Elevated levels of Merkel cell polyoma virus in the anophthalmic conjunctiva.

The human ocular surface hosts a paucibacterial resident microbiome and virome. The factors contributing to homeostasis of this mucosal community are presently unknown. To determine the impact of ocular enucleation and prosthesis placement on the ocular surface microbiome, we sampled conjunctival swabs from 20 anophthalmic and 20 fellow-eye intact conjunctiva. DNA was extracted and subjected to quantitative 16S rDNA PCR, biome representational karyotyping (BRiSK), and quantitative PCR (qPCR) confirmation of specific organisms. 16S ribosomal qPCR revealed equivalent bacterial loads between conditions. Biome representational in silico karyotyping (BRiSK) demonstrated comparable bacterial fauna between anophthalmic and intact conjunctiva. Both torque teno virus and Merkel cell polyoma virus (MCPyV) were detected frequently in healthy and anophthalmic conjunctiva. By qPCR, MCPyV was detected in 19/20 anophthalmic samples compared with 5/20 fellow eyes. MCPyV copy number averaged 891 copies/ng in anophthalmic conjunctiva compared with 193 copies/ng in fellow eyes (p < 0.001). These results suggest that enucleation and prosthesis placement affect the ocular surface flora, particularly for the resident virome. As MCPyV has been shown to be the etiologic cause of Merkel cell carcinoma, understanding the mechanisms by which the ocular surface regulates this virus may have clinical importance.

Exome sequencing in patients with microphthalmia, anophthalmia, and coloboma (MAC) from a consanguineous population.

Next-generation sequencing strategies have resulted in mutation detection rates of 21% to 61% in small cohorts of patients with microphthalmia, anophthalmia and coloboma (MAC), but despite progress in identifying novel causative genes, many patients remain without a genetic diagnosis. We studied a cohort of 19 patients with MAC who were ascertained from a population with high rates of consanguinity. Using single nucleotide polymorphism (SNP) arrays and whole exome sequencing (WES), we identified one pathogenic variant in TENM3 in a patient with cataracts in addition to MAC. We also detected novel variants of unknown significance in genes that have previously been associated with MAC, including KIF26B, MICU1 and CDON, and identified variants in candidate genes for MAC from the Wnt signaling pathway, comprising LRP6, WNT2B and IQGAP1, but our findings do not prove causality. Plausible variants were not found for many of the cases, indicating that our current understanding of the pathogenesis of MAC, a highly heterogeneous group of ocular defects, remains incomplete.

Truncating RAX Mutations: Anophthalmia, Hypopituitarism, Diabetes Insipidus, and Cleft Palate in Mice and Men.

CONTEXT: The transcription factor RAX is a paired-type homeoprotein that plays a critical role in eye and forebrain development of vertebrate species. RAX knockout mice have anophthalmia, cleft palate, and an abnormal hypothalamus and display perinatal lethality. In humans, homozygous or compound heterozygous RAX mutations have been reported to cause bilateral microphthalmia or anophthalmia without consistent associated features. Congenital hypopituitarism can be associated with various eye or craniofacial anomalies; however, the co-occurrence of congenital hypopituitarism, anophthalmia, cleft palate, and diabetes insipidus has been very rare. RESULTS: We report the case of a child with anophthalmia, congenital hypopituitarism, diabetes insipidus, and bilateral cleft lip and palate who had a homozygous frameshift truncating mutation c.266delC (p.Pro89Argfs*114) in exon 1 of the RAX gene. Rax knockout mice show loss of ventral forebrain structures, pituitary, and basosphenoid bone and palate and a misplaced anterior pituitary gland along the roof of the oral cavity. CONCLUSIONS: Our patient's phenotype was more severe than that reported in other patients. Although most of the previously reported patients with RAX mutations showed either a missense or some less severe mutation in at least one of their RAX alleles, our patient was homozygous for truncating mutations that would yield a severe, null protein phenotype. The severity of the genetic defect, the precise match between the knockout mouse and the patient's endocrine phenotypes, and the prominent roles of RAX in eye and pituitary development and diencephalic patterning suggest that the RAX null mutations could fully account for the observed phenotype.

Both a frameshift and a missense mutation of the STRA6 gene observed in an infant with the Matthew-Wood syndrome.

