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Purpose: To evaluate axial length (AL), orbital width (OW) and height (OH) development in congenital microphthalmia and anophthalmia (MICA) using serial ultrasonography measurements., Methods: A longitudinal prospective cohort (n = 74) of unilaterally and bilaterally affected MICA patients was followed from 2013 to 2022 at the university hospital in Amsterdam, the Netherlands. Clinical entity, age, severity category based on axial length, conformer treatment and intra-orbital cysts were registered. The main outcome measures were the absolute and relative growth of AL, OW and OH. Surgical and intra-orbital cyst cases were described separately., Results: Absolute microphthalmic eye size increased in 27/49 (55%) unilateral MICA eyes, but growth arrest/decrease in the remaining could shift the case to a more severe category over time. A final affected/unaffected orbital symmetry ≥80% was seen in the large majority of unilateral cases (45/46 for OW, 43/46 for OH). Cases with AL < 10.5 mm had orbital symmetry <80% more often. Most orbital symmetry changes were seen in moderate and severe unilateral cases treated with 3D-printed conformer therapy starting at age <1 year, with 6/10 (60%) symmetry increase, 30% unchanged symmetry and 10% symmetry decrease. All cases older than 6.5 years (n = 6) did not show any change anymore, regardless of treatment. For bilateral and unilateral mild cases, orbital dimensions kept the same proportions during follow-up, with or without conformer treatment., Conclusions: Using severity categories in MICA based on relative AL may aid the decision to start conformer treatment, as most orbital symmetry changes were seen in moderate and severe unilateral cases receiving 3D-printed conformer therapy that started under age 1., (© 2024 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

Purpose: Cataract surgery in microphthalmic eyes is challenging due to anatomical restraints, hard bulky nucleus. This series aims to evaluate the safety and efficacy of couching of intraocular lens in irido-fundal coloboma with microphthalmos., Setting: Tertiary care centre in South India., Design: Retrospective non-comparative study in eyes with irido-fundal coloboma, corneal diameter < 7 mm and brown cataract. Visual acuity less than 6/60 in other eye., Methods: Anterior chamber entry made, zonules broken and lens dislocated into the vitreous cavity in a controlled manner. Baseline Clinico-demographic details, corrected distance visual acuity (CDVA), Intra-ocular pressure (IOP), corneal diameter, axial length, lens status and post-surgery CDVA, IOP and complications recorded and followed up for atleast 6 months., Results: Fifteen eyes of 15 subjects were evaluated with a mean age 49.4 ± 10.9 years. At baseline, mean IOP 14.5 ± 3.8 mmHg, mean axial length 19.3 ± 0.5 mm, mean corneal diameter was 6.5 ± 0.34 mm and CDVA 2 logMAR which improved to 1.5 logMAR at 3 months (p value 0.002). Transient spike in IOP in 33.3% subjects was medically managed with no significant difference in IOP (p > 0.05) at baseline (14.5 ± 3.8 mmHg), 3 months post-surgery (16 ± 2.8 mmHg) and 6 months post-surgery (14.9 ± 2.5 mmHg). One patient underwent re-couching. No other major complications were noted., Conclusion: Couching of cataractous lens is an effective and safe method in microphthalmic eyes with irido-fundal coloboma as last resort procedure, where no other surgical procedure may work. It provides an ambulatory gain of visual acuity in previously non-ambulatory subjects. Corneal measurements help in determining the subset of patients where couching offers viable option., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Competing Interests: The authors declare that they have no conflict of interest.

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.

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., (Copyright © 2024 SEEN and SED. Published by Elsevier España, S.L.U. All rights reserved.)

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.] .

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&#95;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&#95;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., (© 2023 John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

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., (Copyright © 2023 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.)

