Real-world clinical and molecular management of 50 prospective patients with microphthalmia, anophthalmia and/or ocular coloboma.

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.

Ubiquitous Chromatin Modifiers in Congenital Retinal Diseases: Implications for Disease Modeling and Regenerative Medicine.

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.

Children and young adults with anophthalmia and microphthalmia: Diagnosis and Management.

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.

Rescuing ocular development in an anophthalmic pig by blastocyst complementation.

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 (MITFL247S/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.

Nanoskin: uso para reposição de volume na cavidade anoftálmica / Use of Nanoskin for volume replacement of the eye socket

RESUMO Objetivo: Avaliar a biocompatibilidade da Nanoskin para reposição de volume em cavidades enucleadas ou evisceradas de coelhos. Métodos: Estudo experimental, utilizando implantes de Nanoskin (Innovatecs®, São Carlos, Brasil), celulose bacteriana produzida pela bactéria Acetobacter xylinum tendo como substrato o chá-verde. Implantes de 10mm de diâmetro/5mm de espessura foram colocados em cavidades enucleadas (G1) ou evisceradas (G2) de 21 coelhos, avaliados clinicamente todos os dias, sacrificados aos 7, 30 e 90 dias após a cirurgia. O material foi removido e preparado para exame de microscopia óptica. Resultados: Sinais flogísticos discretos no pósoperatório imediato, não tendo sido evidenciados sinais infecciosos ou extrusão de nenhum implante. Houve aparente redução do volume ao longo do período experimental. Histologicamente ambos os grupos foram muito semelhantes, apresentando aos 7 dias células inflamatórias (predominantemente monócitos e neutrófilos), rede de fibrina e hemácias. A Nanoskin apresentava-se como pequenas esferas, de cor rósea, com pequenos espaços entre elas, permeados por escassas células inflamatórias. As células inflamatórias se modificaram ao longo de período experimental, sendo possível observar aos 30 dias células gigantes multinucleadas e fibroblastos maduros permeando o implante. Aos 90 dias, a estrutura do implante apresentava-se desorganizada, amorfa, com restos necróticos e com áreas ovoides, revestidas por fina membrana rósea, que pareciam se agrupar, vazias ou preenchidas por material acelular, róseo ou acinzentado. Conclusão: A Nanoskin provocou reação inflamatória que levou à reabsorção e redução do volume do implante. Novas formulações devem ser estudadas a fim de ter um produto que seja permanente para reparo da cavidade anoftálmica.

ABSTRACT Objective: The aim of this study was to evaluate the biocompatibility of Nanoskin for replacing volume in enucleated or eviscerated anophthalmic sockets of rabbits. Methods: An experimental study was carried out using enucleated or eviscerated rabbits, which received Nanoskin implants (Innovatecs®, São Carlos, Brazil), a cellulose produced by a bacteria (Acetobacter xylinum) using green tea as substrate. Implants of 10mm diameter/5mm of thickness were used placed in enucleated (G1) or eviscerated (G2) anophthalmic sockets of 21 rabbits.They were clinically examined daily, sacrificed at 7, 30 and 90 days after surgery and the material was removed and prepared for histological examination. Results: There were discrete signs of inflammation in the immediate postoperative period, with no evidence of infection or extrusion in any animal. However apparent reduction of volume during the trial period occurred. Histologically both groups were similar, with inflammatory cells (mainly monocytes and neutrophils), fibrin and hemaceas at 7 days postoperatively.The Nanoskin was presented as small pink spheres, with small gaps between them and permeated by few inflammatory cells. These cells have changed over the study, at 30 days multinucleated giant cells and mature fibroblasts that permeate the implant were observed. At 90 days, the structure of the implant was disorganized, amorphous, with necrotic debris and ovoid areas covered with thin pink membrane that seemed to cluster, empty or filled with no cellular pink or gray material. Conclusion: Nanoskin caused an inflammatory reaction leading to reabsorption and reduction of implant volume. New formulations should be studied in order to have a permanent product to repair the anophthalmic socket.