BACKGROUND: The Matthew-Wood syndrome is associated with mutations of the STRA6 gene. It combines a pulmonary agenesis/hypoplasia; microphthalmia/anophthalmia; congenital cardiac, digestive, and urogenital malformations; and diaphragmatic defects. CASE: A 23-year-old nulliparous woman was referred to our center after a fetal ultrasound examination at 26 weeks of pregnancy revealed an abnormal head shape, a heart malformation, multiple cysts in both kidneys, and dilated ureters. A male baby (46, XY; 3600g; Apgar score 1) was delivered at 38 weeks of gestation and died 1 hr later due to respiratory failure. The diagnosis of Matthew-Wood syndrome was suspected given the association of bilateral anophthalmia, agenesis of the left lung, and heart and kidney defects. It was confirmed by the identification of two deleterious mutations of the STRA6 gene. RESULTS: The child was a compound heterozygote for two previously reported mutations, a paternally inherited missense mutation (c.878C>T [p.Pro293Leu] and a maternally inherited frameshift mutation (c.50_52delACTinsCC [p. Asp17Alafs*55]), producing a premature stop codon. CONCLUSION: The diagnosis of Matthew-Wood syndrome should be considered in all fetuses with microphthalmia/anophthalmia. It requires an extensive ultrasound/MRI examination of the lung, heart, and diaphragm. Birth Defects Research 109:251-253, 2017. © 2017 Wiley Periodicals, Inc.

A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation.

We describe a novel recognizable phenotype characterized by anophthalmia, a distinctive skeletal dysplasia and intellectual disability. Radiographic anomalies include severe rhizomelic shortness of the limbs and abnormal joint formation. Recent exome studies showed that these characteristics are part of the phenotypic spectrum of MAB21L2 gene mutations which cause a range of structural eye malformations such as microphthalmia/anophthalmia and ocular coloboma. The two unrelated individuals described here in detail are heterozygous carriers of the same de novo missense mutation c.151C > T (p.Arg51Cys) in MAB21L2.

Prótese ocular bilateral - relato de caso / Bilateral ocular prosthesis - case report

O presente trabalho visa apresentar um caso clínico de perda bilateral do globo ocular, descrevendo a técnica utilizada na confecção de prótese ocular realizada por graduandos em Odontologia da Escola Bahiana de Medicina e Saúde Pública-EBMSP. A face possui enorme valor estético e expressivo para as pessoas bem como para suas relações em sociedade. Alterações na face geradas pela perda ou atrofia ocular decorrente de traumatismo podem estar relacionadas a diferentes causas e apresentar variados graus de severidade. Os autores apresentam um caso de perda ocular bilateral em um adulto de 57 anos de idade, cujo globo ocular direito apresenta-se atrofiado e o esquerdo havia sido enucleado, ambos decorrentes de trauma. Pacientes portadores de deformidade ocular sofrem de distúrbios funcionais, estéticos e psicológicos. A prótese bucomaxilofacial procura minimizar tais distúrbios com a reabilitação protética, além de reintegrar o indivíduo na sociedade.

This study presents a case of bilateral loss of the eyeball, describing the technique used in the production of ocular prostheses made by dental students at the Medicine and Public Health School of Bahia (Brazil)-EBMSP. The face has great aesthetic and expressive value for people and their relations in society. Alterations in the face as a result of loss or atrophy due to ocular trauma have varied degrees of severity and may be related to different causes. The authors present a case of a 57 years old patients whose right eye was atrophied and the left had been enucleated, due to a trauma. Patients with ocular deformity suffer from functional, aesthetic, and psychological disorders. The bucomaxillofacial prosthesis can be considered an alternative to minimize these disorders with prosthetic rehabilitation, and help to reinstate the individual in society.

Strain differences of the effect of enucleation and anophthalmia on the size and growth of sensory cortices in mice.

Anophthalmia is a condition in which the eye does not develop from the early embryonic period. Early blindness induces cross-modal plastic modifications in the brain such as auditory and haptic activations of the visual cortex and also leads to a greater solicitation of the somatosensory and auditory cortices. The visual cortex is activated by auditory stimuli in anophthalmic mice and activity is known to alter the growth pattern of the cerebral cortex. The size of the primary visual, auditory and somatosensory cortices and of the corresponding specific sensory thalamic nuclei were measured in intact and enucleated C57Bl/6J mice and in ZRDCT anophthalmic mice (ZRDCT/An) to evaluate the contribution of cross-modal activity on the growth of the cerebral cortex. In addition, the size of these structures were compared in intact, enucleated and anophthalmic fourth generation backcrossed hybrid C57Bl/6J×ZRDCT/An mice to parse out the effects of mouse strains and of the different visual deprivations. The visual cortex was smaller in the anophthalmic ZRDCT/An than in the intact and enucleated C57Bl/6J mice. Also the auditory cortex was larger and the somatosensory cortex smaller in the ZRDCT/An than in the intact and enucleated C57Bl/6J mice. The size differences of sensory cortices between the enucleated and anophthalmic mice were no longer present in the hybrid mice, showing specific genetic differences between C57Bl/6J and ZRDCT mice. The post natal size increase of the visual cortex was less in the enucleated than in the anophthalmic and intact hybrid mice. This suggests differences in the activity of the visual cortex between enucleated and anophthalmic mice and that early in-utero spontaneous neural activity in the visual system contributes to the shaping of functional properties of cortical networks.

