EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families.

EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic EPHA2 variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, ≥2 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with >90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic EPHA2 variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C>T, p.(Pro584Leu) and (ii) splice site c.2826-9G>A. To functionally validate pathogenicity, morpholino knockdown of epha2a/epha2b in zebrafish resulted in significantly reduced eye size ± cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the epha2b knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of EPHA2 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.

Congenital microcephaly-linked CDK5RAP2 affects eye development.

Biallelic mutations in the cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2 cause autosomal recessive primary microcephaly type 3 (MCPH3). MCPH is characterized by intellectual disability and microcephaly at birth, classically without further organ involvement. Only recently, congenital cataracts were reported in four patients of one pedigree with MCPH3. Given the lack of a further pedigree with this phenotype, it remained unclear whether this was a true causal relationship. Here we support the link between CDK5RAP2 and eye development by showing that most Cdk5rap2 mutant mice (an/an) exhibit eye malformations ranging from reduced size of one or both eyes (microphthalmia) to total absence of both eyes (anophthalmia). We also detected increased apoptosis in the an/an retinal progenitor cells associated with more mitotic cells. This indicates an important role of Cdk5rap2 in physiologic eye development.

Fetal and neonatal abnormalities due to congenital herpes simplex virus infection: a literature review.

OBJECTIVE: Herpes simplex virus (HSV) infection during pregnancy can cause severe neonatal infections. It is also a rare cause of congenital infections. We aimed to describe fetal and neonatal abnormalities of congenital HSV infection in order to define the features that are accessible to prenatal diagnosis during ultrasound screening and/or during a work-up for congenital malformations. METHODS: We analysed all cases of congenital HSV infection (CHI) described before and/or after birth and identified in Pubed and classified the findings as accessible or not to prenatal diagnosis. RESULTS: Thirty-six cases of congenital herpes infection were reported, of which 15 were described prenatally and 21 postnatally. The most frequently reported malformations accessible to prenatal diagnosis were cerebral anomalies. The most common abnormalities described after birth were skin lesions and keratitis, which are not considered amenable to prenatal ultrasound detection. CHI can due to either HSV1 or HSV2 infection, whether primary or non-primary infection, with or without the presence of maternal symptoms. CONCLUSION: Prenatal ultrasound abnormalities due to CHI are rare, varied and non-specific. There is no clear role for fetal ultrasound in the routine management of women with primary or non-primary HSV infection in pregnancy. However, in fetuses with ultrasound abnormalities suggestive of congenital infection, HSV should still be considered as a differential diagnosis after the more common in utero infections, such as cytomegalovirus, are excluded.

High-throughput transcriptome analysis reveals that the loss of Pten activates a novel NKX6-1/RASGRP1 regulatory module to rescue microphthalmia caused by Fgfr2-deficient lenses.

FGFR signaling is critical to development and disease pathogenesis, initiating phosphorylation-driven signaling cascades, notably the RAS-RAF-MEK-ERK and PI3 K-AKT cascades. PTEN antagonizes FGFR signaling by reducing AKT and ERK activation. Mouse lenses lacking FGFR2 exhibit microphakia and reduced ERK and AKT phosphorylation, widespread apoptosis, and defective lens fiber cell differentiation. In contrast, simultaneous deletion of both Fgfr2 and Pten restores ERK and AKT activation levels as well as lens size, cell survival and aspects of fiber cell differentiation; however, the molecular basis of this "rescue" remains undefined. We performed transcriptomic analysis by RNA sequencing of mouse lenses with conditional deletion of Fgfr2, Pten or both Fgfr2 and Pten, which reveal new molecular mechanisms that uncover how FGFR2 and PTEN signaling interact during development. The FGFR2-deficient lens transcriptome demonstrates overall loss of fiber cell identity with deregulated expression of 1448 genes. We find that ~ 60% of deregulated genes return to normal expression levels in lenses lacking both Fgfr2 and Pten. Further, application of customized filtering parameters to these RNA-seq data sets identified 68 high-priority candidate genes. Bioinformatics analyses showed that the cis-binding motif of a high-priority homeodomain transcription factor, NKX6-1, was present in the putative promoters of ~ 78% of these candidates. Finally, biochemical reporter assays demonstrate that NKX6-1 activated the expression of the high-priority candidate Rasgrp1, a RAS-activating protein. Together, these data define a novel regulatory module in which NKX6-1 directly activates Rasgrp1 expression to restore the balance of ERK and AKT activation, thus providing new insights into alternate regulation of FGFR downstream events.

An application of data mining to identify potential risk factors for anophthalmia and microphthalmia.

