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.

Clinical report of Bosma arhinia microphthalmia syndrome with a new variant on SMCHD1 gene. A case report.

The Bosma syndrome (BAMS: Bosma arhinia microphthalmia syndrome) is a condition first described in 1972. Since then, several reviews have published the cases looking for diagnostic criteria and associated genetic alterations. The mutation in the SMCHD1 gene (Structural Maintenance of Chromosomes flexible Hinge Domain containing protein 1) seems to explain a part of the development of the phenotype. Not all cases show the same alterations or meet the classic diagnostic criteria, and few have undergone genetic analysis. We present a case with a new variant in this gene and an update of the literature on this syndrome with the aim of improving the diagnosis and follow-up of these patients.

Structural Variant Disrupting the Expression of the Remote FOXC1 Gene in a Patient with Syndromic Complex Microphthalmia.

Ocular malformations (OMs) arise from early defects during embryonic eye development. Despite the identification of over 100 genes linked to this heterogeneous group of disorders, the genetic cause remains unknown for half of the individuals following Whole-Exome Sequencing. Diagnosis procedures are further hampered by the difficulty of studying samples from clinically relevant tissue, which is one of the main obstacles in OMs. Whole-Genome Sequencing (WGS) to screen for non-coding regions and structural variants may unveil new diagnoses for OM individuals. In this study, we report a patient exhibiting a syndromic OM with a de novo 3.15 Mb inversion in the 6p25 region identified by WGS. This balanced structural variant was located 100 kb away from the FOXC1 gene, previously associated with ocular defects in the literature. We hypothesized that the inversion disrupts the topologically associating domain of FOXC1 and impairs the expression of the gene. Using a new type of samples to study transcripts, we were able to show that the patient presented monoallelic expression of FOXC1 in conjunctival cells, consistent with the abolition of the expression of the inverted allele. This report underscores the importance of investigating structural variants, even in non-coding regions, in individuals affected by ocular malformations.

Dacryocystocele and Subsequent Dacryocystectomy in a Patient With Bosma Arhinia Microphthalmia Syndrome (BAMS): A Case Report and Review of Literature.

Bosma arhinia microphthalmia syndrome (BAMS) is a rare syndrome consisting of several craniofacial abnormalities, including congenital arhinia. In this case report, the authors present the first case of a patient with BAMS and dacryocystocele who successfully underwent dacryocystectomy. Dacryocystectomy may serve as a viable surgical approach for dacryocystocele in patients with abnormal nasal anatomy. [J Pediatr Ophthalmol Strabismus. 2024;61(3):e16-e18.].

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.

Primary orbital rhabdoid tumour masquerading as atypical persistent foetal vasculature.

We present a case of primary rhabdoid tumour of the orbit. Presenting features at birth included congenital ptosis, conjunctival injection, hyphaema and microphthalmia. The unique presentation caused a late diagnosis following the development of rapid proptosis 6 months later. We suggest that orbital rhabdoid tumour be considered in the differential diagnoses of patients presenting with atypical persistent foetal vasculature features.

Nonsense-mediated mRNA decay affects hyperactive root formation in oculo-facio-cardio-dental syndrome via up-frameshift protein 1.

OBJECTIVES: Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked genetic disorder caused by mutations in the BCL6 co-repressor (BCOR) and is mainly characterized by radiculomegaly (elongated dental roots). All BCOR mutations reported to date have been associated with premature termination codons, indicating that nonsense-mediated mRNA decay (NMD) might play a vital role in the pathogenesis of OFCD syndrome. However, the molecular mechanisms underlying NMD remain unclear. In this study, we investigated the involvement of up-frameshift protein 1 (UPF1), which plays a central role in NMD, in the hyperactive root formation caused by BCOR mutations. METHODS: Periodontal ligament cells, isolated from a Japanese woman with a c.3668delC frameshift mutation in BCOR, and primary human periodontal ligament fibroblasts (HPdLFs) were used for an RNA immunoprecipitation assay to confirm the binding of UPF1 to mutated BCOR. Additionally, the effects of UPF1 on the BCOR transcription levels and corresponding gene expression were determined by performing relative quantitative real-time polymerase chain reactions. RESULTS: RNA immunoprecipitation revealed that UPF1 binds to exon 9 of mutated BCOR. Additionally, UPF1 knockdown via siRNA upregulated the transcription of BCOR, whereas overexpression of wild-type and mutated BCOR with the same frameshift mutation in HPdLFs altered bone morphogenetic protein 2 (BMP2) expression. CONCLUSIONS: Our findings indicate that BCOR mutations regulate the transcription of BCOR via UPF1, which may in turn regulate the expression of BMP2. NMD, caused by a c.3668delC mutation, potentially leads to an OFCD syndrome phenotype, including elongated dental roots.

