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Background Craniofacial microsomia (CFM), also known as the oculo‐auriculo‐vertebral spectrum, comprises a variable phenotype with the most common features including microtia and mandibular hypoplasia on one or both sides, in addition to lateral oral clefts, epibulbar dermoids, cardiac, vertebral, and renal abnormalities. The etiology of CFM is largely unknown. The MYT1 gene has been reported as a candidate based in mutations found in three unrelated individuals. Additional patients with mutations in this gene are required to establish its causality. We present two individuals with CFM that have rare variants in MYT1 contributing to better understand the genotype and phenotype associated with mutations in this gene. Methods/Results We conducted genetic analysis using whole‐exome and ‐genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants. Sanger sequencing was used to confirm these mutations. Conclusion We identified two additional individuals with CFM who carry rare variants in MYT1, further supporting the presumptive role of this gene in the CFM spectrum., We conducted genetic analysis using whole‐exome and ‐genome sequencing in 128 trios with CFM. Two novel MYT1 mutations were identified in two participants, further supporting the presumptive role of this gene in the CFM spectrum.

A 7-month-old domestic medium hair cat presented with facial asymmetry affecting the bony and soft tissue structures of the right side of the head including the maxilla, nose, eye and pinna of the ear. Additionally, neurological dysfunction of the facial and vestibulocochlear nerves on the affected side was present. A congenital malformation affecting the first and second embryologic pharyngeal arches was suspected. This is the first case of hemifacial microsomia of likely congenital origin reported in a cat.

Reconstructing congenital auricular defects due to hemifacial microsomia (HFM) is often required to deal with low hairline and defects of the temporal fascia/muscular systems. In this report, we present two cases of HFM patients (16-year-old and 20-year-old) with positional anomaly of the remnant lobule and 95% low hairline, who were treated with serratus anterior fascial flap (SFF) at the second stage of auricular construction. At the first stage, 3D costal cartilage framework was placed following the removal of hair-bearing skin, and was resurfaced with the pericranial flap. At the second stage, ear elevation was performed with cartilage block grafting, then the free SFF was used to construct cephaloauricular sulcus because of local fascial defect. The pedicles of SFF, subscapular vessels were anastomosed to the cervical vessels. No complications developed during the follow-up period of 4 years in both cases and projections of the constructed ears were satisfactorily maintained. The free SFF is naturally thin and flexible with sufficient circulation and it may be an alternative to temporo-parietal fascia flap in complicated microtia construction in HFM. © 2016 Wiley Periodicals, Inc. Microsurgery 37:436-441, 2017.

Background Craniofacial microsomia (CFM) is a congenital condition with wide phenotypic variability, including hypoplasia of the mandible and external ear. We assembled a cohort of children with facial features within the CFM spectrum and children without known craniofacial anomalies. We sought to develop a standardized approach to assess and describe the facial characteristics of the study cohort, using multiple sources of information gathered over the course of this longitudinal study and to create case subgroups with shared phenotypic features. Methods Participants were enrolled between 1996 and 2002. We classified the facial phenotype from photographs, ratings using a modified version of the Orbital, Ear, Mandible, Nerve, Soft tissue (OMENS) pictorial system, data from medical record abstraction, and health history questionnaires. Results The participant sample included 142 cases and 290 controls. The average age was 13.5 years (standard deviation, 1.3 years; range, 11.1-17.1 years). Sixty-one percent of cases were male, 74% were white non-Hispanic. Among cases, the most common features were microtia (66%) and mandibular hypoplasia (50%). Case subgroups with meaningful group definitions included: (1) microtia without other CFM-related features (n = 24), (2) microtia with mandibular hypoplasia (n = 46), (3) other combinations of CFM- related facial features (n = 51), and (4) atypical features (n = 21). Conclusion We developed a standardized approach for integrating multiple data sources to phenotype individuals with CFM, and created subgroups based on clinically-meaningful, shared characteristics. We hope that this system can be used to explore associations between phenotype and clinical outcomes of children with CFM and to identify the etiology of CFM. Birth Defects Research (Part A) 106:915-926, 2016.© 2016 Wiley Periodicals, Inc.