BACKGROUND: We examined a large number of variables to generate new hypotheses regarding a wider range of risk factors for anophthalmia/microphthalmia using data mining. METHODS: Data were from the National Birth Defects Prevention Study, a multicentre, case-control study from 10 centres in the United States. There were 134 cases of "isolated" and 87 "nonisolated" (with other major birth defects) of anophthalmia/microphthalmia and 11 052 nonmalformed controls with delivery dates October 1997-December 2011. Using random forest, a data mining procedure, we compared the two case types with controls for 201 variables. Variables considered important ranked by random forest were included in a multivariable logistic regression model to estimate odds ratios and 95% confidence intervals. RESULTS: Predictors for isolated cases included paternal race/ethnicity, maternal intake of certain nutrients and foods, and childhood health problems in relatives. Using regression, inverse associations were observed with greater maternal education and with increasing intake of folate and potatoes. Odds were slightly higher with greater paternal education, for increased intake of carbohydrates and beans, and if relatives had a childhood health problem. For nonisolated cases, predictors included paternal race/ethnicity, maternal intake of certain nutrients, and smoking in the home the month before conception. Odds were higher for Hispanic fathers and smoking in the home and NSAID use the month before conception. CONCLUSIONS: Results appear to support previously hypothesised risk factors, socio-economic status, NSAID use, and inadequate folate intake, and potentially provide new areas such as passive smoking pre-pregnancy, and paternal education and ethnicity, to explore for further understanding of anophthalmia/microphthalmia.

Amniotic Band Syndrome: A Review of 2 Cases.

Amniotic band syndrome is a rare congenital disorder caused by entrapment of fetal parts (usually a limb or digits) in fibrous amniotic bands while in utero that presents with complex multisystem anomalies. The authors report 2 children with amniotic band syndrome who presented to the ophthalmic unit of the authors' pediatric hospital. One of them presented with telecanthus, syndactyly, amputated toes, and unilateral epiphora diagnosed as congenital nasolacrimal duct obstruction. She was managed conservatively with lacrimal sac massage and provided with refractive correction while she simultaneously underwent multiple surgeries for correction of clubfoot and craniosynostosis. The second patient presented with cleft lip, cleft palate, multiple constriction bands in upper limbs and fingers with unilateral microphthalmos, microcornea, typical iris coloboma, and retinochoroidal coloboma, very similar to a case reported in literature. These 2 cases provide an overview of the clinical spectrum of ophthalmic manifestations along with their staged optimum rehabilitation.

[Clinical and anatomical features of congenital microphthalmia and anophthalmia in children and conservative methods of rehabilitation]. / Kliniko-anatomicheskie osobennosti vrozhdennogo mikroftal'ma i anoftal'ma u detei i konservativnye metody reabilitatsii.

AIM: To develop a comprehensive classification system of distinctive clinical and anatomical features of congenital microphthalmia and anophthalmia in children and to specify indications, contraindications, and optimal timing of the primary and subsequent prosthetic treatment. MATERIAL AND METHODS: A total of 70 patients with congenital micro- or anophthalmia aged from 1 month to 12 years were examined. Besides the routine ophthalmic examination, all patients underwent eye and orbit ultrasound (axial length measurement and B-scan), computed tomography of the orbits and skull, and immunological tests for infectious diseases (enzyme-linked immunosorbent assays). RESULTS: Basing on the examination RESULTS: we have determined the common types of congenital micro- and anophthalmia in children. We have also developed a stepwise prosthetic treatment aimed at better cosmetic rehabilitation. Indications and contraindications for the use of ocular prostheses in children with congenital micro- and anophthalmia have been identified. CONCLUSION: The proposed method of stepwise prosthetics is the principal option for conservative rehabilitation of children with congenital micro- or anophthalmia.

[The top ten researches of Chinese oculoplastic surgery and orbital disease in recent five years].

Ten researches that may represent the progress in Chinese oculoplastic surgery and orbital disease were selected through voting by specialists from Chinese Society of Ophthalmic Plastics and Orbital Disease. These researches focused on the following fields: the endoscopic navigation system of orbital surgery, orbital bone regeneration and materials, comprehensive sequence treatment of retinoblastoma, the mechanism of thyroid related ophthalmopathy, the intervention strategy and evaluation of orbital development with congenital microphthalmia and anophthalmia, blepharophimosis genotype-phenotype relationship and intervention strategies and clinical study of new materials for frontal muscle suspension. These studies represented the level and influence of Chinese oculoplastics and orbital disease in the international academic community and they were the landmark studies in our areas of expertise.

