Prenatal diagnosis of Treacher Collins syndrome: A case report and literature review.

Treacher Collins syndrome (TCS) should be suspected if the triad of micrognathia, glossoptosis, and posterior cleft palate, and deformed external ears are observed during prenatal ultrasonography, excepting Pierre Robin sequence. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures are conducive to differentiation. Molecular genetics testing can establish a definite diagnosis. A 28-year-old pregnant Chinese woman was referred for systematic ultrasound examination at 24 weeks. Two-dimensional and three-dimensional ultrasound showed polyhydramnios, micrognathia, absence of nasal bone, microtia, secondary cleft palate, mandibular hypoplasia, glossoptosis, and normal limbs and vertebrae. Pierre Robin sequence was misdiagnosed with the triad of micrognathia, glossoptosis, and posterior cleft palate. Final diagnosis of TCS was confirmed by whole-exome sequencing. Visualization of the fetal zygomatic bone and down-slanting palpebral fissures can facilitate a differential diagnosis between Pierre Robin sequence and TCS, with the triad of micrognathia, glossoptosis, and posterior cleft palate.

Prenatally diagnosed microdeletion in the TCOF1 gene in fetal congenital primary Treacher Collins Syndrome.

OBJECTIVE: To study prenatal diagnosis of congenital Treacher Collins syndrome, an etiology of craniofacial abnormalities. CASE REPORT: We present a case of fetal craniofacial abnormalities identified by antepartum sonography screening in the third trimester (28 weeks); features of micrognathia, hypoplastic zygomatic arches and bilateral low-set microtia were detected. Due to the unknown severity of the craniofacial abnormalities and poor prognosis, the parents decided to terminate the fetus after through counselling. A normal female karyotype was detected. The parents consented to chromosome microarray analysis (CMA), which identified a de novo mutation of the TCS1 gene locus on chromosome 5. CONCLUSION: Molecular CMA is an effective tool for prenatal diagnosis of congenital craniofacial abnormalities associated with Treacher Collins syndrome.

A novel de novo missense mutation in EFTUD2 identified by whole-exome sequencing in mandibulofacial dysostosis with microcephaly.

BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare multiple malformation syndrome characterized by malar and mandibular hypoplasia and congenital- or postnatal-onset microcephaly induced by haploinsufficiency of (elongation factor Tu GTP-binding domain-containing 2) EFTUD2. METHODS: We report the case of a 16-month-old boy with MFDM symptoms, including malar and mandibular hypoplasia, microcephaly, micrognathia, midline cleft palate, microtia, auditory canal atresia, severe sensorineural hearing loss, and developmental delay. Whole-exome sequencing (WES) analysis of the patient's family was performed to identify the genetic etiology responsible for this phenotype. RESULTS: We identified a novel de novo missense mutation (c.671G>T, p.Gly224Val) in the EFTUD2. According to the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines, the c.671G>T mutation was classified as likely pathogenic (PS2, PM1, PM2, and PP3). Based on our findings, prenatal diagnosis was performed on the second baby of the proband's parents to exclude the mutation and it was confirmed that the baby did not have the MFDM phenotype after 14 months of follow-up. Furthermore, the zebrafish model confirmed that the EFTUD2 c.671G>T mutation caused a loss of gene function in EFTUD2, and the pathogenicity of the EFTUD2 c.671G>T mutation was classified as pathogenic (PS2, PS3, PM1, and PM2). CONCLUSION: Our results indicate that WES is a useful tool for identifying potentially pathogenic mutations, particularly in rare disorders, and is advantageous for genetic counseling and subsequent prenatal diagnosis. Moreover, the importance of functional assays cannot be underestimated, which could further confirm the pathogenicity of the genetic variants.

Otodental syndrome: Case report and differential diagnosis with Treacher Collins syndrome.

