Optic cup morphogenesis across species and related inborn human eye defects.

The vertebrate eye is shaped as a cup, a conformation that optimizes vision and is acquired early in development through a process known as optic cup morphogenesis. Imaging living, transparent teleost embryos and mammalian stem cell-derived organoids has provided insights into the rearrangements that eye progenitors undergo to adopt such a shape. Molecular and pharmacological interference with these rearrangements has further identified the underlying molecular machineries and the physical forces involved in this morphogenetic process. In this Review, we summarize the resulting scenarios and proposed models that include common and species-specific events. We further discuss how these studies and those in environmentally adapted blind species may shed light on human inborn eye malformations that result from failures in optic cup morphogenesis, including microphthalmia, anophthalmia and coloboma.

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.

Prevalence and prenatal diagnosis of congenital eye anomalies: A population-based study.

OBJECTIVE: To estimate the prevalence and trend of congenital eye anomalies (CEAs) and the rate of prenatal diagnosis over a 10-year period. DESIGN: Retrospective population-based registry study. SETTING: All maternity units in Paris, France, from 2010 to 2020. POPULATION: A cohort of 115 cases of CEA detected among all live births or stillbirths, after 22 weeks of gestation, and terminations of pregnancy. METHODS: The total prevalence of CEAs and prevalence of each specific CEA were calculated using 95% Poisson exact confidence intervals. MAIN OUTCOME MEASURES: The total prevalence of CEAs and the proportion of prenatal diagnosis of CEAs, and their evolution. RESULTS: The prevalence of CEAs was 4.1 (95% CI 3.4-5.0) cases, ranging between 3.1 and 5.7 cases, per 10 000 births. CEAs were prenatally diagnosed in 23.5% of cases. CEAs were bilateral in 51 cases (44.3%), unilateral in 43 cases (37.4%) and missing or unknown in 21 cases (18.3%). Of those with CEAs, 20.9% had genetic anomalies and 53.0% had at least one other extraocular anomaly. When detected prenatally, CEAs were bilateral in 15 cases (55.6%), unilateral in eight cases (29.6%) and missing in the four remaining cases. The prenatal diagnosis rate of CEAs associated with genetic anomalies, CEA cases with at least one other malformation and isolated CEA cases were 29.2%, 26.2% and 13.3%, respectively. CONCLUSIONS: In total, 115 cases of CEAs were observed during the study period, representing a total prevalence of 4.1 cases per 10 000 births. The overall prenatal detection rate of CEAs in our population was 23.5%, which dropped to 13.3% for isolated cases of CEAs.

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.

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.

Prevalence of anophthalmia etiological factors in patients treated in a reference center: A retrospective study.

Background: Ocular prosthesis rehabilitation has an important social, psychological, esthetic, and functional role. Congenital factors, trauma, and tumors, among others, can cause anophthalmia, and it is essential to identify the etiology to guide its prevention and treatment. Methods: The aim of this study was to retrospectively investigate the records of patients treated from 2013 to 2020 by the Oral and Maxillofacial Prosthesis Group, aiming to identify the prevalence of patients with anophthalmia and the etiology of their anophthalmia. After approval by the Human Research Ethics Committee, two calibrated researchers evaluated 520 records, identifying those from patients with anophthalmia. The inclusion criteria were records with complete and legible information from patients with anophthalmia and a description of their etiology. Descriptive statistics were performed, and etiological factors were categorized into trauma, congenital cause, end-stage eye disease, and tumor. Spearman's correlation was performed to verify the relation between gender and anophthalmia etiology, with a 5% significance level. Seventy-two records were included in the study. Results: It was observed that 33.4% of patients were women and 66.6% were men. The etiologies were physical trauma (52.4%), tumor (21.8%), end-stage eye disease (16.6%), and congenital cause (9.2%), and there was no correlation between gender and these etiologies (p = .301). Conclusion: Most of the cases identified were of traumatic origin, which allows the establishment of preventive and educational measures to avoid new cases of anophthalmia.

Review of 37 patients with SOX2 pathogenic variants collected by the Anophthalmia/Microphthalmia Clinical Registry and DNA research study.

SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty-seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2-associated disorder, for this condition.

Long-read genome sequencing resolves a complex 13q structural variant associated with syndromic anophthalmia.

Microphthalmia, anophthalmia, and coloboma (MAC) are a heterogeneous spectrum of anomalous eye development and degeneration with genetic and environmental etiologies. Structural and copy number variants of chromosome 13 have been implicated in MAC; however, the specific loci involved in disease pathogenesis have not been well-defined. Herein we report a newborn with syndromic degenerative anophthalmia and a complex de novo rearrangement of chromosome 13q. Long-read genome sequencing improved the resolution and clinical interpretation of a duplication-triplication/inversion-duplication (DUP-TRP/INV-DUP) and terminal deletion. Sequence features at the breakpoint junctions suggested microhomology-mediated break-induced replication (MMBIR) of the maternal chromosome as the origin. Comparing this rearrangement to previously reported copy number alterations in 13q, we refine a putative dosage-sensitive critical region for MAC that might provide new insights into its molecular etiology.

Post-enucleation socket syndrome-a novel pathophysiological definition.

BACKGROUND: The last definition of the post-enucleation socket syndrome (PESS) by Tyers and Collin-formulated almost 40 years ago in 1982-is predominantly based on the clinical characteristics and does not include the insights of newer studies into the pathophysiological mechanism of the PESS. METHODS: A systematic PubMed literature review regarding the pathophysiological mechanism of the PESS was performed, and results were comprised to give an overview of the current knowledge of the PESS including the exact pathophysiological mechanism. RESULTS: The primarily postulated pathophysiological mechanism of the PESS was the atrophy of orbital tissues, especially of fat, resulting in variable clinical findings. Newer studies using high-resolution computed tomography and magnetic resonance imaging or performing histopathological analyses found no orbital fat atrophy but rather a rotatory displacement of the orbital tissues from superior to posterior and from posterior to inferior together with the retraction of the extraocular muscles and a possible volume loss of the orbital implant by resorption if it is manufactured from hydroxyapatite. PESS results in a backward tilt of the superior fornix, a deep superior sulcus, a pseudo-ptosis, a lower eyelid elongation and laxity, a shallower inferior fornix, as well as enophthalmos and may lead to an inability of wearing ocular prostheses. CONCLUSIONS: A novel and comprehensive definition of the PESS is proposed: PESS is a multifactorial and variable syndrome caused by a rotatory displacement of orbital contents together with the retraction of the extraocular muscles and possible resorption of the orbital implant if it is manufactured from hydroxyapatite.

The rax homeobox gene is mutated in the eyeless axolotl, Ambystoma mexicanum.

BACKGROUND: Vertebrate eye formation requires coordinated inductive interactions between different embryonic tissue layers, first described in amphibians. A network of transcription factors and signaling molecules controls these steps, with mutations causing severe ocular, neuronal, and craniofacial defects. In eyeless mutant axolotls, eye morphogenesis arrests at the optic vesicle stage, before lens induction, and development of ventral forebrain structures is disrupted. RESULTS: We identified a 5-bp deletion in the rax (retina and anterior neural fold homeobox) gene, which was tightly linked to the recessive eyeless (e) axolotl locus in an F2 cross. This frameshift mutation, in exon 2, truncates RAX protein within the homeodomain (P154fs35X). Quantitative RNA analysis shows that mutant and wild-type rax transcripts are equally abundant in E/e embryos. Translation appears to initiate from dual start codons, via leaky ribosome scanning, a conserved feature among gnathostome RAX proteins. Previous data show rax is expressed in the optic vesicle and diencephalon, deeply conserved among metazoans, and required for eye formation in other species. CONCLUSION: The eyeless axolotl mutation is a null allele in the rax homeobox gene, with primary defects in neural ectoderm, including the retinal and hypothalamic primordia.

An age-related algorithm for management of micro-orbitism from anophthalmia: a systematic review with supplemental case reports.