Focal dermal hypoplasia (Goltz-Gorlin syndrome): a new case with a novel variant in the PORCN gene (c.1250T>C:p.F417S) and unusual spinal anomaly.

Focal dermal hypoplasia (FDH; Goltz-Gorlin syndrome; OMIM 305600) is a disorder that features involvement of the skin, skeletal system, and eyes. It is caused by loss-of-function mutations in the PORCN gene. We report a young girl with FDH, microphthalmos associated with colobomatous orbital cyst, dural ectasia and cystic malformation of the spinal cord, and a de novo variant in PORCN. This association has not been previously reported, and based on these observations the phenotypic spectrum of FDH might be broader than previously appreciated. It would be prudent to alter the suggested surveillance for this rare disorder.

Report on ocular biometry of microphthalmos, retinal dystrophy, flash electroretinography, ocular coherence tomography, genetic analysis and the surgical challenge of entropion correction in a rare case of Hallermann-Streiff-Francois syndrome.

PURPOSE: To report new aspects of the phenotype including Retinal dystrophy and surgical challenges in Hallermann-Streiff Francois syndrome (HSFS). METHODS: Detailed phenotype of a female with HSFS was evaluated including skeletal changes, comprehensive eye examination, detailed ocular biometry, electroretinography and macular Ocular coherence tomography. Surgical notes of lid surgery for entropion were reviewed. Genetic screening was also done. RESULTS: Unique Ocular biometry with electroretinography changes, macular folds and fundus changes suggestive of an unreported Retinal dystrophy in a typical patient with HSFS were noted. Surgery was challenging both due to difficulty in endotracheal intubation anaesthesia because of the dento-facial abnormalities and the skin fragility. CONCLUSION: This report provides additional information especially pigmentary retinal dystrophy, macular folds and electroretinography in HSFS. The microphthalmos had overlapping posterior segment findings usually reported with Nanophthalmos and Posterior microphthalmos. The surgical difficulties and outcomes of the rarely encountered adnexal abnormalities emphasize the need for a multi disciplinary approach for appropriate management.

Early retinoic acid deprivation in developing zebrafish results in microphthalmia.

Vitamin A deficiency causes impaired vision and blindness in millions of children around the world. Previous studies in zebrafish have demonstrated that retinoic acid (RA), the acid form of vitamin A, plays a vital role in early eye development. The objective of this study was to describe the effects of early RA deficiency by treating zebrafish with diethylaminobenzaldehyde (DEAB), a potent inhibitor of the enzyme retinaldehyde dehydrogenase (RALDH) that converts retinal to RA. Zebrafish embryos were treated for 2 h beginning at 9 h postfertilization. Gross morphology and retinal development were examined at regular intervals for 5 days after treatment. The optokinetic reflex (OKR) test, visual background adaptation (VBA) test, and the electroretinogram (ERG) were performed to assess visual function and behavior. Early treatment of zebrafish embryos with 100 µM DEAB (9 h) resulted in reduced eye size, and this microphthalmia persisted through larval development. Retinal histology revealed that DEAB eyes had significant developmental abnormalities but had relatively normal retinal lamination by 5.5 days postfertilization. However, the fish showed neither an OKR nor a VBA response. Further, the retina did not respond to light as measured by the ERG. We conclude that early deficiency of RA during eye development causes microphthalmia as well as other visual defects, and that timing of the RA deficiency is critical to the developmental outcome.

The genetics of anophthalmia and microphthalmia.

PURPOSE OF REVIEW: To summarize recent breakthroughs regarding the genes known to play a role in normal ocular development in humans and to elucidate the role mutations in these genes play in anophthalmia and microphthalmia. RECENT FINDINGS: The main themes discussed within this article are the various documented genetic advances in identifying the various causes of anophthalmia and microphthalmia. In addition, the complex interplay of these genes during critical embryonic development will be addressed. SUMMARY: The recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling.

Type III uveal effusion syndrome suspected to be related to pachychoroid spectrum disease: A case report.

INTRODUCTION: We report a case of type III uveal effusion syndrome (UES) suspected to be related to pachychoroid spectrum disease. PATIENT CONCERNS: A 42-year-old man became aware of visual field constriction and deterioration of visual acuity in his right eye. DIAGNOSIS: Upon examination, a bullous non-rhegmatogenous retinal detachment was observed in the inferior 2 quadrants of the right eye fundus, and the subretinal fluid moved with postural changes. The axial length in that eye was 22.36 mm, thus indicating no nanophthalmia. Preoperative indocyanine green angiography revealed dilated choroidal vessels in the posterior pole of the right eye and mild leakage in the late phase. Optical coherence tomography examination revealed choroidal thickening in both eyes. INTERVENTIONS: For treatment, we first performed sclerotomy, and the intraoperative findings showed no thickening of the sclera. Following surgery, reattachment of the retina was not achieved. OUTCOMES: Thus, we next performed vitrectomy, which led to successful reattachment of the retina. LESSONS: In this case, we theorize that pachychoroid spectrum disease might have been involved in the pathogenesis of type III UES.