Craniofacial microsomia (CFM) is a complex condition associated with microtia, mandibular hypoplasia, and preauricular tags. It is the second most common congenital facial condition treated in many craniofacial centers and requires longitudinal multidisciplinary patient care. The purpose of this article is to summarize current recommendations for clinical management and discuss opportunities to advance clinical research in CFM.

An array-CGH on 19-year-old male showed a proximal 1.11 Mb duplication and a distal 1.7 Mb deletion of 22q11.2 regions flanking the Velocardiofacial/DiGeorge syndrome region that remained intact. FISH analyses revealed both abnormalities to be on the same homolog 22. This double rearrangement lead to the co-existence of two syndromes: Cat eye and distal 22q11.2 microdeletion syndromes with a rare associated phenotype of oculo-auriculo-vertebral spectrum (OAVS). A review of the literature indicates that this is the second report of a proximal duplication and the fifth report of a distal deletion and OAVS suggestive of a possible OAVS candidate gene in this region.

To describe pediatric costochondral graft reconstruction of the absent mandibular condyle and to report the short-term and long-term outcomes and complications associated with performing this procedure in young children.Case series with a retrospective chart review.Pediatric otolaryngology clinic and tertiary children's hospital in a metropolitan area.All children treated for an absent mandibular condyle with a costochondral graft at Children's Hospitals and Clinics of Minnesota were identified from 2002 through 2011, and a retrospective chart review was performed.Ten patients aged 3 to 11 years were identified. The most common diagnosis, in 8 of 10 patients, was oculo-auriculo-vertebral syndrome. Three of the patients had a tracheostomy, of which 1 was decannulated following condylar reconstruction. Functional improvement, defined as improved symmetry, chewing, or better oral opening, was observed in 8 of 10 patients. Five patients have required no further surgeries to date, with a mean follow-up time of 3.9 years. Severe overgrowth of the graft was noted in 1 case, and partial or complete resorption of the graft was also noted in 3 cases. Overgrowth occurred after 5.7 years, whereas resorption occurred after an average of 2.5 years.Costochondral grafts are an excellent surgical treatment option for children with severe mandibular malformations. Short-term results show particular improvement in function and mandibular alignment. The mean follow-up time with no revision surgery was substantial and indicates that rib grafting is a good addition to the armamentarium of treatment for this patient population.

Objecives The use of three-dimensional computed tomography (3D-CT) analyses represents a substantial improvement in planning treatment. The aim of this study is to introduce a new three-dimensional (3D) analysis of clinical value for evaluating asymmetry in cases of craniofacial syndrome. Subjects and methods Virtual 3D models were reconstructed from CT images of 62 normal subjects (35 males and 27 females), more than 18 years old. Measurements of asymmetrical skeletal and dentoalveolar relationships were evaluated and standardized data obtained. The feasibility of the new 3D craniofacial analysis was then evaluated on one patient with severe maxillomandibular asymmetry in the form of hemifacial microsomia. Results Standardized 3D data from the analysis were obtained and classified into 6 maxillary measurements, eight mandibular measurements and seven dentoalveolar process measurements. No significant differences were found between males and females (U-Mann–Whitney test, P > 0.05). Useful data of clinical value was provided for planning orthodontic and surgical treatment of asymmetries, as well as a diagnostic chart. Conclusion This method is useful for the clinical evaluation of asymmetry in craniofacial syndromes. The use of 3D analysis facilitates surgical and orthodontic treatment planning.

