Search

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.)

Retinal congenital malformations known as microphthalmia, anophthalmia, and coloboma (MAC) are associated with alterations in genes encoding epigenetic proteins that modify chromatin. We review newly discovered functions of such chromatin modifiers in retinal development and discuss the role of epigenetics in MAC in humans and animal models. Further, we highlight how advances in epigenomic technologies provide foundational and regenerative medicine-related insights into blinding disorders. Combining knowledge of epigenetics and pluripotent stem cells (PSCs) is a promising avenue because epigenetic factors cooperate with eye field transcription factors (EFTFs) to direct PSC fate - a foundation for congenital retinal disease modeling and cell therapy., Competing Interests: Declaration of Interests There are no interests to declare., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Congenital anophthalmia (A) and microphthalmia (M) are rare developmental defects, which could be isolated or syndromic. Our objective was to describe a cohort of children and young adults with A/M treated with ocular prosthesis, emphasizing clinical features, diagnosis, treatment, and follow-up., Methods: Eighteen individuals (10 female) with unilateral A (n = 3) and M (n = 15) with a mean age of 9.5 years (range 0.8-31.8) and treated with ocular prosthesis were included. Data on medical history, clinical examinations and management of ocular prosthesis were collected. Genetic screening with microarray and whole-exome sequencing targeting 121 A/M-related genes was performed., Results: A/M appeared isolated (seven cases) or as part of a syndromic condition (11 cases). In 4/16 patients, mutations were detected in TFAP2A, CHD7, FOXE3 and BCOR-genes. In one patient, a possibly causal microdeletion 10q11 was shown. Associated ocular anomalies such as cataract and cysts were found in 16 (89%) of the A/M eyes, and in nine (50%) ophthalmological findings were found in the fellow eyes. The median ages at which the conformer and ocular prosthesis first were initiated were 7.8 months and 1.5 years. 16/17 patients fulfilled satisfactory orbital growth and cosmetic results when treated with ocular prosthesis from an early age., Conclusion: Based upon our findings, a multidisciplinary approach, including genetic assessment, is necessary to cover all aspects of A/M. Imaging, ultrasound and visual evoked potentials should be included. Early management is crucial for the outcome, in terms of non-ocular findings, vision in the fellow eye, and for facial cosmetic development., (© 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Porcine-derived xenogeneic sources for transplantation are a promising alternative strategy for providing organs for treatment of end-stage organ failure in human patients because of the shortage of human donor organs. The recently developed blastocyst or pluripotent stem cell (PSC) complementation strategy opens a new route for regenerating allogenic organs in miniature pigs. Since the eye is a complicated organ with highly specialized constituent tissues derived from different primordial cell lineages, the development of an intact eye from allogenic cells is a challenging task. Here, combining somatic cell nuclear transfer technology (SCNT) and an anophthalmic pig model ( MITF L 247S/L247S ), allogenic retinal pigmented epithelium cells (RPEs) were retrieved from an E60 chimeric fetus using blastocyst complementation. Furthermore, all structures were successfully regenerated in the intact eye from the injected donor blastomeres. These results clearly demonstrate that not only differentiated functional somatic cells but also a disabled organ with highly specialized constituent tissues can be generated from exogenous blastomeres when delivered to pig embryos with an empty organ niche. This system may also provide novel insights into ocular organogenesis., (© 2018 The Authors. Published under the terms of the CC BY 4.0 license.)

Anophthalmia/microphthalmia (A/M) are rare congenital eye malformations. Early intervention with ocular prosthesis can stimulate orbital growth and prevent facial asymmetry. We reviewed medical records from 18 individuals with A/M (0.8-31 years) treated with ocular prosthesis at Sahlgrenska University Hospital between 2000 and 2012. A majority had other ocular findings. Seven had subnormal visual acuity in the fellow eye, one third were in contact with vision support services and half of the group wore glasses. Eleven individuals had extra-ocular findings such as cardiac defect, hearing impairment and neuropsychiatric disorders, possibly indicating syndromic conditions. We suggest that investigation of A/M children should include ultrasound of the eye, optionally visual evoked potential and magnetic resonance imaging of the CNS. The ophthalmologist should initiate treatment with prosthesis, pediatric assessment, hearing tests and genetic counseling, but should also monitor visual development of the fellow eye.