Canonical Wnt/ß-catenin signalling is essential for optic cup formation.

A multitude of signalling pathways are involved in the process of forming an eye. Here we demonstrate that ß-catenin is essential for eye development as inactivation of ß-catenin prior to cellular specification in the optic vesicle caused anophthalmia in mice. By achieving this early and tissue-specific ß-catenin inactivation we find that retinal pigment epithelium (RPE) commitment was blocked and eye development was arrested prior to optic cup formation due to a loss of canonical Wnt signalling in the dorsal optic vesicle. Thus, these results show that Wnt/ß-catenin signalling is required earlier and play a more central role in eye development than previous studies have indicated. In our genetic model system a few RPE cells could escape ß-catenin inactivation leading to the formation of a small optic rudiment. The optic rudiment contained several neural retinal cell classes surrounded by an RPE. Unlike the RPE cells, the neural retinal cells could be ß-catenin-negative revealing that differentiation of the neural retinal cell classes is ß-catenin-independent. Moreover, although dorsoventral patterning is initiated in the mutant optic vesicle, the neural retinal cells in the optic rudiment displayed almost exclusively ventral identity. Thus, ß-catenin is required for optic cup formation, commitment to RPE cells and maintenance of dorsal identity of the retina.

Whole-genome copy number variation analysis in anophthalmia and microphthalmia.

Anophthalmia/microphthalmia (A/M) represent severe developmental ocular malformations. Currently, mutations in known genes explain less than 40% of A/M cases. We performed whole-genome copy number variation analysis in 60 patients affected with isolated or syndromic A/M. Pathogenic deletions of 3q26 (SOX2) were identified in four independent patients with syndromic microphthalmia. Other variants of interest included regions with a known role in human disease (likely pathogenic) as well as novel rearrangements (uncertain significance). A 2.2-Mb duplication of 3q29 in a patient with non-syndromic anophthalmia and an 877-kb duplication of 11p13 (PAX6) and a 1.4-Mb deletion of 17q11.2 (NF1) in two independent probands with syndromic microphthalmia and other ocular defects were identified; while ocular anomalies have been previously associated with 3q29 duplications, PAX6 duplications, and NF1 mutations in some cases, the ocular phenotypes observed here are more severe than previously reported. Three novel regions of possible interest included a 2q14.2 duplication which cosegregated with microphthalmia/microcornea and congenital cataracts in one family, and 2q21 and 15q26 duplications in two additional cases; each of these regions contains genes that are active during vertebrate ocular development. Overall, this study identified causative copy number mutations and regions with a possible role in ocular disease in 17% of A/M cases.

Mature orbital teratoma with an ectopic tooth and primary anophthalmos.

PURPOSE: To describe the clinicopathologic features and management of an unusual case of orbital teratoma. METHODS: A 7-year-old girl presented with a history of an orbital mass since birth. CT scan showed a large mass lesion involving the right orbit, with absence of the eyeball. An ectopic tooth was identified within the tumor. Lid-sparing exenteration surgery was performed. RESULTS: Histopathologic examination of the excised mass showed presence of elements from all three germ layers, consistent with a diagnosis of mature orbital teratoma. Normal ocular structures were not identified on histopathology. At one year follow-up, there was no tumor recurrence. CONCLUSION: We report an extremely rare and interesting case of a mature orbital teratoma, which was associated with primary anophthalmos and an ectopic tooth.

[Goldenhar's syndrome--case report]. / Zespól Goldenhara-opis przypadku.

Goldenhar's syndrome is a very rare, multiple, developmental disease, with characteristic oculo-auriculo-vertebral triad of abnormalities. Ophthalmological changes are mainly: microphthalmia or anophthalmia and rarely, coloboma of upper eyelid or coloboma of optic nerve head. The aim of the article is to present the case of anophthalmia in the new-born child with phenotype of Goldenhar's syndrome.

The association of sphenoidal encephalocele and right anophthalmia with septo-optic dysplasia: a case report.