Microtia is a congenital anomaly of the ear that ranges in severity from mild structural abnormalities to complete absence of the ear, and can occur as an isolated birth defect or as part of a spectrum of anomalies or a syndrome. Microtia is often associated with hearing loss and patients typically require treatment for hearing impairment and surgical ear reconstruction. The reported prevalence varies among regions, from 0.83 to 17.4 per 10,000 births and the prevalence is considered to be higher in Hispanics, Asians, Native Americans, and Andeans. The etiology of microtia and the cause of this wide variability in prevalence are poorly understood. Strong evidence supports the role of environmental and genetic causes for microtia. Although some studies have identified candidate genetic variants for microtia, no causal genetic mutation has been confirmed. The application of novel strategies in developmental biology and genetics has facilitated elucidation of mechanisms controlling craniofacial development. In this paper we review current knowledge of the epidemiology and genetics of microtia, including potential candidate genes supported by evidence from human syndromes and animal models. We also discuss the possible etiopathogenesis in light of the hypotheses formulated to date: neural crest cells disturbance, vascular disruption and altitude.

The availability of microarray technology has led to the recent recognition of copy number abnormalities of distal chromosome 22q11.2 that are distinct from the better-characterized deletions and duplications of the proximal region. This report describes five unrelated individuals with copy number abnormalities affecting distal chromosome 22q11.2. We report on novel phenotypic features including diaphragmatic hernia and uterine didelphys associated with the distal microdeletion syndrome; and frontomedial polymicrogyria and callosal agenesis associated with the distal microduplication syndrome. We describe the third distal chromosome 22q11.2 microdeletion patient with Goldenhar syndrome. Patients with distal chromosome 22q11.2 copy number abnormalities exhibit inter- and intra-familial phenotypic variability, and challenge our ability to draw meaningful genotype-phenotype correlations.

In 1985, Mardini and Nyhan described three patients from consanguineous families with unilateral complete/partial lung agenesis, congenital cardiac defects, and ipsilateral thumb anomalies. Although there have been many reports of lung agenesis with other malformations, especially hemifacial microsomia and radial ray anomalies, very few demonstrate this triad of defects. We describe three patients with the Mardini-Nyhan association which may represent a distinct entity, although this remains uncertain at present. A fourth patient is also described, the sister of one of the other patients, with complex congenital cardiac disease and bilateral lung lobation abnormalities. This is the first reported incidence of a possible recurrence within a family and suggests, together with the consanguinity observed by Mardini and Nyhan, that recessive inheritance should be considered in genetic counseling for this disorder.

Craniofacial deformities (CFDs) frequently accompany midfacial hypoplasia. The authors evaluated characteristics of maxillary sinuses that had CFDs with variable degrees of midfacial hypoplasia.Cross-sectional survey with chart review.Department of Plastic and Reconstructive Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.We investigated 40 patients with CFDs having midfacial hypoplasia. Study group 1 (SG 1) consisted of eight patients with Crouzon syndrome (16 maxillary sinuses). Study group 2 (SG 2) consisted of 10 patients with midfacial hypoplasia after palatoplasty (20 maxillary sinuses). Study group 3 (SG 3) consisted of 22 patients with Pruzansky grade I hemifacial microsomia (22 maxillary sinuses on the affected sides). Data on volume and three-dimensional distances (height, width, and depth) from computed tomography were collected and compared with each corresponding control group. Correlation coefficient between volume and the three distances was also calculated.The volume, height, width, and depth of the maxillary sinus were significantly decreased in SG 1 (P0.01). In SG 2, only the depth was significantly decreased (P0.05). In SG 3, there were no significant differences in any parameters. A multiple-regression analysis between the volume and the three distances showed a statistically significant relationship for width in SG 1, width and height in SG 2, and all distances in SG 3.There were differences in the structure of the maxillary sinuses among patients with different CFDs.

Tetrasomy 9p is a rare syndrome that has now been described in nearly a score of cases. We present a new case of i(9p) that presented to us early in infancy with significant dysmorphological features, including growth retardation, psycho-motor delay, hemifacial microsomia, auditory canal atresia, high-arched palate, bulbous nose, strabismus, epicanthic folds, congenital heart disease, dislocated hips, hypoplastic external genitalia, simian palmar creases, dysplastic nails and small digits. Chromosomal analysis revealed a 47,XX,idic(9)(q12) karyotype on GTG- and C-banding studies on peripheral blood lymphocytes. Fluorescent in situ hybridization (FISH) studies confirmed the origin of the extra chromosome. A review of the literature and a comparative analysis of the several well-documented cases of i(9p) revealed a pattern of recurring features, including ear malformations, skeletal and joint problems (especially dislocations), hypoplasia of nails and digits, palatal abnormalities, hypertelorism, urogenital anomalies and developmental retardation. In the light of this analysis, we feel that tetrasomy 9p will soon be considered a clinically recognizable syndrome.

