Factors affecting anophthalmic socket reconstruction outcomes using autologous oral mucosal graft.

BACKGROUND: Limited studies have reported surgical outcomes that are defined by strict criteria following grade 2 or 3 socket reconstruction using an oral mucosal graft (OMG). We aimed to determine factors influencing surgical outcomes of anophthalmic socket reconstruction using OMG in patients with grade 2 or 3 socket contractures. METHODS: Thirty-seven patients who underwent socket reconstruction with autologous OMG between January 2007 and December 2017 were retrospectively analyzed. The successful outcome was defined as an eye prosthesis wearing without experiencing displacement and the absence of any re-operations or additional surgeries following socket reconstruction. Factors affecting surgical outcomes were identified using multivariate analysis. RESULTS: A total of 15 male and 22 female patients (mean age: 40.2 ± 17.2 years) were included. The median duration of socket contracture was 21.5 years. Grade 2 and 3 socket contractures, based on Tawfik's classification, were reported in 20 and 17 patients, respectively. Twenty-eight and eight patients underwent socket reconstruction using OMG alone and OMG combined with a hard palate graft, respectively. The success rates of grades 2 and 3 socket contracture reconstruction were 80.0% and 52.9%, respectively. Multivariate analysis demonstrated that only grade 3 contractures were predictive of worse outcomes. At the final visit (mean follow-up: 6.3 years), 34 patients (91.9%) could wear their eye prostheses. CONCLUSIONS: Socket reconstruction using autologous OMG can provide acceptable results in grade 2 and 3 contractures; however, satisfactory results were more significantly reported in grade 2 than in grade 3 contractures.

High Clinical Exome Sequencing Diagnostic Rates and Novel Phenotypic Expansions for Nonisolated Microphthalmia, Anophthalmia, and Coloboma.

Purpose: A molecular diagnosis is only made in a subset of individuals with nonisolated microphthalmia, anophthalmia, and coloboma (MAC). This may be due to underutilization of clinical (whole) exome sequencing (cES) and an incomplete understanding of the genes that cause MAC. The purpose of this study is to determine the efficacy of cES in cases of nonisolated MAC and to identify new MAC phenotypic expansions. Methods: We determined the efficacy of cES in 189 individuals with nonisolated MAC. We then used cES data, a validated machine learning algorithm, and previously published expression data, case reports, and animal models to determine which candidate genes were most likely to contribute to the development of MAC. Results: We found the efficacy of cES in nonisolated MAC to be between 32.3% (61/189) and 48.1% (91/189). Most genes affected in our cohort were not among genes currently screened in clinically available ophthalmologic gene panels. A subset of the genes implicated in our cohort had not been clearly associated with MAC. Our analyses revealed sufficient evidence to support low-penetrance MAC phenotypic expansions involving nine of these human disease genes. Conclusions: We conclude that cES is an effective means of identifying a molecular diagnosis in individuals with nonisolated MAC and may identify putatively damaging variants that would be missed if only a clinically available ophthalmologic gene panel was obtained. Our data also suggest that deleterious variants in BRCA2, BRIP1, KAT6A, KAT6B, NSF, RAC1, SMARCA4, SMC1A, and TUBA1A can contribute to the development of MAC.

Stepwise self-inflating hydrogel expansion for congenital anophthalmia and blind microphthalmia: Over 15 years' experience in China.

BACKGROUND: Self-inflating hydrogel expanders have been used to treat anophthalmia and blind microphthalmia. This study aimed to investigate the long-term outcomes of treatment with self-inflating hydrogel expanders for congenital anophthalmia and blind microphthalmia. METHODS: In this retrospective study, the medical records of 161 patients with anophthalmia and blind microphthalmia who underwent hydrogel expansion were reviewed. We measured the palpebral fissure height (PFH), palpebral fissure length (PFL), and distance between the inner canthal and mid-nasal line (ICMN) before and after surgery. Cox regression analysis was conducted to determine which variables were related to the implantation of spherical expanders following hemispherical expander implantation. RESULTS: After treatment, the PFH and PFL increased significantly (p < 0.001). Complications including expander migration and extrusion occurred in 15 cases. Five patients needed enucleation or further dermis fat graft implantation because of insufficient expansion. The necessity for further spherical expansion was substantially related to a relative axial length (rAL) <0.5 (p = 0.007). CONCLUSION: Self-inflating hydrogel expansion can significantly increase the lid fissure. The occurrence of complications is rare, and surgical intervention can effectively address them. Abnormal eyes with a rAL of less than 0.5 demonstrate a higher possibility of needing additional orbital expansion.

