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Congenital ocular anomalies significantly contribute to global disability, with 15–20% of infant blindness attributed to these anomalies. This study examined anophthalmia, microphthalmia, and coloboma (AMC) through collaborative neonatology and ophthalmology care. The global prevalence of AMC varies: anophthalmia at 0.6–4.2 per 100,000 births and microphthalmia at 2–17 per 100,000 births, with a combined prevalence of up to 30 per 100,000. The prevalence of coloboma, alone or associate with other eye defects is 2–19 per 100,000 live births. Anophthalmia and microphthalmia may present as isolated or genetic syndromes, necessitating comprehensive evaluation. AMC etiology encompasses genetic and environmental factors. Chromosomal aberrations and mutations in genes such as PAX6 , SOX2 , OTX2 , and CHD7 are contributors. Syndromic associations, such as CHARGE (heart defect, atresia choanae, retarded growth and development, genital hypoplasia, ear anomalies/deafness) syndrome, underscore the complexity of this syndrome. Early AMC diagnosis is pivotal for timely intervention. This work provides a literature review offering insights for effective management and genetic counseling in a pediatric context.

Congenital eye malformations are uncommon and in some dog breeds, there is no evidence of their occurrence. This report aimed to describe the clinical and ultrasonographic findings of complex microphthalmia in Central Asian Shepherd dogs. Three 2‐month‐old female Central Asian Shepherd puppies from two litters were referred to our teaching hospital with the owner's complaint of eye abnormalities since birth. The puppies were alert on clinical examination, the vital signs were normal, and no other structural abnormalities were observed. In the ophthalmological assessments of all three dogs, the globe appeared bilaterally small and sunken in the orbit. In the ultrasound of the puppies’ eyes, the lens thickness and axial length of the globe were greater and less than the values measured in the eyes of a healthy puppy of the same age and breed, respectively. Moreover, in all three puppies, the lenses were located in the vitreous chamber and displaced perpendicular to their natural axis. On the basis of this, bilateral complex microphthalmia and congenital ectopia lentis, two ocular malformations of unclear etiology, were diagnosed. Due to the possibility of an association between such malformations and a high grade of inbreeding in kennels, as well as environmental and genetic factors, these conditions can be limited by breeding efforts and pre‐breeding screening plans. Here is a description of the main ultrasound findings in three Central Asian Shepherd puppies with complex microphthalmia, a rare congenital ocular malformation, compared to a healthy puppy of the same breed, age and sex. Accordingly, in dogs with complex microphthalmia, the mean ± standard deviation of axial length (AL) of the globe was shorter, and the vitreous chamber depth (VCD) and lens thickness (LT) were greater than those of the healthy dog. Surprisingly, all patients had ectopia lentis (EL).

Background/aimsMicrophthalmia, anophthalmia and coloboma (MAC) are clinically and genetically heterogenous rare developmental eye conditions, which contribute to a significant proportion of childhood blindness worldwide. Clear understanding of MAC aetiology and comorbidities is essential to providing patients with appropriate care. However, current management is unstandardised and molecular diagnostic rates remain low, particularly in those with unilateral presentation. To further understanding of clinical and genetic management of patients with MAC, we charted their real-world experience to ascertain optimal management pathways and yield from molecular analysis.MethodsA prospective cohort study of consecutive patients with MAC referred to the ocular genetics service at Moorfields Eye Hospital between 2017–2020.ResultsClinical analysis of 50 MAC patients (15 microphthalmia; 2 anophthalmia; 11 coloboma; and 22 mixed) from 44 unrelated families found 44% had additional ocular features (complex) and 34% had systemic involvement, most frequently intellectual/developmental delay (8/17). Molecular analysis of 39 families using targeted gene panels, whole genome sequencing and microarray comparative genomic hybridisation identified genetic causes in, 28% including novel variants in six known MAC genes (SOX2, KMT2D, MAB21L2, ALDH1A3, BCOR and FOXE3), and a molecular diagnostic rate of 33% for both bilateral and unilateral cohorts. New phenotypic associations were found for FOXE3 (bilateral sensorineural hearing loss) and MAB21L2 (unilateral microphthalmia).ConclusionThis study highlights the importance of thorough clinical and molecular phenotyping of MAC patients to provide appropriate multidisciplinary care. Routine genetic testing for both unilateral and bilateral cases in the clinic may increase diagnostic rates in the future, helping elucidate genotype–phenotype correlations and informing genetic counselling.