A family with oculoauriculovertebral dysplasia is reported in which there are nine affected members spanning three consecutive generations. It is concluded that despite the known genetic heterogeneity in this disorder, there is an autosomal dominant form. Thus, genetic counseling can only be given after proper completion of all the necessary clinical and family studies.

An infant with the phenotype of hemifacial microsomia is presented. He was also found to have the karyotype of a sex chromosome abnormality.

Hemifacial microsomia is a congenital asymmetry of the lower face that may be associated with other cranial and extracranial anomalies. The variability of its severity, and wide range of anomalies that have been reported with it in some cases has resulted in these composite manifestations being given a number of names, including oculo-auriculo-vertebral spectrum (OAVS). Etiology is often stated to be a perturbation of embryonic blood flow in the developing region, although other factors may also play a role in some cases. Depending on what is considered to be minimum criteria for affected classification, what is often to be presumed to be a sporadic event in a family may be the more severe manifestation of a familial condition. Etiological factors are clearly heterogeneous, the investigation of which is confounded by not only the lack of a refined affected phenotype, but also the apparent influence of genetic factors in some instances that directly influence phenotype perhaps through alteration of mesodermal development, or indirectly through increased susceptibility to vascular disruption. Future studies likely to advance knowledge in this area will need to incorporate an analysis of who may be minimally affected in families, so that advances in genotyping will have greater power to distinguish genetic factors that may influence OVAS through interaction with environmental factors in particular families. The same genetic-environmental factors and or etiological mechanisms may then be investigated in apparently sporadic cases.

Objective To investigate the incidence of unilateral hypodynamic palate (UHP) and velopharyngeal insufficiency (VPI) in hemifacial microsomia (HFM), and to determine the dysmorphic manifestations having significant associations with UHP/VPI in HFM. Study design This was a nonrandomized study of 48 patients with unilateral HFM without cleft palate. The correlation between each anomaly and UHP/VPI was analyzed statistically. In addition, we observed 4 HFM patients with cleft palate to examine the influence on cleft palate speech. Results The incidence of UHP in HFM was 50.0% and that of VPI was 14.6%. All the VPI patients had UHP. Severe micrognathia and soft tissue deficiency, macrostomia, and mental retardation were significant risk factors for developing VPI in HFM. Moreover, UHP exacerbated speech in HFM with cleft lip and palate. Conclusions Significant correlations were detected between VPI and HFM. This finding should be helpful in the overall management of HFM.

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.

The SALL4 gene encodes a putative zinc finger transcription factor and is located on chromosome 20q13.13-13.2. Mutations in SALL4 have been identified in patients with Okihiro syndrome, which is characterized by radial ray anomalies associated with a Duane anomaly. Here, we report an unusual family in which affected persons show an extremely variable phenotype consistent with either Okihiro syndrome, hemifacial microsomia, or isolated Duane anomaly. A novel nonsense mutation in the SALL4 gene was detected in all affected family members and obligate carriers. This mutation is located in exon 3, only 29 bp 5′ of the most 3′ intron, and would therefore be expected to escape the nonsense mediated mRNA decay pathway, which might explain the phenotypic variablity and mild degree of limb involvement. © 2006 Wiley-Liss, Inc.

