Epicanthus Research Articles

Comprehensive Assessment of Dermatologic and Dysmorphic Manifestations in Patients With Down Syndrome.

Down syndrome (DS), a common chromosomal anomaly caused by trisomy of chromosome 21, is characterized by a broad spectrum of phenotypic characteristics across multiple organ systems, including cardiac defects and leukemia. Dermatological findings are prevalent among individuals with DS; however, these issues are frequently underrecognized and inadequately researched, resulting in a significant gap in the provision of comprehensive healthcare strategies. Given the increased life expectancy of patients with DS and delayed manifestation of many dermatoses, physicians are increasingly encountering dermatological findings in this population. This study aimed to assess the prevalence and types of dermatological findings in individuals with DS, compare them with those in a control group, and emphasize the necessity of incorporating dermatological evaluations into routine health monitoring. This prospective cross-sectional study was conducted from June 2023 to June 2024 and involved 100 genetically confirmed individuals with DS and 100 age- and sex-matched controls. Comprehensive demographic, clinical, and karyotype data were collected for the DS group, and all the participants underwent detailed morphological evaluations. The DS group had a mean age of approximately 6.37 years, whereas the controls were around 7 years old, with no significant differences in age or sex distribution between the groups. Karyotype analysis showed that trisomy 21 was present in 92% of the cases, mosaicism in 6%, and translocation in 2%. Common dermatological findings in the DS group included xerosis cutis (49%), thin and sparse hair (48%), dental caries (34%), delayed tooth eruption (28%), nail dystrophy (25%), fissured tongue (23%), and cheilitis (18%). Significant differences were noted in the prevalence of scabies, bacterial infections, and café au lait macules between the DS and control groups (p < 0.01). Dysmorphic findings in the DS group included epicanthal folds (97%), upslanted palpebral fissures (97%), brachycephaly (91%), and single transverse palmar crease (89%). Significant gender differences were noted in the prevalence of brachycephaly and the sandal gap (p < 0.01). This study highlights the importance of regular dermatological care in enhancing the health management and quality of life of individuals with DS due to the prevalence and variability of dermatological conditions.

De novo variants in ATXN7L3 lead to developmental delay, hypotonia and distinctive facial features.

Deubiquitination is crucial for the proper functioning of numerous biological pathways, such as DNA repair, cell cycle progression, transcription, signal transduction and autophagy. Accordingly, pathogenic variants in deubiquitinating enzymes (DUBs) have been implicated in neurodevelopmental disorders and congenital abnormalities. ATXN7L3 is a component of the DUB module of the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex and two other related DUB modules, and it serves as an obligate adaptor protein of three ubiquitin-specific proteases (USP22, USP27X or USP51). Through exome sequencing and by using GeneMatcher, we identified nine individuals with heterozygous variants in ATXN7L3. The core phenotype included global motor and language developmental delay, hypotonia and distinctive facial characteristics, including hypertelorism, epicanthal folds, blepharoptosis, a small nose and mouth, and low-set, posteriorly rotated ears. To assess pathogenicity, we investigated the effects of a recurrent nonsense variant [c.340C>T; p.(Arg114Ter)] in fibroblasts of an affected individual. ATXN7L3 protein levels were reduced, and deubiquitylation was impaired, as indicated by an increase in histone H2Bub1 levels. This is consistent with the previous observation of increased H2Bub1 levels in Atxn7l3-null mouse embryos, which have developmental delay and embryonic lethality. In conclusion, we present clinical information and biochemical characterization supporting ATXN7L3 variants in the pathogenesis of a rare syndromic neurodevelopmental disorder.

Computer-based facial recognition as an assisting diagnostic tool to identify children with Noonan syndrome