Background/aims: Microphthalmia, 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., Methods: A prospective cohort study of consecutive patients with MAC referred to the ocular genetics service at Moorfields Eye Hospital between 2017-2020., Results: Clinical 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)., Conclusion: This 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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Background: We report a case of uveal effusion in a nanophthalmic eye after topical use of brimonidine., Case Presentation: A 42-year-old male patient with nanophthalmos experienced sudden blurred vision in the right eye after using topical brimonidine when picking up tennis balls repeatedly 6 weeks after bilateral YAG peripheral iridotomy. Ocular examination showed wide choroidal and exudative retinal detachment in the temporal and inferior region, involving the macula. Acute uveal effusion in the right, bilateral nanophthalmos was diagnosed. Oral and topical corticosteroids, combined with topical nonsteroids and atropine led to a complete resolution of the uveal effusion after one month., Conclusion: This case suggested a possible causal relationship between the topical use of brimonidine and acute uveal effusion in patients with nanophthalmos. Topical brimonidine should be used with caution in nanophthalmic eyes., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Microophthalmos or 'dwarf eye' is characterized by an axial length 2 standard deviation less than age-matched controls. It is classified into nanophthalmos, relative anterior microphthalmos, and posterior microphthalmos based on the anterior segment: posterior segment ratio. Nanophthalmos can occur in association with optic disc drusen, foveoschisis, and retinitis pigmentosa, as an autosomal recessive syndrome linked to mutations in the MFRP gene. We report a case of bilateral nanophthalmos and pigmentary retinopathy with angle closure glaucoma and optic disc pit in one eye. We believe this to be the first case presenting with optic disc pit in association with nanophthalmos., Case Presentation: A 56-year-old female presented with bilateral small eyes, high hypermetropia, shallow anterior chamber depth, increased lens thickness, mid-peripheral retinal flecks, and macular edema. She also had high intraocular pressure in the right eye, with a disc cupping of 0.9 with an Optic disc pit. The macular edema in the right eye was found to occur in association with the Optic disc pit, whereas, in the left eye, it was associated with intra-retinal hemorrhages and diagnosed as macular branch retinal vein occlusion secondary to hypertension. She was started on anti-glaucoma medications in both eyes and planned for Anti-VEGF injection in the left eye., Conclusion: This case report is unique as it reports an association of Nanophthalmos with Optic Disc pit, with an associated angle closure glaucoma in the same eye, an association which has never been previously reported in the literature., (© 2023. The Author(s).)

Microphtalmos with orbital cyst is a rare congenital abnormality of the eye and orbit that is caused by incomplete closure of the embryonic fissure. The cysts project through in a coloboma of the affected eye. It may be sporadic or genetic. Herein, the authors present a 32-year-old mother with unilateral and her 4-month-old daughter with bilateral microphtalmos and accompanying orbital cyst., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

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 Relevance: Posterior microphthalmos (PM) is a rare developmental disorder characterised by high hyperopia, short axial length, presence of retinal papillomacular fold and relatively normal anterior segment findings., Background: The purpose of the study was to compare the retinal arcade distance from fovea between PM cases and to correlate axial shortening in PM eyes with imaging findings., Methods: This retrospective, comparative case series included 24 eyes of 12 patients with PM as cases and an equal number of age- and sex-matched controls. Retinal findings on optical coherence tomography (OCT), OCT-angiography, Multicolour® image, axial length and corneal biometry were computed, compared and correlated between two groups., Results: Retinal papillomacular fold was noted in all 24 PM eyes. Retinal arcade narrowing was noted in PM (p < 0.001). The central retina (p < 0.001) and choroid (p = 0.003) was thick in PM. Corneal biometry showed shorter axial length (p < 0.001), high keratometry readings (p < 0.001) and small corneal diameters (p = 0.011) in PM. Vessel density (p = 0.031) on OCTA was denser and foveal avascular zone area (p = 0.033) reduced in PM. Strong negative correlation of axial length with spherical equivalent (r = > -0.804;p < 0.001), vessel density (r = > -0.803; p = <0.001) and K1 (r = > -0.76; p < 0.001) and K2 (r = > -0.67; p = 0.001) keratometry readings was noted in PM. Significant positive correlation was noted between axial length and anterior chamber depth (r = 0.75; p < 0.001), foveal avascular zone area (r = 0.56; p = 0.033) and corneal diameter (r = 0.65; p = 0.001). Vessel density on OCT-angiography correlated positively with central corneal thickness (r = 0.552;p = 0.005) and corneal powers K1 (r = 0.709; p = 0.001) and K2 (r = 0.56; p = 0.004) and negatively with corneal diameter (r = > -0.521; p = 0.033)., Conclusion: Increased choroidal thickening and retinal vascular arcade narrowing were two important, interesting observations noted with PM. Intercorrelation between the axial length, OCT, OCT-angiography and corneal biometry helped in understanding the pathogenesis and the structural and vascular changes in PM eyes.