Pseudoephedrine is contained in decongestants such as the Sudafed line of products. It is an alpha-adrenergic receptor agonist, which causes blood vessel constriction, including the therapeutic effect of reducing airflow resistance in the nasal cavity. Pseudoephedrine is one of the most commonly used medications in pregnancy, with an estimated 25% of women exposed. It has been demonstrated that alpha-adrenergic receptor agonists slow uterine blood flow, but their effects have not been studied in relation to most reproductive outcomes in animals or humans. Two analyses of health maintenance organization pharmacy data identified 9 malformed infants among 902 first-trimester pseudoephedrine exposures, suggesting no association with birth defects overall; however, studies of such data sets often lack sufficient power to identify risks for specific birth defects. The related compounds, epinephrine, ephedrine, and phenylephrine, have been associated with hemorrhages and cardiovascular and limb malformations in animal models. Risk of ventricular septal defects was associated with decongestant use in pregnant women in 1 recent study. The vasoconstrictive effects of these drugs raise the hypothesis that their use in early pregnancy might increase the risk of vascular disruption defects. Case-control studies, which often do have power to identify risks related to specific birth defects, have explored this hypothesis. Decongestant use in the first trimester has been associated with small increases in risks of 3 defects thought to arise, at least in some instances, from vascular disruption-gastroschisis, small intestinal atresia, and hemifacial microsomia. These findings are somewhat consistent in terms of magnitude of effect and suggest that risks are even greater among women also exposed to the vasoconstrictive effects of cigarette smoking. There are, however, limitations to these studies, including the possibilities of inaccurate recall of exposures and confounding by indication. In addition, the majority of decongestant use is in oral form and the question of whether intranasal formulations carry risk has not been adequately addressed.

Objective To define parameters that enable the objective diagnosis of anomalies of the position and/or size of the fetal mandible in utero. Design Fetuses at 18–28 gestational weeks were examined by two- and three-dimensional ultrasound. The study included normal fetuses and fetuses with syndromes associated with known mandible pathology: Pierre Robin sequence or complex (n = 8); hemifacial microsomia (Treacher–Collins syndrome, n = 3); postaxial acrofacial dysostosis (n = 1). Fetuses with Down syndrome (n = 8) and cleft lip and palate without Pierre Robin sequence or complex (n = 18) were also studied. Retrognathia was assessed through the measurement of the inferior facial angle, defined on a mid-sagittal view, by the crossing of: 1) the line orthogonal to the vertical part of the forehead at the level of the synostosis of the nasal bones (reference line); 2) the line joining the tip of the mentum and the anterior border of the more protruding lip (profile line). Micrognathia was assessed through the calculation of the mandible width/maxilla width ratio on axial views obtained at the alveolar level. Mandible and maxilla widths were measured 10 mm posteriorly to the anterior osteous border. Results In normal fetuses, the inferior facial angle was constant over the time span studied. The mean (standard deviation) value of the inferior facial angle was 65.5 (8.13)°. Consequently, an inferior facial angle value below 49.2° (mean—2 standard deviations) defined retrognathism. All the fetuses with syndromes associated with mandible pathology had inferior facial angle values below the cut-off value. Using 49.2° or the rounded-up value of 50° as a cut-off point, the inferior facial angle had a sensitivity of 1.0, a specificity of 0.989, a positive predictive value of 0.750 and a negative predictive value of 1.0 to predict retrognathia. In normal fetuses, the mandible width/maxilla width ratio was constant over the time interval studied. The mean (standard deviation) value was 1.017 (0.116). Consequently, a mandible width/maxilla width ratio

The correction of facial asymmetry in complex hemifacial microsomia presents a challenging problem for reconstructive surgeons. Numerous microsurgical flaps have been introduced for reconstruction of facial asymmetry. This article reports our experience in facial soft tissue reconstruction with microsurgical anterolateral thigh fasciocutaneous flap transfer in six patients with hemifacial microsomia. This flap, which has a reliable vascular pedicle and relatively thin pliable soft tissue, can provide an ideal treatment for facial asymmetry in hemifacial microsomia.

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.

