and in 27 controls. Sixteen genes were located in the deleted region, including BIR1C and OCLN, which are involved in apoptosis. Haploinsufficiency of these genes may be contributing to the phenotype in this patient. To our knowledge, there are no previous reports of this 5q13.2 deletion in a patient with oculo-auriculo-vertebral spectrum.     

Assocition between “plagiocephaly” and hemifacial microsomia

Fifteen of 155 patients with hemifcial microsomia were noted to have frontal plagiocephaly. These patients were examined to determine whether the frontal flattening was either secondary to deformation, the result of unilateral coronal synostosis, or part of the spectrum of hemifacial microsomia. The patients were categorized as having deformational versus synostotic frontal plagiocephaly by documenting position of the supraorbital rims, nasal root, ears, malar eminences, chin point, and the palperbral fissure height. Other extracraniofacial anomalies were also noted. Fourteen of 15(93%) patients had characteristic deformational abnormalities. Only 1/15(7%) had an elevated orbit, suggestive of unilateral coronal synostosis, but theis diagnosis was not radiographically confirmed. Frontal deformational plagiocephaly was ipsilateral to the side predominantly affreted by hemifacial microsomia in all but on e patient. Patients with hemifacial microsomia-deformational frontal plagiocephaly often had ipsilateral torticollis, cervical spine abnormalities, and anomalies outside the craniofacial region. This was in contrast to patients with deformational frontal plagiocephaly, in the absence of hemifacial microsomia, who frequently had ipsilateral torticollis but no other anomalies. This study also undrscores possible confusion in defferentiating hemifacial microsomia from deformaional hemifacial hypoplasia on physical exaination. The association of deformational frontal plagiocephaly and hemifacial microsomia belies a rigid etiologic label of deformational versus malformative anomaly. © 1993 Wiley-Liss, Inc.     

Meckel–Gruber Syndrome: a population-based study on prevalence,prenatal diagnosis,clinical features,and survival in Europe

Meckel–Gruber Syndrome is a rare autosomal recessive lethal ciliopathy characterized by the triad of cystic renal dysplasia, occipital encephalocele and postaxial polydactyly. We present the largest population-based epidemiological study to date using data provided by the European Surveillance of Congenital Anomalies (EUROCAT) network. The study population consisted of 191 cases of MKS identified between January 1990 and December 2011 in 34 European registries. The mean prevalence was 2.6 per 100 000 births in a subset of registries with good ascertainment. The prevalence was stable over time, but regional differences were observed. There were 145 (75.9%) terminations of pregnancy after prenatal diagnosis, 13 (6.8%) fetal deaths, 33 (17.3%) live births. In addition to cystic kidneys (97.7%), encephalocele (83.8%) and polydactyly (87.3%), frequent features include other central nervous system anomalies (51.4%), fibrotic/cystic changes of the liver (65.5% of cases with post mortem examination) and orofacial clefts (31.8%). Various other anomalies were present in 64 (37%) patients. As nowadays most patients are detected very early in pregnancy when liver or kidney changes may not yet be developed or may be difficult to assess, none of the anomalies should be considered obligatory for the diagnosis. Most cases (90.2%) are diagnosed prenatally at 14.3±2.6 (range 11–36) gestational weeks and pregnancies are mainly terminated, reducing the number of LB to one-fifth of the total prevalence rate. Early diagnosis is important for timely counseling of affected couples regarding the option of pregnancy termination and prenatal genetic testing in future pregnancies.     

Hemifacial microsomia and variants: pedigree data

Ear malformations occur per se or together with other congenital anomalies. Many syndromes with ear malformations have been described. We have studied propositi with hemifacial microsomia (HFM) or Goldenhar syndrome (GS), also called oculoauriculovertebral "dysplasia" (OAV). In addition to ear malformations some individuals may have a small and/or malformed mandible, epibulbar, or conjunctival lipodermoids and anomalies of the cervical spine. Other malformations may also be seen. At present, the cause of these disorders is unclear. Here we present pedigree data on 97 propositi, 44 of whom had a family history of the same or similar anomaly. First-degree relatives were most often affected (35/433, 8%). Of 176 sibs tabulated, 11 (6%) were considered affected. The pattern of occurrence in many families suggested multifactorial determination, although other interpretations are possible. The occurrence of differing anomalies within a family suggests that the disorders constitute a single entity. The most frequent anomaly was a mild ear malformation (preauricular node or tag). This suggests a broad phenotypic spectrum. These data are useful for purposes of genetic counseling.     

Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum

The oculo-auriculo-vertebral spectrum (OAVS) (OMIM % 164210) is a common developmental disorder characterized by hemifacial microsomia, epibulbar tumours, ear malformation and vertebral anomalies. Although rare familial cases suggest that OAVS has a genetic basis, no genetic defect has been identified so far. In a patient with OAVS and a chromosomal translocation t(4;8) we have found that the chromosome 4 breakpoint is 76.4 kb distal to the BAPX1 gene, which plays an essential role in craniofacial development. We did not detect any BAPX1 mutation in 105 patients, but observed a strong allelic expression imbalance (sAEI) in fibroblasts from five of 12 patients, but not in nine normal controls (Fisher's exact test, P=0.038). sAEI was de novo in one patient and inherited in two other patients. Prolonged cell culture or treatment with the histone deacetylase inhibitor Trichostatin A led to reactivation of the downregulated allele. We propose that epigenetic dysregulation of BAPX1 plays an important role in OAVS.     

Autosomal dominant microtia and ocular coloboma: new syndrome or an extension of the oculo-auriculo-vertebral spectrum?

The oculo-auriculo-vertebral (OAV) spectrum is an etiologically heterogeneous condition classically consisting of microtia, hemifacial microsomia, epibulbar dermoids, and vertebral anomalies. Other eye findings described in OAV include upper eyelid colobomas, ptosis, and varying degrees of microphthalmia or even anophthalmia. Iris and/or retinal colobomas have rarely been reported. We describe two familial cases of apparent OAV with ocular colobomas. We postulate that iris and/or retinal colobomas associated with OAV may represent a subgroup within the OAV spectrum with autosomal dominant inheritance, as in the families described herein. Since microtia can result from aberrant migration of neural crest cells into the first and second branchial arches during early embryonic development, and concomitant deficient neural crest migration into the developing eye can lead to ocular coloboma and or iris heterochromia, it may be that the altered gene or genes in our familial cases are involved with regulation of neural crest development.     

Oculoauriculovertebral abnormalities in children of diabetic mothers

Maternal diabetes is known to have teratogenic effects. Malformations including neural tube defects, caudal dysgenesis, vertebral defects, congenital heart defects, femoral hypoplasia, and renal anomalies are described in infants of diabetic mothers. However, craniofacial anomalies have rarely been reported in such infants. Here we document craniofacial anomalies of patients born to diabetic mothers. We describe two patient populations: individuals evaluated through our genetics services for multiple malformations and individuals identified through a database search in our craniofacial clinic. The first group consists of 14 individuals evaluated in our genetics clinics who were born to diabetic mothers and had craniofacial anomalies. The second group consists of seven individuals who were identified from a craniofacial database search of patients with hemifacial microsomia and who were born to diabetic mothers. Thus, both groups were born to diabetic mothers and had hemifacial microsomia (67%), microtia (52%), hearing loss (43%), epibulbar dermoids (24%), and fused cervical vertebrae (24%). Therefore, the teratogenic effects of maternal diabetes probably include such craniofacial malformations as the oculoauriculovertebral/Goldenhar complex. Infants of diabetic mothers should be evaluated for craniofacial anomalies. Conversely, mothers of infants with craniofacial anomalies should be evaluated for diabetes to aid in counseling concerning cause and recurrence risks.     

Goldenhar's Syndrome (oculo-auriculo-vertebral dysplasia) with congenital facial nerve palsy

Goldenhar's Syndrome (oculo-auriculo-vertebral dysplasia) is a wide spectrum of congenital anomalies that involves structures arising from the first and second branchial arches. In this report, a case of a male infant, with the features of hemi facial microsomia, anotia, vertebral anomalies, congenital facial nerve palsy and lagophthalmos is described. Although the syndrome itself is not uncommon, the presence of congenital facial nerve palsy, which has been reported in rare cases, prompted this case report.     

Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification

Oculo-auriculo-vertebral spectrum (OMIM164210) is a phenotypically and probably also a genetically heterogeneous disorder, characterized by anomalies of the ear (mostly microtia), hemifacial microsomia, and defects of the vertebral column. Associated clinical findings include anomalies of the eye and brain, and developmental delay. We have evaluated the clinical data and photographs of 53 unrelated patients with OAVS, all presenting with either isolated microtia or preauricular tags in association with hemifacial microsomia as minimal diagnostic criteria; five had a positive family history for OAVS. Based on the main clinical findings and unilateral or bilateral involvement, we have developed a new classification system for OAVS, consisting of six subgroups. There is a statistically significant correlation between the subgroup and number of associated clinical findings, and a statistically significant difference regarding prognosis in uni- and bilaterally affected patients, suggesting that this classification is clinically relevant to the categorization of patients with OAVS. The newly developed scoring system (two points for each main clinical finding and one for each associated clinical finding) presented here, also aids prognosis, especially for delay of motor development and brain anomalies, and statistical analysis revealed significant clustering between different clinical findings of OAVS confirming the clinical impression previously published by several authors.     

Enamel defects: a developmental marker for hemifacial microsomia

We have observed primary tooth enamel defects in 4 children with hemifacial microsomia. The distribution of enamel defects was concordant with the laterality of craniofacial anomalies in these patients and was most pronounced on the maxillary incisors. Since the location of enamel defects serves as a chronicle for the events of tooth formation, we propose that enamel defects may serve as a developmental marker for the events leading to hemifacial microsomia.     

A unique case of progressive hemifacial microsomia or Parry-Romberg syndrome associated with limb and brain anomalies with normal neurological findings: A review of the literature

In this report, we describe an unusual case of progressive hemifacial atrophy or Parry-Romberg syndrome in a 10-year-old girl with progressive hemifacial microsomia and limb anomalies who had brain magnetic resonance imaging (MRI) findings of white matter hyper-intensities. Patients typically present with neurological manifestations such as epilepsy, facial pain, and migraines and ophthalmological symptoms in conjunction with white matter lesions. The patient demonstrated normal cognition and psychomotor development despite the presence of white matter lesions in her frontal lobe that is commonly associated with neurological symptoms. This report brings attention to the complicated relationship between facial, limb and brain imaging findings in Parry-Romberg syndrome and differentiates it from hemifacial microsomia syndrome.     

Three-generation family with resemblance to Townes-Brocks syndrome and Goldenhar/oculoauriculovertebral spectrum

The Townes-Brocks syndrome (TBS) is comprised of a triad including characteristic anal, thumb, and ear anomalies. There are many other organ system abnormalities which may be present. However, the literature does not emphasize craniofacial findings except with reference to the typical ear configuration. A three-generation family is described in which craniofacial manifestations were prominent and a Goldenhar-like condition was considered as the most likely diagnosis. However, with the recent birth of an affected male who had an imperforate anus, the diagnosis of TBS was also considered. The family manifests a variety of Goldenhar-like findings, including epibulbar dermoids, hemifacial microsomia, preauricular tags, macrostomia, and micrognathia in addition to classical ear, radial, and anal findings of TBS. We report on this family to point out a possible biological relationship of these two conditions. © 1996 Wiley-Liss, Inc.     

Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy

This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000–2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71–2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46–0.64), 1.04 (95% CI 0.92–1.17) and 0.30 (95% CI 0.24–0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19–5.36 per 1000), proportion prenatally diagnosed (50–100%) and proportion of prenatally diagnosed resulting in TOPFA (13–67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.     

Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome)

The oculo-auriculo-vertebral spectrum (OAVS) is a non-random association of microtia, hemifacial microsomia with mandibular hypoplasia, ocular epibulbar dermoid, and cervical vertebral malformations. Congenital heart defects (CHDs) have been reported in 5-58% of the patients. We analyze the frequency and anatomic features of CHD in a series of 87 patients with OAVS examined between January 1990 and February 2007 with normal chromosomes, ranging in age between 0.1 and 16.8 years. A twin pregnancy occurred in eight cases (dizygotic in six cases and monozygotic in two). CHDs were diagnosed in 28/87 (32%) patients, and classified into categories of postulated developmental mechanisms including 9 (32%) atrial and ventricular septal defects, 11 (39%) conotruncal defects, 4 (14%) targeted growth defects, two (7%) with situs and looping defects, one (4%) with a left-sided obstructive lesion and one (4%) with patent ductus arteriosus. As noted in other series, the most common individual CHDs were ventricular septal defect (six patients) and tetralogy of Fallot (TOF) (classic or with pulmonary atresia) (six patients). Comparing the frequencies of CHDs groups observed in the OAVS patients with the findings of the Emilia-Romagna Registry which ascertained CHDs prevalence in the general population, conotruncal defects, targeted growth defects, and heterotaxia were significantly associated with OAVS.     