Purpose: To describe the choroidal variations in posterior microphthalmos (PM)., Methods: In this observational case series, four eyes of two patients diagnosed as PM based on the characteristic clinical features were included. Multimodal retinal imaging with clinical fundus documentation using ultrawide field fundus camera, optical coherence tomography (OCT) and indocyanine green angiography (ICGA) was done for these cases., Results: Multimodal imaging of these cases confirmed the variations in the choroid in PM cases. In both cases, on OCT, the retina and choroid were thick. retinal papillomacular fold (RPMF) was noted in all four eyes. On ICGA, the dye transit time from the arm to choroid and retina were within normal limits. Choroidal vasculature in the far retinal periphery was reduced and was noted as hypocyanescent areas anterior to the equator while the density of choroidal vessels was significantly more posterior to the equator. Vortex veins were not visualised in both cases., Conclusion: Choroidal structure and vessels undergo alterations in PM. Further validation of these findings is required in a larger cohort of PM cases.

Purpose: To describe a case of retinitis pigmentosa and nanophthalmos in a patient with attenuated Hunter's syndrome., Methods: Fundus photography, total field electroretinogram, ultrasound, computerized visual field examination, biochemical examination and genetic testing were obtained., Results: The fundus exam showed diffuse arteriolar attenuation, optic disc with regular contours, and pigment agglomerates like "bone spicules" in the middle periphery. Ultrasound examination revealed scleral thickening and short axial diameter in both eyes. The total field electroretinogram exam showed a subnormal result with greater impairment of the scotopic phase of the exam. Computerized visual field examination demonstrated a diffuse reduction in retinal sensitivity in the periphery. Biochemical examination showed increased urine glycosaminoglycan excretion and iduronate-2-sulphatase activity (IDS) deficiency in leukocytes, confirming the type II mucopolysaccharidosis. Molecular analysis revealed a novel missense mutation (p.A77D) in the IDS gene., Conclusion: The case report is about a patient presented an attenuated form of the syndrome, with no cognitive impairment. Ophthalmologic follow-up is still an important part of multidisciplinary treatment for Hunter's syndrome., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Best vitelliform macular dystrophy (BVMD), caused by pathogenic variants of the BEST1 gene, has not been reported in association with cataracts and ocular malformations. We reported a case with a complex ocular phenotype comprising microphthalmia, microcornea, cataract, and vitelliform macular dystrophy., Case Presentation: A six-year-old girl manifested photophobia and a poor visual behavior. A thorough ophthalmic examination revealed the patient to have bilateral microphthalmia, microcornea, congenital cataract, and Best vitelliform macular dystrophy (BVMD). Whole exome sequencing (WES) identified one variant in the BEST1 and one variant in CRYBB2 genes: c.218 T > G p.(Ile73Arg) and c.479G > C p.(Arg160Pro). The first variant was inherited from the proband's father, who was diagnosed with subclinical BVMD, while the second was a de novo variant. A minigene assay showed that c.218 T > G in BEST1 did not affect pre-mRNA splicing., Conclusions: This case suggests that the complex ocular phenotype comprising BVMD and congenital cataract with microphthalmia cannot be explained by variation in one gene but is caused by variants in BEST1 and CRYBB2. This case highlights the importance of general clinical evaluation and comprehensive genetic testing for diagnosing complex eye diseases., (© 2023. The Author(s).)