The experience with free flaps and conventional reconstructive procedures for 118 patients with Rombergapos;s disease and hemifacial microsomia over a 10-year period is presented. The groin free flap was used most frequently for patients with Rombergapos;s disease, whereas the scapular free flap was used for patients with hemifacial microsomia. The rectus abdominis or the latissimus dorsi free flap was chosen only when additional volume was required. To achieve better contour, secondary procedures, such as defatting the flap, pedicled temporal fascial flaps, cartilage and bone grafts, orthognathic surgery, and bone distraction were performed in severe cases. For patients with Rombergapos;s disease, excellent results were achieved in 35% (n = 28) of mild cases, in 72% (n = 27) out of 38 moderately and in 41% (n = 5) out of 12 severely affected patients. In hemifacial microsomia group (n = 40) excellent results were obtained in 66% of cases. © 2000 Wiley-Liss, Inc. MICROSURGERY 20:167–172 2000

A rare pathological mandible, manifesting bilateral absence of the condyles, is discussed. The pathology was identified as hemifacial microsomia. The mandible, dated to the Byzantine period in Israel, manifests bilateral aplasia of the condyles and extreme shortness, but normal width, of the body. The extremely well-developed coronoid process, the grooved masseter insertion area, and the manifestation of a medial pterygoid tubercle (MPT) suggest hypertrophy of the occlusal muscles. The presence of a large MPT is considered a Neanderthal autapomorphy. Studying the biomechanic forces acting on the deformed mandible in hemifacial microsomia patients may shed light on the mastication process in Neanderthals.

Two hundred free flaps for reconstructing the head and neck regions in 192 patients with non-oncological pathology were studied. Pathological entities included Romberg's disease, hemifacial microsomia, acquired facial palsy, trauma, and burn sequelae. Indications for selecting a specific free flap for reconstructing each case, details of anastomoses, reexploration, flap success, operative time, length of hospitalization, and complications were studied. The long-term results of cosmetic and function were also obtained. Patient age ranged from 6 to 40 years. The most common diagnosis was Romberg's disease 39% (n = 75), followed by hemifacial microsomia 20% (n = 40). The free flap most frequently used was the scapular 32% (n = 64), followed by the groin free flap 21% (n = 42). A total of 190 flaps (95%) were successful, whereas only 10 (5%) were lost. The mean operative time was 5:30 h and the average hospital stay was only 6 days. There were no major complications and no deaths in the study group. The patients were followed for at least 1 year in all cases. It is concluded that free flaps are safe and reliable procedures for reconstructing complex head and neck non-oncological defects.

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 thirty-first 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 inherited as an autosomal or X-linked dominant condition.

Pulmonary agenesis is a rare malformation that can be isolated or associated with other anomalies. We became interested in pulmonary agenesis after evaluation of a child with right pulmonary agenesis, an unlobed left lung, bilateral cleft lip and palate, maxillary and mandibular hypoplasia, bilateral microtia, bilateral radial ray hypoplasia, horseshoe kidney, and complex congenital heart disease. A review of the occurrence of pulmonary agenesis with other congenital anomalies uncovered a striking association with ipsilateral radial ray defects and/or hemifacial microsomia. The presence of bilateral facial or radial ray anomalies was indicative of bilateral pulmonary involvement. A review of the cases of pulmonary agenesis and associated anomalies at the Children's Hospital and Medical Center confirmed the association of pulmonary agenesis and ipsilateral involvement of face and/or radial ray. The association of pulmonary agenesis and ipsilateral malformations may shed light on its pathogenesis. Although the cause of these associated anomalies remains unclear, abnormalities in the development of the aortic arches during embryogenesis is an attractive hypothesis.