Purposes Congenital microphthalmia with orbital cyst (CMOC) is a severe ocular developmental malformation. This article aims to provide assistance for genetic counseling and further exploration of more effective treatments. Methods A combined systematic search of PubMed electronic database by using Boolean operators AND and OR was conducted, choosing the following keywords: “microphthalmos”, “microphthalmia”, “cyst”, “morbidity”, “congenital cystic eye”, “histopathological”, “molecular genetics”, “syndrome”, “treatment”, “therapy”, “surgery” and “surgical” etc. After the initial screening of these articles, repetitive literatures were excluded. Results 63 articles were selected. This article reviewed the research progress on the incidence of CMOC, its relationship with congenital microphthalmos and congenital cystic eye, histopathology and molecular genetics studies, particularly the syndromes associated with this condition and the current treatment status. Conclusion CMOC is essentially a disease caused by gene mutations, and there is no effective treatment that achieves consistent relief. Further research to clarify the genotype-phenotype and inheritance patterns of this disease may be a valuable research direction for exploring effective treatment methods and guiding clinical genetic counseling.

Jeanne Amiel, Bernd Wollnik, Bruno Reversade and colleagues report de novo missense mutations in SMCHD1 in patients with Bosma arhinia microphthalmia syndrome (BAMS) and isolated arhinia. Mechanistic studies support a key role for SMCHD1 in nasal development and suggest that the mutations in patients may function via a gain-of-function mechanism. Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.

Purpose To investigate the postoperative clinical outcomes and axial length (AL) growth of infants with congenital cataracts and microphthalmos following first-stage cataract surgery. Design Retrospective case-control study. Methods Setting: Single centre. Infants with congenital cataract that met the inclusion criteria were classified into two groups: the microphthalmos and comparison groups. All infants underwent a thorough ophthalmologic examination before surgery, and one week, 1 month, 3 months, and every 3 months after surgery. Results This study enrolled 21 infants (42 eyes) in the microphthalmos group and 29 infants (58 eyes) in the comparison group. More glaucoma-related adverse events were observed in the microphthalmos group (7 eyes, 16.7%) than in the comparison group (0 eyes, 0%) ( p  < 0.001). At each subsequent follow-up, the comparison group had a greater AL than the microphthalmos group (all p  < 0.001), and AL growth was significantly higher in the comparison group than in the microphthalmos group (all p  = 0.035). Visual acuity improvement in the microphthalmos group was similar to that of the comparison group. Conclusion Early surgical intervention improves visual function in infants with congenital cataracts and microphthalmos although with a higher incidence of glaucoma-related adverse events. After cataract removal, the AL growth of microphthalmic eyes is slower than that of normally developed eyes.