Management of pediatric anophthalmia and resultant micro-orbitism is challenging. The efficacy and safety of treatment methods vary with age as bony changes grow recalcitrant to implants in those at skeletal maturity and osteotomies become technically challenging following frontal sinus pneumatization. This study aims to review methods for managing micro-orbitism and develop an age-based treatment approach. A systematic literature review was conducted. Data were screened and extracted by two investigators and relevant English-language primary-literature was analyzed. Information on sample-size, number of orbits, intervention, age, complications, and prosthetic retention was obtained. Representative case reports are presented, in addition. Nineteen studies met inclusion: 294 orbits in 266 patients were treated. Two studies reported distraction-osteogenesis. Two studies utilized bone grafting. Osteotomies were performed in 41 patients from three studies. Use of solid implants was detailed in two studies. Three studies described osmotic implant. Four studies described inflatable implants. Other techniques were described by three of the included studies, two of which utilized dermis-fat grafting. All but one study were observational case reports or case series. Across all studies regardless of surgical technique, risk of bias and heterogeneity was high due to attrition bias and selective outcomes-reporting. Selection of therapy should be tailored to skeletal-age to optimize outcomes; those 0-4 yrs are managed with dermis-fat grafts, 5-7 yrs managed with implants, and 8+ yrs managed with osteotomies. For those 8+ yrs with aerated frontal sinuses or insufficient bone stock, we propose onlay camouflage prosthetics which improve projection, increase orbital volume, and avoid risk for frontal sinus injury.

Outcomes of the use of orbital hydrogel expanders in the management of congenital anophthalmia: CT-based orbital parameter analysis.

PURPOSE: To evaluate the outcomes of orbital hydrogel expanders in the management of congenital anophthalmia. METHODS: In this retrospective one-armed cohort study, a chart review was performed of eight children with congenital anophthalmia who underwent orbital expansion using orbital hydrogel tissue expander from January 2006 to July 2018. Computed tomography (CT) of orbital parameters was evaluated before and after surgery. Changes in the orbital parameters were correlated with clinical factors. RESULTS: The study sample comprised 11 anophthalmic orbits of eight children (seven males, one female; median age = 12 months), with a median postoperative follow-up of 3.8 years. The anophthalmic orbital parameters after hydrogel expander implantation improved significantly compared to preoperative assessment as follows: mean orbital height improved from 21.7 mm to 25.4 mm (P < .001); width from 19.2 mm to 23.8 mm (P < .001); depth from 27.5 mm to 32.6 mm (P = .008); and volume from 3.7 cm3 to 5.3 cm3 (P = .001). Despite enlargement in all dimensions, the anophthalmic orbits with hydrogel expander had a significantly lower development than the normal orbits, mainly in height and volume. At the last postoperative visit, four (36.4%) cases had fornices deep enough to maintain the conformer. Migration and extrusion occurred in two (18.2%) cases. CONCLUSIONS: Orbital hydrogel expander can improve the orbital development in congenital anophthalmia. However, the enlargement is not as extensive as that observed in the normal orbit. Orbital expanders associated with external conformers were not sufficient to induce normal growth of lids and fornix.

Non-syndromic anophthalmia/microphthalmia can be caused by a PORCN variant inherited in X-linked recessive manner.

Anophthalmia and microphthalmia (A/M) represent severe developmental ocular malformations, corresponding, respectively, to absent eyeball or reduced size of the eye. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome. Genetic heterogeneity has been demonstrated, and many genes have been reported to be associated with A/M. The advances in high-throughput sequencing have proven highly effective in defining the molecular basis of A/M. Nevertheless, there are still many patients with unsolved genetic background of the disease, who pose a significant challenge in the molecular diagnostics of A/M. Here we describe a family, with three males affected with the non-syndromic A/M. Whole exome-sequencing performed in Patient 1, revealed the presence of a novel probably pathogenic variant c.734A>G, (p.[Tyr245Cys]) in the PORCN gene. Pedigree analysis and segregation of the identified variant in the family confirmed the X-linked recessive pattern of inheritance. This is the first report of X-linked recessive non-syndromic A/M. Until now, pathogenic variants in the PORCN gene have been identified in the patients with Goltz syndrome, but they were inherited in X-linked dominant mode. The ocular phenotype is the only finding observed in the patients, which allows to exclude the diagnosis of Goltz syndrome.