BACKGROUND Concerns have been raised that more infants with Goldenhar syndrome were born to U.S. Gulf War veterans than expected. Goldenhar syndrome is considered a variant of the malformation hemifacial microsomia (HFM). We used data collected from a case-control study of HFM to estimate risk in relation to parental military service and, in particular, Gulf War service. METHODS Cases with HFM who were three years old or younger were identified at craniofacial clinics in 24 U.S. cities and matched to controls by age and pediatrician. The mothers of 232 cases and 832 controls were interviewed between April 1996 and November 2002 about pregnancy events and exposures, including military service before the child was born and Gulf War deployment five to 11 years before the child was born. Odds ratios were adjusted for family income, race, and body mass index in early pregnancy. RESULTS Four (1.7%) case mothers and 10 (1.2%) control mothers served in the military. Among fathers, 30 (12.9%) cases and 100 (12.0%) controls served in the military. The parents of four (1.7%) cases and 23 (2.8%) controls served in the Gulf War (multivariate adjusted odds ratio [MVOR], 0.8; 95% confidence interval [CI], 0.3–2.3). All four case parents with Gulf War service were in the Army compared to 9 of 23 control parents. The MVOR for parental Gulf War service in the Army was 2.8 (95% CI, 0.8–9.6). The corresponding MVOR for any parental service in the Army was 2.4 (95% CI, 1.4–4.2), based on 22 cases and 45 controls. CONCLUSIONS The risk of HFM in offspring was not associated with parental service in the Gulf War five to 11 years before birth. The odds ratio for service in the Army was independent of Gulf War service and was associated with a modest increase in risk. Our findings for service in the Army may be confounded by unmeasured lifestyle factors. Birth Defects Research (Part A), 2005. © 2005 Wiley-Liss, Inc.

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.

Oculoauriculovertebral spectrum, or Goldenhar syndrome, is characterized by varying degrees of prevalently unilateral underdevelopment of craniofacial structures (orbit, ear, mandible) and spinal anomalies. We report the prenatal ultrasonographic diagnosis made at 24 weeks' gestation in a family with a negative history. The prenatal diagnosis was suspected due to the presence of marked hemifacial microsomia and moderate ipsilateral cerebellar hemisphere hypoplasia in the absence of facial clefting.

We studied the neurodevelopmental profile of infants and toddlers with oculo-auriculo-vertebral spectrum (OAV) and determined if certain physical manifestations were indicative of a poor neurodevelopmental prognosis. Twenty-four patients with OAV, aged birth to 57 months, were seen in the Department of Medical Genetics at Children's National Medical Center for multidisciplinary evaluations, including neurodevelopmental assessments. Fifty-eight percent of these children scored more than 2 standard deviations below the mean in at least one domain of development. There was no difference in developmental outcome of boys versus girls, children affected unilaterally on the right side versus left side, and those with severe clinical manifestations versus those with a milder form. Children with OAV and abnormal muscle tone had lower cognitive, gross motor, and expressive language scores (P = 0.05, P = 0.002, and P = 0.02, respectively). Those affected bilaterally had lower cognitive, fine motor, receptive language, and expressive language scores (P = 0.06, P = 0.03, P = 0.03, P = 0.02, respectively). Children with cervical spine abnormalities had lower cognitive, fine motor, and expressive language scores (P = 0.02, P = 0.04, and P = 0.04, respectively). We conclude that infants and toddlers with OAV are at increased risk for neurodevelopmental delay, especially those with abnormal muscle tone, bilateral involvement, and cervical vertebral anomalies. The complexity of the neurodevelopmental problems is strongly suggestive of central nervous system disturbances. Patients with OAV need comprehensive evaluation by a multidisciplinary team to define potential neurodevelopmental delays, allow for early intervention services, and promote an optimal developmental outcome.

The phenotypes of hemifacial microsomia-VATER, VATER, and sirenomelia patients suggest a sequence of overlapping developmental abnormalities. The malformations of 247 hemifacial microsomia (HFM) patients with one or more anomalies in other body regions were analyzed and compared with those of 255 VATER and 101 sirenomelia patients studied in the same fashion. The HFM patients were analyzed in four subgroups delineated by the number of their concomitant VATER ascertainment abnormalities (VAA). Three or more VAA occurred in 33 HFM patients who were designated to have the HFM-VATER phenotype and while no significant alteration of the HFM phenotype was found, there were notable differences in the analyses of the 20 malformation categories studied. Analyzed in separate heart and blood vessel (BV) categories, occurrences of BV defects in HFM patients with 0–1 VAA were low (4–6%) and due to anomalies other than sigle umbilical arteries (SUA). The BV abnormalities increased to 20% in the HFM with two VAA, HFM-VATER, and VATER phenotypes with equal occurrence of SUA and other BV anomalies. The incidence of SUA was markedly increased (64%) in the sirenomelia. Heart defects rose from 22% to 40% with the increasing VAA in individual HFM patients but were less in VATER (29%) and sirenomelia (21%) patients and were attributed to complex conotruncal, and other early embryonic anomalies. Unilateral agenesis of paired organs systems occurred frequently and, possibly, can be attributed to an absent blood supply. Each phenotype of the sequence also had increased VAA, rib/vertebrae hypersegmentation, and monozygotic twinning. The variation in the incidences of malformations in the three phenotypes can be attributed to their relative location in the craniocranial organogenesis sequence of normal human embryologic development. © 1993 Wiley-Liss, Inc.