Introduction Microphthalmos and nanophthalmos are uncommon ocular conditions, whereby affected eyes have smaller dimensions compared to the normal population. Microphthalmos and nanophthalmos present several challenges to ophthalmologists; they have spontaneous and post-operative sequelae such as high hyperopia, angle-closure glaucoma, uveal effusion syndrome, and retinal detachment. This systematic review and meta-analysis intends to assess the prevalence of both the spontaneous complications associated with nanophthalmos and microphthalmos, as well as the post-surgical complications associated with nanophthalmos or microphthalmos. Methods and analysis Articles will be searched for, on four online databases: PubMed, EMBASE, Scopus, and Web of Science. Two independent reviewers will identify the studies according to prespecified inclusion and exclusion criteria. All studies included with participants diagnosed with microphthalmos or nanophthalmos in one or both eyes, will be included if they have (i) more than 4 cases and (ii) defined microphthalmos/nanophthalmos as an axial length of < 21 mm or a high lens/eye volume ratio. Nanophthalmos may have an additional diagnostic criterion of posterior wall thickness greater than 1.7 mm. The prevalence of the following complications will be assessed: high hyperopia (spherical equivalent >3D), angle closure glaucoma, uveal effusion syndrome, retinal detachment, and chorioretinal folds. Studies that will be excluded are those that have not adequately defined the criteria for the diagnosis of nanophthalmos or microphthalmos, those studies that have less than five cases, studies with criteria not defined above, and deemed unsuitable, and studies in languages other than English with no published translation. Relevant data will be extracted and assessed for the risk of bias in each article using a modified Joanna Briggs Institute (JBI) assessment tool. The data will then be pooled to determine the prevalence of complications among patients with microphthalmos and nanophthalmos. If the data allows, subgroup analysis will be carried out according to axial length as well as subtype of microphthalmos/nanophthalmos (simple, complex, relative anterior, and posterior). Discussion Although nanophthalmos is an uncommon condition that affects the eye, its management and complications can be sight-threatening. Thus, it is important to counsel patients and their families correctly (in the case of children) upon diagnosis and prior to any surgical intervention. This can only be done if the overall prevalence of complications is known. Registration PROSPERO CRD42021227847

Michael Talkowski, David FitzPatrick, Erica Davis and colleagues report rare inherited or de novo missense variants in SMCHD1 in arhinia patients. Some of the same mutations in SMCHD1 are known to cause a phenotypically distinct muscular dystrophy disorder, FSHD2, and the distinct clinical features of the two disorders suggests that additional genes interact with SMCHD1 to cause arhinia. Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans -acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Purpose: The retinal vasculature is heavily invested by pericytes. Small GTPase R-Ras is highly expressed in endothelial cells and pericytes, suggesting importance of this Ras homolog for the regulation of the blood vessel wall. We investigated the specific contribution of pericyte-expressed R-Ras to the development of the retinal vasculature. Methods: The effect of R-Ras deficiency in pericytes was analyzed in pericyte-targeted conditional Rras knockout mice at birth and during the capillary plexus formation in the neonatal retina. Results: The offspring of these mice frequently exhibited unilateral microphthalmia. Analyses of the developing retinal vasculature in the eyes without microphthalmia revealed excessive endothelial cell proliferation, sprouting, and branching of the capillary plexus in these animals. These vessels were structurally defective with diminished pericyte coverage and basement membrane formation. Furthermore, these vessels showed reduced VE-cadherin staining and significantly elevated plasma leakage indicating the breakdown of the blood-retinal barrier. This defect was associated with considerable macrophage infiltration in the retina. Conclusions: The normal retinal vascular development is dependent on R-Ras expression in pericytes, and the absence of it leads to unattenuated angiogenesis and significantly weakens the blood-retinal barrier. Our findings underscore the importance of R-Ras for pericyte function during the normal eye development.

Microphthalmia and coloboma are structural malformations of the eyes that arise from defective morphogenesis and are among the most severe defects associated with paediatric blindness. Frizzled class receptor 5 (FZD5) is a Wnt receptor expressed in the developing eye, and individuals with variants in FZD5 exhibit microphthalmia/coloboma, supporting a role for this receptor in human eye formation. Here, we show that zebrafish fzd5 mutants homozygous for complete loss-of-function or predicted dominant-negative alleles display no obvious eye defects during embryogenesis. Rather, they develop eye defects comparable to those described in humans only upon simultaneous abrogation of additional genes associated with ocular malformations. Thus, eye development can occur normally in the absence of Fzd5 in zebrafish, but mutants are sensitised to developing eye malformations. By exploiting the sensitised nature of the fzd5 mutants, we further identified angio-associated migratory cell protein (aamp) as a novel gene involved in eye morphogenesis. Overall, our study confirms the importance of considering multiple genetic contributions when searching for the molecular aetiology of ocular malformations in humans.