BACKGROUND: Otodental syndrome and Treacher Collins syndrome are rare diseases that have similar clinical features, which can complicate the diagnostic process. These syndromes cause skeletal and dental abnormalities, the differential diagnosis can be based on clinical signs but only the genetic analysis can confirm it. The aim of this case report is to describe and compare clinical signs of these syndromes. CASE REPORT: A 7-year-old patient came to our department: he presented abnormal tooth shapes and sizes, delayed teeth replacement and micrognathia. After extra- and intra-oral examination and radiographic exams, a clinical diagnosis of otodental syndrome was made, and a genetic testing was requested to confirm the diagnosis. CONCLUSION: Dental management of patients with otodental syndrome is challenging due to agenesis, teeth malformation, lack of space for permanent dentition. Proper treatment decision is crucial to obtain the best result for the patient.

Three-dimensional comparison of mandibular morphology in young people with Treacher Collins syndrome and Pierre Robin sequence.

INTRODUCTION: Treacher Collins syndrome (TCS) and nonsyndromic Pierre Robin sequence (PRS) share mandibular deficiency as a similar clinical finding. This study aimed to compare the mandibular size and morphology of subjects with TCS and PRS. METHODS: Group TCS was composed of 17 subjects (7 male, 10 female) with a mean age of 11.5 years (standard deviation, 4.4) from a single center. Group PRS was composed of 17 subjects paired by age and sex with group TCS. Preorthodontic cone-beam computed tomography examinations of all patients were evaluated using Mimics Innovation Suite 17.0 (Materialise, Leuven, Belgium). Nine 3-dimensional measurements were performed in segmented 3D images of the mandible. Intragroup comparisons were performed using paired t tests. Intergroup comparisons were performed using analysis of variance and Tukey tests. The significance level considered was 5%. RESULTS: TCS showed a significant dimensional difference between less and more affected sides for ramus, condyles, and mandibular body. The mandibular dimensions in PRS were more symmetrical. Group TCS presented a smaller mandibular effective length and mandibular body length compared with PRS. The condyle width and height and the ramus width were also decreased in TCS. The gonial angle was greater in TCS compared with the PRS group. CONCLUSIONS: Young subjects with TCS presented a smaller, more vertical, and more asymmetrical mandible compared with nonsyndromic PRS.

Craniofacial and Upper Airway Development in Patients With Treacher Collins Syndrome.

ABSTRACT: This study evaluated age-associated morphology changes in the cranial base, facial development, and upper airway of patients with Treacher Collins syndrome (TCS). A total of 33 preoperative computed tomographic images (TCS, n = 14; control, n = 19) were included in the study and divided into three age-related subgroups (2-6 years, 7-18 years, and older than 18 years). Linear, angular cephalometric measurements and upper airway volumes were collected. All measurements were analyzed using ProPlan CMF software (version 3.0; Materialize, Leuven, Belgium). The association between aging and upper airway morphology was analyzed. Compared to control subjects, TCS patients had a smaller cranial base, maxilla, and nose; they also had reduced upper airway volume compared to control subjects. The observed differences were most significant in patients between the ages of 7 and 18 years. This study used computed tomography-based three-dimensional analyses to provide a detailed description of age-related changes that occur in craniofacial measurements and upper airway volumes in children, adolescents, and young adult patients with TCS in China. These data can be used to evaluate individual patients with TCS and to select treatment to improve the growth of the craniofacial region.

Treacher Collins Syndrome: A Case Report.

Treacher collins syndrome (TCS) or Franceschetti syndrome is an autosomal dominant inherited disorder with variable expressivity. It affects mainly craniofacial structure that derives from 1st and 2nd branchial arches approximately between the 20th day and 12th week of intrauterine life. This syndrome has different clinical types. Most common features are antimongoloid slanting of the palpebral fissures, hypoplasia of zygoma, maxilla & mandible with various eye and ear abnormalities. Here we present a case of an 11 days old female neonate, who was ill looking, dyspnoeic having significant facial profile, multiple congenital anomalies and dolicocephaly; admitted in the department of Neonatology, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh on 7th August 2020. After taking all the diagnostic assistance of the multidisciplinary approach mainly on the basis of clinical features and radiology we diagnosed the case as TCS. We managed the patient by maintaining temperature, giving nutritional support and injectable antibiotic, took consultation from Otolaryngology department then we discharged the baby with proper counseling, advised regarding further follow up and to consult with paediatric surgeon and cardiologist.