BackgroundNoonan syndrome (NS) is a rare genetic disease, and patients who suffer from it exhibit a facial morphology that is characterized by a high forehead, hypertelorism, ptosis, inner epicanthal folds, down-slanting palpebral fissures, a highly arched palate, a round nasal tip, and posteriorly rotated ears. Facial analysis technology has recently been applied to identify many genetic syndromes (GSs). However, few studies have investigated the identification of NS based on the facial features of the subjects.ObjectivesThis study develops advanced models to enhance the accuracy of diagnosis of NS.MethodsA total of 1,892 people were enrolled in this study, including 233 patients with NS, 863 patients with other GSs, and 796 healthy children. We took one to 10 frontal photos of each subject to build a dataset, and then applied the multi-task convolutional neural network (MTCNN) for data pre-processing to generate standardized outputs with five crucial facial landmarks. The ImageNet dataset was used to pre-train the network so that it could capture generalizable features and minimize data wastage. We subsequently constructed seven models for facial identification based on the VGG16, VGG19, VGG16-BN, VGG19-BN, ResNet50, MobileNet-V2, and squeeze-and-excitation network (SENet) architectures. The identification performance of seven models was evaluated and compared with that of six physicians.ResultsAll models exhibited a high accuracy, precision, and specificity in recognizing NS patients. The VGG19-BN model delivered the best overall performance, with an accuracy of 93.76%, precision of 91.40%, specificity of 98.73%, and F1 score of 78.34%. The VGG16-BN model achieved the highest AUC value of 0.9787, while all models based on VGG architectures were superior to the others on the whole. The highest scores of six physicians in terms of accuracy, precision, specificity, and the F1 score were 74.00%, 75.00%, 88.33%, and 61.76%, respectively. The performance of each model of facial recognition was superior to that of the best physician on all metrics.ConclusionModels of computer-assisted facial recognition can improve the rate of diagnosis of NS. The models based on VGG19-BN and VGG16-BN can play an important role in diagnosing NS in clinical practice.

Medial Epicanthoplasty with the Skin Re-Draping Technique: Technical Refinements for Predictable outcomes.

The epicanthus is a common feature of the Asian eyes. A prominent medial epicanthal fold gives the impression of a blunted affect and the procedure for its removal, the medial epicanthoplasty, is a very commonly requested by Asian patients. This may be performed as an isolated procedure or more commonly in combination with the upper blepharoplasty. Many conventional medial epicanthoplasty techniques are based on skin flaps transposition and excisions, usually variations of the V-Y, W or Z-plasties (1-4). While these have been variably successful at correcting the epicanthal fold, the common problem is significant scarring in the medial canthal and lower eyelid regions (5-8). This is particularly problematic in Asian patients with greater tendencies for hypertrophic scarring and scar hypo or hyper-pigmentation (9). Recently, the skin re-draping method, designed with incisions limited within the margins of the medial canthus and precise and targeted disruption of the underlying fibromuscular tissues, has emerged as the preferred surgical technique for many Asian surgeons because of its effectiveness and superior aesthetic outcomes(6, 10-12). This technique delivers the most inconspicuous incisions and is advantageous because it is effective in eliminating epicanthal folds of various severities. Precise execution of this technique is difficult, given the complex 3-dimensional anatomy of the epicanthus. This paper presents a detailed explanation of surgical concepts of the skin re-draping epicanthoplasty and provide a step-by-step guide to performing this procedure in a safe and effective manner.

Ileal Atresia in Down Syndrome, A Rare Finding

A 37-week-old baby boy was born by cesarean section to a 40-yearold G7P6006 mother who tested positive for 21+ by noninvasive prenatal testing. At delivery, the baby had features of Down Syndrome, including low-set ears, bilateral epicanthal folds, a flat nasal bridge, a protruding tongue, a Simian crease on the right hand, an umbilical hernia, and excess skin on the nape of the neck. He presented with Apgar’s of 7 and 8. He was admitted to the NICU requiring CPAP due to respiratory distress, kept NPO, and started on IV fluids. When feeds were started at the end of the first day of life, he was noted to have episodes of bilious emesis, with abdominal distention, and failure to pass meconium till 36 hours of life.

Waardenburg or Blepharophimosis ptosis epicanthus inversus syndrome? – An enigmatic riddle

Waardenburg syndrome (WS) is a genetic disorder that may be discernible right at birth. The syndrome is well known to have heterogeneous expression; the range, and severity of which may vary greatly from case to case, even among the individuals of the same household. Here, we report a 19-year-old female who was initially diagnosed as a case of Blepharophimosis ptosis epicanthus inversus syndrome (BPES) and referred to our subspecialty clinic for undergoing surgery. On examination, she had medial canthal dystopia, telecanthus, synorphys, and similar facial features in a first-degree family member. These features were suggestive of WS. After that, the primary diagnosis was revised; systematic evaluation was performed, surgical correction for her telecanthus was ventured with a favourable outcome. Both WS and BPES may present with similar facial features and thereby pose a clinical dilemma. Such misdiagnosis may hinder proper evaluation and management of any underlying systemic associations.

