Genotype-phenotype correlation at codon 1740 of SETD2.

The SET domain containing 2, histone lysine methyltransferase encoded by SETD2 is a dual-function methyltransferase for histones and microtubules and plays an important role for transcriptional regulation, genomic stability, and cytoskeletal functions. Specifically, SETD2 is associated with trimethylation of histone H3 at lysine 36 (H3K36me3) and methylation of α-tubulin at lysine 40. Heterozygous loss of function and missense variants have previously been described with Luscan-Lumish syndrome (LLS), which is characterized by overgrowth, neurodevelopmental features, and absence of overt congenital anomalies. We have identified 15 individuals with de novo variants in codon 1740 of SETD2 whose features differ from those with LLS. Group 1 consists of 12 individuals with heterozygous variant c.5218C>T p.(Arg1740Trp) and Group 2 consists of 3 individuals with heterozygous variant c.5219G>A p.(Arg1740Gln). The phenotype of Group 1 includes microcephaly, profound intellectual disability, congenital anomalies affecting several organ systems, and similar facial features. Individuals in Group 2 had moderate to severe intellectual disability, low normal head circumference, and absence of additional major congenital anomalies. While LLS is likely due to loss of function of SETD2, the clinical features seen in individuals with variants affecting codon 1740 are more severe suggesting an alternative mechanism, such as gain of function, effects on epigenetic regulation, or posttranslational modification of the cytoskeleton. Our report is a prime example of different mutations in the same gene causing diverging phenotypes and the features observed in Group 1 suggest a new clinically recognizable syndrome uniquely associated with the heterozygous variant c.5218C>T p.(Arg1740Trp) in SETD2.

Altered ratios of pro- and anti-angiogenic VEGF-A variants and pericyte expression of DLL4 disrupt vascular maturation in infantile haemangioma.

Infantile haemangioma (IH), the most common neoplasm in infants, is a slowly resolving vascular tumour. Vascular endothelial growth factor A (VEGF-A), which consists of both the pro- and anti-angiogenic variants, contributes to the pathogenesis of IH. However, the roles of different VEGF-A variants in IH progression and its spontaneous involution is unknown. Using patient-derived cells and surgical specimens, we showed that the relative level of VEGF-A165 b was increased in the involuting phase of IH and the relative change in VEGF-A isoforms may be dependent on endothelial differentiation of IH stem cells. VEGFR signalling regulated IH cell functions and VEGF-A165 b inhibited cell proliferation and the angiogenic potential of IH endothelial cells in vitro and in vivo. The inhibition of angiogenesis by VEGF-A165 b was associated with the extent of VEGF receptor 2 (VEGFR2) activation and degradation and Delta-like ligand 4 (DLL4) expression. These results indicate that VEGF-A variants can be regulated by cell differentiation and are involved in IH progression. We also demonstrated that DLL4 expression was not exclusive to the endothelium in IH but was also present in pericytes, where the expression of VEGFR2 is absent, suggesting that pericyte-derived DLL4 may prevent sprouting during involution, independently of VEGFR2. Angiogenesis in IH therefore appears to be controlled by DLL4 within the endothelium in a VEGF-A isoform-dependent manner, and in perivascular cells in a VEGF-independent manner. The contribution of VEGF-A isoforms to disease progression also indicates that IH may be associated with altered splicing. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

The incidence, clinical features, and management of essential infantile esotropia in the United Kingdom. A British Ophthalmology Surveillance Unit (BOSU) study.

BACKGROUND/OBJECTIVES: A national study was undertaken through the British ophthalmology surveillance unit (BOSU) to determine the incidence, presenting features and management of essential infantile esotropia (EIE) in the UK. METHODS: Data from a prospective national observational study of newly diagnosed EIE presenting to clinicians in the United Kingdom over a 12-month period were collected. Cases with a confirmed diagnosis by a clinician of a constant, non-accommodative esotropia ≥20 prism dioptres (PD), presenting at ≤12 months, with no neurological or ocular abnormalities were identified through BOSU. Follow-up data were collected at 12 months. RESULTS: A total of 57 cases were reported giving an incidence of EIE of 1 in 12,828 live births. The mean age of diagnosis and intervention were 7.05 ± 2.6 months (range 2-12) and 14.7 ± 4.9 months (range 6.5-28.1), respectively. Management was surgical in 59.6%, botulinum toxin alone in 22.8%, and 17.5% were observed. The preoperative angle of esotropia was smaller in the observation group (P = 0.04). The postoperative angle of esotropia was not statistically significant between botulinum toxin or surgery (P = 0.3), although the age of intervention was earlier in the botulinum group (P = 0.007). Early intervention (before 12 months of age) did not influence the post-intervention motor outcomes between 0 and 10 prism dioptres of esotropia (P = 0.78). CONCLUSIONS: The incidence of EIE in the UK is considerably lower than reported in other population-based studies. The preferred method of treatment was surgical with earlier intervention in those treated with botulinum toxin. An early age of intervention (<12 months) did not influence motor outcomes.

