A recurrent de novo MAX p.Arg60Gln variant causes a syndromic overgrowth disorder through differential expression of c-Myc target genes.

Cyclin D2 (CCND2) stabilization underpins a range of macrocephaly-associated disorders through mutation of CCND2 or activating mutations in upstream genes encoding PI3K-AKT pathway components. Here, we describe three individuals with overlapping macrocephaly-associated phenotypes who carry the same recurrent de novo c.179G>A (p.Arg60Gln) variant in Myc-associated factor X (MAX). The mutation, located in the b-HLH-LZ domain, causes increased intracellular CCND2 through increased transcription but it does not cause stabilization of CCND2. We show that the purified b-HLH-LZ domain of MAXArg60Gln (Max∗Arg60Gln) binds its target E-box sequence with a lower apparent affinity. This leads to a more efficient heterodimerization with c-Myc resulting in an increase in transcriptional activity of c-Myc in individuals carrying this mutation. The recent development of Omomyc-CPP, a cell-penetrating b-HLH-LZ-domain c-Myc inhibitor, provides a possible therapeutic option for MAXArg60Gln individuals, and others carrying similar germline mutations resulting in dysregulated transcriptional c-Myc activity.

Surgical interventions for bilateral congenital cataract in children aged two years and under.

BACKGROUND: Congenital cataracts are lens opacities in one or both eyes of babies or children present at birth. These may cause a reduction in vision severe enough to require surgery. Cataracts are proportionally the most treatable cause of visual loss in childhood, and are a particular problem in low-income countries, where early intervention may not be possible. Paediatric cataracts provide different challenges to those in adults. Intense inflammation, amblyopia (vision is obstructed by cataract from birth which prevents normal development of the visual system), posterior capsule opacification and uncertainty about the final trajectory of ocular growth parameters can affect results of treatment. Two options currently considered for children under 2 years of age with bilateral congenital cataracts are: (i) intraocular lens (IOL) implantation; or (ii) leaving a child with primary aphakia (no lens in the eye), necessitating the need for contact lenses or aphakic glasses. Other important considerations regarding surgery include the prevention of visual axis opacification (VAO), glaucoma and the route used to perform lensectomy. OBJECTIVES: To assess the effectiveness of infant cataract surgery or lensectomy to no surgery for bilateral congenital cataracts in children aged 2 years and under. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 1); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov and the WHO ICTRP. The date of the search was 25 January 2022. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) that compared infant cataract surgery or lensectomy to no surgery, in children with bilateral congenital cataracts aged 2 years and younger. This update (of a review published in 2001 and updated in 2006) does not include children over 2 years of age because they have a wider variety of aetiologies, and are therefore managed differently, and have contrasting outcomes. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Two review authors extracted data independently. We assessed the risk of bias of included studies using RoB 1 and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We identified three RCTs that met our inclusion criteria with each trial comparing a different aspect of surgical intervention for this condition. The trials included a total of 79 participants under 2 years of age, were conducted in India and follow-up ranged from 1 to 5 years. Study participants and outcome assessors were not masked in these trials. One study (60 children) compared primary IOL implantation with primary aphakia. The results from this study suggest that there may be little or no difference in visual acuity at 5 years comparing children with pseudophakia (mean logMAR 0.50) and aphakia (mean logMAR 0.59) (mean difference (MD) -0.09 logMAR, 95% confidence intervals (CIs) -0.24 to 0.06; 54 participants; very low-certainty evidence), but the evidence is very uncertain. The evidence is very uncertain as to the effect of IOL implantation compared with aphakia on visual axis opacification (VAO) (risk ratio (RR) 1.29, 95% CI 0.23 to 7.13; 54 participants; very low-certainty evidence). The trial investigators did not report on the cases of amblyopia. There was little evidence of a difference betwen the two groups in cases of glaucoma at 5 years follow-up (RR 0.86, 95% CI 0.24 to 3.10; 54 participants; very low-certainty evidence). Cases of retinal detachment and reoperation rates were not reported. The impact of IOL implantation on adverse effects is very uncertain because of the sparse data available: of the children who were pseudophakic, 1/29  needed a trabeculectomy and 8/29 developed posterior synechiae. In comparison, no trabeculectomies were needed in the aphakic group and 2/25 children had posterior synechiae (54 participants; very low-certainty evidence).  The second study (14 eyes of 7 children under 2 years of age) compared posterior optic capture of IOL without vitrectomy versus endocapsular implantations with anterior vitrectomy (commonly called 'in-the-bag surgery'). The authors did not report on visual acuity, amblyopia, glaucoma and reoperation rate. They had no cases of VAO in either group. The evidence is very uncertain as to the effect of in-the-bag implantation in children aged under 1 year. There was a higher incidence of inflammatory sequelae: 4/7 in-the-bag implantation eyes and 1/7 in optic capture eyes (P = 0.04, 7 participants; very low-certainty evidence). We graded the certainty of evidence as low or very low for imprecision in all outcomes because their statistical analysis reported that a sample size of 13 was needed in each group to achieve a power of 80%, whereas their subset of children under the age of 1 year had only 7 eyes in each group. The third study (24 eyes of 12 children) compared a transcorneal versus pars plana route using a 25-gauge transconjunctival sutureless vitrectomy system. The evidence is very uncertain as to the effect of the route chosen on the incidence of VAO, with no cases reported at 1 year follow-up in either group. The investigators did not report on visual acuity, amblyopia, glaucoma, retinal detachment and reoperation rate. The pars plana route had the adverse effects of posterior capsule rupture in 2/12 eyes, and 1/12 eyes needing sutures. Conversely, 1/12 eyes operated on by the transcorneal route needed sutures. We graded the outcomes with very low-certainty because of the small sample size and the absence of a priori sample size calculation. AUTHORS' CONCLUSIONS: There is no high level evidence for the effectiveness of one type of surgery for bilateral congenital cataracts over another, or whether surgery itself is better than primary aphakia. Further RCTs are required to inform modern practice about concerns, including the timing of surgery, age at which surgery should be undertaken, age for implantation of an IOL and development of complications, such as reoperations, glaucoma and retinal detachment. Standardising the methods used to measure visual function, along with objective monitoring of compliance with the use of aphakic glasses/contact lenses would greatly improve the quality of study data and enable more reliable interpretation of outcomes.