The Application of Reverse Z-Plasty Design in Medial Canthal Skin Redundancy Reconstruction Surgery.

To investigate the clinical outcomes of reverse Z-plasty in the reconstruction of epicanthal fold. We conducted a retrospective analysis on clinical data from patients who underwent medial canthal skin redundancy reconstruction surgery from September 2019 to January 2023. The surgical procedure involved a preoperative design for the incision line, suborbicularis oculi dissection to create a muscle flap, and the use of a reverse Z-flap for the reconstruction of the lateral canthal fold. Postoperative follow-up assessments focused on the intercanthal distance, positional changes of the medial canthus point, alterations in the medial canthus angle, and patient satisfaction levels. The statistical evaluation was carried out utilizing paired t -tests, with a P -value of less than 0.05 denoting statistical significance. Postsurgery, the lacrimal prominences were less exposed, and inner canthal angles naturally reshaped. Inconspicuous scarring with diminished reverse Z-plasty marks was noted within 3 months. The average ICD has increased by 3 to 6mm, corresponding to elongation ratios of 9.09% to 28.30%. Preoperatively, the ICD averaged 31.25±2.32mm, expanding postoperatively to 35.19±2.26mm. The canthal angle enlarged significantly from 49.031±6.627 to 62.188±6.662. Inner canthal points shifted notably postsurgery, with a decrease in x-value and an increase in y-value, signalling a movement upwards and away from the nose. Patient satisfaction is high. The reverse Z-plasty technique has proven to be an effective approach for reconstructing the epicanthal fold. The clarity and precision of the incision design, coupled with the stability of postoperative results, demonstrate that this method can reliably achieve successful epicanthal fold reconstruction.

Macular hypoplasia and high myopia in 48, xxyy syndrome: a unique case of 48, xxyy syndrome that presents with high myopia and macular dysplasia

BackgroundAmong sex chromosome aneuploidies, 48, XXYY syndrome is a rare variant. This condition is marked by the existence of an additional X and Y chromosome in males, leading to a diverse range of physical, neurocognitive, behavioral, and psychological manifestations. Typical characteristics include a tall stature and infertility. Other phenotypes include congenital heart defects, skeletal anomalies, tremors, obesity, as well as the potential for type 2 diabetes and/or peripheral vascular disease.Case presentationA 6-year-old boy, who had been experiencing progressive vision deterioration in both eyes for the past two years, presented with a history of poor vision, delayed motor skills. The patient was diagnosed with micropenis in the pediatric outpatient clinic. Sparse hair, an unusually tall stature and craniofacial dysmorphology characterized by ocular hypertelorism, depressed nasal bridge, and epicanthic folds were observed. Comprehensive ophthalmic examination revealed high myopia and grade 3 macular hypoplasia. Diagnostic investigations including karyotype analysis and whole-exome sequencing identified an anomalous male karyotype comprising two X and two Y chromosomes, confirming a diagnosis of 48, XXYY syndrome.ConclusionsThis study underscores the rare association of high myopia and grade 3 macular dysplasia with 48, XXYY syndrome. To our knowledge, this case marks the first recorded instance of macular dysplasia in a patient with 48, XXYY syndrome. This novel finding enhances our understanding of this syndrome’s phenotypic variability.

Clinical Features and Cardiac Anomalies of Children with Down Syndrome. A Literature Report