Targeted ablation of connexin50 in mice results in microphthalmia and zonular pulverulent cataracts.

In the ocular lens, gap junctional communication is a key component of homeostatic mechanisms preventing cataract formation. Gap junctions in rodent lens fibers contain two known intercellular channel-forming proteins, connexin50 (Cx50) and Cx46. Since targeted ablation of Cx46 has been shown to cause senile-type nuclear opacities, it appears that Cx50 alone cannot meet homeostatic requirements. To determine if lens pathology arises from a reduction in levels of communication or the loss of a connexin-specific function, we have generated mice with a targeted deletion of the Cx50 gene. Cx50-null mice exhibited microphthalmia and nuclear cataracts. At postnatal day 14 (P14), Cx50-knockout eyes weighed 32% less than controls, whereas lens mass was reduced by 46%. Cx50-knockout lenses also developed zonular pulverulent cataracts, and lens abnormalities were detected by P7. Deletion of Cx50 did not alter the amounts or distributions of Cx46 or Cx43, a component of lens epithelial junctions. In addition, intercellular passage of tracers revealed the persistence of communication between all cell types in the Cx50-knockout lens. These results demonstrate that Cx50 is required not only for maintenance of lens transparency but also for normal eye growth. Furthermore, these data indicate that unique functional properties of both Cx46 and Cx50 are required for proper lens development.

Microphthalmos-anophthalmos-coloboma (MAC) spectrum in two brothers with Renpenning syndrome due to a truncating mutation in the polyglutamine tract binding protein 1 (PQBP1) gene.

Background: Patients with intellectual disability syndromes frequently have coexisting abnormalities of ocular structures and the visual pathway system. The microphthalmos, anophthalmos, and coloboma (MAC) spectrum represent structural developmental eye defects that occur as part of a syndrome in one-third of cases. Ophthalmic examination may provide important diagnostic clues in identifying these syndromes.Purpose: To provide a detailed and comprehensive description of the microphthalmos, anophthalmos, and coloboma (MAC) spectrum in two brothers with intellectual disability and dysmorphism.Methods: The two brothers underwent a detailed ophthalmic and systemic evaluation. A family pedigree was obtained and exome sequencing was performed in the proband.Results: The two brothers aged 4 and 7 years had intellectual disability, microcephaly, short stature, and characteristic dysmorphic features. Ophthalmic evaluation revealed the presence of the MAC spectrum in both boys. Genetic testing led to the detection of an X-linked hemizygous truncating mutation in the nuclear polyglutamine-binding protein 1 (PQBP1) gene confirming the diagnosis of X-linked recessive Renpenning syndrome.Conclusion: The presence of X-linked intellectual disability and characteristic dysmorphism, in a patient with the MAC spectrum should raise the suspicion of Renpenning syndrome. PQBP1 mutation testing is confirmatory. A comprehensive systemic evaluation is mandatory in all patients with the MAC spectrum and intellectual disability.

Microphthalmia Syndrome 9: Case Report of a Newborn Baby with Pulmonary Hypoplasia, Diaphragmatic Eventration, Microphthalmia, Cardiac Defect and Severe Primary Pulmonary Hypertension.

BACKGROUND The pulmonary hypoplasia/agenesis, diaphragmatic hernia/eventration, anophthalmia/microphthalmia, and cardiac defect (PDAC) syndrome is a rare medical condition presumably of autosomal recessive way of inheritance with only a few reported cases. Recessive mutations in the STRA6 and both recessive and dominant mutations in RARB gene have been identified as the cause of anophthalmia/microphthalmia and other abnormalities included in the PDAC spectrum. However, those mutations have not been found in all PDAC syndrome cases reviewed from the literature. CASE REPORT We report a case of a full-term living male infant with pulmonary hypoplasia, left diaphragmatic eventration, bilateral microphthalmia, congenital cardiac defects, and severe pulmonary hypertension. CONCLUSIONS The main feature in the reported cases was anophthalmia/microphthalmia. Therefore, screening for the other associated congenital anomalies is highly suggested. Mutations in STRA6 and RARB genes are commonly encountered in this spectrum. However, whole exome sequencing of suspected cases and their parents is recommended to detect possible de novo mutations. Further reports are needed to identify risk factors and prognosis of this rare syndrome.

