Assessment of tear film parameters in females with refractive errors using a single device: An observational study.

This observational study aimed to evaluate the use of a single portable device to assess the non-invasive tear break-up time (NITBUT), tear meniscus height (TMH), and lipid layer patterns (LLP) in young females with refractive errors (REs). The study was conducted at the College of Applied Medical Science (Female campus), Riyadh, Saudi Arabia between January 5, 2021 to May 15, 2021. Forty young females, with mean age of 23.0± 4.3 years with REs (-2.53 ± 2.05 D) and 40 females, mean age 23.8± 4.5 years with healthy eyes were recruited. The tests were administered in the following order: Ocular Surface Disease Index (OSDI), followed by NITBUT, TMH, and LLP. Significant differences (via Mann-Whitney U test) were noted in the median ocular surface disease index (OSDI; p˂0.001), NITBUT (p=0.035), TMH (p=0.009), and LLP (p˂0.001) scores between the study and control groups. Females with REs have significantly lower lipid layer, TMH, and NITBUT scores than those with healthy eyes.

Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

Biallelic deletion in a minimal CAPN15 intron in siblings with a recognizable syndrome of congenital malformations and developmental delay.

Calpainopathies constitute a heterogeneous group of disorders resulting from deficiencies in calpains, calcium-specific proteases that modulate substrates by limited proteolysis. Clinical manifestations depend on tissue-specific expression of the defective calpain and substrate specificity. CAPN15, encoding the Drosophila small optic lobes (sol) homolog, was recently found to cause various eye defects in individuals carrying bi-allelic missense variants. Here we report on two siblings with manifestations reminiscent of Johanson-Blizzard syndrome including failure to thrive, microcephaly, global developmental delay, dysmorphic features, endocrine abnormalities and congenital malformations, in addition to eye abnormalities. Exome sequencing identified a homozygous 47 base-pair deletion in a minimal intron of CAPN15, including the splice donor site. Sequencing of cDNA revealed single exon skipping, resulting in an out-of-frame deletion with a predicted premature termination codon. These findings expand the phenotypic spectrum associated with CAPN15 variants, and suggest that complete loss-of-function is associated with a recognizable syndrome of congenital malformations and developmental delay, overlapping Johanson-Blizzard syndrome and the recently observed brain defects in Capn15 knockout (KO) mice. Moreover, the data highlight the unique opportunity for indel detection in minimal introns.

Minor dysmorphic features in a patient with papillorenal syndrome: A Case Report.

Papillorenal syndrome, also known as renal coloboma syndrome, is characterised by congenital optic disc anomalies and renal abnormalities. Mutations in the PAX2 gene, which plays a critical role in embryogenesis, cause this syndrome. Other related anomalies are less commonly observed. To our knowledge, this is the first case reported in the literature in which Papillorenal syndrome accompanied various dysmorphic features.

Structural malformations of the brain, eye, and pituitary gland in PHACE syndrome.

PHACE syndrome is the association of segmental facial hemangiomas with congenital arterial, brain, cardiac, and ocular anomalies. Structural brain malformations affect 41-52% of PHACE patients and can be associated with focal neurologic deficits, developmental delays, and/or intellectual disability. To better characterize the spectrum of structural brain and other intracranial anomalies in PHACE syndrome, MRI scans of the head/neck were retrospectively reviewed in 55 patients from the PHACE Syndrome International Clinical Registry and Genetic Repository. All registry patients with a diagnosis of definite PHACE syndrome who had MRI scans of satisfactory quality were included. Of 55 patients, 34 (62%) demonstrated ≥1 non-vascular intracranial anomaly; structural brain malformations were present in 19 (35%). There was no difference in the prevalence of brain anomalies between genders. Brain anomalies were more likely in patients with S1 and/or S2 distribution of facial hemangioma. The most common structural brain defects were cerebellar hypoplasia (25%) and fourth ventricle abnormalities (13%). Dandy-Walker complex and malformations of cortical development were present in 9% and 7%, respectively. Extra-axial findings such as pituitary anomalies (18%) and intracranial hemangiomas (18%) were also observed. Six patients (11%) had anomalies of the globes or optic nerve/chiasm detectable on MRI. Brain malformations comprise a diverse group of structural developmental anomalies that are common in patients with PHACE syndrome. Along with brain malformations, numerous abnormalities of the pituitary, meninges, and globes were observed, highlighting the need for careful radiologic assessment of these structures in the neuroimaging workup for PHACE syndrome.