Paediatric case of peripapillary choroidal neovascularisation associated with optic disc drusen treated with aflibercept.

Peripapillary choroidal neovascularisation (PPCNV) associated with optic disc drusen is a rare complication that can result in severe vision impairment in children. We report the first case of paediatric PPCNV secondary to optic disc drusen successfully treated with intravitreal aflibercept. A 6-year-old girl presented with a one week history of reduced vision in her right eye with best-corrected visual acuity of 20/500. Fundus examination revealed bilateral elevated discs with a peripapillary pigmentary lesion in the right eye. Optical coherence tomography of the right eye showed marked subfoveal fluid. Both B-scan ultrasonography and fundus autofluorescence demonstrated findings consistent with optic disc drusen. Diagnosis of PPCNV was further confirmed on fluorescein fundus angiography. The child received three intravitreal aflibercept injections with complete resolution of the subfoveal fluid. Her visual acuity improved to 20/25 with no recurrence at a 16-month follow-up. No adverse side effects were reported.

Retinopathy of prematurity in the United Kingdom: retreatment rates, visual and structural 1-year outcomes.

AIMS: To evaluate retreatment rates, visual and anatomical outcomes at 1-year postnatal age in infants treated for retinopathy of prematurity (ROP) METHODS: Longitudinal national surveillance study of infants treated for ROP in the United Kingdom between December 2013 and December 2014, supported by the British Ophthalmic Surveillance Unit. Here we report retreatment rates, anatomical, visual and refractive outcomes at 1-year follow-up. RESULTS: One-year follow-up forms were completed for 168 children of the original cohort of 327 (51.4%). Twenty-two had at least one retreatment: 17/153 right eyes (REs, 11.1%) after initial diode laser, and 5/14 REs (35.7%) after initial injection of anti-vascular endothelial growth factor (VEGF) antibody. Median (interquartile range) RE best-corrected visual acuity was 0.6 (0.4-1.0) (n = 46 REs), and median acuity both eyes open 0.4 (0.3-0.7) logMAR (n = 89). Median spherical equivalent (RE) was 0.44 (-1.3 to 1.3) dioptre (D) (n = 116). Median astigmatism (RE) was 0.5 (0-1.0) D (n = 111), and median anisometropia 0.125 (0-0.75) D (n = 116). Twenty-four children (20.5%) had been prescribed glasses. Sight impairment certification eligibility information was available for 131 children: 11 (8.4%) were eligible to be certified as sight impaired, and 5 (3.8%) as severely sight impaired. CONCLUSIONS: Retreatment rates are in line with previous reports, and appear higher after initial anti-VEGF antibody than after initial diode laser. Refractive outcomes are in line with previous studies, with a trend towards early emmetropia and myopia following diode laser, particularly in more severe ROP.