Posterior microphthalmos, retinitis pigmentosa, and foveoschisis caused by a mutation in the MFRP gene: a familial study.

Background: To characterize the phenotype and genotype of a rare syndrome associating posterior microphthalmos (PM), retinitis pigmentosa (RP), and foveoschisis in a consanguineous Spanish family. Methods: The study involved five family members, consisting of three siblings and their parents. All members underwent comprehensive eye examinations for best corrected visual acuity, axial length and refractive error, electroretinography (ERG), fundus photography, retinal fluorescein angiography (FA), and optical coherence tomography (OCT). Clinical exome sequencing of more than 6,000 clinically relevant genes (SureSelect Focused Exome, Agilent) was performed using the Illumina HiSeq 3000 system. Candidate variants were validated and segregated by Sanger sequencing. Results: The affected siblings had bilateral shortening of the posterior ocular segment and normal anterior segment dimensions. The fundoscopy, ERG, and FA results were compatible with RP. Macular OCT analysis revealed schisis of the outer retinal layer. Our data analysis pipeline identified a homozygous frameshift mutation in exon 5 of the membrane frizzled-related protein (MFRP) gene (c.498delC; p.Asn167Thrfs*25). Conclusion: Our study confirmed the association of PM with RP as an autosomal recessive syndrome. Although this has previously been described, it seems that there are some constant (i.e., PM and RP) and some variable features (i.e., optic nerve drusen and foveoschisis). The MFRP mutation has also been detected in other studies associating PM with RP. Analysis of a larger series of cases at the clinical and genetic levels would certainly help us to better understand the phenotype-genotype correlations of this syndrome.

Loss of the mitochondrial i-AAA protease YME1L leads to ocular dysfunction and spinal axonopathy.

Disturbances in the morphology and function of mitochondria cause neurological diseases, which can affect the central and peripheral nervous system. The i-AAA protease YME1L ensures mitochondrial proteostasis and regulates mitochondrial dynamics by processing of the dynamin-like GTPase OPA1. Mutations in YME1L cause a multi-systemic mitochondriopathy associated with neurological dysfunction and mitochondrial fragmentation but pathogenic mechanisms remained enigmatic. Here, we report on striking cell-type-specific defects in mice lacking YME1L in the nervous system. YME1L-deficient mice manifest ocular dysfunction with microphthalmia and cataracts and develop deficiencies in locomotor activity due to specific degeneration of spinal cord axons, which relay proprioceptive signals from the hind limbs to the cerebellum. Mitochondrial fragmentation occurs throughout the nervous system and does not correlate with the degenerative phenotype. Deletion of Oma1 restores tubular mitochondria but deteriorates axonal degeneration in the absence of YME1L, demonstrating that impaired mitochondrial proteostasis rather than mitochondrial fragmentation causes the observed neurological defects.

Nutrient intake in women before conception and risks of anophthalmia and microphthalmia in their offspring.

BACKGROUND: We previously explored associations between nutrients including folate and other macro and micronutrients and risks of anophthalmia or microphthalmia in the National Birth Defects Prevention Study. In the current study, we expand those previous results with larger sample sizes and conduct analyses with an additional diet quality index using more recent data. METHODS: The National Birth Defects Prevention Study is a population-based, multicenter case-control study of over 30 major birth defects, with estimated due dates from October 1997 to December 2011. Cases were 224 infants diagnosed with anophthalmia or microphthalmia. Controls were 11,109 live-born, nonmalformed infants randomly selected by each study center. Mothers completed a standardized, computer-assisted telephone interview between 6 weeks and 24 months after delivery. Mothers responded to a shortened food frequency questionnaire, assessing their nutrient intake for the year before pregnancy, and questions about periconceptional (2 months before to 2 months after conception) vitamin supplement use. Nutrient intake quartiles were based on the intake among controls. RESULTS: Among vitamin supplement users, odds of anophthalmia/microphthalmia were decreased for women with intake levels in the highest quartile of folate (0.56, 95% confidence interval [CI] 0.32-0.98), magnesium (0.42, 95% CI 0.22-0.82), and vitamin E (0.50, 95% CI 0.29-0.89). Among women not reporting vitamin supplement use, the odds were significantly increased for beta-carotene (2.5, 95% CI 1.10-5.68) and decreased for retinol (0.37, 95% CI 0.19-0.73). CONCLUSIONS: In this expanded analysis, we observed associations for a few nutrients, specifically forms of vitamin A. However, the heterogeneity of results by form and vitamin use necessitates further inquiry.