Generation of the induced pluripotent stem cell line IOCVi001-A from a patient with the MFRP-related retinitis pigmentosa-nanophthalmos syndrome.

Retinitis pigmentosa (RP) is the most common retinal degeneration in humans and is characterized by the progressive degeneration of rods and cones and retinal pigment epithelium. We generated the IOCVi001-A induced pluripotent stem cell (iPSC) line from dermal fibroblast of a patient with a homozygous c.498_499insC (p.(Asn167Glnfs⁎34) variant in the Membrane-type frizzled related protein (MFRP) gene, a genetic defect causing a syndrome characterized by RP and small eye size (nanophthalmos). IOCVi001-A displayed normal stemness, expressed pluripotent stem cell markers and displayed a normal karyotype. This iPSC line can be used for in vitro disease modeling for complex forms of RP.

Oculo-facio-cardio-dental (OFCD) syndrome: a case report.

BACKGROUND: Oculo-facio-cardio-dental (OFCD) syndrome is a rare condition that affects the eyes, face, heart, and teeth of patients. One notable dental characteristic of OFCD is radiculomegaly, or root gigantism, which highlights the role of dentists in detecting this syndrome. OFCD is an X-linked dominant syndrome that results from a variant in the BCOR gene. Our study presents the first documented case of OFCD in Vietnam and reports a novel BCOR gene variant observed in this case. CASE PRESENTATION: A 19-year-old Vietnamese female patient with an extremely long root with an abscess was clinically examined for the expression of OFCDs. The radiograph and the variant in BCOR gene were also evaluated. We identified abnormalities in the teeth, as well as ocular, facial, and cardiac features, with radiculomegaly of the canines being a specific symptom for OFCDs. The patient's genetic analysis revealed a pathogenic heterozygous deletion at intron 11 of the BCOR gene, representing a novel variant. CONCLUSION: Oculo-facio-cardio-dental syndrome (OFCD) is an extremely rare condition characterized by abnormalities in the eyes, face, heart, and teeth, often caused by variants in the BCOR gene. Radiculomegaly, or enlarged dental roots, is a key diagnostic feature of OFCD, and early detection is crucial for preventing future dental complications.

Microphthalmia and anterior segment dysgenesis due to a double gene variant in GJA8 and CRYGC.

INTRODUCTION: To report a family with severe ocular disorder caused by double gene variants in causative genes of autosomal dominant cataracts, GJA8 and CRYGC. CASE PRESENTATION: A 5-month-old boy with poor vision and enophthalmos was referred to our hospital. Further ocular examination showed horizontal nystagmus, iris abnormalities with pinpoint pupils, and extreme microphthalmia with axial right and left eye lengths of 13.48 mm and 13.75 mm, respectively. Digenic heterozygous variants (c.269T > G, p.Leu90Arg in CRYGC and c.151G > A, p.Asp51Asn in GJA8) have been detected based on the whole exome sequencing. His mother, who carried variant in CRYGC (c.269T > G, p.Leu90Arg), had nuclear cataract, microcornea and nystagmus, while his father, who carried variant in GJA8 (c.151G > A, p.Asp51Asn), showed bilateral membranous cataract, microphthalmia, sclerocornea, glaucoma, and nystagmus. CONCLUSIONS: To our knowledge, this is the first report of a patient with variants in two cataract-related genes. Importantly, patient with double heterozygous variants in two dominantly inherited genes may suffer more serious phenotypes than those with heterozygous variant in a single dominantly inherited gene. Whole exome or genome sequencing is necessary for a genetic diagnosis in case of multiple gene variants.