Extracraniofacial anomalies in Treacher Collins syndrome: A multicentre study of 248 patients.

Treacher Collins syndrome (TCS) is a congenital malformation of the craniofacial structures derived from the first and second pharyngeal arches. The craniofacial deformities are well described in the literature. However, little is known about whether there are associated extracraniofacial anomalies. A retrospective study was conducted using data from four craniofacial units. Medical charts were reviewed for the presence and type of extracraniofacial anomalies, as well as age at diagnosis. A possible correlation between the severity of the phenotype and the presence of extracraniofacial anomalies was assessed using the Hayashi classification. A total of 248 patients with TCS were identified; 240 were confirmed to have TCS, of whom 61 (25.4%) were diagnosed with one or more extracraniofacial anomalies. Ninety-five different extracraniofacial anomalies were found; vertebral (n=32) and cardiac (n=13) anomalies were most frequently seen, followed by reproductive system (n=11), central nervous system (n=7), and limb (n=7) anomalies. No correlations between tracts were found. Extracraniofacial anomalies were more prevalent in these patients with TCS compared to the general population (25.4% vs 0.001-2%, respectively). Furthermore, a positive trend was seen between the severity of the syndrome and the presence of extracraniofacial anomalies. A full clinical examination should be performed on any new TCS patient to detect any extracraniofacial anomalies on first encounter with the craniofacial team.

[Three-dimensional measurement analysis of midface morphology in Treacher Collins syndromes].

OBJECTIVE: To three-dimensionally calculate the craniofacial parameters of midface of patients with Treacher Collins syndrome (TCS) in China, in order to understand the changes in the spatial position relationship between the various anatomical structures of the midface. METHODS: CT imaging data of TCS patients and age- and gender-matched normal populations between January 2013 and July 2020 was retrospectively analyzed. A total of 33 cases met the selection criteria for inclusion in the study, including 14 cases in the TCS group and 19 cases in the control group. ProPlan CMF 3.0 software was used to perform three-dimensional digital reconstruction of the craniofacial bone, measure the anatomical parameters of the midface, and analyze its morphological structure; at the same time perform three-dimensional digital reconstruction of the upper airway for morphological analysis (measure upper airway volume). RESULTS: CT images analysis revealed that all 14 patients with TCS presented the typical features with downward slanting of the palpebral fissures and different degrees of zygomatico-orbital complex dysplasia. Cephalometric and morphological analysis of the midface revealed that, multiple transverse diameters of the midface of TCS patients were significantly decreased when compared with the control group ( P<0.05), such as the width of the maxillary base, the length of the maxillary complex, and some distances related to the nasal morphology; but the distance between bilateral orbitales increased in TCS group ( P<0.05). Several anteroposterior distances in TCS group were decreased significantly when compared to control group and the distance between the skull base point and the posterior nasal spine was the most shortened ( P<0.05). But there was no significant difference of the distance between nasion and anterior nasal spine, which represented anterior midface height, between groups ( P>0.05). The skull base angle and SNB angle (the angle between the sella point-nose root point-inferior alveolar seat point) of the TCS group both decreased when compared with the control group ( P<0.05), but there was no significant difference in SNA angle (the angle between the sella point-nose root point-upper alveolar seat point) between the two groups ( P>0.05). The total volume of the upper airway was (24 621.07±8 476.63) mm 3 in the TCS group, which was significantly lower than that of the control group [(32 864.21±13 148.74) mm 3] ( t=2.185, P=0.037). CONCLUSION: The transverse distances, anteroposterior distances, and multiple craniofacial angles measurement of TCS patients were significantly decreased when compared to the control group, presented with different degrees of zygomatico-orbital complex dysplasia, nasal and maxillary dysplasia, but there was no obvious restriction in face height development. Reduced internal diameters of the upper airway maybe responsible for the decreased upper airway volume of patients with TCS.

Prenatal features of mandibulofacial dysostosis Guion-Almeida Type.

