Comparison of Piezosurgery and Conventional Osteotomy for Orbital Hypertelorism Surgical Correction.

The purpose of this study was to compare the safety and effect of piezosurgery with conventional osteotomy in a box-shifting procedure for orbital hypertelorism (ORH) correction surgery. This study retrospectively analyzed the clinical record of 10 ORH patients aged from 5 to 12 years, and they were second-degree ORH with an interorbital distance (IOD) of 35 to 37.8 mm. Three of them received the osteotomy with piezosurgery (the piezosurgery group), whereas the other 7 patients received osteotomy with the conventional osteotomy method (the control group). They were compared with age and preoperative IOD. All the patients' IOD was effectively improved to normal range after the surgery. The results showed that the application of piezosurgery did not prolong the surgery time (piezosurgery group: 8.3±0.5 hours; control group: 8.7±1.4 hours, P =0.68). Furthermore, the patients in the piezosurgery group had less drainage volume (piezosurgery group: 79.1±12 mL; the control group: 170±41.3 mL, P =0.0065) and shorter postoperative hospital stay (piezosurgery group: 8.3±2.0 d; control group: 12.43±2.29 d, P =0.029). There were 2 patients who had wound infections, 1 in the piezosurgery group and 1 in the control group, respectively. However, 1 patient in the control group suffered from cerebrospinal fluid leakage. On the basis of the results, the application of piezosurgery benefited the patients on a better and smoother recovery course with less drainage and shorter hospital stays. The advantages of piezosurgery are the fine and precise osteotomy and the protection for soft tissue, which make it a comparatively safe and effective tool for craniofacial surgery, especially for young patients.

Augmentation of bone morphogenetic protein signaling in cranial neural crest cells in mice deforms skull base due to premature fusion of intersphenoidal synchondrosis.

Craniofacial anomalies (CFAs) are a diverse group of disorders affecting the shapes of the face and the head. Malformation of the cranial base in humans leads CFAs, such as midfacial hypoplasia and craniosynostosis. These patients have significant burdens associated with breathing, speaking, and chewing. Invasive surgical intervention is the current primary option to correct these structural deficiencies. Understanding molecular cellular mechanism for craniofacial development would provide novel therapeutic options for CFAs. In this study, we found that enhanced bone morphogenetic protein (BMP) signaling in cranial neural crest cells (NCCs) (P0-Cre;caBmpr1a mice) causes premature fusion of intersphenoid synchondrosis (ISS) resulting in leading to short snouts and hypertelorism. Histological analyses revealed reduction of proliferation and higher cell death in ISS at postnatal day 3. We demonstrated to prevent the premature fusion of ISS in P0-Cre;caBmpr1a mice by injecting a p53 inhibitor Pifithrin-α to the pregnant mother from E15.5 to E18.5, resulting in rescue from short snouts and hypertelorism. We further demonstrated to prevent premature fusion of cranial sutures in P0-Cre;caBmpr1a mice by injecting Pifithrin-α through E8.5 to E18.5. These results suggested that enhanced BMP-p53-induced cell death in cranial NCCs causes premature fusion of ISS and sutures in time-dependent manner.

3MC syndrome: molecular findings in previously reported and milder patients expand the natural history and phenotypic spectrum.

The 3MC syndromes types 1-3 (MIM#257920, 265050 and 248340, respectively) are rare autosomal recessive genetic disorders caused by pathogenic variants in genes encoding the lectin complement pathway. Patients with 3MC syndrome have a distinctive facial phenotype including hypertelorism, highly arched eyebrows and ptosis. A significant number of patients have bilateral cleft lip and palate and they often exhibit genitourinary and skeletal anomalies. A clinical clue to 3MC syndrome is the presence of a characteristic caudal appendage. Genetic variants in MASP1, COLEC11 and COLEC10 genes have been identified as the causation of this syndrome, yet relatively few patients have been described so far. We consolidate and expand current knowledge of phenotypic features and molecular diagnosis of 3MC syndrome by describing the clinical and molecular findings in five patients. This includes follow-up of two brothers whose clinical phenotypes were first reported by Crisponi et al in 1999. Our study contributes to the evolving clinical and molecular spectrum of 3MC syndrome.

