UNASSIGNED: Orbital hypertelorism is a rare congenital condition caused by craniofacial malformations. It consists of complete orbital lateralization, characterized by an increase in distance (above the 95th percentile) of the inner canthal (ICD), outer canthal, and interpupillary distances. It can be approached surgically, and the main techniques are box osteotomy and facial bipartition. The surgical procedure is usually performed before the age of 8. We describe here two patients who underwent late surgical correction using the box osteotomy technique.
UNASSIGNED: Patient 1: A 13-year-old female presenting isolated hypertelorism with 5 cm ICD and left eye amblyopia. Patient 2: A 15-year-old female with orbital hypertelorism, 4.6 cm ICD, and nasal deformity. Both patients underwent orbital translocation surgery and had no neurological disorders.
UNASSIGNED: The article reports two cases of isolated hypertelorism treated late with the box osteotomy technique. Both surgeries were successful, with no postoperative complications. It appears that it is possible to obtain good surgical results even in patients who have not been able to undergo surgery previously.

The X-linked form of Opitz BBB/G syndrome (OS) is a monogenic disorder in which symptoms are established early during embryonic development. OS is caused by pathogenic variants in the X-linked gene MID1 Disease-associated variants are distributed across the entire gene locus, except for the N-terminal really interesting new gene (RING) domain that encompasses the E3 ubiquitin ligase activity. By using genome-edited human induced pluripotent stem cell lines, we here show that absence of isoforms containing the RING domain of MID1 causes severe patterning defects in human brain organoids. We observed a prominent neurogenic deficit with a reduction in neural tissue and a concomitant increase in choroid plexus-like structures. Transcriptome analyses revealed a deregulation of patterning pathways very early on, even preceding neural induction. Notably, the observed phenotypes starkly contrast with those observed in MID1 full-knockout organoids, indicating the presence of a distinct mechanism that underlies the patterning defects. The severity and early onset of these phenotypes could potentially account for the absence of patients carrying pathogenic variants in exon 1 of the MID1 gene coding for the N-terminal RING domain.

Snijders Blok-Campeau syndrome (SNIBCPS, OMIM# 618205) is an extremely infrequent disease with only approximately 60 cases reported so far. SNIBCPS belongs to the group of neurodevelopmental disorders (NDDs). Clinical features of patients with SNIBCPS include global developmental delay, intellectual disability, speech and language difficulties and behavioral disorders like autism spectrum disorder. In addition, patients with SNIBCPS exhibit typical dysmorphic features including macrocephaly, hypertelorism, sparse eyebrows, broad forehead, prominent nose and pointed chin. The severity of the neurological effects as well as the presence of other features is variable among subjects. SNIBCPS is caused likely by pathogenic and pathogenic variants in CHD3 (Chromodomain Helicase DNA Binding Protein 3), which seems to be involved in chromatin remodeling by deacetylating histones. Here, we report 20 additional patients with clinical features compatible with SNIBCPS from 17 unrelated families with confirmed likely pathogenic/pathogenic variants in CHD3. Patients were analyzed by whole exome sequencing and segregation studies were performed by Sanger sequencing. Patients in this study showed different pathogenic variants affecting several functional domains of the protein. Additionally, none of the variants described here were reported in control population databases, and most computational predictors suggest that they are deleterious. The most common clinical features of the whole cohort of patients are global developmental delay (98%) and speech disorder/delay (92%). Other frequent features (51-74%) include intellectual disability, hypotonia, hypertelorism, abnormality of vision, macrocephaly and prominent forehead, among others. This study expands the number of individuals with confirmed SNIBCPS due to pathogenic or likely pathogenic variants in CHD3. Furthermore, we add evidence of the importance of the application of massive parallel sequencing for NDD patients for whom the clinical diagnosis might be challenging and where deep phenotyping is extremely useful to accurately manage and follow up the patients.