Facial dysostoses are clinically and genetically heterogeneous conditions characterized by congenital craniofacial anomalies which result from abnormal development of the first two pharyngeal arches and their derivatives during embryogenesis. Mandibulofacial dysostosis Guion-Almeida type (MFDGA) is a rare and relatively new syndrome described in the literature, first identified by Guion-Almeida et al. in 2000 and 2006. Another 108 cases have been documented after that. Prenatal diagnosis of this syndrome has not been described yet. Here we present the prenatal ultrasound findings in a case where MFDGA was confirmed after delivery. We suggest that MFDGA should be included in the prenatal differential diagnosis of syndromes with micrognathia and craniofacial anomalies.

Comparison Between Treacher Collins Syndrome and Pierre Robin Sequence: A Cephalometric Study.

OBJECTIVE: The aim of this study was to compare the dentoskeletal pattern of Treacher Collins syndrome (TCS) and nonsyndromic Pierre Robin sequence (PRS). DESIGN: Retrospective. SETTING: Single center. PATIENTS: Eighteen patients diagnosed with TCS (Group TCS) or PRS (Group PRS) in rehabilitation treatment at a single center. Group TCS was composed of 9 patients (4 male, 5 female) with a mean age of 12.9 years (standard deviation = 4.8). Group PRS was composed of 9 patients paired by age and sex with group TCS. MAIN OUTCOME MEASURE(S): Cone beam computed tomography-derived cephalometric images taken before the orthodontic or the orthodontic-surgical treatment were analyzed using Dolphin Imaging (Dolphin Imaging 11.0 & Management Solutions). Variables evaluating the cranial base, the maxillary and mandibular skeletal components, maxillomandibular relationship, the vertical components and the dentoalveolar region were measured. Intergroup comparisons were performed using t tests. The significance level considered was 5%. RESULTS: Intergroup differences in the mandible size and growth pattern were observed. Group TCS showed a smaller mandibular length (Co-Go, Co-Gn) and a higher palatal plane (SN-Palatal Plane) and mandibular plane angles (SN-Go.Gn) compared to group PRS. No differences between TCS and PRS were observed for the sagittal position of the maxilla, maxillomandibular relationship, and dental components. CONCLUSIONS: Treacher Collins syndrome presented a decreased mandible and a more severe vertical growth pattern compared to PRS.

Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

BACKGROUND: Treacher Collins syndrome (TCS) is the most common mandibulofacial dysostosis with an autosomal dominant or rarely recessive manner of inheritance. It is still challenging to make a definite diagnosis for affected fetuses with TCS only depending on the ultrasound screening. Genetic tests can contribute to the accurate diagnosis for those prenatal cases. METHODS: Targeted exome sequencing was performed in a fetus of a Chinese family, who presenting an abnormal facial appearance by prenatal 2D and 3D ultrasound screening, including micrognathia, nasal bridge pit, and abnormal auricle. The result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR). RESULTS: A novel 2-6 exons deletion of TCOF1 gene was identified and confirmed by the MLPA and qPCR in the fetus, which was inherited from the affected father with similar facial anomalies. CONCLUSION: The heterozygous deletion of 2-6 exons in TCOF1 results in the TCS of this Chinese family. Our findings not only enlarge the spectrum of mutations in TCOF1 gene, but also highlight the values of combination of ultrasound and genetics tests in diagnosis of craniofacial malformation-related diseases during perinatal period.

Imaging of the Fetal Zygomatic Bone: A Key Role in Prenatal Diagnosis of First Branchial Arch Syndrome.