Presence and development of strabismus in children with telecanthus, epicanthus and hypertelorism.

Purpose: To study the presence and development of strabismus in children with telecanthus, epicanthus, and hypertelorism. Methods: This is a prospective, longitudinal, and observational study. Sixty children aged between 6 months and 18 years with telecanthus, epicanthus, and hypertelorism in isolation or in combination were recruited. A detailed analysis of the history, determination of best corrected visual acuity, complete evaluation of strabismus, and ocular examination were carried out. The presence of telecanthus, epicanthus, and hypertelorism and associated strabismus, if any, was noted. All children were followed up for a minimum and maximum period of 12 and 18 months, respectively, to analyze the strabismus (previously present) and for detection of strabismus in those who did not have. The data were analyzed descriptively with mean and standard deviation. Chi square test and Fishers exact test were used to analyze the data between the groups. A P value less than 0.05 was considered to be statistically significant. Results: Telecanthus was the most common lid feature (55%). At baseline, ten (16.66%) children had strabismus (six: esotropia; four: exotropia). Two (3.33%) children underwent surgery. One child developed exotropia at the third follow-up (18 months). At the end of the study, 11 (18.33%) children had strabismus. No significant association was seen between lid characteristics and the type of strabismus. Conclusion: Children with telecanthus, epicanthus, and hypertelorism in isolation or in combination may or may not have associated strabismus. These features can pose difficulty in strabismus diagnosis, which mandates a careful examination, especially in younger age groups and small-angle strabismus. On the other hand, children without strabismus need longer follow-up to detect the development of strabismus and to initiate further management at the earliest.

Clinical and genetic approach in the characterization of newborns with anorectal malformation.

OBJECTIVE: This study aimed to investigate clinical, surgical, and genetic data of neonates with anorectal malformation (ARM). STUDY DESIGN: A retrospective observational study was conducted on neonates with ARM as an isolated type (group 1), with ≤2 (group 2), and with ≥3 associated malformations (group 3), born between 2009 and 2020. Distribution of ARM, associated abnormalities and genetic testing were analyzed, and risk factors for adverse outcomes were identified. RESULTS: The 45 ARM cases (36% females) were divided as follows: 13 neonates belonging to group 1 (29%), 8 to group 2 (18%), and 24 to group 3 (53%). Cases were equally distributed over 11 years. Krickenbeck anatomy was: without fistula/imperforate anus (18%), perineal fistula (36%), rectourethral fistula (4%), rectovesical fistula (2%), vestibular fistula (4%), cloaca (4%), and rare ARMs (31%). Groups showed differences in anthropometric data, Krickenbeck anatomy, and intensive care burden. Additional major congenital abnormalities were prevalent specific of VATER/VACTERL spectrum (vertebral/anorectal/cardiac/tracheoesophageal/renal/limb defects), but also Hirschsprung disease was found in 3/20 biopsies (15%). The most frequent minor abnormality was a single umbilical artery. In group 3, we identified four de novo microdeletions at 8p23.2, 8q13.3, Xp22.31-p22.2, Xq28, four de novo microduplications at 1p36.32, 6p24.1-p23, 13q14.11, 15q11.2, one microdeletion at 9q33.1 inherited from the affected mother, one microdeletion at 7q35 inherited from the unaffected father, one structurally uncharacterized rearrangement involving 9p23-q34.3. Thus, we attributed the Xq28 deletion with inactivated FAM58A gene in one girl to the X-linked dominant STAR syndrome (toe syndactyly-telecanthus-anogenital/renal malformations). CONCLUSIONS: Despite the great physical and social burden on ARM patients and their parents, in the majority of cases, the etiology is largely unknown and attributed to be multifactorial. In females, STAR syndrome should be part of the differential diagnosis. Associated malformations of other organ systems interact in outcome parameters.

Detection of ocular hypertelorism among Indian children.