Opitz GBBB syndrome (GBBB) is an X-linked disease characterized by midline defects, including congenital heart defects. We present our diagnostic approach to the identification of GBBB in a consanguineous family in which two males siblings were concordant for a total anomalous connection of pulmonary veins and minor facial dysmorphias.
Targeted exome sequencing analysis of a 380-gene panel associated with cardiovascular disease was performed on the propositus. Interpretative analysis of the exome results was conducted, and 3D models of the protein changes were generated.
We identified a NM_000381.4:c.608G>A;p.(Arg203Gln) change in MID1, affecting the conformation of the B-box 2 domain of the protein, with a zinc finger structure and associated protein interactions. This clinical phenotype is consistent with GBBB; however, the type of congenital heart disease observed in this case has not been previously reported.
A new likely pathogenic variant on MID1 c.608G>A was found to be associated with Opitz GBBB syndrome.

(1) Background: Orbital and midface malformations occur in multiple craniofacial disorders. Depending on the deformity, surgical corrections include orbital box osteotomy (OBO), Le Fort III (LFIII), monobloc (MB), and facial bipartition (FB). The aim of this study was to determine the effect of these procedures on ocular outcomes. (2) Methods: A retrospective analysis was performed. All patients with craniofacial disorders who had previously undergone midface surgery were included. The Wilcoxon signed ranks test was used for statistical analysis. (3) Results: In total, 63 patients were included: two patients were treated by OBO, 20 by LFIII, 26 by MB, and 15 by FB. Pre-operatively, strabismus was present in 39 patients (61.9%), in whom exotropia was most common (n = 27; 42.9%), followed by esotropia (n = 11; 17.5%). Postoperatively, strabismus significantly worsened (p = 0.035) in the overall population (n = 63). Pre-operative binocular vision (n = 33) was absent in nine patients (27.3%), poor in eight (24.2%), moderate in 15 (45.5%), and good in one (3.0%). Postoperatively, binocular vision significantly improved (p < 0.001). Before surgery, the mean visual acuity (VA) in the better eye was 0.16 LogMAR (Logarithm of the Minimum Angle of Resolution), and 0.31 LogMAR in the worse eye. Furthermore, pre-operative astigmatism was present in 46 patients (73.0%) and hypermetropia in 37 patients (58.7%). No statistical difference was found for VA (n = 51; p = 0.058) postoperatively. (4) Conclusions: Midface surgery has a direct and indirect substantial effect on several ocular outcomes. This study emphasizes the importance of appropriate ophthalmological evaluation in patients with craniofacial disorders undergoing midface surgery.

Opitz G/BBB syndrome is a rare condition characterized by three significant anomalies; hypertelorism, cleft lip and palate, and hypospadias. However, other anomalies may be associated. Herein, we report a 4-year-old child presented with penoscrotal hypospadias. On examination, hypertelorism and cleft lip and palate were noticed, suggesting a diagnosis of Opitz G/BBB syndrome. The cleft lip was corrected in the first year, and a two-staged surgical approach was implemented for penoscrotal hypospadias. In the first stage, the chordee was corrected and urethral plate was reconstructed using a tabularized incised plate urethroplasty and testicular tunica vaginalis flap. In the second stage, the remanent hypospadias was corrected, and the meatal opening reached its normal location. In conclusion, a two-staged surgical approach for the treatment of penoscrotal hypospadias associated with Opitz G/BBB syndrome may provide excellent outcomes in early-recognized cases. The urologist should pay attention to abnormal facial characteristics in patients with hypospadias.

Hypertelorism and hypospadias are the main characteristics of telecanthus-hypospadias syndrome; however, it can also include other midline structural anomalies, such as cleft lip and palate, cryptorchidism, congenital heart problem, laryngotracheal cleft, esophageal fistula, and irregular scrotum. Here, we describe an eight-year-old male who was brought to us for cleft lip repair, but upon evaluation, the other listed anomalies were discovered. He had hypertelorism, hypospadias, a ventricular septal defect, and a history of cryptorchidism. A multidisciplinary approach involved pediatricians, oral surgeons, cardiologists, and pediatric surgeons. The patient underwent surgery for first-stage hypospadias correction and was advised to follow up for additional surgery and maintenance procedures before being discharged. We wish to report this case with the aim to enlighten budding pediatricians and surgeons about this rare syndrome.