OBJECTIVES: First arch syndromes are congenital defects caused by failure of neural crest cells to migrate into the first branchial arch. First arch syndrome is classified into 2 main clinical manifestations: Treacher Collins syndrome, characterized by bilateral underdevelopment of the zygomatic bones; and Pierre Robin sequence. The aim of this study was to describe the feasibility of visualization of the fetal zygomatic bone and assess its application in cases referred for features suggestive of first arch syndrome. METHODS: A prospective cohort study was conducted. The feasibility of visualization of the zygomatic bone was performed in 50 sequential fetuses with a normal anatomic scan between 12 and 24 weeks' gestation using 3-dimensional sonography. Following this, cases referred for targeted scans for suspected first branchial arch syndrome were assessed for the presence or absence of the zygomatic bones. RESULTS: Visualization of the fetal zygomatic bone was feasible in all low-risk cases. Cases referred for targeted scans included 11 isolated cases of micrognathia or retrognathia, 3 cases of microtia, and 3 cases of auricular or facial vestiges. Within this group, the zygomatic bones were visualized in all but 2 cases. No associated extrafacial malformations were detected; therefore, this phenotype was consistent with Treacher Collins syndrome. CONCLUSIONS: Prenatal imaging of the zygomatic bones offers a clinically based sonographic approach to cases referred for features suggestive of first arch syndrome and enables differentiation between the 2 main clinical manifestations: Treacher Collins syndrome and Pierre Robin sequence.

Neurocristopathies: Enigmatic Appearances of Neural Crest Cell-derived Abnormalities.

The neural crest is an important transient structure that develops during embryogenesis in vertebrates. Neural crest cells are multipotent progenitor cells that migrate and develop into a diverse range of cells and tissues throughout the body. Although neural crest cells originate from the ectoderm, they can differentiate into mesodermal-type or endodermal-type cells and tissues. Some of these tissues include the peripheral, autonomic, and enteric nervous systems; chromaffin cells of the adrenal medulla; smooth muscles of the intracranial blood vessels; melanocytes of the skin; cartilage and bones of the face; and parafollicular cells of the thyroid gland. Neurocristopathies are a group of diseases caused by the abnormal generation, migration, or differentiation of neural crest cells. They often involve multiple organ systems in a single person, are often familial, and can be associated with the development of neoplasms. As understanding of the neural crest has advanced, many seemingly disparate diseases, such Treacher Collins syndrome, 22q11.2 deletion syndrome, Hirschsprung disease, neuroblastoma, neurocutaneous melanocytosis, and neurofibromatosis, have come to be recognized as neurocristopathies. Neurocristopathies can be divided into three main categories: dysgenetic malformations, neoplasms, and combined dysgenetic and neoplastic syndromes. In this article, neural crest development, as well as several associated dysgenetic, neoplastic, and combined neurocristopathies, are reviewed. Neurocristopathies often have clinical manifestations in multiple organ systems, and radiologists are positioned to have significant roles in the initial diagnosis of these disorders, evaluation of subclinical associated lesions, creation of treatment plans, and patient follow-up. Online supplemental material is available for this article. ©RSNA, 2019.

Mandibulofacial dysostosis with microcephaly: a syndrome to remember.

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare condition that causes abnormalities of the head and face. Other major extracranial malformations may also be found. The authors present a case of an MFDM in a 35 weeks newborn with antenatal growth restriction. The patient required resuscitation at birth and was diagnosed with oesophageal atresia with tracheoesophageal fistula at day 1. At physical examination he presented multiple congenital malformations including prominent forehead, plagiocephaly, low-set ears, malformed auricles, hypertelorism, downward-slanting eyes, micrognathia, everted lower lip, short neck, wide-spaced nipples and inguinal hernia. Imaging investigation showed dysplasia of the inner ear with agenesis of the vestibular-cochlear nerves and global cerebral atrophy. Analysis of the EFTUD2 gene revealed that the patient was a heterozygous carrier of a pathogenic mutation (c.831_832del[p.Lys277Asnsf*7]), which has not been previously described. This case illustrates the challenges faced in diagnosing and treating MFDM patients.

Visual diagnosis in utero: Prenatal diagnosis of Treacher-Collins syndrome using a 3D/4D ultrasonography.