Background & objectives: Ocular hypertelorism constitutes an important component of many clinical syndromes. It is typically recommended to use inter-pupillary distance (IPD) for objective evaluation of ocular hypo/hypertelorism. Barring infancy, there is a scarcity of data on this anthropometric parameter relating to the ocular apparatus. This study aims to study auxological dynamics of IPD in children of Indian origin. Methods: A total of 3622 ( 2239 males and, 1383 females) normal, healthy Indian children of North-western origin, aged one month to 14 yr comprised the sample for this study. Inner and outer-canthal distance were measured using standardized anthropometric techniques. None of the children who participated in this study had craniofacial dysmorphism or any body deformity. Mean (standard deviation SD) and percentiles were calculated for IPD in male and female subjects at different age levels. Results: IPD increased from 4.68±0.21 to 6.19±0.36 cm in males and from 4.59±0.26 to 6.08±0.25 cm in females between one month and 14 yr of age. Boys in general, possessed larger IPD than girls, however, the gender differences became significant (P≤0.05) at 10, 11, 16-18 and 22-24 months, respectively, and five and 10 yr of age, respectively. Interpretation & conclusions: The results of this study suggest that the patients having IPD less than the 3rd percentile should be treated as cases of hypotelorism while, those exceeding 97th percentile as cases of hypertelorism. The use of percentile grids presented for IPD may be used to detect ocular hypotelorism and hypertelorism in male and female children to corroborate diagnosis of different syndromes.

SPECC1L Mutations Are Not Common in Sporadic Cases of Opitz G/BBB Syndrome.

Opitz G/BBB syndrome (OS) is a rare genetic developmental condition characterized by congenital defects along the midline of the body. The main clinical signs are represented by hypertelorism, laryngo-tracheo-esophageal defects and hypospadias. The X-linked form of the disease is associated with mutations in the MID1 gene located in Xp22 whereas mutations in the SPECC1L gene in 22q11 have been linked to few cases of the autosomal dominant form of this disorder, as well as to other genetic syndromes. In this study, we have undertaken a mutation screening of the SPECC1L gene in samples of sporadic OS cases in which mutations in the MID1 gene were excluded. The heterozygous missense variants identified are already reported in variant databases raising the issue of their pathogenetic meaning. Recently, it was reported that some clinical manifestations peculiar to OS signs are not observed in patients carrying mutations in the SPECC1L gene, leading to the proposal of the designation of 'SPECC1L syndrome' to refer to this disorder. Our study confirms that patients with diagnosis of OS, mainly characterized by the presence of hypospadias and laryngo-tracheo-esophageal defects, do not carry pathogenic SPECC1L mutations. In addition, SPECC1L syndrome-associated mutations are clustered in two specific domains of the protein, whereas the missense variants detected in our work lies elsewhere and the impact of these variants in the function of this protein is difficult to ascertain with the current knowledge and will require further investigations. Nonetheless, our study provides further insight into the SPECC1L syndrome classification.

Computer-Assisted Frontofacial Monobloc Advancement and Facial Bipartition for Pfeiffer Syndrome: Surgical Technique.

BACKGROUND: In patients with Pfeiffer syndrome, several corrections are required to correct facial retrusion, maxillary deficiency, or even hypertelorism. The frontofacial monobloc advancement (FFMA) and the facial bipartition (FB) are the gold standard surgeries. We present the correction of this deformity using a simultaneous computer-assisted FFMA and FB. METHODS: The 3-dimensional surgical planning defined the virtual correction and bone-cutting guide in view of the FFMA and FB. Coronal and intraoral approaches were combined to perform the osteotomies. Four internal distractors were also placed for the postoperative distraction osteogenesis. RESULTS: We reported 2 cases of computer-assisted surgery with satisfying outcomes. The sagittal deficiency (fronto-facial retrusion) was corrected by FFMA and the transversal abnormality (i.e., hypertelorism and maxillary deficiency) by the FB, then followed by an internal distraction osteogenesis. CONCLUSIONS: Computer-assisted surgery is helpful and a reliable option for the management of complex faciocraniosynostosis such as hypertelorism and frontofacial retrusion.

Prenatal diagnosis of Roberts syndrome in a Chinese family based on ultrasound findings and whole exome sequencing: a case report.