Characterization of neural damage and neuroinflammation in Pax6 small-eye mice.

Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies.

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.

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.

Age and light damage influence Fzd5 regulation of ocular growth-related genes.

Genetic and environmental factors can independently or coordinatively drive ocular axis growth. Mutations in FRIZZLED5 (FZD5) have been associated with microphthalmia, coloboma, and, more recently, high myopia. The molecular mechanism of how Fzd5 participates in ocular growth remains unknown. In this study, we compiled a list of human genes associated with ocular growth abnormalities based on public databases and a literature search. We identified a set of ocular growth-related genes from the list that was altered in the Fzd5 mutant mice by RNAseq analysis at different time points. The Fzd5 regulation of this set of genes appeared to be impacted by age and light damage. Further bioinformatical analysis indicated that these genes are extracellular matrix (ECM)-related; and meanwhile an altered Wnt signaling was detected. Altogether, the data suggest that Fzd5 may regulate ocular growth through regulating ECM remodeling, hinting at a genetic-environmental interaction in gene regulation of ocular axis control.

Actualización clínica en nanoftalmos: características, enfermedades y complicaciones asociadas / Clinical update in nanophthalmos: Features, diseases and complications associated

El nanoftalmos es una condición congénita infrecuente del globo ocular que se caracteriza por un menor tamaño de los segmentos anterior y posterior en ausencia de una malformación ocular definida. Tradicionalmente se han descrito alteraciones anatómicas asociadas como una longitud axial corta, esclera engrosada, córnea con menor diámetro, cámara anterior estrecha y aumento de la relación entre el volumen del cristalino y el globo ocular. La causa se desconoce, aunque se han descrito múltiples mutaciones que podrían estar asociadas. En la actualidad, falta todavía una definición y una clasificación consensuada. Su relevancia clínica deriva de la asociación con múltiples afecciones oculares que pueden limitar la función visual como son hipermetropía elevada, ambliopía, glaucoma de ángulo cerrado, desprendimiento de retina y catarata. Asimismo, tanto la cirugía de catarata como la de glaucoma siguen constituyendo un desafío en estos ojos en los que el riesgo de numerosas complicaciones tanto intraoperatorias como postoperatorias es significativamente más elevado. El tratamiento del nanoftalmos tiene una doble orientación. Es preciso tratar las enfermedades asociadas y, además, reducir y controlar las complicaciones quirúrgicas. Esta revisión pretende realizar una actualización de lo publicado en los últimos años en relación con esta enfermedad. (AU)

Nanophthalmos is a rare congenital condition of the eyeball that is characterized by a smaller size of the anterior and posterior segments without associated ocular malformations. Typical features that have traditionally been described in these eyes are short axial length, thickened sclera, cornea with a smaller diameter, narrow anterior chamber, and an increased lens to globe volume ratio. However, at present, there is still a lack of recognized diagnostic criteria for nanophthalmos and a classification of its severity. Its clinical relevance stems from the increased risk of multiple ocular conditions, such as high hyperopia, amblyopia, angle-closure glaucoma, retinal detachment, and cataracts. Likewise, in relation to surgery in these eyes, there are particularities in cataract and glaucoma surgery and with a greater risk of associated intra- and postoperative complications. In this way, the treatment of nanophthalmos focuses on controlling the associated eye conditions and reducing and controlling surgical complications. This review aims to update what has been published in recent years regarding nanophthalmos. (AU)

Aplicación orbitaria de productos de relleno para optimización de simetría en pacientes con microftalmia o cavidades anoftálmicas adquiridas: revisión de la literatura / Aplicación orbitaria de productos de relleno para optimización de simetría en pacientes con microftalmia o cavidades anoftálmicas adquiridas: revisión de la literatura Orbital administration of fillers for optimization of symmetry in patients with microphthalmos or acquired anophthalmic sockets: A review