An 8-month-old Great Swiss Mountain dog was presented with a suspected right-sided microphthalmos, malformed and blind globe which was present since birth. On magnetic resonance imaging an ellipsoid macrophthalmos with absence of the normal retrobulbar tissue was detected. Histology revealed a dysplastic uvea with unilateral cyst formation associated with mild lymphohistiocytic inflammation. The ciliary body covered the posterior side of the lens unilaterally and showed focal metaplastic bone formation. Slight cataract formation as well as diffuse panretinal atrophy and intravitreal retinal detachment was evident. Preoperative diagnostic imaging procedure is recommended in eyes that clinically demonstrate as microphthalmos and are planned to be enucleated. As described in this case report the bulbus may be macrophthalmic which potentially complicates the enucleation. The performance of such a procedure at a site with ophthalmologic and soft tissue expertise is advisable. To the authors' knowledge this is the first report of a macrophthalmos with multiple ocular defects in a dog., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

Background: Membrane frizzled-related protein (MFRP) plays a critical role in ocular development. MFRP mutations are known to cause nanophthalmos and, in some cases, retinitis pigmentosa, foveoschisis, and/or optic nerve head (ONH) drusen. The broad clinical spectrum of MFRP mutations necessitates further investigation of specific genotype-phenotype relationships., Materials and Methods: We reviewed ophthalmologic and genetic medical records of two affected siblings and one unaffected sibling., Results: Genetic testing revealed variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans in the two affected siblings. In both cases, photopic and scotopic responses were markedly reduced on electroretinogram (ERG), with greater decrease in scotopic function. Optical coherence tomography for both siblings revealed non-cystoid thickening. Blunted foveal reflexes were also observed in both siblings. Notably, foveal avascular zone abnormalities were seen on fundus autofluorescence in only one affected sibling., Conclusions: MFRP-related ocular disease may be underrecognized due to its presentation with high hyperopia and possibly subtle retinal findings. Presence of variants MFRP c.855T>A, p.(Cys285*) and MFRP c.1235T>C, p.(Leu412Pro) in trans resulted in nanophthalmos and retinitis pigmentosa without associated foveoschisis or ONH drusen in our patients, consistent with the incomplete phenotype previously described in Neri et al. Abnormalities in the foveal avascular zone have been noted in other case studies and were inconsistently associated with the variants described here, representing a potential area for future investigation.

Purpose: We sought to compare the prediction accuracy of 6 intraocular lens (IOL) formulas, namely, the Haigis, Hoffer Q, Holladay I, SRK/T, Barrett Universal II and Hoffer QST formulas, in microphthalmic eyes, including those with nanophthalmos and relative anterior microphthalmos (RAM)., Design: Retrospective case series., Methods: Twenty-six eyes with nanophthalmos (axial length [AL] 16.84 ± 1.36 mm, range 15.25 mm-19.82 mm) and 12 eyes with RAM (corneal diameter 8.41 ± 0.92 mm, range 7.00 mm-9.50 mm) receiving cataract surgery were included. The IOL Master 500 was used for biometry; thus, lens thickness (LT) was omitted in the IOL power calculation. The mean and median arithmetic and absolute prediction errors (PEs) of the 6 original calculation formulas, the absolute PEs of the 6 formulas after optimization, and the proportion of PEs within ±0.25 diopters (D), ±0.5 D, ±1 D, and ±2 D with each formula were compared. The factors influencing PE were analyzed by multivariate regression., Results: In the nanophthalmos group, the overall prediction results were shifted to myopia. The original Haigis formula had the smallest median absolute PE (1.61 D, P < 0.001), and the optimized Haigis formula had the highest proportion of PEs within ±0.25 D, ±0.5 D, and ±1 D. In the RAM group, the overall prediction results were not significantly different from 0 (P > .05). No significant difference was found among the formulas before optimization (P = .146) and after optimization (P = .161), but the optimized Barrett Universal II formula had the highest proportion of PEs within ±1 D and ±2 D., Conclusions: When omitting the LT parameter in the calculation, the Haigis formula was the most accurate in cataract patients with nanophthalmos (AL <20 mm) among the 6 IOL calculation formulas, and the Barrett Universal II formula had the highest accuracy in cataract patients with RAM (corneal diameter ≤9.5 mm)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: To describe the presentation and treatment outcomes of a cohort of children with primary aphakia (PA)., Methods: Clinical photographs and ultrasound biomicroscopy (UBM) images of children presenting with sclerocornea and undetermined anterior segment dysgenesis between July 2017 and December 2020 were reviewed retrospectively. Children who had no crystalline lens visible on UBM were included., Results: A total of 124 UBM images were captured for 124 children with cloudy corneas. Twelve children were identified with congenital primary aphakia: 5 had bilateral buphthalmos, 2 had buphthalmos in one eye and microphthalmos in the other, and 5 had bilateral sclerocornea-microphthalmia complex. All patients had a peculiar silvery-blue corneal appearance, with fine vascularization on the corneal surface. The overall corneal thickness was 409.1 ± 8.7 μm. The intraocular pressure (IOP) in eyes with glaucoma was 24.5 ± 7.3 mm Hg; in microphthalmic eyes, 11.4 ± 3.4 mm Hg (P <0.001). The raised IOP was treated with limited trans-scleral cyclophotocoagulation under transillumination and topical antiglaucoma medications. Children with glaucoma gained ambulatory vision with spectacles., Conclusions: Congenital primary aphakia has a characteristic clinical appearance and may present as buphthalmos or microphthalmos, depending on the extent of dysgenesis. Incisional surgery may result in phthisis because of ciliary body dysgenesis and unpredictable aqueous production., (Copyright © 2022 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.)