The use of occlusive contact lenses after failure of conventional for treatment of amblyopia.

PURPOSE: The purpose of this study was to evaluate the usefulness and assess the risks associated with occlusive contact lenses (OCLs) use to treat refractory amblyopia in children who failed the conventional amblyopia treatment with patching and atropine penalization. METHODS: This was a retrospective case series of all children treated with an OCL in the sound eye over an 8-year period. Data were collected on the age, gender, and type of amblyopia, previous treatment received, and its duration. The compliance, tolerance, and adverse effects of OCL were recorded. RESULTS: There were 12 patients of which 10 were male. The mean age at the time of OCL use was 47.3 months (range 26-86 months). Anisometropic amblyopia was present in 1, combined anisometropia and strabismus in 3, strabismic amblyopia in 5, and stimulus deprivation amblyopia in 3. All patients had conventional patching for a mean period of 14 months, followed by atropine penalization in nine patients for a mean period of 4 months. The mean duration of OCL use ranged from 2 weeks to 6 months. There were nine patients with visual improvement (75%). The mean improvement seen was 0.4 log of the minimum angle of resolution. There was no occlusion amblyopia. Four patients had conjunctivitis; one had a peripheral corneal abrasion. CONCLUSION: The OCL is a useful adjunct in the treatment of amblyopia that is refractory to conventional treatment. The side effect profile is acceptable, but patients require close monitoring.

Prevalence of peripapillary hyperreflective ovoid mass-like structures (PHOMS) in suspected papilloedema in children.

PURPOSE: Suspected papilloedema is a frequent cause of referral to paediatric ophthalmology clinics. Recent publications have described a new finding called peripapillary hyperreflective ovoid mass-like structures (PHOMS) that may cause pseudopapilloedema. We evaluated the optical coherence tomography (OCT) scans of the optic nerve in all children referred with suspected papilloedema for the presence of PHOMS and report their frequency. METHODS: The optic nerve OCT scans from children seen in our suspected papilloedema virtual clinic between August 2016 and March 2021 were evaluated for the presence of PHOMS by three assessors. A Fleiss' kappa statistic was calculated to test the agreement between the assessors for the presence of PHOMS. RESULTS: A total of 220 scans from 110 patients were evaluated during the study period. The mean patient age was 11.2 SD ± 3.4, (range 4.1-16.8). PHOMS were identified in at least one eye in 74 (67.3%) patients. Of these, 42 (56.8%) patients had bilateral and 32 (43.2%) had unilateral PHOMS. Excellent agreement between assessors for the presence of PHOMS (Fleiss' kappa 0.9865) was observed. PHOMS were common in association with other identified causes of pseudopapilloedema (81.25%) but were also common in papilloedema (66.67%) and otherwise normal discs (55.36%). CONCLUSIONS: Misdiagnosis of papilloedema can lead to unnecessary and invasive tests. PHOMS are found frequently within the paediatric population referred for suspected disc swelling. They appear to be an independent cause of pseudopapilloedema but are often seen in conjunction with true papilloedema and other causes of pseudopapilloedema.

Stress and cataract surgery: A nationwide study evaluating surgeon burnout.