BACKGROUND: Roberts syndrome (RBS) is a rare autosomal recessive disorder caused by variations in the ESCO2 gene; however, prenatal diagnosis of RBS has never been reported in Chinese families. Additionally, fetal-specific phenotypic characteristics associated with ESCO2 variants have not been reported. CASE PRESENTATION: A fetus in a healthy, nonconsanguineous Chinese family with multiple serious congenital malformations was diagnosed prenatally. Two consecutive fetuses in this family presented with tetraphocomelia, growth restriction, cleft lip and palate bilaterally, and other abnormalities. The main phenotypic characteristics of this case were strongly suspected to be associated with RBS. Finally, whole exome sequence analysis revealed the insertion of a homozygous base pair in exon 6 of the ESCO2 gene (NM_001017420.3, c.1111insA, NP_001017420.1, p.Thr371fs). Both of the couples were heterozygous carriers for this variant. CONCLUSION: We are the first to report a prenatal case of RBS diagnosed in a Chinese family. Here, we have confirmed that the rare variant is a definite pathogenic variant, and we provide detailed phenotypic characteristics for the prenatal diagnosis of RBS due to this causative variant.

Esco2 and cohesin regulate CRL4 ubiquitin ligase ddb1 expression and thalidomide teratogenicity.

Cornelia de Lange syndrome (CdLS) and Roberts syndrome (RBS) are severe developmental maladies that arise from mutation of cohesin (including SMC3, CdLS) and ESCO2 (RBS). Though ESCO2 activates cohesin, CdLS and RBS etiologies are currently considered non-synonymous and for which pharmacological treatments are unavailable. Here, we identify a unifying mechanism that integrates these genetic maladies to pharmacologically-induced teratogenicity via thalidomide. Our results reveal that Esco2 and cohesin co-regulate the transcription of a component of CRL4 ubiquitin ligase through which thalidomide exerts teratogenic effects. These findings are the first to link RBS and CdLS to thalidomide teratogenicity and offer new insights into treatments.

ALX-Related Frontonasal Dysplasias: Clinical Characteristics and Surgical Management.

AIM: The term frontonasal dysplasia (FND) represents a spectrum of anomalies and its genetics have not been well defined. Recently, the critical role of the aristaless-like homeobox (ALX) gene family on the craniofacial development has been discovered. In the present study, we aimed to propose a systematic surgical treatment plan for the ALX-related FNDs according to the genotypic classification as well as demonstrating their clinical characteristics to help surgeons diagnose the underlying pathology accurately. DESIGN: Single-institution retrospective. SETTING: Tertiary health care. PATIENTS AND METHODS: Eighty-nine FND cases were evaluated. Eight of them had ALX1-related FND3, 3 had ALX3-related FND1, and 2 had ALX4-related FND2. Phenotype characteristics of ALX-related FNDs were evaluated, and relevant surgical interventions were assessed. RESULTS: The ALX1-related FND3 phenotype is striking due to the involvement of the eyes in addition to the presence of hypertelorism, facial clefts, and nasal deformities. A widened philtrum and prominent philtral columns are remarkable features of the ALX3-related FND1, whereas the ALX4-related FND2 has more severe deformities: severe hypertelorism, brachycephaly, large parietal bone defects, broad nasal dorsum, and alopecia. Facial bipartition, box osteotomies, eyelid coloboma repair, cleft lip and palate repair, nasal reconstruction, and fronto-orbital advancement can be performed in ALX-related FNDs based on the characteristics of each subtype. CONCLUSIONS: This genetic classification system will help surgeon diagnose patients with FND with unique features and draw a roadmap for their treatment with a better surgical perspective.

Genetic architecture of orbital telorism.

The interocular distance, or orbital telorism, is a distinctive craniofacial trait that also serves as a clinically informative measure. While its extremes, hypo- and hypertelorism, have been linked to monogenic disorders and are often syndromic, little is known about the genetic determinants of interocular distance within the general population. We derived orbital telorism measures from cranial magnetic resonance imaging by calculating the distance between the eyeballs' centre of gravity, which showed a good reproducibility with an intraclass correlation coefficient of 0.991 (95% confidence interval 0.985-0.994). Heritability estimates were 76% (standard error = 12%) with a family-based method (N = 364) and 39% (standard error = 2.4%) with a single nucleotide polymorphism-based method (N = 34 130) and were unaffected by adjustment for height (model II) and intracranial volume (model III) or head width (model IV). Genome-wide association studies in 34 130 European individuals identified 56 significantly associated genomic loci (P < 5 × 10-8) across four different models of which 46 were novel for facial morphology, and overall these findings replicated in an independent sample (N = 10 115) with telorism-related horizontal facial distance measures. Genes located nearby these 56 identified genetic loci were 4.9-fold enriched for Mendelian hypotelorism and hypertelorism genes, underlining their biological relevance. This study provides novel insights into the genetic architecture underlying interocular distance in particular, and the face in general, and explores its potential for applications in a clinical setting.