Purpose: To review and summarize current management of anophthalmic syndrome-enophthalmos, superior sulcus syndrome, lower eyelid laxity, and upper eyelid ptosis., Methods: The authors performed a PubMed search of all articles published in English on the management of anophthalmic socket syndrome., Results: A review of 37 articles demonstrated that anophthalmic syndrome occurs in a significant proportion of this patient population. Primary prevention through careful selection of primary orbital implant is ideal. Residual mild deficits can then be corrected through prosthesis modification. When modification of the prosthesis is no longer sufficient, specifically targeted procedures become necessary., Conclusions: Ocularists and oculoplastic surgeons should work together closely to treat anophthalmic syndrome. Future studies should establish uniform measurement criteria as the next step in validating the benefit and limitation of each technique.

Objective: To describe the complication of anterior filler displacement following injection of calcium hydroxylapatite gel (Radiesse) for anophthalmic enophthalmos correction., Methods: Retrospective case series of patients who experienced anterior filler displacement following orbital injection of calcium hydroxylapatite. Data includes patient demographics, indication for injection, route and volume of injection, description of postinjection complications, and final outcome., Results: Four cases of anterior filler displacement and expansion following injection of calcium hydroxylapatite were identified. The patients' ages ranged from 33 to 64 years old. All 4 patients underwent multiple prior orbital surgeries and suffered from anophthalmic enophthalmos. Injectable calcium hydroxylapatite was delivered transcutaneously, to the deep extraconal orbital space, via 27-gauge, 1.25-inch retrobulbar needles. Each patient received an initial 1.3 ml of filler, with 1 patient receiving an additional 0.8 ml. Within 1 week, all patients experienced prominent, edematous lower eyelids. A CT scan of 1 patient radiographically documented anterior migration of the filler material. Two patients required transconjunctival excision of the filler and infiltrated orbital fat. Histopathologic examination of 1 specimen revealed chronic foreign body granulomatous inflammation. Two patients were treated medically, with resolution of clinical findings over 6 to 9 months., Conclusions: Anterior filler displacement is a potential complication of orbital volume augmentation with injectable calcium hydroxylapatite. Patients should be counseled regarding this possibility when considering options for the treatment of anophthalmic enophthalmos. A history of multiple prior orbital surgeries, with associated tissue disruption and scarring, may be a risk factor for filler displacement.

Purpose: To describe the clinical features of children with anophthalmos, microphthalmos, and typical coloboma (AMC)., Design: Descriptive, observational, cross-sectional study of the United Kingdom., Participants: A total of 135 children with AMC newly diagnosed over an 18-month period beginning in October 2006., Methods: Cases were identified using active surveillance through an established ophthalmic surveillance system. Eligible cases were followed up 6 months after first notification., Main Outcome Measures: Phenotypic characteristics, both ocular and systemic, clinical investigations, causes, and interventions., Results: A total of 210 eyes (of 135 children) were affected by AMC, of which 153 had isolated coloboma or coloboma with microphthalmos. The most common colobomatous anomaly was a chorioretinal defect present in 109 eyes (71.2%). Some 44% of children were bilaterally visually impaired. Systemic abnormalities were present in 59.7% of children, with craniofacial anomalies being the most common. Children with bilateral disease had a 2.7 times higher odds (95% confidence interval, 1.3-5.5, P = 0.006) of having systemic involvement than unilaterally affected children. Neurologic imaging was the most frequent investigation (58.5%) performed. Less than one third (30.3%) of the children with microphthalmos had ocular axial lengths measured. Eight children had confirmed genetic mutations. Approximately half (49.2%) of the children required ocular intervention., Conclusions: Colobomatous defects were the most common phenotype within this spectrum of anomalies in the United Kingdom. The high frequency of posterior segment colobomatous involvement means that a dilated fundal examination should be made in all cases. The significant visual and systemic morbidity in affected children underlines the importance of a multidisciplinary approach to management., (Copyright © 2012 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Neurofibromatosis type 1 (NF-1) is an autosomal dominant, multisystem disorder, affecting approximately 1 of 3500 people. Ocular disorders, such as Lisch nodules, optic gliomas, and anterior segment defects, are typical with clinical presentation. Anophthalmia, as a rare eye malformation, has never been reported in patients with NF-1. We report a 27-year-old patient in whom clinical manifestations of café au lait spots, neurofibromas, osseous orbital dysplasia, and anophthalmia were observed. The diagnosis of NF-1 was made, according to clinical course and brain computed tomography and magnetic resonance imaging. Because the patient refused aggressive management approaches, she was managed conservatively and is well on follow-up. We suggest that patients presenting with anophthalmia need serious evaluation and that NF-1 needs to be considered in the differential diagnosis.