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.

We report on partial dup(22q), growth deficiency, and the facioauriculovertebral sequence including hemifacial microsomia, cleft lip and palate, preauricular tags, and hearing loss in one patient. No endocrine or systemic cause for growth deficiency was identified. The case illustrates applicability of chromosome analysis in syndrome-associated growth failure, and a previously unreported associated chromosome abnormality.

WOS: 000184516300020, PubMed ID: 12884440

We report on a 4-year-old first-born monozygotic twin girl with a hypoplastic left face, mandible and zygoma, left microtia without an external auditory canal, a U-shaped cleft palate, right ectopic-fused kidneys, a blindly ending vaginal pouch, and absent uterus. We review 3 other cases with the manifestations of the Rokitansky and the facio-auriculo-vertebral sequence. The anomalies in these disorders can be thought of as deriving from an early defect or disruption in fetal mesoderm or its progenitor tissue at the time of primitive streak formation. They are frequently associated with other mesodermally derived defects or sequences and may together represent an extended polytopic field defect. While such speculation on how these spatially separated anomalies develop is probably simplistic, the concept of a mesodermal "malformation" spectrum is helpful in reminding the clinician to look for other mesodermal defects when one mesodermally derived defect or sequence is detected.

In 1952, Goldenhar described a pair of monozygotic twins who were discordant for epibulbar dermoids, auricular appendages, malformations of the auricle, and hemifacial microsomia. Eighteen twin pairs have subsequently been described in which at least one member exhibited these manifestations. We report on an additional pair of discordant dichorionic monozygotic male twins. All of the 5 monozygotic twin pairs for which placental information is available have been discordant and 2 of these had dichorionic membranes. The failure of discordant monozygotic twins to be limited to monochorionic pairs argues against the hypothesis that developmental abnormalities arising from the placental vascular anastomoses that are commonly found in monozygotic twins is the probable explanation for the discordant expression of these traits in twins.

Thirty-five of 1,488 pediatric otologic cases had congenital facial nerve weakness. A cause was generally not found, but two probably had nuclear dysgenesis; one may have had an intracanalicular lesion; two cases resulted from teratogens, one from poor intrauterine environment, and three from genetic complications. Five had total unilateral paralysis; one had bilateral palsy. Frequent associated anomalies were microtiaatresia, hemifacial microsomia, facial clefts, Moebius syndrome, and congenital conductive sensorineural loss.

Four patients are presented with the Goldenhar syndrome (GS) and cranial defects consisting of plagiocephaly, microcephaly, skull defects, or intracranial dermoid cysts. Twelve cases from the literature add hydrocephalus, encephalocele, and arhinencephaly to a growing list of brain anomalies in GS. As a group, these patients emphasize the variability of GS and the increased risk for developmental retardation with multiple, severe, or unusual manifestations. The temporal relation of proposed teratogenic events in GS provides an opportunity to reconstruct biological relationships within the 3-5-week human embryo.

We present a case of terminal del(22q) with Goldenhar complex including hemifacial microsomia, bilateral epibulbar dermoids, preauricular tags with sensorineural hearing loss, vertebral anomalies, and CNS and renal malformations. The case illustrates causal heterogeneity of the Goldenhar complex and a previously unreported associated chromosome deletion.

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.