BACKGROUND: We aimed to evaluate the nationwide prevalence of stress induced burnout among cataract surgeons. We believe that knowledge of these factors can help formulate a solution to this underreported problem. METHODS: A three-part nationwide cross-sectional survey was disseminated with via the Royal College of Ophthalmologists (RCOphth) in the United Kingdom(UK). All consultants, trainees and specialty doctors and associate specialists(SAS) were invited to participate. We evaluated burnout using the Maslach Burnout Inventory (MBI). Logistic regression modelling was completed to look at factors linked to high level burnout in certain domains. RESULTS: A total of 406 respondents completed our survey. Prevalence of cataract surgery-related high burnout was estimated at 3.45% (Section A and/or B) and 40% within Personal Accomplishment (PA)(Section C of the MBI). Multiple factors were associated with increased burnout within PA: Increasing age: 61+ OR: 2.99 (1.02-8.78, p = 0.05), Number of cataract operations completed: >3000 OR 2.98 (1.03-8.64, p = 0.04), Lists per week: 2: OR 2.99 (1.38-6.47, p < 0.01), 2.5: OR 8.95 (2.58-31.02, p < 0.01), 3 or more: OR 2.64 (1.07-6.54, p = 0.04). Sleeping 8 h or more was found to be protective OR 0.52 (0.28-0.96, p = 0.04). 17% of respondents indicated they would be willing to give up cataract surgery if given the opportunity. CONCLUSION: The prevalence of stress induced burnout by cataract surgery appears to be present in a minority of surgeons. There appears to be a significant reduction in the feeling of personal achievement within the profession. A large proportion of this cohort appears to be willing to give up surgical responsibilities.

Risk factors for having diabetic retinopathy at first screening in persons with type 1 diabetes diagnosed under 18 years of age.

OBJECTIVE: To determine the risk factors for having diabetic retinopathy (DR) in children and young people (CYP) with type 1 diabetes (T1DM) at first screening. METHODS: Records from the Diabetes Eye Screening Wales (DESW) service for people in Wales, UK, with T1DM diagnosed under age 18 years were combined with other electronic health record (EHR) data in the Secure Anonymised Information Linkage (SAIL) Databank. Data close to the screening date were collected, and risk factors derived from multivariate, multinomial logistic regression modelling. RESULTS: Data from 4172 persons, with median (lower quartile, upper quartile) age 16.3 (13.0, 22.3) years and duration of diabetes 6.6 (2.3, 12.3) years were analysed. 62.6% (n = 2613) had no DR, 26.7% (n = 1112) background DR, and 10.7% (n = 447) had referable DR (RDR). No RDR was observed under 19 years of age. Factors associated with an increased risk of DR were diabetes duration, elevated HbA1c, and diastolic blood pressure. People diagnosed with T1DM at 12 years or older had an additional risk for each year they had diabetes compared to those diagnosed before age 12 controlling for the diabetes duration (odds ratios 1.23 and 1.34, respectively). CONCLUSIONS: This study found that 37.4% of the study cohort had DR at first screening, the risk being greater the longer the duration of diabetes or higher the HbA1c and diastolic blood pressure. In addition, people diagnosed at 12 years of age or over were more likely to have DR with each additional year with diabetes.

Ocular findings in pediatric patients with partial agenesis of corpus callosum.

PURPOSE: To evaluate the ocular associations with corpus callosum agenesis. METHODS: All children who had corpus callosum agenesis diagnosed by computed tomography or magnetic resonance imaging scans during a 10-year period were included in the study. A complete ophthalmological assessment was undertaken. Data were collected for age, sex, neurological findings, visual acuity, refractive errors, ocular motility defects, and ocular abnormalities. There were no children with Aicardi syndrome in the study. RESULTS: Nineteen children with corpus callosum agenesis were identified, of whom 13 were examined. All had partial agenesis of the corpus callosum. Visual acuity was better than 20/60 in 5 children (38%), between 20/60 and 20/200 in 3 children (23%), and less than 20/200 in 5 children (38%). Refractive errors were present in 8 children (62%), strabismus in 6 children (46%), nystagmus in 2 children (15%), hypoplastic discs in 3 children (23%), and microphthalmos in 1 child (8%). CONCLUSION: Non-syndromic corpus callosum agenesis may be associated with several ocular defects. Poor visual acuity, refractive errors, and strabismus predominate and need to be appropriately addressed to optimize visual function in these children. Global developmental delay (62%) and epilepsy (46%) were the most common neurological associations in this series.

Is the severity of refractive error dependent on the quantity and extent of retinal laser ablation for retinopathy of prematurity?