Introduction: Congenital anophthalmos and microphthalmos are reported to occur in 1-20/100 000 newborn infants. The conditions may be characterised by associated pathology in the fellow eye when unilateral disease is present and/or by complex systemic anomalies., Methods: We conducted a review of 75 patients with congenital anophthalmos or blind microphthalmos who were examined in our department from 1997 to 2008. Data on pregnancy, birth and family history were collected. Patients were screened for any pathology in the fellow eye in unilateral disease and for any systemic anomaly., Results: Sixteen patients had blind unilateral microphthalmos. To date there has been only one case of bilateral microphthalmos. Congenital anophthalmos was unilateral in 38 and bilateral in 20 patients. Only one of the children had a positive family history for anophthalmos. None of the mothers had had problems in pregnancy or during delivery. There were more associated systemic findings in anophthalmic (50%) than in microphthalmic (17.6%) patients. Typically, the pathology was characterised by Goldenhar's syndrome, facial clefts and developmental cerebral anomalies. Four out of 16 patients with unilateral microphthalmos (25%) and 18 out of 38 patients with unilateral anophthalmos (47.4%) had anomalies in the fellow eye, predominantly coloboma, dermoid, sclerocornea and glaucoma. On account of this pathology in a single eye, two (12.5%) of the patients with unilateral microphthalmos and 13 (34.2%) of the patients with unilateral anophthalmos, as well as all 20 patients with bilateral anophthalmos, were classified as legally blind. Therefore the overall blindness rate was 17.6% in microphthalmos and 3.4 times higher (56.9%) in anophthalmos., Conclusions: All children born with congenital anophthalmos or microphthalmos require a thorough clinical examination by an experienced ophthalmologist to rule out pathology in the fellow eye in unilateral disease and by a paediatrician to screen for any associated systemic anomalies.

Purpose: To evaluate the use of orbital polyacrylamide gel injection for the correction of anophthalmic enophthalmos., Methods: Noncontrolled clinical trial of 21 patients (14 with ocular implants, 5 with phthisis bulbi, and 2 with dermis-fat graft). Orbital CT was performed to estimate the volume of polyacrylamide gel needed to restore orbital volume. Polyacrylamide gel was injected using a 22-gauge (30 x 0.7 mm) needle transcutaneously inserted in the lateral third of the lower eyelid, directed to the orbital muscle cone. A second injection was administered 15 days later, if necessary. CT was repeated 30 days after the last procedure. Exophthalmometry was performed before and 90 days after the procedure., Results: The mean total volume injected per orbit was 2.4 +/- 0.7 ml (range, 1-3.5 ml). The volume of the enophthalmic orbit increased from 26.9 +/- 5.0 ml to 29.3 +/- 4.9 ml (p < 0.001). The mean difference in exophthalmometry readings was 3.3 +/- 1.6 mm (range, 1.5-8.0 mm) before the procedure and 1.0 +/- 0.9 mm (range, 0.0-3.0 mm) after 3 months (p < 0.001). Adjustment of the ocular prosthesis or fabrication of a new one was necessary in 11 patients (52.4%), and the mean volume of the ocular prosthesis was reduced from 2.0 +/- 0.6 ml to 1.6 +/- 0.6 ml (p = 0.003). All patients were satisfied with the aesthetic results. No serious adverse events were observed. The initial results were maintained 1 year after the procedure., Conclusions: Polyacrylamide gel injection in the orbital space effectively reduces enophthalmos in ocular prosthesis wearers.