OBJECTIVE: We present a case with prenatal diagnosis of Treacher-Collins syndrome in which micrognathia and other facial and ear abnormalities were described using a three- and four-dimensional (3D/4D) ultrasonography in utero. CASE REPORT: A 39-year-old Japanese pregnant woman was referred because of polyhydramnios at 29 weeks' gestation. Conventional ultrasonography showed a hypoplastic mandible on the sagittal section of fetal head. Continuous observation using a 3D ultrasonography additionally demonstrated bilateral downslanting palpebral fissures with symmetry and macrostomia as well as micrognathia. Both ears were microtia and no polydactyly or missing fingers were found. CONCLUSION: The advantage of the rendering mode of 3D images covering entire face including ears and limbs was enhanced by a continuous observation, so called 4D ultrasonography, under a condition of polyhydramnios, providing visual diagnosis in utero.

A Case of Nager Syndrome Diagnosed Before Birth.

Nager syndrome is a rare disease involving severe micrognathia and upper limb shortening. In this report, we describe a case in which micrognathia of the fetus was suspected based on the observation of upper limb shortening during detailed B mode and 3D/4D ultrasonographic observation, and combined fetal MRI and 3D-CT led to a prenatal diagnosis of Nager syndrome. Upon birth, because severe micrognathia caused airway obstruction and made it difficult to spread the larynx for intubation, effective ventilation could not be carried out and a tracheostomy was necessary. Since a differential diagnosis of Nager syndrome can be made based on the fact that micrognathia typically co-occurs with upper limb shortening, it is possible to diagnose the disease before birth and prepare for life-saving measures accordingly.

Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Dysostosis type 1.

Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene.

Modified Lefort Distraction Osteogenesis for the Treatment of Nager Syndrome-Associated Midface Hypoplasia: Technique and Review.

The surgical management of midface hypoplasia in the setting of Nager syndrome remains a significant challenge for craniofacial surgeons. This study describes a novel technique using distraction osteogenesis and modified osteotomies for the treatment of midface bony defects in an 11-year-old child with Nager syndrome.Presurgical 3-dimensional planning was performed to design the osteotomies and placement of distractors. The surgical approach required upper buccal sulcus and extended transconjunctival incisions only. Osteotomies were performed from the pyriform aperture through the orbit to include the lateral orbital wall, with bilateral osteotomy of the zygomas through the anterior arch via the transconjunctival incision. Distraction of the en bloc midface segment was successfully performed using external distractors. Bone grafting was not required. There were no complications.External distraction was well tolerated and there were no intraoperative or postoperative complications. The distractors were removed uneventfully after consolidation. The midface was successfully advanced without the need for bone grafting or bicoronal incision. The occlusal plane was leveled and the aesthetic appearance of the child was improved.Symmetrical midface hypoplasia in the context of Nager syndrome can be successfully corrected with en bloc distraction osteogenesis of the maxilla and bilateral zygomas through modified osteotomies that exclude the upper nasal pyramid. The approach is simplified and the need for bicoronal incision and bone grafting is mitigated in this technique, which the authors have named Lefort 2.5.

Orbital volume and shape in Treacher Collins syndrome.

Orbito-palpebral reconstruction is a challenge in Treacher Collins syndrome (TCS). This study investigates orbital phenotypes in TCS using cephalometry and orbital shape analysis. Eighteen TCS and 52 control patients were included in this study, using the Dr Warehouse database. Orbital cephalometry was based on 20 landmarks, 10 planes, 16 angles, and 22 distances. Orbits were segmented. Registration-based, age-specific mean models were generated using semi-automatic segmentation, and aligned and compared using color-coded distance maps - mean absolute distance (MAD), Hausdorff distance (HD), and Dice similarity coefficient (DSC). Symmetry was assessed by mirroring and DSC computing. Central orbital depth (COD) and medial orbital depth (MOD) allowed 100% of orbits to be classified. COD and lateral orbital depth (LOD) were different from the controls. Average MAD between TCS and controls was ≤1.5 mm, while for HD it was >1.5 mm, and for DSC <1. TCS orbits were more asymmetrical than controls, and orbital volumes were smaller when age was considered as a confounding factor, and had a trend for normalization with age. This report emphasizes the importance of combining different morphometric approaches in the phenotype characterization of non-trivial structures such as the orbit, and supports composite skeletal and soft-tissue strategies for the management of the peri-orbital region.