Identification of novel homozygous variants in FOXE3 and AP4M1 underlying congenital syndromic anophthalmia and microphthalmia.

BACKGROUND: Anophthalmia and microphthalmia are severe developmental ocular disorders that affect the size of the ocular globe and can be unilateral or bilateral. The disease is found in syndromic as well as non-syndromic forms. It is genetically caused by chromosomal aberrations, copy number variations and single gene mutations, along with non-genetic factors such as viral infections, deficiency of vitamin A and an exposure to alcohol or drugs during pregnancy. To date, more than 30 genes having different modes of inheritance patterns are identified as causing anophthalmia and microphthalmia. METHODS: In the present study, a clinical and genetic analysis was performed of six patients with anophthalmia and microphthalmia and/or additional phenotypes of intellectual disability, developmental delay and cerebral palsy from a large consanguineous Pakistani family. Whole exome sequencing followed by data analysis for variants prioritization and validation through Sanger sequencing was performed to identify the disease causing variant(s). American College of Medical Genetics and Genomics (ACMG) guidelines were applied to classify clinical interpretation of the prioritized variants. RESULTS: Clinical investigations revealed that the affected individuals are afflicted with anophthalmia. Three of the patients showed additional phenotype of intellectual disability, developmental delays and other neurological symptoms. Whole exome sequencing of the DNA samples of the affected members in the family identified a novel homozygous stop gain mutation (NM_012186: c.106G>T: p.Glu36*) in Forkhead Box E3 (FOXE3) gene shared by all affected individuals. Moreover, patients segregating additional phenotypes of spastic paraplegia, intellectual disability, hearing loss and microcephaly showed an additional homozygous sequence variant (NM_004722: c.953G>A: p.Arg318Gln) in AP4M1. Sanger sequencing validated the correct segregation of the identified variants in the affected family. ACMG guidelines predicted the variants to be pathogenic. CONCLUSIONS: We have investigated first case of syndromic anophthalmia caused by variants in the FOXE3 and AP4M1. The present findings are helpful for understanding pathological role of the mutations of the genes in syndromic forms of anophthalmia. Furthermore, the study signifies searching for the identification of second variant in families with patients exhibiting variable phenotypes. In addition, the findings will help clinical geneticists, genetic counselors and the affected family with respect to prenatal testing, family planning and genetic counseling.

Unusual onset of Graves' disease associated with thymic hyperplasia in a 5-year-old girl with congenital bilateral clinical anophthalmia: diagnostic and therapeutic challenges.

OBJECTIVES: Graves' disease (GD) is a rare auto-immune disorder in pediatric population. The association between GD and thymic hyperplasia was rarely reported in children. Diagnosis and management of GD are challenging in children. CASE PRESENTATION: This report presents the case of a 5-year-old girl with a personal history of asthma and congenital bilateral isolated clinical anophthalmia who presented with acute congestive heart failure, sinus tachycardia and atypical signs of orbitopathy with edema and erythema of the lower right eyelid and excessive tearing. The diagnosis of GD was based on detecting a suppression of serum TSH level and the presence of high titers of TRAbs. Relapse occurred after 10 months of antithyroid drugs with chief complaints of palpitations, dyspnea and dysphagia. Computed tomography showed heterogeneous anterior mediastinal mass with no invasion into the surrounding tissue. The marked shrinkage of the mass after radioiodine therapy supported the diagnosis of thymic hyperplasia associated with GD. CONCLUSIONS: The presence of clinical anophthalmia may be a confusing factor for the diagnosis of Graves' ophthalmopathy. Recognition of the association between GD and thymic hyperplasia would avoid invasive diagnostic procedures and unnecessary surgical resection. Radioiodine therapy may be used in young children with repeated relapses of GD.

Associated anomalies in anophthalmia and microphthalmia.