Purpose: To evaluate the cytologic features of conjunctival epithelium in anophthalmic sockets with an ocular prosthesis, using an impression cytology technique and to determine the clinical factors associated with these changes., Methods: In a prospective case-controlled study, 40 consecutive unilateral anophthalmic patients who wore an ocular prosthesis were recruited. A questionnaire on the care of the prosthesis included total wearing period, frequency of cleaning, frequency of polishing, cleaning solution, and eye drop use. The degree of inflammation of the anophthalmic conjunctival socket was evaluated. Impression cytology specimens were taken from the upper tarsal conjunctiva, the bulbar conjunctiva, and the lower tarsal conjunctiva of each socket, and from the contralateral eye (to serve as an internal matched control). The goblet cell density and the nucleus-to-cytoplasm ratio of the epithelial cells were measured. The relevance of these conjunctival cytologic features to the various factors of prosthesis care or conjunctival inflammation was analyzed., Results: In the anophthalmic sockets, the conjunctiva showed squamous metaplasia at all 3 areas sampled. The goblet cell density was significantly decreased and the nucleus-to-cytoplasm ratio of the epithelial cells was significantly increased compared with the control eyes (p<0.05, on all 3 areas sampled, Wilcoxon signed rank test). These conjunctival cytologic changes were not significantly associated with total wearing time, frequency of polishing, cleaning solution, or eye drops use (p>0.05, Spearman's correlation test)., Conclusions: Squamous metaplasia with decreased goblet cell density and increased nucleus-to-cytoplasm ratio occurred in anophthalmic conjunctival sockets but was not associated with particular aspects of prosthesis care.

Congenital anophthalmia and microphthalmia are rare developmental defects of the globe. They often arise in conjunction with other ocular defects such as coloboma and orbital cyst. They may also be part of more generalised syndromes, such as CHARGE syndrome. Anophthalmia, microphthalmia, and coloboma are likely to be caused by disturbances of the morphogenetic pathway that controls eye development, either as a result of primary genetic defect, or external gestational factors, including infection or drugs that can influence the smooth processes of morphogenesis. The ophthalmologist is often the primary carer for children with anophthalmia and microphthalmia, and as such can coordinate the multidisciplinary input needed to offer optimal care for these individuals, including vision and family support services. They are able to assess the vision and maximise the visual potential of the child and they can also ensure that the cosmetic and social impact of anophthalmia or microphthalmia is minimised by starting socket expansion or referring to a specialist oculoplastics and prosthetics unit. A coordinated approach with paediatrics is necessary to manage any associated conditions. Genetic diagnosis and investigations can greatly assist in providing a diagnosis and informed genetic counselling.

A 66-year-old man who presented with anophthalmic enophthalmos desired improvement in his appearance without invasive surgery. A nonincisional technique for volume augmentation in the anophthalmic socket with injectable calcium hydroxylapatite was performed. Clinical improvement was determined by comparison of preoperative and 6-month postoperative exophthalmometry values and photographs. Injectable calcium hydroxylapatite successfully increased orbital volume in this anophthalmic patient.

Objective: The aim of the present work was to establish a method for orbital volume calculation based on MR scanning data for the sake of better radiation hygiene., Materials and Methods: The orbital volumes of 35 ophthalmologically healthy children were calculated on the basis of MRI scans. After data transfer to a separate workstation, volumetric analysis was carried out by two independent radiologists using semi-automated software. The accuracy of the calculated values was compared with orbital volumes measured by anatomic preparations and given in studies by various authors., Results: Volume calculation was possible in all patients using MRI data. There is an acceptable agreement with the presented anatomic facts and the measured values of Bentheley. In the Wilcoxon test there was not a big difference between the courses of the values (p = 0.507)., Conclusion: Even though we can obtain a better image of the bizarre structure of the bony orbits with CT, MR-based volumetry of the orbit is a reliable method and is not burdened by radiation exposure. It can thus be an important condition for the planning and the controlling of modern therapeutic concepts in treating anophthalmos and microphthalmos.