Twenty-year trends in the prevalence of Down syndrome and other trisomies in Europe: impact of maternal age and prenatal screening

This study examines trends and geographical differences in total and live birth prevalence of trisomies 21, 18 and 13 with regard to increasing maternal age and prenatal diagnosis in Europe. Twenty-one population-based EUROCAT registries covering 6.1 million births between 1990 and 2009 participated. Trisomy cases included live births, fetal deaths from 20 weeks gestational age and terminations of pregnancy for fetal anomaly. We present correction to 20 weeks gestational age (ie, correcting early terminations for the probability of fetal survival to 20 weeks) to allow for artefactual screening-related differences in total prevalence. Poisson regression was used. The proportion of births in the population to mothers aged 35+ years in the participating registries increased from 13% in 1990 to 19% in 2009. Total prevalence per 10 000 births was 22.0 (95% CI 21.7–22.4) for trisomy 21, 5.0 (95% CI 4.8–5.1) for trisomy 18 and 2.0 (95% CI 1.9–2.2) for trisomy 13; live birth prevalence was 11.2 (95% CI 10.9–11.5) for trisomy 21, 1.04 (95% CI 0.96–1.12) for trisomy 18 and 0.48 (95% CI 0.43–0.54) for trisomy 13. There was an increase in total and total corrected prevalence of all three trisomies over time, mainly explained by increasing maternal age. Live birth prevalence remained stable over time. For trisomy 21, there was a three-fold variation in live birth prevalence between countries. The rise in maternal age has led to an increase in the number of trisomy-affected pregnancies in Europe. Live birth prevalence has remained stable overall. Differences in prenatal screening and termination between countries lead to wide variation in live birth prevalence.     

Oculo-Auriculo-Vertebral complex and uncommon associated anomalies: Report on 8 unrelated Brazilian patients

We report on 8 Brazilian patients with the oculo-auriculo-vertebral (OAV) complex with associated uncommon anomalies of hydrocephalus, porencephalic cyst, hand abnormalities, terminal/paraxial hemimelia, Klippel-Feil anomaly, Rokitansky sequence, fibrous dysplasia, and dextrocardia. Our patients show that in some instances a definite diagnosis can be difficult within the wide clinical picture of the OAV complex. © 1992 Wiley-Liss, Inc.     

Epidemiology of orofacial clefts in a Danish county over 35 years – Before and after implementation of a prenatal screening programme for congenital anomalies

In 2004 the Danish National Board of Health changed its screening recommendations. Since 2005 a first trimester screening for Down syndrome and a prenatal ultrasound screening for congenital anomalies in the second trimester of pregnancy has been offered to all pregnant women.The aim of this study was to describe the prevalence of cleft lip with or without cleft palate and cleft palate in a Danish area and to describe associated anomalies and the development in prenatal diagnosis over time. The study was based on data from the EUROCAT Registry for Funen County. The registry is based on multiple data sources and includes information about live births, fetal deaths with a gestational age >20 weeks and terminations of pregnancy after prenatal diagnosis of severe fetal anomaly. The study included all fetuses/infants out of a population of 182,907 births diagnosed with orofacial clefts born between 1980 and 2014. There were 271 cases diagnosed with cleft lip with or without cleft palate and 127 cases diagnosed with cleft palate, giving a prevalence of 14.8 per 10,000 births for cleft lip with or without cleft palate and 6.9 per 10,000 births for cleft palate. There were no significant changes in prevalence over time for the two anomalies, calculated with and without inclusion of genetic and chromosomal cases. Overall 66 cases were diagnosed prenatally (17% of total). For isolated cleft lip with or without cleft palate none of the 157 cases born before 2005 were diagnosed prenatally compared to 34 of 58 cases (59%) born in 2005–2014 (p?<?0.01). The proportion of liveborn infants with multiple congenital anomalies also changed after 2005 with 15% (39/266) of all liveborn infants with orofacial clefts born 1980–2004 having multiple anomalies compared to 7% (7/96) in 2005–2014 (p?<?0.05).The implementation of the new screening programme in 2005 has given a major change in prenatal detection rate and reduced the proportion of liveborn infants with orofacial clefts classified as multiple congenital anomaly cases. The prevalence of cleft lip with or without cleft palate was higher than reported from many other countries.