Congenital Ocular Abnormalities in Free-Ranging White-Tailed Deer.

Congenital ocular abnormalities in cervids have been previously reported as individual cases from various regions of the United States and include microphthalmia, anophthalmia, congenital cataracts, dermoids, and colobomata. A common underlying cause for these abnormalities, such as nutritional deficiencies, environmental toxin exposures, or genetic mutations, has not been established. This retrospective study summarized and compared cases of suspected congenital ocular abnormalities in free-ranging white-tailed deer ( Odocoileus virginianus) submitted to the Southeastern Cooperative Wildlife Disease Study (SCWDS) in Athens, Georgia, to the preexisting literature. Of 3645 accessions of white-tailed deer submitted to SCWDS, 15 qualifying case records were found. An additional 15 cases were reported previously in the literature. Conditions described in SCWDS cases included microphthalmia (8/15), congenital cataracts (3/15), anophthalmia (2/15), colobomata (1/15), anterior segment dysgenesis (1/15), ectopic lacrimal gland tissue (1/15), and congenital blindness with corneal opacity (1/15). Most (11/15; 73%) of the SCWDS cases were male fawns with an average age of 4 months at presentation, consistent with previously described cases. Most animals had bilateral abnormalities with few extraocular congenital abnormalities, also consistent with existing reports. Cases were variably tested for various infectious agents at the time of submission; 2 cases were seropositive for bluetongue virus. Spatiotemporal clustering of cases was not evident. This study provided a concise and systematic summary of known existing cases of congenital ocular defects in fawns but did not identify a cause.

Atypical Presentation of PHACE Syndrome: Hidden Facial Hemangioma.

PHACE(S) syndrome is a neurocutaneous syndrome with a wide array of presentations. The most known and present trait is facial hemangioma > 5 cm. The name is an acronym for Posterior fossa malformations, infantile Hemangiomas, Arterial anomalies, aortic Coarctation, Eye abnormalities, and middle-line malformations of the Sternum. The exact etiopathogenic mechanism of this syndrome is not fully understood, and its treatment depends on detailed and individualized assessment. The aim of this paper is to describe a child with a throat hemangioma, vascular malformations, cognitive delay, and other anomalies to illustrate the neuroimaging found in this syndrome.

[The research progress of LGR4 in the eye development and related diseases].

LGR4, also known as GPR48, is a member of the leucine-rich, G protein-coupled receptor family. It is widely expressed in tissues of the reproductive system, urinary system, sensory organs, digestive system, and central nervous system. LGR4 plays an important role in the development of various organs and cancer development and progression by modulating multiple signaling pathways. Recent studies have revealed that LGR4 is related with many kinds of human diseases such as gastrointestinal carcinomas. Eye development is a dynamic process regulated by a number of growth factors and cytokines. LGR4 is extensively expressed in the eyes in a finely tuned spatiotemporal pattern. Mice lacking LGR4 have been found to display anterior segment dysgenesis, including microphthalmia, iris hypoplasia, iridocorneal angle malformation and corneal dysgenesis, cataract and other defects. Here we review the role of LGR4 in the eye development and related molecular mechanisms. (Chin J Ophthalmol, 2017, 53: 236-240).

Assessment of PAX6 alleles in 66 families with aniridia.

We report on PAX6 alleles associated with a clinical diagnosis of classical aniridia in 81 affected individuals representing 66 families. Allelic variants expected to affect PAX6 function were identified in 61 families (76 individuals). Ten cases of sporadic aniridia (10 families) had complete (8 cases) or partial (2 cases) deletion of the PAX6 gene. Sequence changes that introduced a premature termination codon into the open reading frame of PAX6 occurred in 47 families (62 individuals). Three individuals with sporadic aniridia (three families) had sequence changes (one deletion, two run-on mutations) expected to result in a C-terminal extension. An intronic deletion of unknown functional significance was detected in one case of sporadic aniridia (one family), but not in unaffected relatives. Within these 61 families, single nucleotide substitutions accounted for 30/61 (49%), indels for 23/61 (38%), and complete deletion of the PAX6 locus for 8/61 (13%). In five cases of sporadic aniridia (five families), no disease-causing mutation in the coding region was detected. In total, 23 unique variants were identified that have not been reported in the Leiden Open Variation Database (LOVD) database. Within the group assessed, 92% had sequence changes expected to reduce PAX6 function, confirming the primacy of PAX6 haploinsufficiency as causal for aniridia.