Background: Clinical diagnosis of Down syndrome is based on the characteristic features and associated malformations. Nonetheless, there is significant individual diversity in the clinical presentation. Not every physical characteristic may be present, particularly in infants. At the same, congenital heart abnormalities (CHD) remain a major predictor of death in children with Down syndrome (DS) despite improvements in surgical therapy for these conditions. The effects of DS vary from person to person, with some people having a significant impact while others are well and capable of living unassisted as adults. So, this study is done to understand the pattern of clinical features and cardiac anomalies in various research reports.Aim: This scoping review aims to describe the frequency and distribution of clinical features and cardiac anomalies in children with Down syndrome and to consider the clinical implications of this knowledge.Methods: Medline, CINHAL, and PubMed databases were searched electronically to identify pertinent articles from 2000 to 2023. Children with Down syndrome and cardiac comorbidities aged 18 years or younger met the inclusion criteria. Articles that were not peer-reviewed or written in English were disqualified at the title or abstract level.Results: Literature revealed that the common physical and dysmorphic features found in individuals with Down syndrome include flat facial profile, epicanthal folds, upward slanting eyes, hypotonia, small ears, short neck, protruding tongue, small hands and feet, brushfield spots, sandal gap, and short stature. It's important to note that while these physical features are commonly associated with Down syndrome, not all individuals will exhibit every characteristic, and the severity can vary greatly among individuals.A high prevalence of CHD was reported in DS children from a group where consanguinity was relatively frequent. The prevalence of congenital heart disease in children with Down syndrome is the highest reported, especially when the researchers have used diagnostic ultrasound. VSD and AVSD, followed by persistent ductus arteriosus, and tetralogy of Fallot are the most common CHD in DS children. Recent research suggests that though the incidence of CHD in DS children has remained stable over time, there may be trends in some forms of CHD, with a rise in isolated, less severe kinds and a reduction in complicated, more severe ones. Individuals with Down syndrome can lead fulfilling lives with appropriate support and resources.Conclusion: All neonates with a new diagnosis or suspicion of DS must undergo comprehensive screening, which includes clinical examination, ECG, and echocardiography in the second trimester combined with fetal echocardiography when the fetal ultrasonography raises the likelihood of an abnormality. Literature proves that regardless of the existence of DS, early CHD repair is advised for newborns susceptible to biventricular surgery. For the most part, DS is not linked to an increased perioperative risk for CHD.Understanding DS heterogeneity will help professionals provide better prenatal counseling, assist parents in establishing focused early interventions to improve daily activities and the quality of life for their children, and assist policy-makers in providing and allocating resources for disability services. A sustaining commitment to scientific and clinical research studies is necessary to enhance the quality of life and survival for DS patients from infancy into adulthood.

A Novel Dental and Maxillofacial Sign in Aarskog Syndrome: A Family Case and Review of the Literature

Objective: To describe a case of a novel mutation with dental and maxillofacial expression in a family with Aarskog syndrome and to conduct a literature review to determine the importance of a multidisciplinary approach in the pathology. Methods: The authors described a family of a father and mother and 7 children (5 sons affected). The first child is evaluated for multiple mandibular osteolytic lesions and dental malocclusion with eruption disorders. The patient presents facial features of Aarskog syndrome, such as hypertelorism and eyelid ptosis with epicanthal folds, but also an unusual sign of numerous comedones distributed over the body. A literature review on dental and maxillofacial signs in Aarskog syndrome was conducted on Scopus and Pubmed with specific keywords. Results: Osteolytic lesions are described as orthokeratotic keratocysts with giant cellular, foreign body type, calcifications, and bone spicules. A recurrence occurred 2 years after surgery of keratocysts. Ten articles were selected for the description of dental and maxillofacial features associated with Aarskog syndrome. Discussion: Literature has paid little attention to different phenotypic characterizations in the maxillofacial region of patients with Aarskog syndrome. It is important to determine an early diagnosis to provide the best treatments for patients. The family described has some peculiarities: (1) a new nucleotide variation, (2) the sample size, (3) features as multiple comedones of the body, and keratocysts of the jaws are never described in the literature. Conclusion: Clinical and radiological maxillofacial signs, often not evaluated in Aarskog syndrome, should be considered early to obtain an optimal treatment.

Medial Epicanthal Fold Correction Using a Y-W Epicanthoplasty in Asian Eyelids.