Background: Posterior microphthalmos (PM) is a rare condition with poor visual prognosis even after amblyopia treatment. We report a case of PM with achievement of good visual acuity and disappearance of papillomacular retinal folds (PFs) over a period of 7 years., Case Presentation: A girl aged 3 years and 5 months was referred to our hospital, after poor visual acuity was identified at a medical checkup for 3-year-olds. She had severe spherical hyperopia: + 17.25 D in the right eye (RE) and + 18 D in the left eye (LE). Her corrected visual acuity was 20/200 in the RE and 20/250 in the LE. PFs were observed in both eyes on optical coherence tomography (OCT), and the diagnosis of PM was made based on the normal corneal diameter and anterior chamber depth. During the course of the disease, a gradual decrease in the height of the PFs was observed on OCT. The corrected visual acuity at age 10 years was 20/20 in the RE and 20/25 in the LE., Conclusions: The visual prognosis of PM is poor, and only one case with good visual acuity has been reported in the literature. The patient in the present case not only developed good visual acuity, but also showed improvement in macular morphology, which was not noted in previous reports. Early diagnosis of PM and early amblyopia treatment is important for the visual development in PM., (© 2022. The Author(s).)

Introduction: PITX3 has been reported to be associated with congenital cataracts, anterior segment mesenchymal dysgenesis, Peters' anomaly, and microphthalmia. In this case, an infant with unilateral buphthalmos, corneal staphyloma and corneal fistula carrying a variant in PITX3 was reported., Case Description: We describe a 4-month-old female infant who was referred to our Eye Clinic because of gradual enlargement of the eyeball in the right eye and whitish opacity in both eyes. Buphthalmos with long axial length (22.04 mm), macrocornea with diffuse corneal oedema and opacity (14.50 mm*14.50 mm) and high intraocular pressure (23.78 mmHg) were detected in the right eye. Microphthalmia with short axial length (16.23 mm), microcornea with diffuse corneal oedema and opacity (7.50 mm*6.50 mm) were detected in the left eye. A 360° trabeculotomy was performed for the right eye. However, corneal staphyloma and corneal fistula in the right eye were detected 6 months after the surgery. A variant in exon 4 of PITX3 (c.640&#95;656dup (p. Gly220Profs*95)) was identified in the proband but was not detected in her healthy parents., Conclusion: A novel phenotype characterized by unilateral buphthalmos, corneal staphyloma and corneal fistula in an infant were reported to be associated with PITX3 in our study. Our study expands the scope of the clinical heterogeneity of PITX3 variants. It also improves our understanding and increases the attention given to patients with PITX3 variants., (© 2022. The Author(s).)

Objective: To explore the genetic basis for a Chinese pedigree affected with microphthalmia., Methods: Clinical data of the proband was collected. Whole exome sequencing (WES) was carried out to screen potential pathogenic variants in the proband. Candidate variant was verified by Sanger sequencing of the proband and his family members. Pathogenicity of the variant was predicted by searching the PubMed database and bioinformatic analysis. Sanger sequencing of amniotic fluid sample was carried out for prenatal diagnosis., Results: The proband and his father were found to harbor a heterozygous c.151C>G (p.R51G) variant of the MAB21L2 gene. The same variant was not found in his mother and grandparents. Based on the guidelines of American College of Medical Genetics, the c.151C>G (p.R51G) variant was predicted as likely pathogenic., Conclusion: The c.151C>G (p.R51G) variant of the MAB21L2 gene probably underlay the microphthalmia in the proband. Above finding has facilitated prenatal diagnosis for this pedigree.