Infants with anophthalmia and microphthalmia (an/microphthalmia) have often other associated congenital anomalies. The reported frequency and the types of these associated anomalies vary between different studies. The purpose of this investigation was to assess the frequency and the types of associated anomalies among cases with an/microphthalmia in a geographically well defined population of northeastern France of 387,067 consecutive pregnancies from 1979 to 2007. Of the 98 infants with an/microphthalmia born during this period (prevalence at birth of 2.53 per 10,000), 88.8 % had associated anomalies. Cases with associated anomalies were divided into recognizable conditions (25 (25.5%) cases with chromosomal and 17 (17.3%) cases with non chromosomal conditions), and non recognizable conditions (45-45.9%- cases with multiple congenital anomalies -MCA). Trisomy 13 and trisomy 18 were the most frequent chromosomal abnormalities. Amniotic bands sequence, oculo-auriculo-vertebral spectrum, CHARGE syndrome and VACTERL association were most often present in recognizable non chromosomal conditions. Anomalies in the musculoskeletal, cardiovascular and central nervous systems were the most common other anomalies in cases with MCA and non recognizable conditions. However, given the limitation of the limited numbers of cases there should be urging caution in interpreting these results. In conclusion the frequency of associated anomalies in infants with anophthalmia and microphthalmia emphasizes the need for a thorough investigation of these cases. Routine screening for other anomalies especially musculoskeletal, cardiac and central nervous systems anomalies may need to be considered in infants with anophthalmia and microphthalmia, and referral of these cases for genetic counselling seems warranty.

Microbiological evaluation of conjunctival anopthalmic flora after using digital 3D-printed ocular prosthesis compared to conventional one: a randomized clinical trial.

BACKGROUND: This study aims to assess the influence of using 3D-printed acrylic resin versus conventional Poly-methyl methacrylate (PMMA) for fabricating ocular prostheses on the biofilm and microbial flora of anophthalmic socket. METHODS: A randomized controlled trial was designed as a parallel group study. Participants were allocated randomly into two groups: the control group, which received conventionally fabricated ocular prostheses (CG, n = 11), and the test group, which received digitally 3D-printed ocular prostheses (DG, n = 11). Microbiological analysis was conducted before prosthesis insertion and three months after using the ocular prosthesis. Swab samples were inoculated on blood agar, MacConkey's agar, and Sabouraud's dextrose agar (SDA) for isolating Gram-positive, Gram-negative, and fungal organisms, respectively. Subsequently, the plates were incubated at 37 degrees Celsius for 48 h. Additionally, a validated questionnaire was used for subjective clinical evaluation, including parameters such as comfort level, socket discharge, lacrimation, and frequency of lubrication for each ocular prosthesis patient in both groups. RESULTS: Test group (DG, n = 11) exhibited a positive, though statistically insignificant, difference (p > 0.001) in microbial growth when compared to the control group (CG, n = 11). A statistically significant difference was observed in comfort levels between the two groups, with more comfort level within group II (test group) patients. While parameters such as discharge amount, discharge location, lacrimation and lubrication frequency displayed statistically insignificant differences between the two groups, all parameters showed improved results after three months of prosthesis use. CONCLUSIONS: The choice of ocular prosthesis fabrication technique did not yield a statistically significant difference in anophthalmic flora. However, the 3D-printed acrylic resin, as an artificial eye material, displayed potential advantages in reducing the colonization of opportunistic pathogens. All subjective clinical evaluation parameters exhibited enhanced outcomes after three months of prosthesis use, emphasizing the need for an adaptation period during which patients complains are alleviated. In comparison with PMMA, 3D-printed acrylic resin showcased a certain degree of anti-colonization ability against pathogenic bacteria, along with a significant level of patient comfort, suggesting its potential as a promising material for ocular prostheses. TRIAL REGISTRATION: This parallel double-blinded RCT has been registered at ClinicalTrials.gov with identification number: NCT05584865, 18/10/2022.

Improved Reverse Postauricular Island Flap for Repair of Lower Conjunctival Fornix Retraction.

ABSTRACT: Repair of lower conjunctival fornix retraction is a great challenge for plastic surgeons in the aspects of orbital prosthesis retaining and cosmetic appearance. Hereby, a 25-year-old woman, suffering from lower conjunctival fornix retraction after the removal of retinoblastoma and radiotherapy, was undertaking the treatment with an improved reverse postauricular island flap for expansion of the lower conjunctival fornix, and volume augmentation of the anophthalmic socket in one stage. The flap was based on the parietal branch of the superficial temporal artery and its vascular architecture to the postauricular vascular system, and successfully transferred by passing through a subcutaneous tunnel. The satisfactory result indicated that the mentioned technique may be a good option in surgical rehabilitation of the stable depth of the lower conjunctival fornix, not only from the reliable blood supply and the suitable thickness of the flap but also from the less donor morbidity without an exposed unsightly scar. LEVEL OF EVIDENCE: Level V.