The first adolescent case of Fraser syndrome 3, with a novel nonsense variant in GRIP1.

Fraser syndrome is characterized by cryptophthalmos, syndactyly and other autopod defects, and abnormalities of the respiratory and urogenital tracts. Biallelic variants in GRIP1 can cause Fraser syndrome 3 (FRASRS3), and five unrelated FRASRS3 cases have been reported to date. Four cases are fetuses with homozygous truncating variants. The remaining case is an almost 9-year-old Turkish girl compound heterozygous for a truncation variant and a possibly frame-shift intragenic deletion. We present a 15.5-year old Pakistani boy with homozygous truncating variant c.1774C>T (p.Gln592Ter). Of the hallmarks of the disease, the boy has cryptophthalmia, midface retrusion, very low anterior hairline, hair growth on temples extending to the supraorbital line and also on alae nasi, agenesis of right kidney, and cutaneous syndactyly of fingers and toes but no symptoms in any other organs, including lungs, anorectal system, genitalia, and umbilical system. This case is the oldest known individual with FRASRS3, and our findings show that a homozygous GRIP1 truncating variant can manifest with a non-lethal phenotype than in the reported cases with such variants, expanding the phenotypic and mutational spectrum of GRIP1.

Anxiety and depression in patients wearing prosthetic eyes.

PURPOSE: To investigate anxiety and depression levels in prosthetic eye-wearing patients using standardized psychometric instruments, to define factors associated with these psychological diseases, and to identify a potential healthcare gap. METHODS: A total of 295 prosthetic eye wearers were screened using the 7-item generalized anxiety disorder scale (GAD-7) and the 9-item patient health questionnaire (PHQ-9). Scores of GAD-7 and PHQ-9 were correlated with scores of general physical and mental health functioning, vision-related quality of life, appearance-related distress, appearance-related social function, and further biosocial factors. RESULTS: Five patients (2%) had a pre-diagnosed anxiety disorder, and 20 patients (7%) had a pre-diagnosed depression. However, our screening revealed 26 patients (9%) with anxiety symptoms, 31 patients (11%) with depression symptoms, and 40 patients (14%) suffering from both anxiety and depression symptoms. This underdiagnosing for both anxiety and depression disorders was significant (p < 0.001, respectively). Higher GAD-7 scores were significantly associated with higher PHQ-9 scores, lower appearance-related social function, lower mental health functioning, and female gender (p ≤ 0.021, respectively). Higher PHQ-9 scores were significantly associated with lower physical and mental health functioning, higher educational degree, and non-traumatic eye loss (p ≤ 0.038, respectively). CONCLUSIONS: Anxiety and depression disorders seem to be underdiagnosed in prosthetic eye wearers and to have higher incidence compared with the general population. Therefore, a psychometric screening should be routinely implemented in the clinical care. For a successful long-term rehabilitation, integrated care by a multidisciplinary team including ophthalmic plastic surgeons, ophthalmologists, ocularists, general practitioners, and psychologists is essential.

Measuring quality of care and life in patients with an ocular prosthesis.