Background/aims: The reason for visual impairment in patients with nanophthalmos and posterior microphthalmos is not completely understood. Therefore, this study aims to investigate foveal structure, and the impact of demographic, clinical and imaging parameters on best-corrected visual acuity (BCVA) in these conditions., Methods: Sixty-two eyes of 33 patients with nanophthalmos (n=40) or posterior microphthalmos (n=22), and 114 eyes of healthy controls with high-resolution retinal imaging including spectral-domain or swept-source optical coherence tomography images were included in this cross-sectional case-control study. Foveal retinal layer thickness was determined by two independent readers. A mixed-effect model was used to perform structure-function correlations and predict the BCVA based on subject-specific variables., Results: Most patients (28/33) had altered foveal structure associated with loss of foveal avascular zone and impaired BCVA. However, widening of outer nuclear layer, lengthening of photoreceptor outer segments, normal distribution of macular pigment and presence of Henle fibres were consistently found. Apart from the presence of choroidal effusion, which had significant impact on BCVA, the features age, refractive error, axial length and retinal layer thickness at the foveal centre explained 61.7% of the variability of BCVA., Conclusion: This study demonstrates that choroidal effusion, age, refractive error, axial length and retinal layer thickness are responsible for the majority of interindividual variability of BCVA as well as the morphological foveal heterogeneity in patients with nanophthalmos or posterior microphthalmos. This might give further insights into the physiology of foveal development and the process of emmetropisation, and support clinicians in the assessment of these disease entities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine the area of the surface foveal avascular zone (FAZ) in children with posterior microphthalmos (PM), high hyperopia, and normal eyes using optical coherence tomography (OCT) and OCT angiography (OCTA)., Methods: Thirty-six children were studied including 6 cases 12 eyes of PM (mean age 9.5 ± 5.2 years), 15 cases 30 eyes of high hyperopia (6.9 ± 1.5 years), and 15 cases 30 eyes of healthy individuals (8.7 ± 1.7 years). The B- and C-scan images in all children were recorded by OCT and OCTA with a scanning area of 3.0 × 3.0 mm centered on the fovea. All images were corrected for axial length differences, and the area of the FAZ surface and central macular thickness (CMT) was measured manually and compared., Results: The area of FAZ in the PM group was 0.007 ± 0.003 mm 2 , which was significantly smaller than that in the high hyperopia eyes at 0.286 ± 0.108 mm 2 and healthy eyes at 0.318 ± 0.129 mm 2 (both P < 0.001). The CMT in the PM group was 401.58 ± 33.60 mm, which was significantly thicker than in the high hyperopia eyes at 202.93 ± 12.28 mm and the normal eyes at 204.43 ± 18.76 mm. The area of the FAZ and CMT in the hyperopia group did not differ significantly from that of the normal healthy eyes., Conclusion: These findings indicate that patients with PM have a hypoplastic macular region, which must be considered in any treatment of these eyes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Competing Interests: None

Competing Interests: None

Purpose: To describe a series of patients treated for congenital microphthalmia associated with orbital cyst and recommend a management protocol., Methods: This retrospective case series comprised 6 patients (7 eyes) who attended an oculoplastic tertiary medical center from 2001 to 2018. Clinical, treatment, and outcome data were collected from the electronic files. Main outcome measures were preservation of vision and cosmetic appearance., Results: Four patients were diagnosed at birth. Six cysts were located inferiorly and one superiorly. Two patients had a visual potential of light perception or better in the affected eye. In 4 eyes, the cyst was initially retained and the eye was fitted with a custom-made conformer. In 1 eye, the fornices were too shallow for a conformer, warranting fornix reconstruction and cyst excision. Early surgery was required in 1 eye for an expanded cyst and large orbit volume, and in another eye the cyst had overgrown the orbit, causing bone erosion and remodeling. Cosmetic results were good in 3 of the eyes in which the cyst was retained in early childhood, stimulating orbital growth., Conclusions: Congenital microphthalmia with orbital cyst is rare. Management should focus on preserving visual potential, especially in unilateral cyst cases when the other eye is also microphthalmic. Otherwise cosmetic symmetry is the main concern; cyst retention combined with ocular conformers may stimulate socket expansion. The authors found that, in most cases, if treated early, enucleation was avoidable during cyst excision. Early assessment, meticulous follow-up, and individually tailored treatment are warranted. [ J Pediatr Ophthalmol Strabismus . 2022;59(3):192-199.] .