Management of external ocular prosthesis by ocularists: results of an online survey conducted in Brazil and Spain.

PURPOSE: To analyse the ocularist's perspective on the management of the anophthalmic socket and external ocular prosthesis (EOP). METHODS: Ocularists from two countries were invited to participate in an online questionnaire. Data were collected on demographics, anophthalmic socket and EOP management (manufacturing, use, cleaning), complications, follow-up visits and multidisciplinary care. The frequency and proportions of the responses were statistically analysed. RESULTS: The questionnaire was addressed to 20 Brazilian and 17 Spanish ocularists, obtaining a response rate of 65% and 64.7%, respectively. 62.5% of respondents were men. The most common cause of anophthalmia in Brazil (69.2%) and Spain (36.4%) is an eye disease (chi square: p = 0.188). Polymethylmethacrylate (PMMA) is the most commonly used material in EOP manufacture (chi square: p = 0.448), and 70.8% reported using customized EOPs (chi square: p = 0.069). Deposits are frequently observed in both countries (chi square: p = 0.157). Changing the prosthesis is recommended after 5 to 10 years by Brazilian ocularists, and after less than 5 years of use by Spanish ocularists (81.8%) (chi square: p = 0.041). Annual follow-up is recommended by Spanish ocularists (45.5%), while semestral (38.5%) and case-dependent (38.5%) follow-up is recommended by Brazilian ocularists (chi square: p = 0.267). Daily cleaning is advocated by 61.5% of Brazilian ocularists and once a month by 45.5% of Spanish ocularists (chi square: p = 0.098), with 75% of ocularists from both countries not recommending EOP removal at night (Fisher´s exact test: p = 0.166). Good communication between ocularists and ophthalmologists was reported by 87.5% of our responders (chi square: p = 0.642). CONCLUSION: Although there are no unified protocols on the management of EOPs, Brazilian and Spanish ocularists follow similar guidelines. Differences between countries were the patients´ referral and the prosthesis´ useful life.

Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients.

Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2, and one novel deep intronic splice variant in PXDN. An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants.

Clinical, genetic and biochemical signatures of RBP4-related ocular malformations.

BACKGROUND: The retinoic acid (RA) pathway plays a crucial role in both eye morphogenesis and the visual cycle. Individuals with monoallelic and biallelic pathogenic variants in retinol-binding protein 4 (RBP4), encoding a serum retinol-specific transporter, display variable ocular phenotypes. Although few families have been reported worldwide, recessive inherited variants appear to be associated with retinal degeneration, while individuals with dominantly inherited variants manifest ocular development anomalies, mainly microphthalmia, anophthalmia and coloboma (MAC). METHODS: We report here seven new families (13 patients) with isolated and syndromic MAC harbouring heterozygous RBP4 variants, of whom we performed biochemical analyses. RESULTS: For the first time, malformations that overlap the clinical spectrum of vitamin A deficiency are reported, providing a link with other RA disorders. Our data support two distinct phenotypes, depending on the nature and mode of inheritance of the variants: dominantly inherited, almost exclusively missense, associated with ocular malformations, in contrast to recessive, mainly truncating, associated with retinal degeneration. Moreover, we also confirm the skewed inheritance and impact of maternal RBP4 genotypes on phenotypical expression in dominant forms, suggesting that maternal RBP4 genetic status and content of diet during pregnancy may modify MAC occurrence and severity. Furthermore, we demonstrate that retinol-binding protein blood dosage in patients could provide a biological signature crucial for classifying RBP4 variants. Finally, we propose a novel hypothesis to explain the mechanisms underlying the observed genotype-phenotype correlations in RBP4 mutational spectrum. CONCLUSION: Dominant missense variants in RBP4 are associated with MAC of incomplete penetrance with maternal inheritance through a likely dominant-negative mechanism.

Prenatal diagnosis of bilateral anophthalmia: Identifying de novo SOX2 variant.