El tratamiento de la asimetría facial en pacientes con microftalmos o cavidades anoftálmicas adquiridas suele requerir cirugías reconstructivas agresivas. En los últimos años se han publicado trabajos sobre el uso de rellenos para optimizar la simetría del tejido orbitario, como técnicas mínimamente invasivas.Por este motivo, hemos realizado una revisión sistemática de la literatura publicada hasta el momento sobre la administración orbitaria de rellenos para el tratamiento de la pérdida de volumen. Se identificaron 14 artículos que cumplían con los criterios de selección; en los que se analizó el material utilizado, la técnica de inyección, el estudio anatómico de los pacientes antes del procedimiento y la presencia de complicaciones asociadas. Los materiales utilizados como relleno son: la grasa autóloga, la hidroxiapatita cálcica, el colágeno, el ácido hialurónico o el gel de poliacrilamida. Se aplicaron técnicas estándar de inyección peribulbar y retrobulbar, con escasas complicaciones asociadas, siendo la má grave el desarrollo de cuadros vaso-vagales. El seguimiento de los pacientes suele limitarse en la mayoría de los estudios a 12 meses, con variaciones significativas en la exoftalmometría posprocedimiento. En conclusión, la utilización de rellenos parece una práctica segura y con buenos resultados, aunque se precisan estudios con tiempo de seguimiento más prolongado que los publicados hasta el momento. (AU)

The treatment of facial asymmetry in patients with microphthalmos or acquired anophthalmic cavities usually requires aggressive reconstructive surgeries. In recent years, studies have been published on the use of fillers to optimize orbital tissue symmetry, as minimally invasive techniques.For this reason, we performed a systematic review of the literature published to date on the use of fillers for the treatment of volume loss in acquired anophthalmic or microphthalmic cavities. Fourteen articles were reviewed in which the material used, the injection technique, the anatomical study of the patients before the procedure and the presence of associated complications were analyzed.Various materials have been used as fillers, including autologous fat, calcium hydroxyapatite, collagen, hyaluronic acid, or polyacrylamide gel. Standard peribulbar and retrobulbar injection techniques were applied, with few associated complications, the most serious being the development of vasovagal symptoms. Patient follow-up is usually limited in most studies to 12 months.In Conclusion, the use of fillers seems to be a safe practice, with good results and few complications, although studies with longer follow-up times than those published to date would be required. (AU)

Orbital administration of fillers for optimization of symmetry in patients with microphthalmos or acquired anophthalmic sockets: A review.

The treatment of facial asymmetry in patients with microphthalmos or acquired anophthalmic sockets usually requires aggressive reconstructive surgeries. In recent years, studies have been published on the use of fillers to optimize orbital tissue symmetry, as minimally invasive techniques. For this reason, we performed a systematic review of the literature published to date on the use of fillers for the treatment of volume loss in acquired anophthalmic or microphthalmic cavities. Fourteen articles were reviewed in which the material used, the injection technique, the anatomical study of the patients before the procedure and the presence of associated complications were analyzed. Various materials have been used as fillers, including autologous fat, calcium hydroxyapatite, collagen, hyaluronic acid, or polyacrylamide gel. Standard peribulbar and retrobulbar injection techniques were applied, with few associated complications, the most serious being the development of vasovagal symptoms. Patient follow-up is usually limited in most studies to 12 months. In Conclusion, the use of fillers seems to be a safe practice, with good results and few complications, although studies with longer follow-up times than those published to date would be required.

Clinical update in nanophthalmos: Features, diseases and complications associated.

Nanophthalmos is a rare congenital condition of the eyeball that is characterised by a smaller size of the anterior and posterior segments without associated ocular malformations. Typical features that have traditionally been described in these eyes are short axial length, thickened sclera, cornea with a smaller diameter, narrow anterior chamber, and an increased lens to globe volume ratio. However, at present, there is still a lack of recognised diagnostic criteria for nanophthalmos and a classification of its severity. Its clinical relevance stems from the increased risk of multiple ocular conditions, such as high hyperopia, amblyopia, angle-closure glaucoma, retinal detachment, and cataracts. Likewise, in relation to surgery in these eyes, there are particularities in cataract and glaucoma surgery and with a greater risk of associated intra- and postoperative complications. In this way, the treatment of nanophthalmos focuses on controlling the associated eye conditions and reducing and controlling surgical complications. This review aims to update what has been published in recent years regarding nanophthalmos.