Many surgical techniques for managing epicanthal folds have been reported, but their main drawbacks include a noticeable scar in Asians, acute medial canthal angle, and applicability only in mild or moderate epicanthal folds. This study described a novel surgical technique, Y-W epicanthoplasty, and assessed the medial canthal shape and scarring in patients who underwent Y-W epicanthoplasty. Patients with moderate or severe epicanthal folds between January 2004 and February 2017 were included in this study. Pre- and postoperative intercanthal distance (ICD), inner canthal angle (ICA), and interpupillary distance (IPD) were measured. The ICD ratios (ICD/IPD) and extent of postoperative scarring were evaluated. A Y-W epicanthoplasty was performed on 18 patients. The ICD ratio of the total study cohort showed a significant reduction following surgery (preoperative ICD ratio=0.62±0.04, postoperative ICD ratio=0.58±0.03, P<0.001). The ICA was 51.8±7.7° and 49.8±5.6° in the pre- and postoperative periods, respectively (P=0.086) Eleven patients showed no apparent scar, and 6 patients were found to have minimal scarring that was visible only under close inspection. One patient had a hypertrophic scar that was successfully managed with triamcinolone acetonide injections. Y-W epicanthoplasty can provide good aesthetic results without a visible scar in patients with moderate-to-severe epicanthal folds. The Y-W epicanthoplasty avoids a medially extended skin incision and excessive tension on the skin flaps. Moreover, an acutely shaped or webbed medial canthus after epicanthoplasty can be prevented by adding a small triangular flap. The Y-W epicanthoplasty procedure is simple and straightforward, and it is appropriate for moderate-to-severe epicanthal fold correction.

Novel FOXL2 variants in two Chinese families with blepharophimosis, ptosis, and epicanthus inversus syndrome.

Introduction: Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare inherited disorder. This study was aimed to identify and functionally validate FOXL2 variants in two Chinese families with BPES. Methods: The proband and his family members were subjected to whole-exome sequencing to identify disease-associated variants. Several bioinformatic tools were used to computationally predict altered proteins. In vitro functional assays were conducted by transfecting wild-type and mutant FOXL2 cDNAs into HEK-293 cells, followed by subcellular localization assays, luciferase reporter gene assays, and quantitative real-time polymerase chain reaction. Results: The clinical features of BPES, including small palpebral fissures, ptosis, telecanthus, and epicanthus inversus, were present in all affected patients. Two novel mutations were detected, c.292T>A and c.383G>T. Whole-exome sequencing analysis and prediction software suggested that these mutations were pathogenic. Functional studies showed that these two point mutations decreased FOXL2 protein expression, resulting in subcellular mislocalization and aberrant transcriptional activity of the steroidogenic acute regulatory protein gene promoter. Conclusion: Our results add to the current understanding of known FOXL2 variants in, and our in vitro experiments provide reference data and insights into the etiology of BPES. Further studies are needed to identify the possible mechanisms underlying the action of this mutation on the development of BPES.

Emanuel syndrome due to unusual pattern

BackgroundThe hallmarks of Emanuel syndrome are pre- and postnatal growth retardation, microcephaly, global developmental delay, ear anomalies, and in males, heart, kidney, and genital abnormalities.ResultsThis study describes the atypical features of Emanuel syndrome, a rare chromosomal disorder. The patient had several physical features that are common in Emanuel syndrome, such as microcephaly, hypotonia, and ear anomalies. However, he exhibited certain unusual characteristics, including the lack of a prominent forehead, epicanthic folds, and a downward slanting palpebral fissure. There was infratentorial brain involution with a minor infarction in the left cerebral hemisphere and cerebellar hypoplasia on the magnetic resonance imaging (MRI) scan of the brain. Additionally, the patient had bilateral mild hearing loss and an aberrant epileptogenic pattern on the electroencephalogram (EEG). Orodental examination showed a long philtrum, everted fissured thick lower lip, highly attached labial frenum, and prominent median palatine raphe. The karyotype revealed 45XY t(11;22)(p15.5;q11.22), which is different from the typical karyotype of Emanuel syndrome.ConclusionsThis case sheds light on the possibility of alternative genetic mechanisms, beyond chromosomal abnormalities, in patients presenting with multiple congenital anomalies and facial dysmorphism.

Epicanthoplasty: Social and historical perspectives

The epicanthus is a fold of skin covering the inner corner of the eye which blends into the nasal skin. It is a cosmetic feature of many populations of the world. The surgical alteration of this structure was first developed for the epicanthus found in such congenital genetic conditions as Down syndrome in the West. In the past century and a half, in what may be a reaction to the Western portrayal of skin overlying the eye and of Shakespeare's descriptions of characters with epicanthic folds, surgical techniques have arisen for pure cosmetic intent to alter the Asian eyelid. These procedures have almost wholly become undertaken by patients and surgeons of East Asian descent. Since 1989, the epicanthus surgery literature has been penned predominantly by authors of East Asian descent.