A proposal for a new classification of complications in craniosynostosis surgery.

OBJECTIVE Complications have been used extensively to facilitate evaluation of craniosynostosis practice. However, description of complications tends to be nonstandardized, making comparison difficult. The authors propose a new pragmatic classification of complications that relies on prospective data collection, is geared to capture significant morbidity as well as any "near misses" in a systematic fashion, and can be used as a quality improvement tool. METHODS Data on complications for all patients undergoing surgery for nonsyndromic craniosynostosis between 2010 and 2015 were collected from a prospective craniofacial audit database maintained at the authors' institution. Information on comorbidities, details of surgery, and follow-up was extracted from medical records, anesthetic and operation charts, and electronic databases. Complications were defined as any unexpected event that resulted or could have resulted in a temporary or permanent damage to the child. RESULTS A total of 108 operations for the treatment of nonsyndromic craniosynostosis were performed in 103 patients during the 5-year study period. Complications were divided into 6 types: 0) perioperative occurrences; 1) inpatient complications; 2) outpatient complications not requiring readmission; 3) complications requiring readmission; 4) unexpected long-term deficit; and 5) mortality. These types were further subdivided according to the length of stay and time after discharge. The overall complication rate was found to be 35.9%. CONCLUSIONS The proportion of children with some sort of complication using the proposed definition was much higher than commonly reported, predominantly due to the inclusion of problems often dismissed as minor. The authors believe that these complications should be included in determining complication rates, as they will cause distress to families and may point to potential areas for improving a surgical service.

Treatment trends for retinopathy of prematurity in the UK: active surveillance study of infants at risk.

OBJECTIVES: To estimate the incidence of severe retinopathy of prematurity (ROP) requiring treatment and describe current treatment patterns in the UK. DESIGN: Nationwide population-based case ascertainment study via the British Ophthalmic Surveillance Unit and a national collaborative ROP special interest group. Practitioners completed a standardised case report form (CRF). SETTING: All paediatric ophthalmologists providing screening and/or treatment for retinopathy in the UK were invited to take part. PARTICIPANTS: Any baby with ROP treated or referred for treatment between 1 December 2013 and 30 November 2014, treated with laser, cryotherapy, vascular endothelial growth factor (VEGF) inhibitor or vitrectomy/scleral buckling, or a combination. MAIN OUTCOME MEASURE: Incidence of ROP requiring treatment. RESULTS: We received 370 CRFs; 327 were included. Denominator from epidemiological data: 8112 infants with birth weight of <1500 g. The incidence of ROP requiring treatment was 4% (327/8112, 95% CI 3.6% to 4.5%). Median gestational age was 25 weeks (IQR 24.3-26.1), and median birth weight 706 g (IQR 620-821). Median age at first treatment was 80 days (IQR 71-96). 204 right eyes (62.39%) had type 1 ROP, and 27 (8.26%) had aggressive posterior ROP. Infants were also treated for milder disease: 9 (2.75%) right eyes were treated for type 2 ROP, and 74 (22.63%) for disease milder than type 1 with plus or preplus, which we defined here as 'type 2 plus' disease. First-line treatment was diode laser photoablation of the avascular retina in 90.5% and injection of VEGF inhibitor in 8%. CONCLUSIONS: ROP treatment incidence in the UK is 2.5 times higher than previously estimated. 8% of treated infants receive intravitreal VEGF inhibitor, currently unlicensed. Research is needed urgently to establish safety and efficacy of this approach. Earlier treatment and increasing numbers of surviving premature infants require an increase in appropriate eye care facilities and staff. TRIAL REGISTRATION NUMBER: NCT02484989.

Monitoring the changing pattern of delivery of paediatric epilepsy surgery in England--an audit of a regional service and examination of national trends.

PURPOSE: The demand for paediatric epilepsy surgery in the UK greatly exceeds the number of operations performed. Hence, Children's Epilepsy Surgery Service (CESS) was commenced in 2012. This study is aimed to characterise the changes in service delivery in the North East of England Paediatric Neuroscience Network and nationally. METHODS: A retrospective cohort study of paediatric epilepsy surgery in Leeds between 2005 and 2012 is presented followed by analysis of British Paediatric Neurosurgical Group (BPNG) data before and after CESS commissioning. RESULTS: During the study period, 42 children underwent epilepsy surgery in Leeds. The commonest aetiologies were neoplasm (33%), focal cortical dysplasia (19%) and mesial temporal sclerosis (19%). Seizure outcome was 71 % EngelI and 83% EngelI+II. Complications included one infection (2%), two temporary (5%) and one permanent (2%) motor deficits, three new/worsened visual field deficits (7%). There were six re-craniotomies (14%). The BPNG data show a 48% increase in paediatric epilepsy surgery in England between 2009 (90 cases) and 2012 (133 cases), and a 20% fall in 2013 (106 cases)--the first calendar year for CESS. On average, 64% of all operations were performed in London. CONCLUSIONS: The number of children receiving surgery for epilepsy in England had increased annually up to, and declined after, the establishment of CESS centres. The yearly caseload in neurosurgical units outside of London is small. The outcomes from Leeds are comparable to those published elsewhere. Other UK units are encouraged to publish outcomes to facilitate patient, commissioner and provider decision making.