Purpose: To report the association of congenital nasolacrimal duct occlusion and clinical anophthalmos in an eight-year-old girl., Methods: A case report. The patient suffered from epiphora and clinical anophthalmos on the right side since birth. This paper presents the clinical presentation, workup, and surgical approach of the case., Results: The nasolacrimal system of the patient was occluded on irrigation. Computed tomography showed a blockage at the level of the sac-duct junction, an enlarged nasolacrimal duct below the obstruction, and a sclera-like ball of tissue surrounded by extraocular muscles in the right orbit. Treatment included a right bicanalicular silicon intubation performed under general anesthesia., Conclusion: This case may represent a new association that has not been previously reported.

We placed spheres of synthetic hydroxyapatite (calcium chloride combined with sodium phosphate) in the eviscerated or enucleated orbital cavity of rats in order to evaluate the biocompatibility of this material with the orbital cavity. The study was conducted on 50 albino rats, 25 of which were submitted to enucleation and 25 to evisceration of one eye. The animals were sacrificed 7, 15, 21, 30 and 60 days after surgery and the orbital content was submitted to histopathological examination. A reaction of the young granulation tissue type was observed first. The hydroxyapatite was gradually surrounded by a granulomatous macrophage inflammatory response and covered with dense connective tissue that formed a sort of "mesh" septating and supporting progressively smaller blocks of the substance. The same type of reaction was observed in the enucleated and eviscerated cavities. We conclude that synthetic hydroxyapatite is an inert nonallergenic material which is appropriate for volume replacement in the anophthalmic cavity.

We report on the risk factors, associations and outcome of 5 children with bilateral clinical anophthalmos. Our study showed no gestational, environmental or hereditary association but confirmed strong association with multiple systemic abnormalities.

Purpose: To better characterize congenital anophthalmos and microphthalmos in order to distinguish which patients need surgical treatment., Materials and Methods: A retrospective study of 42 cases with congenital anophthalmos and microphthalmos over a 16 years period was performed. Seven anophthalmos, 20 microphthalmic globes with no associated colobomatous orbital cyst and 15 microphthalmic globes associated with colobomatous orbital cyst were observed. Complete history, pediatrical and ophthalmological examination, electrophysiological feature, oculo-cerebral imagery and karyotype on each of the patients were reviewed., Results: Among all patients, lack of development of the lids was observed in 45% of cases. In our group of anophthalmos, 100% had micro-orbit. In our group of microphthalmic globes with no associated colobomatous orbital cyst, 30% had micro-orbit and in our group of microphthalmic globes associated with colobomatous orbital cyst, 6% had micro-orbit. 75% of patients had ocular anomalies and 39% had systemic anomalies, mostly on the face. Aetiology were found in 36% of cases. Visual evoked potentials and retinal electric feature were useful to better determine visual function., Conclusion: Expandable orbital prosthesis would appear to be the most effective therapy for certain cases of anophthalmos and microphthalmos with micro-orbit.

Background: Congenital anophthalmos is a rare condition in which intervention at an early age can stimulate orbital expansion and maximise facial symmetry. Much is still unknown, however, regarding the degree of soft tissue and bony orbital growth achieved using the orbital expanders presently available., Methods: A retrospective review of 59 congenitally anophthalmic orbits in 42 patients was carried out., Results: The soft tissue and bony orbital expansion achieved using serial solid shapes is reported, and experience with hydrophilic expanders and inflatable silicone expanders is reviewed., Conclusion: Although serially fitted solid shapes in the orbit lead to increased expansion of orbital soft tissue and bone compared with no orbital implant, further orbital tissue enlargement is required. The inflatable silicone expander may allow more rapid and extensive orbital tissue expansion, but design changes are needed to achieve this.

In anophthalmos the forces which stimulate development and growth of the bony orbit are absent. As a result these cases have not only a tiny socket but also an underdeveloped bony orbit, which cannot retain an artificial eye. The small conjunctival sac and bony orbit can be mechanically enlarged by means of Hema socket expanders. This hydrophilic material can be manufactured in different forms and sizes and expands the socket and orbit by increasing in volume after hydration. After expanding the conjunctival sac to a certain size the next-larger form is fitted to the socket; the procedure is repeated until an artificial eye can be worn.

The management of congenital anophthalmos is difficult under the best of circumstances. Therapy is directed towards enlargement of the sorbet by expansion and/or surgical techniques. Early expansion therapy within the first year of life appears to be warranted in view of the differential orbital growth rates.