Outcomes for expanded polytetrafluoroethylene strip in frontalis suspension surgery

ABSTRACT Purpose This study evaluates surgical outcomes and complication rates of frontalis suspension with expanded polytetrafluoroethylene (ePTFE). Methods This retrospective cohort study reviewed all patients undergoing frontalis suspension surgery using ePTFE as the sling material from January 1 2012 to March 3 2020 by a single surgeon at a single academic center. Two different surgical techniques were evaluated in the placement of the sling material. Demographic, clinical, and operative data were extracted. Outcome data including postoperative lid height, reoperation, and complication rate were extracted for the cohort and compared between the two surgical techniques. Descriptive statistics were utilized. Results Sixty-four eyes from 49 unique patients were included in this study. Forty-three (67.2%) patients had isolated congenital blepharoptosis; 14 (21.9%) had blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES); and 2 (3.1%) had cranial nerve III palsy. Fifty-one (79.7%) patients had no prior blepharoptosis surgery. Lid crease incision and stab incision techniques were utilized for 24 (37.5%) and 40 (62.5%) eyes, respectively. Overall, 21 (32.8%) eyes required reoperation with ePTFE to achieve appropriate eyelid height or contour. Only one patient experienced implant infection, requiring removal of ePTFE sling after a second reoperation. There were no cases of implant exposure or granuloma formation noted during the study period. Conclusion An ePTFE strip soaked in cefazolin prior to utilization in surgery is a viable material for frontalis suspension surgery, with a lower infectious or inflammatory complication rate than previously reported. However, reoperation rate was still relatively high.

The Medial Canthus Fibrous Band's Impact on Epicanthal Fold Severity and Classification in Asians: Implications for Epicanthoplasty.

The epicanthal fold (EF) is a semilunar skin fold located in the medial canthus in most Asians. The medial canthus fibrous band (MCFB) reportedly plays a critical role in EF formation. Variations in MCFB shape and size affect the severity and type of EF. We aimed to analyze MCFB variations in different types and severities of EF and explore the effect of the MCFB resection epicanthoplasty technique (MCFB epicanthoplasty). Surgical videos of 40 patients undergoing MCFB epicanthoplasty in our department were reviewed. The MCFB (area), transverse dimension, vertical dimension, upper eyelid direction length (UEDL), and lower eyelid direction length (LEDL) were measured. For aesthetic assessment, 37 patients were followed up for 6 months; intercanthal distance (ICD) and horizontal lid fissure length (HLFL) were measured. Preoperative and postoperative ICD/HLFL ratios were compared. Postoperative scar recovery was evaluated with the Patient and Observer Scar Assessment Scale. Statistical significance was set at P < .05. The MCFB diameter and area were larger for severe EF than for moderate EF (P < .01). Patients with severe EF had larger LEDL than UEDL (P < .01). The tarsalis type had a larger LEDL than the palpebralis type with the same severity (P < .01). MCFB epicanthoplasty yielded favorable postoperative cosmetic effects and scar recovery. Postoperative ICD decreased, while HLFL increased compared to preoperative values (P < .001). The ICD/HLFL ratio was significantly lower postoperatively than preoperatively (P < .001). Postoperative ICD/HLFL ratio was 1.2:1. The MCFB affects the severity and type of EF. MCFB epicanthoplasty effectively corrected moderate to severe EF.

De novo KAT6B mutation causes Say–Barber–Biesecker–Young–Simpson variant of Ohdo syndrome in an Iranian boy: a case report