Background: Next-generation sequencing has been proven to be a reliable method for the detection of genetic causes in heterogeneous ocular disorders. In this report an NGS-based diagnostic approach was taken to uncover the genetic etiology in a patient with coloboma and microphthalmia, a highly heterogeneous disease with intrafamilial phenotypic variability., Materials and Methods: Next generation sequencing using a targeted panel of 316 genes, was carried out in the proband. Prioritized variants were then identified and confirmed using Sanger sequencing. Prenatal diagnosis of the detected variant was then performed in the family., Results: A novel de novo frameshift variant c.157&#95;164delTTCACTCG (p.Phe53fs) in OTX2 , leading to a truncated protein, was identified. Prenatal diagnosis identified the same variant in the fetus., Conclusions: This report demonstrates the importance of genetic counseling and underscores the efficiency and effectiveness of targeted NGS as a means of detecting variants in inherited eye disorders.

Purpose: To report ocular outcome, somatic co-morbidities, genetics, and quality of life in children born with anophthalmia (A) or microphthalmia (M)., Methods: Thirty-five children (19 boys) with A/M underwent ophthalmological examinations and a review of medical records. Parents of 12/22 cases completed the Pediatric Quality of Life Inventory (PedsQL)., Results: Age at examination ranged from 7 months to 18 years (median 2.3 years). Ten cases were totally blind or had light perception. Isolated A/M occurred in 16/35 cases, while somatic, psychomotor, neuroradiological and/or genetic pathology occurred in 19/35 cases both in the bilateral (7/9) and in the unilateral group (12/26). Among 26 unilateral cases, 4/16 with one normal eye had associated problems compared to 9/10 if the contralateral eye was pathological ( p < .01). There was an increased risk for heart defects in children with psychomotor delay ( p = .04). Pathogenic genetic abnormalities were identified in 10/24 cases. Neuroimaging demonstrated pathology in 14/20 cases with corpus callosum dysgenesis (6/20) being the most common. The median total PedsQL score of parent reports for ages 2-12 was 52.4 (range 22.6-100)., Conclusions: Somatic, psychomotor and/or neuroradiological pathologies were more common in bila-teral than unilateral cases, but the difference was not significant. There was decreased risk in unilateral cases with one normal eye. Genetic defects occurred in both unilateral and bilateral cases. Health-related quality of life was reduced.

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., (© 2022. The Author(s).)

Background: Oculo-facio-cardio-dental syndrome is a rare X-linked dominant syndrome, characterized by radiculomegaly, congenital cataracts, dysmorphic facial features, and congenital heart disease. Because of the rarity, this syndrome could be misdiagnosed by the clinician, especially for the infant who may present only one to two systems involved., Case Presentation: Here we report a 3-month-old female infant presenting with typical clinical manifestations of oculo-facio-cardio-dental syndrome, like ocular, facial, cardiac, and skeletal abnormalities, and the genetic analyses of the proband and her parents were provided. Genetic evaluations were completed using whole exon sequencing, which revealed a novel heterozygous mutation between exons 7 and 14 of the BCOR gene(OMIM:300485) in this patient but not in her parents. This mutation is likely to encode a premature stop codon producing a truncated protein. Our patient was diagnosed early enough to allow for the cardiac defects to be treated first, and she will be closely followed up to ensure that any new presentations are treated in a timeous manner., Conclusion: This patient fits the diagnostic criteria for oculo-facio-cardio-dental syndrome and is the youngest oculo-facio-cardio-dental syndrome patient ever reported, which is most important for her prognosis. In addition, this manuscript also describes a novel potenitally causative mutation for this syndrome., (© 2022. The Author(s).)