Genetically induced redox stress occurs in a yeast model for Roberts syndrome.

Roberts syndrome (RBS) is a multispectrum developmental disorder characterized by severe limb, craniofacial, and organ abnormalities and often intellectual disabilities. The genetic basis of RBS is rooted in loss-of-function mutations in the essential N-acetyltransferase ESCO2 which is conserved from yeast (Eco1/Ctf7) to humans. ESCO2/Eco1 regulate many cellular processes that impact chromatin structure, chromosome transmission, gene expression, and repair of the genome. The etiology of RBS remains contentious with current models that include transcriptional dysregulation or mitotic failure. Here, we report evidence that supports an emerging model rooted in defective DNA damage responses. First, the results reveal that redox stress is elevated in both eco1 and cohesion factor Saccharomyces cerevisiae mutant cells. Second, we provide evidence that Eco1 and cohesion factors are required for the repair of oxidative DNA damage such that ECO1 and cohesin gene mutations result in reduced cell viability and hyperactivation of DNA damage checkpoints that occur in response to oxidative stress. Moreover, we show that mutation of ECO1 is solely sufficient to induce endogenous redox stress and sensitizes mutant cells to exogenous genotoxic challenges. Remarkably, antioxidant treatment desensitizes eco1 mutant cells to a range of DNA damaging agents, raising the possibility that modulating the cellular redox state may represent an important avenue of treatment for RBS and tumors that bear ESCO2 mutations.

Pseudo-Roberts Syndrome: An Entity or Not?

Background: Roberts syndrome is a genetic disorder characterized by tetra-phocomelia with abnormalities of ESCO2. We report a male stillborn with tetra-phocomelia and no ESCO2 mutation. Case report: Pre- and post-natal imaging and autopsy findings included schizencephaly, phocomelia of four limbs, micrognathia, oligodactyly, and cardiopulmonary malformations. Microcephaly on pre-natal imaging was not confirmed by autopsy examination. Karyotype, prenatal chromosome microarray and ESCO2 gene testing were normal. Conclusion: Given the various skeletal anomalies found on autopsy and imaging evaluations, at least phenotypically, our case appeared to conform into Roberts syndrome spectrum. Since the infant did not have the mutation associated with this disorder, this infant could be labeled as the first report of a pseudo-Roberts syndrome because many of his phenotypic anomalies are characteristic of Roberts syndrome in absence of the ESCO2 gene mutation.

Esthesioneuroblastoma Presenting With Orbital Hypertelorism and Foster-Kennedy Syndrome.

ABSTRACT: Esthesioneuroblastoma is a rare neoplasm originating from the olfactory neuroepithelium at the cribriform plate. The superior nasal cavity is primarily affected. Morbidity and mortality are related to locally destructive growth as well as metastatic potential. Orbital involvement is associated with decreased survival. The authors describe a case of advanced esthesioneuroblastoma with bilateral orbital involvement, presenting with a rare constellation of orbital hypertelorism and Foster-Kennedy Syndrome.

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.

[Research Advances of Human Homologue of Mouse Progressive Ankylosis Protein and Bone and Joint Diseases].

The human homologue of mouse progressive ankylosis protein(ANKH)is an inorganic pyrophosphate transport regulator,which regulates tissue mineralization by controlling the level of inorganic pyrophosphate.It plays an important role in the pathogenesis and development of bone and joint diseases,such as ankylosing spondylitis,craniometaphyseal dysplasia,and articular cartilage calcification.This review summarizes the progress of research on ANKH and the above-mentioned diseases.