Complete sternal cleft - A rare congenital malformation and its repair in a 3-month-old boy: A case report.

Complete midline sternal cleft is a rare congenital anomaly resulting from failed midline ventral fusion of the sternal bars. Very few cases of complete sternal cleft have been described in literature. We present a case of complete sternal cleft in a 3-month-old child. The patient underwent primary closure of the defect using stainless steel wires.

Walker-Warburg syndrome: A case report of congenital muscular dystrophy with hydrocephalus.

Walker-Warburg Syndrome is a genetically heterogeneous disease with autosomal recessive inheritance characterized by brain and eye deformities, profound mental retardation, congenital muscular dystrophy, and early death. This case study demonstrates a mutation on chromosome 12q14 in the TMEM5 gene (RXYLT1; 605862), which encodes a transmembrane protein with glycosyltransferase function. We present a case of a full-term male baby delivered by Cesarean section due to macrocephaly. At birth, the newborn had hypotonia and respiratory distress, requiring mechanical ventilation. On examination the patient was found to have macrocephaly, generalized hypotonia, hyporeflexia, and retinal degeneration. Genetic testing revealed a homozygous variant in the RXYLT1 gene, consistent with the diagnosis of autosomal recessive muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A10. The patient underwent a ventriculoperitoneal shunt and received supportive management. WWS is a fatal disease, and most affected children do not survive beyond the age of 3. Prenatal screening, ultrasonography and magnetic resonance imaging can aid in the detection and confirmation of abnormal brain development in WWS cases.

Exome sequencing identifies novel genes underlying primary congenital glaucoma in the National Birth Defects Prevention Study.

BACKGROUND: Primary congenital glaucoma (PCG) affects approximately 1 in 10,000 live born infants in the United States (U.S.). PCG has a autosomal recessive inheritance pattern, and variable expressivity and reduced penetrance have been reported. Likely causal variants in the most commonly mutated gene, CYP1B1, are less prevalent in the U.S., suggesting that alternative genes may contribute to the condition. This study utilized exome sequencing to investigate the genetic architecture of PCG in the U.S. and to identify novel genes and variants. METHODS: We studied 37 family trios where infants had PCG and were part of the National Birth Defects Prevention Study (births 1997-2011), a U.S. multicenter study of birth defects. Samples underwent exome sequencing and sequence reads were aligned to the human reference sample (NCBI build 37/hg19). Variant filtration was conducted under de novo and Mendelian inheritance models using GEMINI. RESULTS: Among candidate variants, CYP1B1 was most represented (five trios, 13.5%). Twelve probands (32%) had potentially pathogenic variants in other genes not previously linked to PCG but important in eye development and/or to underlie Mendelian conditions with potential phenotypic overlap (e.g., CRYBB2, RXRA, GLI2). CONCLUSION: Variation in the genes identified in this population-based study may help to further explain the genetics of PCG.

Eye Abnormalities in Children with Fetal Alcohol Spectrum Disorders: A Systematic Review.

PURPOSE: Although eye abnormalities are reported in fetal alcohol spectrum disorders (FASD), no systematic review based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines has been undertaken. Our aim was to document the range and prevalence of eye abnormalities reported in children with prenatal alcohol exposure (PAE) and/or FASD. METHODS: Searches of electronic databases and manual searches. Eligible articles were observational studies in children with PAE and/or FASD; peer reviewed journal articles in the English language; and studies reporting quantitative or frequency data on functional/structural eye abnormalities. Pooled prevalence, odds ratio, and mean differences were calculated. RESULTS: Of the 1,068 retrieved articles 36 were eligible, including articles on children with diagnosed fetal alcohol syndrome/FASD (N = 31); PAE (N = 3); and FASD or PAE without FASD (N = 2). Structural and functional eye abnormalities were identified, the most prevalent being short palpebral fissure length (66.1%), visual impairment (55.5%), epicanthus (53.5%), subnormal stereoacuity (53.0%), abnormal retinal tortuosity (50.5%), impaired fixation ability (33.3%), telecanthus (31.7%), optic nerve hypoplasia (30.2%), and small optic discs (27.0%). Compared to non-exposed controls, strabismus, subnormal vision, ptosis, short palpebral fissure length, microphthalmos, smaller optic disc area, and retinal vessel tortuosity were more prevalent in children with FASD. CONCLUSIONS: Examination of eyes and vision should be considered in children with PAE and suspected or diagnosed FASD to enable early identification and optimal management. This first comprehensive, systematic literature review demonstrates the variety and frequency of eye abnormalities reported in PAE/FASD.