[Anophthalmia and microphthalmia requires multidisciplinary care. Many of the children also have other medical problems]. / Anoftalmi och mikroftalmi kräver multi-disciplinär vård - Många av barnen har även andra medicinska problem.

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.

Anophthalmic syndrome: a review of management.

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.

Cavidades anoftálmicas atípicas en el Instituto Cubano de Oftalmología "Ramón Pando Ferrer" / Atypical anophthalmic cavities observed in patients seen at "Ramón Pando Ferrer" Cuban Institute of Ophthalmology

OBJETIVO: describir el comportamiento de las cavidades anoftàlmicas atípicas. MÉTODOS: se realizó un estudio descriptivo prospectivo en pacientes con cavidades anoftálmicas atípicas atendidos en la consulta de Cirugía Plástica Ocular, en el período de enero de 2009 a julio de 2010. Se analizaron diferentes variables como sexo, edad, alteraciones de la cavidad y tratamiento quirúrgico. RESULTADOS: del total de los pacientes vistos en la consulta, 57 % pertenecían al sexo masculino. El 43 % se encontraba entre los 30 y 49 años. El 90,2 % presentó alteraciones conjuntivales, y la de mayor representatividad fue la retracción del fornix inferior, con el 33,8 %. Dentro de las técnicas quirúrgicas, la reinserción conjuntival del fondo de saco fue la más utilizada y se realizó en el 38 % de los pacientes. CONCLUSIONES: el mayor número de pacientes vistos pertenecen al sexo masculino y al grupo de edades entre 30 y 49 años. Predominaron las alteraciones conjuntivales y dentro de ellas la retracción del fornix inferior. La técnica más utilizada fue la reinserción de la conjuntiva.

OBJECTIVE: to describe the behavior of atypical anophthalmic cavities. METHODS: aprospective and descriptive study was conducted in patients with atypical anophthalmic cavities seen in the ocular plastic surgery service from January 2009 to July 2010. The analyzed variables were sex, age, cavity abnormalities, and surgical treatment. RESULTS: of all patients seen, 57 % were males and 43 % were 30 to 49 years-old. In this group, 90,2 % had conjunctival anomalies, being the inferior fornix retraction the most significant with 33.8 %. Among the surgical techniques used, the conjunctival reinsertion of the fornix was the most performed in 38% of cases. CONCLUSIONS: the highest number of patients was males and the predominant age group was 30-49 years; conjunctival alterations were predominant, mainly the inferior fornix retraction. The most used technique was the reintegration of the conjunctiva.

[Give attention to standardized management of orbital development in Chinese with microphthalmos or anophthalmos].

Congenital and acquired microphthalmos or anophthalmos are common ocular disorders that cause facial disfigurement in children. It is important to have timely and reasonable treatment to promote orbital growth. At present status, many patients miss the optimum opportunity for orbital reconstruction because of non-standardized management in China. The correct management for promoting orbital growth in microphthalmos or anophthalmos is thus elaborated. Conformers with progressively increasing size can be used in children at 1-3 years of age; while orbital implants could be used after 3-5 years of age. Rational and regular evaluation of the efficacy is critical for guiding the treatment process.

Anterior filler displacement following injection of calcium hydroxylapatite gel (Radiesse) for anophthalmic orbital volume augmentation.

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.

Anophthalmos, microphthalmos, and Coloboma in the United kingdom: clinical features, results of investigations, and early management.

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.

Anophthalmia: an uncommon manifestation of neurofibromatosis type 1.

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.

Systemic and ophthalmological anomalies in congenital anophthalmic or microphthalmic patients.

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.

Intraorbital polyacrylamide gel injection for the treatment of anophthalmic enophthalmos.

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.

Conjunctival cytologic features in anophthalmic patients wearing an ocular prosthesis.

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.

A practical guide to the management of anophthalmia and microphthalmia.

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.