Presumed non-accidental injury with retinal haemorrhages--findings from a tertiary referral centre in the United Kingdom.

AIM: To describe the clinical and demographic features of patients with retinal haemorrhages from presumed non-accidental injury (NAI) at a tertiary referral centre in Leeds over a 2-year period. METHODS: All patients with retinal haemorrhages from presumed NAI between 1 January 2007 and 31 December 2008 were retrospectively identified from the hospital RetCam® (Clarity Medical System, Pleasanton, CA, USA) database. Case-notes, fundus photographs and radiological studies were retrieved for all patients and examined. RESULTS: Over the study period, 14 infants had retinal haemorrhages secondary to presumed NAI. All were male with a mean age of 18 ± 15 weeks (range 2-47) and came from areas with a mean Index of Multiple Deprivation (IMD 2007) rank of 34 ± 27% (range 0.97-68). Seizure/collapse was the reason for presentation in 71% (10/14). Retinal haemorrhages were bilateral in 64% (9/14) and unilateral in 36% (5/14). They were single-layered in 71% (10/14) and multi-layered in 29% (4/14). Subdural haemorrhages were found in 93% (13/14) and were symmetrical in 77% (10/13). Skeletal survey was positive in 28% (4/14). CONCLUSIONS: In the context of presumed NAI, there is a strong association between presence of retinal haemorrhages and the likelihood of underlying subdural haemorrhage. In this region, male infants under 12 months, from deprived areas, appear to constitute a vulnerable group.

Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR).

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder that disrupts the development of the retinal vasculature and can result in blindness. FEVR is genetically heterogeneous and mutations in four genes, NDP, FZD4, LRP5, and TSPAN12, encoding components of a novel ligand-receptor complex that activates the Norrin-ß-catenin signaling pathway, account for approximately 50% of cases. We recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to identify recessive TSPAN12 mutations in FEVR patients. METHODS: Mutation screening was performed by directly sequencing PCR products generated from genomic DNA with primers designed to amplify the coding sequence of TSPAN12. Splicing defects were verified by reverse transcriptase PCR of leukocyte cDNA. RESULTS: TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of 10 retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harboring two TSPAN12 mutations. CONCLUSIONS: We report for the first time recessive mutations in TSPAN12 and describe the first genetic cause for the clinical variation seen in FEVR families. Our data raise the possibility that patients with severe FEVR actually may harbor two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-ß-catenin signaling pathway.

Whole-exome sequencing identifies mutations in GPR179 leading to autosomal-recessive complete congenital stationary night blindness.

Congenital stationary night blindness (CSNB) is a heterogeneous retinal disorder characterized by visual impairment under low light conditions. This disorder is due to a signal transmission defect from rod photoreceptors to adjacent bipolar cells in the retina. Two forms can be distinguished clinically, complete CSNB (cCSNB) or incomplete CSNB; the two forms are distinguished on the basis of the affected signaling pathway. Mutations in NYX, GRM6, and TRPM1, expressed in the outer plexiform layer (OPL) lead to disruption of the ON-bipolar cell response and have been seen in patients with cCSNB. Whole-exome sequencing in cCSNB patients lacking mutations in the known genes led to the identification of a homozygous missense mutation (c.1807C>T [p.His603Tyr]) in one consanguineous autosomal-recessive cCSNB family and a homozygous frameshift mutation in GPR179 (c.278delC [p.Pro93Glnfs(∗)57]) in a simplex male cCSNB patient. Additional screening with Sanger sequencing of 40 patients identified three other cCSNB patients harboring additional allelic mutations in GPR179. Although, immunhistological studies revealed Gpr179 in the OPL in wild-type mouse retina, Gpr179 did not colocalize with specific ON-bipolar markers. Interestingly, Gpr179 was highly concentrated in horizontal cells and Müller cell endfeet. The involvement of these cells in cCSNB and the specific function of GPR179 remain to be elucidated.