Disruption of fetal eye development caused by insulin-induced maternal hypoglycemia in rats.

We previously revealed that insulin-induced severe and long-lasting maternal hypoglycemia in rats caused anophthalmia and microphthalmia in fetuses; however, it remained unclear whether hypoglycemia-induced eye anomalies were developmental retardation or disruption, and when and how they developed. Hence, we induced hypoglycemia in pregnant Sprague-Dawley rats by injecting insulin from Days 6 to 11 of pregnancy and performed periodical histopathological examination of fetal eyes from embryonic days (E)10 to 20. On E10, optic vesicle had developed normally both in the control and insulin-treated group; however, on E11, optic cup (OC) had developed in the control group but not in the insulin-treated group. On E12, neural retina (NR), retinal pigmented epithelium (RPE), lens, and presumptive cornea had been observed in the control group. In contrast, lens pit and OC with remaining space between RPE and NR had developed in the insulin-treated group. From E13 to E15, developmental disruption characterized by defects, hypoplasia, and degeneration in the retina, lens, and cornea was observed in the insulin-treated group, resulting in anophthalmia or microphthalmia on E20. Moreover, the expression of MITF and chx10, which are essential for early eye development by expressing in the presumptive retina and lens and regulating each other's expression level, was ectopic and suppressed on E11. In conclusion, insulin-induced maternal hypoglycemia caused developmental disruption, but not simple developmental retardation of fetal eyes, and its trigger might be a failure of presumptive retina and lens to interact on E11.

Clinical and neurodevelopmental outcomes based on brain imaging studies in a Colombian cohort of children with probable antenatal Zika virus exposure.

BACKGROUND: Our aim was to describe the neuroimaging and clinical evaluations of children with antenatal Zika-virus (ZIKV) exposure. METHODS: The Colombian National Institute of Health performed serial clinical evaluations of children with probable antenatal ZIKV exposure (i.e., born to ZIKV symptomatic mothers or born with birth defects compatible with ZIKV infection, regardless of laboratory results) over 2 years that included head circumference (HC), eye examination, and neurodevelopmental assessments. Clinical neuroimaging studies (head computed tomography and/or brain magnetic resonance imaging) were analyzed for abnormalities, two-dimensional measurements were made of the right and left frontal and occipital cortical thickness. Two abnormal patterns were defined: Pattern 1 (sum of four areas of cortex <6 cm) and Pattern 2 (sum of four areas of cortex ≥6 cm and < 10 cm). RESULTS: Thirty-one children had a neuroimaging study; in 24, cortical thickness was measured. The median age at the first visit was 8 (range: 6-9) months and 22 (range: 19-42) months at the last evaluation. In the 24 cases with cortical measurements, three were normal, 12 were in Pattern 1, and nine were in Pattern 2. Children within Pattern 1 had lower mean HC at birth and in follow-up (both p < .05) and a higher frequency of structural eye abnormalities (p < .01). A trend towards poorer neuromotor development was seen in Pattern 1, although not statistically significant (p = .06). CONCLUSION: Brain imaging classification based on cortical measurements correlate with ophthalmologic abnormalities and HC. Cortical thickness may be a marker for clinical outcomes in children with congenital ZIKV infection.

Ocular manifestations in classic homocystinuria.

BACKGROUND: Classic homocystinuria (HCU), or cystathionine beta-synthase (CBS) deficiency, is a rare inborn error of methionine metabolism. Main clinical features may include skeletal and vascular manifestations, developmental delay, intellectual disability and eye disorders. MATERIAL AND METHODS: This is an observational and retrospective study aiming at describing eye abnormalities presented by a cohort of late-diagnosed HCU patients. Data regarding ophthalmological evaluation included visual acuity, refraction, biomicroscopy, Perkins tonometry, fundus examination, retinography, biometry, ocular ultrasound, optical coherence tomography, anterior segment photography and topography. RESULTS: Ten patients with HCU (20 eyes) were included. The most frequent findings were ectopia lentis(n = 20) and myopia (n = 9). Biometry, ultrasound, OCT and topography findings were available for four patients. One patient had keratoconus; one had abnormal retinal pigmentation; and two had lens surgery scars with irregular astigmatism. CONCLUSIONS: Eye abnormalities are very frequent in late-diagnosed HCU patients. The presence of ectopia lentis should always raise the diagnostic hypothesis of HCU.