BACKGROUND/AIM: To test the hypothesis severity of acquired refractive error in Retinopathy of Prematurity (ROP) is dependent on the quantity of laser treatment delivered. METHODS: Two groups (treated and untreated infants) were age and weight matched. Data on the number of laser burns and Retcam II retinal images were analysed using computer aided design software to determine the proportion of area treated. Data were collected until the age of 6 years. RESULTS: The study comprises 43 infants (86 eyes). Twenty-one infants (42 eyes) in the treated group, mean gestational age (GA) was 26.40 (±2.5) weeks versus 27.30 (±1.7) weeks in the matched untreated group (P = 0.650). Birth weight (BW) in the treated group was 812 g (±86) and 804 g (±135) (P = 0.185) in the untreated group. Mean refractive error at 72 months was -2.23 (±4.06) in the treated group and +2.04 (±0.90) in the untreated group (P < 0.005). At 72 months 50% of treated eyes were myopic versus 19% of controls (P = 0.013). Mean laser burns applied were 1855 (±659), mean proportion of retina treated 45% (±10). Myopic eyes had a mean treatment area of 49% (±13) versus 43% (±10) hypermetropia and 42% (±5) emmetropia (P = 0.030). A larger treatment area was associated with a higher degree of myopia and anisometropia at 72 months (P < 0.050). These associations were not found for hypermetropia. CONCLUSIONS: The extent of myopia after retinal laser ablation for ROP is higher if a greater number of laser burns or a larger proportion of the retina is treated.

Bifocals and Down's syndrome: correction or treatment?

PURPOSE: Accommodation is reduced in approximately 75% of children with Down's syndrome (DS). Bifocals have been shown to be beneficial and they are currently prescribed regularly. Clinical observations suggest the likelihood of improving accommodative ability after bifocal wear. The aim of the study is to evaluate the potential use of bifocals as a treatment for the reduced accommodation. METHODS: Clinical records of 40 children from the Cardiff Down's Syndrome Vision Research Unit, who were prescribed bifocals, were reviewed. Accommodation was noted before wearing the bifocals and during either their latest visit or when the children stopped using bifocals. Accommodation was reassessed during a follow up visit for the children who stopped wearing bifocals. Development of accommodation before bifocal commencement, age at bifocal prescription, gender, type of refractive error, visual acuity and the presence of strabismus were examined to evaluate their contribution to accommodation improvement. RESULTS: The accommodative ability of 65% (n = 26) of the children improved (through the distance part of the lens) after using the bifocals. More than half of those developed accurate accommodation without the use of bifocals (n = 14). Accommodative responses did not show any improvement with age before the children began wearing bifocals. Accurate accommodation was sustained after returning to single vision lenses in all examined children. The age distribution of the children on bifocal commencement was diverse. Presence of strabismus, refractive error type, visual acuity and gender did not have any effect on gaining improvement. CONCLUSIONS: Bifocals are an effective correction for the reduced accommodation in children with DS and also act to improve accommodation with a success rate of 65%. Bifocal wear can therefore be temporary, i.e. a 'treatment' for the deficit, in at least one third of children.

Spontaneous resolution of stage 4B retinopathy of prematurity.

An unfavorable outcome occurs in 31% of cases of treated severe threshold retinopathy of prematurity (ROP) and includes a retinal detachment of the posterior pole. Early treatment with laser of high risk prethreshold or type 1 ROP has significantly reduced this complication. However, despite prompt laser treatment, retinal detachments continue to be seen. Treatment of tractional partial retinal detachments involving the posterior pole (stage 4B ROP) is surgical. Successful reattachment of stage 4B ROP with a lens-sparing vitrectomy is high. The authors describe an infant who had spontaneous reattachment after stage 4B ROP.

Heterochromia irides and mistaken identity of retinoblastoma.

Retinoblastoma is the most common intraocular malignancy of infancy which frequently manifests with a white pupillary reflex. We report a case of delayed presentation of a child with retinoblastoma in his left eye because parents thought the change in iris colour in this eye was due to the innocent heterochromia irides that was previously diagnosed in his elder sibling. This late presentation necessitated enucleation of the affected eye followed by chemotherapy.

Fresh frozen plasma (Octaplas) and topical heparin in the management of ligneous conjunctivitis.

Ligneous conjunctivitis is a rare form of chronic recurrent membranous conjunctivitis with reduced plasminogen activity. It is characterized by the formation of characteristic firm ("woody") membranes on the tarsal conjunctiva. Similar lesions may occur on other mucous membranes. When treated with local excision, ligneous conjunctivitis is invariably associated with recurrences. Various therapeutic modalities, including topical heparin, cyclosporine, fresh frozen plasma (FFP), plasminogen, and amniotic membrane transplantation have been reported to reduce postoperative recurrences. We present 2 cases of recurrent ligneous conjunctivitis in children successfully managed with surgical excision under cover of FFP transfusion, amniotic membrane grafting, and combined with concomitant postoperative administration of topical heparin, steroids.

Tear sample collection using cellulose acetate absorbent filters.