A 26 year old nulligravida presented at 24 weeks gestation for the second opinion of abnormal fetal profile and mid-face views on ultrasound at another institution. A detailed fetal anatomic ultrasound at our facility revealed the absence of fetal lens and globes bilaterally consistent with bilateral anophthalmia (HP: 0000528) without other anomalies. Karyotype and chromosomal microarray analysis were completed from amniocentesis sample. After these results, duo exome testing with paternal sequencing was completed from proband amniotic fluid sample and parental blood samples. A pathogenic variant in SOX2 (NM_003106.3: c.513C>G p.(Tyr171*Ter)) with heterozygous autosomal dominant inheritance resulted. On duo exome testing with paternal segregation analysis, the variant was found to be consistent with likely sporadic de novo inheritance. The SOX2 variant reported is consistent with the fetal phenotype in this case. While germline mosaicism could exist, this identified variant provided the family with a likely explanation for this proband's finding. This ultrasound and genetic testing allowed the family to make decisions related to planning in current and future pregnancies.

Clinical Characterization of Congenital Anophthalmic and Microphthalmic Cavities in Inidviduals With Craniofacial Anomalies.

OBJECTIVE: Measure the frequency of anophthalmic and microphthalmic patients with craniofacial anomalies (FCAs). DESIGN: Descriptive, cross-sectional, retrospective study. SETTING: Hospital for Rehabilitation of Craniofacial Anomalies of the University of São Paulo (HRAC-USP). The medical records of patients treated at HRAC from 2000 to 2012 with a diagnosis of congenital anophthalmia or microphthalmia were examined. Patients were excluded for secondary anophthalmia, incomplete medical records, or information that could not be accessed. OUTCOME MEASURES: Frequency of anophthalmia and microphthalmia; the proportions and diagnoses of associated FCAs; impairment of ocular appendages; extracranial or facial anomalies; genetic alterations; and surgical approach. RESULTS: A total of 56 patients had anophthalmia (52.3%), 35 had microphthalmia (32.7%), and 16 patients had both (15%). Individuals with FCAs associated with microphthalmia, anophthalmia, or both totaled 74, corresponding to 69.2%. Anophthalmia was more likely than microphthalmia to be accompanied by FCAs, at 76.4% of patients ( P < 0.05). Cleft lip and palate were the main malformations associated with anophthalmia (23.64%), with microphthalmia (45%), and with both (44.44%). Reconstructive surgery was done in 63.6% of cases. The ocular attachments were compromised in 71% of cases. Extracraniofacial malformations were found in 9.3% of patients. Only 7 records contained karyotypes, and no changes directly related to anophthalmia or microphthalmia were found. CONCLUSION: Anophthalmia is more frequent than microphthalmia and is more often accompanied by FCA. Cleft lip and cleft palate are the most frequent concomitant malformations.

Cryptophthalmos: associated syndromes and genetic disorders.

PURPOSE: Cryptophthalmos is a rare congenital condition caused by anomalous eyelid development where the eyelid folds do not develop or fail to separate. Cryptophthalmos can be unilateral or bilateral and can occur in isolation or as part of an underlying syndrome. We aim to identify genetic syndromes associated with cryptophthalmos to facilitate genetic diagnosis. METHODS: We performed a retrospective medical record review of all patients diagnosed with cryptophthalmos followed at a single center between 2000 and 2020. The analysis included medical history, clinical examination findings, and genetic testing results. RESULTS: Thirteen patients were included, 10 (77%) males, mean age of 2.4 years. Eight (61%) had bilateral cryptophthalmos, and 4 (31%) had complete cryptophthalmos. Associated ocular abnormalities included corneal opacities (13/13, 100%), upper eyelid colobomas (12/13, 92%), and microphthalmia/clinical anophthalmia (3/13, 23%). All cases of complete cryptophthalmos had bilateral disease. An underlying clinical or molecular diagnosis was identified in 10/13 (77%) cases, including Fraser syndrome (n = 5), amniotic band syndrome (n = 1), FREM1-related disease (n = 1), Goldenhar versus Schimmelpenning syndrome (n = 1), MOTA syndrome (n = 1), and CELSR2-related disease (n = 1). CONCLUSION: This is the first report of a possible association between cryptophthalmos and biallelic CELSR2 variants. Children with cryptophthalmos, especially those with extra-ocular involvement, should be referred for comprehensive genetic evaluation.

ALDH1A3-related congenital microphthalmia-8 due to a novel frameshift variant.