PURPOSE: In patients with an anophthalmic condition, the primary determinants of success of ocular prosthetic rehabilitation are satisfaction with care and quality of life (QoL). The aim of this study is to develop a condition-specific questionnaire as a patient-reported outcome measure for patients with an ocular prosthesis. METHODS: Observational cross-sectional prospective study. We included 100 patients (52 female, 48 male, > 18 years old) with an anophthalmic and ocular prosthetic condition existing for 2 years or more. The patients completed a pre-tested 72-item questionnaire regarding their experience on living with an ocular prosthesis in four domains of QoL: single vision and care, wearing comfort, physical appearance and motility, and psychosocial functioning. Associations with demographic factors and condition- and prosthesis-related variables were investigated with multivariate analysis. The questionnaire was reduced with principal component analysis to obtain the Global Ocular Prosthesis Score (GOPS). RESULTS: Satisfaction scores for each QoL domain were high with a mean visual analogue score between 7.2 and 7.6. Patients were generally satisfied with the physical appearance of the artificial eye and reported adequate psychosocial functioning. Patients described the reduced peripheral visual field and socket discharge as chief complaints. The test was reduced to a 20-item questionnaire. The mean GOPS was 70.87 (median 75.00). CONCLUSIONS: Patients with longstanding ocular prosthetic wear are satisfied with their physical appearance and report adequate psychosocial functioning. A concise 20-item questionnaire for the anophthalmic condition is a valuable tool to quantitatively measure patient-reported outcome of ocular prosthetic rehabilitation. TRIAL REGISTRATION NUMBER: NCT04321382, 03/2020, retrospectively registered.

A rare association of right hemicerebral dysgenesis with congenital anophthalmia in a neonate.

Congenital anophthalmia is rare and can occur due to various etiologies, including genetic defects, teratogenic exposures, and vascular disruptions. We report a rare case of right-sided congenital anophthalmia and hemicerebral dysgenesis in association with ipsilateral hemicerebral vascular dysgenesis in a neonate. Postnatal neuroimaging was conspicuous for a "bare orbit sign." A unilateral cranial neurocristopathy was suspected to be an underlying etiopathology for such a diffuse defect.

Transcutaneous approach for orbital augmentation with alloplastic implants in acquired anophthalmia.

Purpose: To report the outcomes of a transcutaneous surgical technique for orbital volume augmentation with secondary alloplastic implants in acquired anophthalmia.Methods: Retrospective case note review of patients who underwent secondary orbital implant insertion through a subciliary incision between January 2006 and December 2017. Collected data included age, gender, type and cause of primary surgery, time interval before secondary implantation, and details of secondary implantation surgery. The main outcome parameters included postoperative appearance, grade of superior sulcus deformity (SSD), implant centration, and prosthesis function.Results: Thirty-eight patients ranging from 2 to 54 years had undergone secondary alloplastic orbital implant placement through the subciliary approach. The mean follow-up was 5.3 years (range: 1-10 years). All the patients showed satisfactory orbital volume with the average SSD was grade 0.74. There were no cases with implant exposure or extrusion. Implant migration occurred in six cases (15.8%). Fitting a prosthesis was possible in all cases.Conclusion: Subciliary secondary orbital implantation is proved to be effective in correcting volume deficiency in acquired anophthalmia with rapid rehabilitation while avoiding anterior surface breakdown and implant exposure.

The Effect of Congenital and Acquired Bilateral Anophthalmia on Brain Structure.

The aim of this study was to compare the pattern of changes in brain structure resulting from congenital and acquired bilateral anophthalmia. Brain structure was investigated using 3T magnetic resonance imaging (MRI) in Oxford (congenital) or Manchester (acquired). T1-weighted structural and diffusion-weighted scans were acquired from people with anophthalmia and sighted control participants. Differences in grey matter between the groups were quantified using voxel-based morphometry and differences in white matter microstructure using tract-based spatial statistics. Quantification of optic nerve volume and cortical thickness in visual regions was also performed in all groups. The optic nerve was reduced in volume in both anophthalmic populations, but to a greater extent in the congenital group and anophthalmia acquired at an early age. A similar pattern was found for the white matter microstructure throughout the occipitotemporal regions of the brain, suggesting a greater reduction of integrity with increasing duration of anophthalmia. In contrast, grey matter volume changes differed between the two groups, with the acquired anophthalmia group showing a decrease in the calcarine sulcus, corresponding to the area that would have been peripheral primary visual cortex. In contrast, the acquired anophthalmia group showed a decrease in grey matter volume in the calcarine sulcus corresponding to the area that would have been peripheral primary visual cortex. There are both qualitative and quantitative differences in structural brain changes in congenital and acquired anophthalmia, indicating differential effects of development and degeneration.

Ocular coloboma: Genetic variants reveal a dynamic model of eye development.

Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2-19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.