BackgroundSay–Barber–Biesecker–Young–Simpson (SBBYS) (OMIM #603736, Ohdo syndrome variant) is a rare type of severe blepharophimosis intellectual disability syndrome, which is generally characterized by a global developmental delay, distinctive facial features, and intellectual disability with multiple congenital anomalies, including skeletal involvement, missing, or underdeveloped kneecaps, and genital anomalies, in affected males. It has been shown that mutations in the KAT6B gene, which is a lysine acetyltransferase-encoding gene, have been associated with SBBYS syndrome. All the known variants are dominant de novo mutations that result in protein truncation.Case presentationA 14-year-old Iranian Azeri boy with an intellectual disability, distinct dysmorphic facial features such as open-mouth expression, sparse medial eyebrows, widely spaced upward-slanted eyes, epicanthal folds, broad nasal bridge, low-set ears, anteverted ears, short philtrum, hypertelorism, microphthalmia is presented in this case study. Cryptorchidism was reported. Neurologically, the patient presented with poor eye contact, hypotonia, and speech difficulties. In the skeletal X-ray, underdeveloped kneecaps with some new features were observed.ConclusionWe present the first case of SBBYS syndrome in association with some new anomaly features in the Iranian population. Based on this diagnosis, we could provide the patient with a suitable plan of management as well as appropriate genetic counseling for his family.

Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES): Brief review of genetics, clinical presentation, and management

Abstract Blepharophimosis, ptosis, epicanthus inversus syndrome (BPES) is a rare genetic disorder characterized primarily by four distinct features including telecanthus. BPES is an autosomal dominant disorder caused by mutations in the FOXL2 gene located on chromosome 3q23. Two types of BPES has been described, type 1 BPES with ovarian insufficiency and type 2 with only major ocular features. Various other associations including lid dysplasia, strabismus, refractive error and lacrimal duct anomalies are noted. This review article aims to provide a comprehensive overview of BPES syndrome, including its genetics, clinical manifestations, differential diagnosis, and management options.

Deletion of cis-regulatory Element in FOXL2 Promoter in a Chinese Family of Type II Blepharophimosis-ptosis-epicanthus Inversus Syndrome with Polydactyly.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a relatively uncommon autosomal-dominant genetic disorder, primarily attributed to mutations in the forkhead box L2 (FOXL2) gene. Albeit the involvement of protein-coding regions of FOXL2 has been observed in the majority of BPES cases, whether deficiencies in regulatory elements lead to the pathogenesis remains poorly understood. Herein, an autosomal-dominant BPES type II family was included. Peripheral venous blood has been collected, and genomic DNA has been extracted from leukocytes. A whole exome sequencing analysis has been performed and analyzed (Deposited in NODE database: OER422653). The promoter region of FOXL2 was amplified using polymerase chain reaction (PCR). The luciferase reporter assay was performed to identify the activity of this region. In this study, we present a Chinese family diagnosed with type II BPES, characterized by the presence of small palpebral fissures, ptosis, telecanthus, and epicanthus inversus. Notably, all male individuals within the family display polydactyly. A 225-bp deletion in the 556-bp 5'-upstream to transcription start site of FOXL2 , decorated by multiple histone modifications, was identified in affected members of the family. This deletion significantly decreased FOXL2 promoter activity, as measured by the luciferase assay. Conclusively, a novel 255-bp-deletion of the FOXL2 promoter was identified in Chinese families with BPES. Our results expand the spectrum of known FOXL2 mutations and provide additional insight into the genotype-phenotype relationships of the BPES pathogenesis. In addition, this study indicates the important role of genetic screening of cis-regulatory elements in testing heritable diseases.

Expanded phenotypic spectrum of FOXL2 Variant c.672_701dup revealed by whole-exome sequencing in a rare blepharophimosis, ptosis, and epicanthus inversus syndrome family

IntroductionBlepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare genetic disease with diverse ocular malformations. This study aimed to investigate the disease-causing gene in members of a BPES pedigree presenting with the rare features of anisometropia, unilateral pathologic myopia (PM), and congenital cataracts.MethodsThe related BPES patients underwent a comprehensive ocular examination. Next, whole-exome sequencing (WES) was performed to screen for the disease-causing genetic variants. A step-wise variant filtering was performed to select candidate variants combined with the annotation of the variant's pathogenicity, which was assessed using several bioinformatic approaches. Co-segregation analysis and Sanger sequencing were then conducted to validate the candidate variant.ResultsThe variant c.672_701dup in FOXL2 was identified to be the disease-causing variant in this rare BPES family. Combined with clinical manifestations, the two affected individuals were diagnosed with type II BPES.ConclusionThis study uncovered the variant c.672_701dup in FOXL2 as a disease causal variant in a rare-presenting BPES family with anisometropia, unilateral pathogenic myopia, and/or congenital cataracts, thus expanding the phenotypic spectrum of FOXL2.