Septo-optic dysplasia (SOD) is an extremely rare congenital anomaly, characterized with optic nerve hypoplasia and absence of septum pellucidum and/or pituitary dysfunction. In addition to classical findings of SOD, we report for the first time an 11-year-old boy, with encephalocele extending to the right sphenoidal sinus, right anophthalmia and normal pituitary functions. Despite all the major anomalies, the patient's presenting symptoms were very few and during the 11-year period the SDO had caused no complaints in our case. These findings show that the SOD course may be fairly benign. No neurological problem was encountered in the patient's follow-up, except headache. We believe that SOD should be kept in mind because of its rarity and the severity of its combined pathologies.

Restoration of an atrophic eye socket with custom made eye prosthesis, utilizing digital photography.

Ocular defects may cause several ocular and orbital disorders, which require surgical intervention. These defects are psychologically disturbing for the patients, and therefore, they require immediate management and rehabilitation by a team of specialist. Ocular prosthesis may be either readymade (stock) or custom made. Fabrication of a custom ocular prosthesis allows for a range of variations during construction. The iris can also be custom made by ocular painting or by digital photography. The optimum cosmetic and functional results of a custom-made prosthesis enhance the patient's rehabilitation to a normal life style. This paper elaborates the technique for fabrication of a custom-made ocular prosthesis for an atrophic eye socket utilizing digital photography.

Development of extraocular muscles requires early signals from periocular neural crest and the developing eye.

OBJECTIVES: To identify and explain morphologic changes of the extraocular muscles (EOMs) in anophthalmic patients. METHODS: Retrospective medical record review of patients with congenital anophthalmia, using magnetic resonance imaging and intraoperative findings to characterize EOM morphology. We then used molecular biology techniques in zebrafish and chick embryos to determine the relationships among the developing eye, periocular neural crest, and EOMs. RESULTS: In 3 human patients with bilateral congenital anophthalmia and preoperative orbital imaging, we observed a spectrum of EOM morphologies ranging from indiscernible muscle tissue to well-formed, organized EOMs. Timing of eye loss in zebrafish and chick embryos correlated with the morphology of EOM organization in the orbit (eye socket). In congenitally eyeless Rx3 zebrafish mutants, or following genetic ablation of the cranial neural crest cells, EOMs failed to organize, which was independent of other craniofacial muscle development. CONCLUSIONS: Orbital development is dependent on interactions between the eye, neural crest, and developing EOMs. Timing of the ocular insult in relation to neural crest migration and EOM development is a key determinant of aberrant EOM organization. Additional research will be required to study patients with unilateral and syndromic anophthalmia and assess for possible differences in clinical outcomes of patients with varied EOM morphology. CLINICAL RELEVANCE: The presence and organization of EOMs in anophthalmic eye sockets may serve as a markers for the timing of genetic or teratogenic insults, improving genetic counseling, and assisting with surgical reconstruction and family counseling efforts.

Avaliação Comparativa de Duas Técnicas de Moldagem da Cavidade Anoftálmica / Comparative Evaluation of Two Impression Techniques of the Anophthalmic Socket

Objetivo: A correta adaptação da prótese ocular na cavidade anoftálmica é fundamental para que ocorra uma boa mobilidade da prótese ocular, aspecto primordial na dissimulação da condição artificial presente em uma prótese ocular. Este trabalho avalia comparativamente a técnica de moldagem com seringa e seringa com moldeira acrílica em um grupo de 15 pacientes submetidos à enucleação do globo ocular. Método: Os grupos de estudo, constituídos de acordo com as técnicas de moldagem, foram avaliados mediante a confecção de corpos de prova em resina acrílica de lenta polimerização para observação do diâmetro transversal, diâmetro vertical e área das moldagens. Os corpos de prova foram submetidos à captação de imagens com lupa estereoscópica e câmara digital e as imagens foram processadas no programa ImageLab 2000®. Resultados: A análise estatística Postos Sinalizados de Wilcoxon (p≤0,05) mostrou que o diâmetro transverso foi semelhante em ambas as técnicas de moldagem. O menor diâmetro vertical observado com a técnica da seringa foi estatisticamente significante (p≤0,05). A área da superfície da mucosa da cavidade anoftálmica abrangida pela moldagem foi significantemente maior na técnica de moldagem com seringa e moldeira acrílica (p≤0,05). Conclusão: A técnica de moldagem com seringa e moldeira acrílica proporciona melhor direcionamento do material de moldagem no sentido súpero-inferior, o que determina uma maior área de contato da prótese com a superfície da mucosa. Considerando que a mobilidade de uma prótese ocular é dependente de uma boa adaptação da prótese na superfície da mucosa, pode-se inferir que a técnica de moldagem com seringa e moldeira acrílica acoplada deverá favorecer a mobilidade e a estética das próteses oculares