Microphthalmia (MCOP) is a group of rare developmental malformations of eye with often reduced size of the eyeball, leading to blindness. Affecting about 1 in 7000 live births, MCOP can occur due to either environmental or genetic factors. Isolated microphthalmia-8 (MCOP8) has been proved to be caused by autosomal recessive mutations of the ALDH1A3 gene (MIM*600463) encoding aldehyde dehydrogenase 1 family, member A3. Herein, we report an 8-year-old boy with vision problems since birth from a first-cousin consanguineous parents. The main symptoms of the patient included severe bilateral microphthalmia, cyst in the left eye and blindness. The child developed behavioral disorders at the age of 7. It should be noted that there is no family history of the disease. To identify the genetic factor underlying the pathogenesis in this case Whole Exome Sequencing (WES) was performed and followed by Sanger sequencing. A novel pathogenic variant, c.1441delA (p.M482Cfs*8), in the ALDH1A3 gene was detected by WES in the proband. Further prenatal diagnosis is highly suggested to the family for the future pregnancies.

SOX2 pathogenic variants with normal eyes: Expanding the phenotypic spectrum.

SOX2 pathogenic variants, though rare, constitute the most commonly known genetic cause of clinical anophthalmia and microphthalmia. However, patients without major ocular malformation, but with multi-system developmental disorders, have been reported, suggesting that the range of clinical phenotypes is broader than previously appreciated. We detail two patients with bilateral structurally normal eyes along with 11 other previously published patients. Our findings suggest that there is no obvious phenotypic or genotypic pattern that may help set apart patients with normal eyes. Our patients provide further evidence for broadening the phenotypic spectrum of SOX2 mutations and re-appraising the designation of SOX2 disorder as an anophthalmia/microphthalmia syndrome. We emphasize the importance of considering SOX2 pathogenic variants in the differential diagnoses of individuals with normal eyes, who may have varying combinations of features such as developmental delay, urogenital abnormalities, gastro-intestinal anomalies, pituitary dysfunction, midline structural anomalies, and complex movement disorders, seizures or other neurological issues.

Holoprosencephaly with a Special Form of Anophthalmia Result from Experimental Induction of bmp4, Oversaturating BMP Antagonists in Zebrafish.

Vision is likely our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.

Clinical and genetic analysis further delineates the phenotypic spectrum of ALDH1A3-related anophthalmia and microphthalmia.

Biallelic pathogenic variants in ALDH1A3 are responsible for approximately 11% of recessively inherited cases of severe developmental eye anomalies. Some individuals can display variable neurodevelopmental features, but the relationship to the ALDH1A3 variants remains unclear. Here, we describe seven unrelated families with biallelic pathogenic ALDH1A3 variants: four compound heterozygous and three homozygous. All affected individuals had bilateral anophthalmia/microphthalmia (A/M), three with additional intellectual or developmental delay, one with autism and seizures and three with facial dysmorphic features. This study confirms that individuals with biallelic pathogenic ALDH1A3 variants consistently manifest A/M, but additionally display neurodevelopmental features with significant intra- and interfamilial variability. Furthermore, we describe the first case with cataract and highlight the importance of screening ALDH1A3 variants in nonconsanguineous families with A/M.

Conjunctival sac microbiome in anophthalmic patients: Flora diversity and the impact of ocular prosthesis materials.

Purpose: To explore the changes of bacterial flora in anophthalmic patients wearing ocular prosthesis (OP) and the microbiome diversity in conditions of different OP materials. Methods: A cross-sectional clinical study was conducted, involving 19 OP patients and 23 healthy subjects. Samples were collected from the upper, lower palpebral, caruncle, and fornix conjunctiva. 16S rRNA sequencing was applied to identify the bacterial flora in the samples. The eye comfort of each OP patient was determined by a questionnaire. In addition, demographics information of each participant was also collected. Results: The diversity and richness of ocular flora in OP patients were significantly higher than that in healthy subjects. The results of flora species analysis also indicated that in OP patients, pathogenic microorganisms such as Escherichia Shigella and Fusobacterium increased significantly, while the resident flora of Lactobacillus and Lactococcus decreased significantly. Within the self-comparison of OP patients, compared with Polymethyl Methacrylate (PMMA), prosthetic material of glass will lead to the increased colonization of opportunistic pathogens such as Alcaligenes, Dermabacter and Spirochaetes, while gender and age have no significant impact on ocular flora. Conclusions: The ocular flora of OP patients was significantly different from that of healthy people. Abundant colonization of pathogenic microorganisms may have an important potential relationship with eye discomfort and eye diseases of OP patients. PMMA, as an artificial eye material, demonstrated potential advantages in reducing the colonization of opportunistic pathogens.