Abnormal retinal pigment epithelium melanogenesis as a major determinant for radiation-induced congenital eye defects.

Recent studies highlighted a link between ionizing radiation exposure during neurulation and birth defects such as microphthalmos and anophthalmos. Because the mechanisms underlying these defects remain largely unexplored, we irradiated pregnant C57BL/6J mice (1.0 Gy, X-rays) at embryonic day (E)7.5, followed by histological and gene/protein expression analyses at defined days. Irradiation impaired embryonic development at E9 and we observed a delayed pigmentation of the retinal pigment epithelium (RPE) at E11. In addition, a reduced RNA expression and protein abundance of critical eye-development genes (e.g. Pax6 and Lhx2) was observed. Furthermore, a decreased expression of Mitf, Tyr and Tyrp1 supported the radiation-induced perturbation in RPE pigmentation. Finally, via immunostainings for proliferation (Ki67) and mitosis (phosphorylated histone 3), a decreased mitotic index was observed in the E18 retina after exposure at E7.5. Overall, we propose a plausible etiological model for radiation-induced eye-size defects, with RPE melanogenesis as a major determining factor.

Ophthalmologic findings in the Cornelia de Lange syndrome.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a congenital disorder characterized by multisystem abnormalities, including distinct ophthalmologic findings. In recent years, advances in molecular genetics have begun to provide new insight into the characterization of these clinical features and the genetic basis of the syndrome. MATERIALS AND METHODS: We included 37 articles that were identified through an electronic search in PubMed and through the reference lists of previously conducted reviews. Studies of 30 or more patients were used to report frequencies of common and less common findings. Genotype-phenotype studies were used to provide additional information when available. RESULTS: Ocular anomalies are present in most patients with CdLS. Common findings include long eyelashes, synophrys, hirsutism of the eyebrows, peripapillary pigment ring, and myopia. Less common findings include hyperopia, ptosis, blepharitis, short palpebral fissure length, down-slanting palpebral fissures, mild microcornea, strabismus, nystagmus, and optic nerve abnormalities. CONCLUSIONS: This review provides a comprehensive summary of the ophthalmologic findings in CdLS. Mutations in certain genes may be associated with specific ocular abnormalities, although future genotype studies are needed to further characterize these relationships.

Biometric Alterations of Mouse Embryonic Eye Structures Due to Short-Term Folic Acid Deficiency.

PURPOSE: Folic acid (FA) is an essential nutrient for normal embryonic development. FA deficiency (FAD) in maternal diet increases the risk of several defects among the progeny, especially, neural tube defects. The eye begins its development from the neural tube; however, the relationship between FAD and ocular development in the offspring has been little explored and it isn't known how the FAD affects the formation of the eye. Our objective was to analyze the effect of maternal FAD on mouse embryos ocular biometry. METHODS: Female mice C57/BL/6J were distributed into three different groups, according to the assigned diet: control group fed a standard FA diet (2 mg FA/kg), FAD group for short term fed (0 mg FA/kg + 1% succinylsulfathiazole) from the day after mating until day 14.5 of gestation, and FAD group for long term fed the same FA-deficient diet for 6 weeks prior mating and continued with this diet during gestation. A total of 57 embryos (19 embryos of each dietary group) at 14.5 gestational days were evaluated. As indicators of changes in ocular biometry, we analyze two parameters: area and circularity of the lens and whole eye, and the area of the retina. The program used in the treatment and selection of the areas of interest was ImageJ. The statistical analysis was performed by IBM SPSS Statistics 19. RESULTS: Regarding the measures of the area, FA-deficient lenses and eyes were smaller than that of controls. We have also observed increase in the size of the neural retina, spatially, in embryos from females fed FAD diet during long term. On the other hand, as regard to circularity measures, we have seen that eyes and lenses were more circular than control. CONCLUSION: Maternal FAD diet for a very short term generates morphological changes in ocular structures to the offspring.