Objective: An excellent adaptation of the ocular prosthesis to the walls of the anophthalmic socket is fundamental to attain a good mobility of the artificial eye, a primordial aspect in dissimulating the artificial aspect of the prosthesis. This study compares the direct syringe impression technique to the impression taked with syringe and acrylic stock tray in a group of 15 patients submitted to eye enucleation. Methods: The study groups were established according to the impression technique employed and evaluated by means of specimens made of heat polymerizing resin in relation to transversal diameter, vertical diameter and area. The specimens were submitted to a stereoscopic glass and the images generated by a digital camera were processed by the software ImageLab 2000®. Results: The Wilcoxon rank-signed test (p≤0.05) showed that the transversal diameter was similar in both impression techniques. However, the smaller vertical diameter provided by the direct syringe technique was statiscally significant (p≤0.05). The area of the mucous surface of the anophthalmic socket registered during the impression taken with syringe and acrylic tray was significantly larger (p≤0.05). Conclusion: The syringe and acrylic tray impression technique provides a better distribution of the impression material, mainly in the superoinferior direction, and this accounts for the larger contact of the prosthesis with the mucous surface. Considering that the mobility of the ocular prosthesis is dependent of a good adaptation of the prosthesis on the mucous surface, the syringe and acrylic tray impression technique shall improve the mobility and aesthetics of ocular prosthesis

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.

Congenital cystic eye with multiple dermal appendages and intracranial congenital anomalies.

Congenital cystic eye (anophthalmia with cyst) is an extremely rare anomaly discovered at birth with few reported cases in the literature, resulting from partial or complete failure during invagination of the primary optic vesicle during fetal development. Herein we present the radiographic, ultrasound, and magnetic resonance imaging findings of a unique case of congenital cystic eye associated with dermal appendages and advanced intracranial congenital anomalies in a 3-month-old boy.

Anophthalmia and microphthalmia.

Anophthalmia and microphthalmia describe, respectively, the absence of an eye and the presence of a small eye within the orbit. The combined birth prevalence of these conditions is up to 30 per 100,000 population, with microphthalmia reported in up to 11% of blind children. High-resolution cranial imaging, post-mortem examination and genetic studies suggest that these conditions represent a phenotypic continuum. Both anophthalmia and microphthalmia may occur in isolation or as part of a syndrome, as in one-third of cases. Anophthalmia/microphthalmia have complex aetiology with chromosomal, monogenic and environmental causes identified. Chromosomal duplications, deletions and translocations are implicated. Of monogenic causes only SOX2 has been identified as a major causative gene. Other linked genes include PAX6, OTX2, CHX10 and RAX. SOX2 and PAX6 mutations may act through causing lens induction failure. FOXE3 mutations, associated with lens agenesis, have been observed in a few microphthalmic patients. OTX2, CHX10 and RAX have retinal expression and may result in anophthalmia/microphthalmia through failure of retinal differentiation. Environmental factors also play a contributory role. The strongest evidence appears to be with gestational-acquired infections, but may also include maternal vitamin A deficiency, exposure to X-rays, solvent misuse and thalidomide exposure. Diagnosis can be made pre- and post-natally using a combination of clinical features, imaging (ultrasonography and CT/MR scanning) and genetic analysis. Genetic counselling can be challenging due to the extensive range of genes responsible and wide variation in phenotypic expression. Appropriate counselling is indicated if the mode of inheritance can be identified. Differential diagnoses include cryptophthalmos, cyclopia and synophthalmia, and congenital cystic eye. Patients are often managed within multi-disciplinary teams consisting of ophthalmologists, paediatricians and/or clinical geneticists, especially for syndromic cases. Treatment is directed towards maximising existing vision and improving cosmesis through simultaneous stimulation of both soft tissue and bony orbital growth. Mild to moderate microphthalmia is managed conservatively with conformers. Severe microphthalmia and anophthalmia rely upon additional remodelling strategies of endo-orbital volume replacement (with implants, expanders and dermis-fat grafts) and soft tissue reconstruction. The potential for visual development in microphthalmic patients is dependent upon retinal development and other ocular characteristics.

Congenital cystic eye: features on MRI.

Congenital cystic eye is a rare cause of cystic orbital lesion. The condition is recognized at birth as a large orbital mass in place of a normal eye. Only 29 cases have been reported previously. We report a case of unilateral congenital cystic eye with multiple brain anomalies in the form of agenesis of corpus callosum and grey matter heterotopias. In this case report we highlight the MRI features of this entity, which have not been described previously in the literature.