Introduction: Congenital microphthalmos can either occur alone (simple microphthalmos) or be associated with other ocular malformations, such as sclerocornea or cataract (complex microphthalmos). As this is a rare condition, there are no uniform recommendations for treatment., Material and Methods: Retrospective case series of 103 patients or a total of 114 eyes with congenital microphthalmos, with reporting of age, sex, visual acuity, pupil reaction, axial length, horizontal width of the palpebral fissure, type of therapy performed and complications., Results: All patients would have been able to be fitted with a prosthesis primarily. The size of the palpebral fissure depended on the underlying findings: "bilateral microphthalmos" < "microphthalmos and healthy fellow eye" < "microphthalmos and fellow anophthalmos". In order to assess visual (residual) function in an infant in the first weeks or months of life, the pupillary response is of the upmost importance in deciding on therapy, especially in unilateral disease, and as assessed with the indirect light response of the healthy eye. In about half of the cases, conservative prosthetic treatment was sufficient. After the successful initial fitting of a prosthesis, the prosthesis was enlarged according to the ocularist's instructions. If the eye length difference was so large that symmetry could not be achieved even with a double-walled prosthesis, volume filling with retrobulbar implanted self-swelling pellet expanders (osmed GmbH, Ilmenau) was offered. In almost one third of the patients, no surgical therapy or prosthetic treatment was performed. The reason for this was usually the presence of minimal visual function of the microphthalmos - ranging from light perception to hand movements., Conclusions: In the case of visual function of the microphthalmos, surgical measures should not be indicated or only with extreme caution, since the preservation of the existing visual acuity must be regarded as having priority over the cosmetic findings. In cases of asymmetry or underdeveloped palpebral fissure, therapy can be started early in the first year of life without fear of resulting complications., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht./The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Purpose: To report a case of posterior microphthalomos (PM) related to PRSS56 gene mutation with long term follow up with multimodal imaging findings., Methods: Single retrospective case report., Results: A 43-year old male patient presented in 2009 with bilateral reduced vision. Clinical examination and multimodal imaging showed features consistent with posterior microphthalmos with prominent bilateral horizontal papillomacular retinal folds. Posterior pole hyperautofluorescent RPE deposits were present. Gradual worsening of visual acuity and rod and cone photoreceptor function more so on the left was demonstrated during the 8 years of follow up., Conclusion: Hyperautofluorescent RPE deposits may occur in patients with posterior microphthalmos and such patient's may experience only gradual disease progression over long term follow up.

Background: Report of clinical findings relating to the lacrimal system in congenital clinical anophthalmos and severe blind microphthalmos (MAC-complex patients)., Methods: A retrospective study of the notes of 207 consecutive patients treated surgically at least once with highly hydrophilic self-inflating expanders for MAC between 1998 and 2021. The lacrimal drainage system was always probed and irrigated under general anaesthesia before any other procedure was started., Results: 64 patients were excluded due to possible misdiagnosis because of previous lid or orbit surgery elsewhere or due to missing data. The analysis therefore included 67 girls and 76 boys aged between 1 and 126 months (median age: 5 months). 72 patients presented with unilateral and 42 with bilateral anophthalmos, and 24 had unilateral and 5 bilateral microphthalmos; consequently, 286 orbits (of which, 190 with probable pathology) were available for assessment. In unilateral cases the lacrimal system on the normal side was never affected. On the anophthalmic or microphthalmic side the lacrimal system was normal in 68 orbits only (35.8%). The most frequent finding was canalicular stenosis (91 orbits; 48%). Common canaliculus stenosis was observed in 12 orbits (6.3%) and nasolacrimal duct obstruction in 9 orbits (4.7%). There were four cases of punctal aplasia, but no other anomalies. In unilateral MAC pathologic findings during lacrimal probing were found to be associated with anatomical malformation of the contralateral fellow eye. Only in unilateral anophthalmos there was a significant association with cleft lip and palate, which was not found in the three other groups., Conclusions: In congenital clinical anophthalmos the lacrimal system is affected in up to 66.5% of cases, mostly due to canalicular stenosis. Even if there is no clear evidence of an embryological connection, this association is certainly not a random finding., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht./The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)