Use of inter-pupillary distance (IPD) for objective evaluation of ocular hypertelorism and hypotelorism is recommended to corroborate diagnosis of syndromic conditions. In view of complete absence of serial data on growth of IPD, this study aims to unfold auxological dynamics of IPD in Down syndrome (DS) children of Indian origin. Inner canthal distance (ICD) and outer canthal distance (OCD) were measured on a total of 1,125 (male: 752, female: 373) DS children, aged 0 to 3 months to 10 years at 6 monthly age intervals using a \"Digimatic Sliding Caliper\" in the Growth Laboratory/Growth Clinic of the Institute. Using Feingold and Bossert (1974) formula, IPD at each age was calculated from ICD and OCD measured among male and female DS children. IPD, like OCD and ICD increased un-interruptedly among DS children. IPD grew rapidly up to 5 years thereafter, its rapidity became slower. Boys in general, possessed larger IPD than girls, however, gender differences became statistically significant up to first 4 years of life. Our study children possessed significantly smaller IPD as compared with their normal Indian counterparts. None of our DS children depicted ocular hypertelorism while hypotelorism, was noticed amongst 4.9% male and 16.8% female DS patients. Comparison with normative IPD data failed to establish existence of ocular hypertelorism in DS children (<10 years) of north-western Indian origin. Use of age and gender-specific data presented for IPD of DS children may be made for comparative purpose to ascertain inter-population variability.

UNASSIGNED: This study aimed to determine the orbital dimensions of Omani subjects who had been referred for computed tomography (CT) of the brain at Sultan Qaboos University Hospital, Muscat, Oman. Good knowledge of the normal orbital dimensions is clinically essential for successful surgical outcomes. Racial, ethnic and regional variations in the orbital dimensions have been reported.
UNASSIGNED: A total of 273 Omani patients referred for CT scans of the brain were retrospectively evaluated using an electronic medical records database. The orbital dimensions were recorded using both axial and sagittal planes of CT images.
UNASSIGNED: The mean orbital index (OI) was found to be 83.25 ± 4.83 mm and the prevalent orbital type was categorised as the mesoseme. The mean orbital index was 83.34 ± 5.05 mm and 83.16 ± 4.57 mm in males and females, respectively, with their difference not being statistically significant (P = 0.76). However, a statistically significant association was observed between the right and left orbits regarding horizontal distance (P <0.05) and vertical distance (P <0.01) of orbit and OI (P <0.05). No significant difference between the OI and age groups was observed in males and females. The mean interorbital distance and interzygomatic distance were found to be 19.45 ± 1.52 mm and 95.59 ± 4.08 mm, respectively. These parameters were significantly higher in males (P <0.05).
UNASSIGNED: Results of the present study provide reference values of orbital dimensions in Omani subjects. Mesoseme, a hallmark of Caucasian people, is discovered to be the prevalent orbital type of Omani subjects.

Craniofrontonasal Syndrome is a very rare dominant X-linked genetic disorder characterized by symptoms such as hypertelorism, craniosynostosis, eye alterations, bifid nose tip, and longitudinal ridging and splitting of nails. Heterozygous females are usually the patients severely affected. To date, clinical or genetic data have not been published for these patients in Colombia. Here we report a female proband with coronal craniosynostosis, hypertelorism, strabismus, rotational nystagmus, high-arched palate, dental crowding, scoliosis, severe pectus excavatum, unilateral breast hypoplasia, and brachydactyly; diagnosed with Craniofrontonasal Syndrome with the novel heterozygous variant c.374A>C (p.Glu125Ala) in the EFNB1 gene. So far, she has been treated with physical therapy and surgical correction of the bifid nose and an umbilical hernia. To the best of our knowledge, this is the first report of a patient with this rare genetic disorder in Colombia, expanding its mutational spectrum and highlighting the importance of genetic evaluation of patients with craniosynostosis and facial dysmorphism.