PURPOSE: To assess the use of cellulose acetate filter rods as a technique for tear collection. METHOD: The cellulose acetate rod (CR) was compared with the 'standard' glass capillary tube (CT), in a series of experiments, to assess: sample collection by collected volume size; the effect of tear stimulation on total tear protein concentration and major tear protein concentrations; and technique invasiveness. RESULTS: No difference was found in concentrations for total protein, IgA (secretory immunoglobulin A), lactoferrin and lysozyme (p > 0.05) with no clinically significant increase in serum albumin to show serum leakage. Sample volume was higher for CR (p < 0.005) and sample volume increased for stimulated collection with CR (p = 0.001). Dilution effect of a stimulated sample size was reliably shown only with CR (r = -0.66, p = 0.011). Using bovine albumin standard with CR and CT, a smaller sample volume (p < 0.001) and a higher protein concentration (p < 0.001) were extracted with CR. CONCLUSION: The cellulose rod offers a suitable alternative to the glass CT. It is able to quickly absorb a sample, allowing use for a wide range of sample sizes, while being minimally invasive.

Cortical visual impairment in hypomelanosis of Ito.

Hypomelanosis of Ito is a multisystem disorder that is thought to be due to chromosomal mosaicism. The authors report a case of cortical visual impairment in an infant diagnosed as having hypomelanosis of Ito. Cortical dysplasia was evident on magnetic resonance imaging and its presence in key areas of the visual pathway may explain the patient's cortical visual impairment.

Familial unilateral Brown syndrome.

We present a two-generation family with Brown syndrome. The proband was a six and a half-year-old female who presented with a history of failure of dextro-elevation of her left eye. A full ophthalmic evaluation was consistent with a left Brown syndrome. Family history revealed that her mother was operated on as a child for left Brown syndrome and examination of her four and a half-year-old sibling showed similar affection in the left eye. Autosomal dominant inheritance has been postulated in this condition. To our knowledge this is the first report of three members of a two-generation family with left-sided Brown syndrome. Genetic counseling of Brown syndrome cases is advised; nevertheless, identification of the responsible gene should shed more light on its genetics.

Abusive head trauma and the triad: a critique on behalf of RCPCH of 'Traumatic shaking: the role of the triad in medical investigations of suspected traumatic shaking'.

The Swedish Agency for Health Technology Assessment and Assessment of Social Services (SBU) has recently published what they purported to be a systematic review of the literature on 'isolated traumatic shaking' in infants, concluding that 'there is limited evidence that the so-called triad (encephalopathy, subdural haemorrhage, retinal haemorrhage) and therefore its components can be associated with traumatic shaking'. This flawed report, from a national body, demands a robust response. The conclusions of the original report have the potential to undermine medico-legal practice. We have conducted a critique of the methodology used in the SBU review and have found it to be flawed, to the extent that children's lives may be put at risk. Thus, we call on this review to be withdrawn or to be subjected to international scrutiny.

The effect of laryngeal mask airway insertion on intraocular pressure measurement in children receiving general anesthesia.

PURPOSE: To study changes in intraocular pressure (IOP) in children while under general anesthesia before and after laryngeal mask airway (LMA) insertion. DESIGN: Prospective, comparative study. METHOD: IOP was measured in children after induction and one minute after LMA insertion. Children younger than 16 years who were scheduled to undergo elective ophthalmic surgery while receiving a general anesthetic were included. Children with a history of glaucoma or previous intraocular surgery were excluded. Data were collected on the age of the child, IOP, heart rate (HR), end tidal CO2, and blood pressure (BP) before and after LMA insertion. RESULTS: Sixty-six children with a mean age of 5.5 +/- 3.6 years (range, four months to 16 years) were included in the study. The mean IOP was 13.6 +/- 3.9 mm Hg and 13.6 +/- 3.6 mm Hg in right and left eyes, respectively, before LMA insertion and 15.5 +/- 3.8 mm Hg and 15.2 +/- 3.8 mm Hg in right and left eyes, respectively, after LMA insertion (P = .001). A decrease in BP was significantly associated with an increase in IOP (P = .008), and the interaction between the change in the BP, HR, and CO2 affected the change in IOP measured after insertion of the LMA (P = .04). There was no correlation between the age of the child and the change in IOP measured after insertion of the LMA. CONCLUSIONS: In our study, a small but significantly higher IOP was found after LMA insertion than before. It is recommended that the measurement of IOP in children receiving a general anesthetic is carried out before the insertion of the LMA.