Prognosis for splicing factor PRPF8 retinitis pigmentosa, novel mutations and correlation between human and yeast phenotypes.

PRPF8-retinitis pigmentosa is said to be severe but there has been no overview of phenotype across different mutations. We screened RP patients for PRPF8 mutations and identified three new missense mutations, including the first documented mutation outside exon 42 and the first de novo mutation. This brings the known RP-causing mutations in PRPF8 to nineteen. We then collated clinical data from new and published cases to determine an accurate prognosis for PRPF8-RP. Clinical data for 75 PRPF8-RP patients were compared, revealing that while the effect on peripheral retinal function is severe, patients generally retain good visual acuity in at least one eye until the fifth or sixth decade. We also noted that prognosis for PRPF8-RP differs with different mutations, with p.H2309P or p.H2309R having a worse prognosis than p.R2310K. This correlates with the observed difference in growth defect severity in yeast lines carrying the equivalent mutations, though such correlation remains tentative given the limited number of mutations for which information is available. The yeast phenotype is caused by lack of mature spliceosomes in the nucleus, leading to reduced RNA splicing function. Correlation between yeast and human phenotypes suggests that splicing factor RP may also result from an underlying splicing deficit.

Unilateral retinal hemorrhages with subarachnoid hemorrhage in a 5-week-old infant: is this nonaccidental injury?

PURPOSE: Retinal hemorrhages are an important sign in the setting of nonaccidental injury (NAI) (abusive head injury) in young infants and form a very important part of the evidence in support of the diagnosis. The diagnosis of NAI has serious social and legal implications. Other causes of retinal hemorrhages in an infant, such as birth trauma, accidental head injury, subarachnoid hemorrhage, other less common disorders of clotting, leukemia, and infections such as endocarditis, need to be considered and ruled out in making a diagnosis of NAI. METHODS: Descriptive case report. RESULTS: A 5-week-old child presented with rapid onset of symptoms of drowsiness and hypotonia, unilateral retinal hemorrhages, and an intracranial hemorrhage in the posterior fossa. NAI was high on the list of differential diagnosis, which caused considerable anxiety in the parents. The cause of the intracranial hemorrhage only became apparent at repeat neuroimaging several weeks later. CONCLUSIONS: The case is presented to point out arteriovenous malformation as a possible cause of retinal hemorrhages in this age group where an early diagnosis of the etiology is often not possible. A diagnosis of NAI, commonly associated with a similar clinical presentation, can have serious social and legal implications.

Cogan's syndrome: a rare cause of meningoencephalitis.

We report a 14-year-old boy who presented with meningoencephalitis. Other features particularly auditory, vestibular, and ocular lead to the diagnosis of Cogan's syndrome. Treatment with prednisolone resulted in a rapid improvement and recovery of his hearing. Cogan's syndrome is a rare primary vasculitis, characterized by ocular, auditory, and vestibular symptoms, which can have significant morbidity and mortality. Presentation with a meningoencephalitic picture is unusual. Increased awareness of its clinical features among pediatricians and pediatric neurologists should lead to earlier diagnosis and increased recognition of the serious systemic manifestations. Early use of prednisolone can prevent hearing loss and can also be useful in treating the other vasculitic manifestations.

Familial exudative vitreoretinopathy and DiGeorge syndrome: a new locus for familial exudative vitreoretinopathy on chromosome 22q11.2?

PURPOSE: To describe a patient with DiGeorge syndrome in association with familial exudative vitreoretinopathy (FEVR). DESIGN: Observational case report. PARTICIPANTS: A newborn female and her parents. METHODS: Family members were examined by slit-lamp biomicroscopy and indirect ophthalmoscopy. Deletion mapping was performed by fluorescent in situ hybridization and genotyping. Mutation screening was undertaken by direct sequencing. MAIN OUTCOME MEASURES: The presence or absence of a microdeletion on chromosome 22q11.2 in the patient and her parents and mutation screening of FZD4 and LRP5 in the patient. RESULTS: The patient had classical features of DiGeorge syndrome and FEVR. A de novo microdeletion on chromosome 22q11.2 was found in the patient, confirming the diagnosis of DiGeorge syndrome. No mutations were identified in the known FEVR genes. CONCLUSIONS: Patients with DiGeorge syndrome should have a dilated retinal examination to look for signs of FEVR. Chromosome 22q11.2 may represent a novel locus for FEVR.

Pseudo-Foster Kennedy Syndrome due to unilateral optic nerve hypoplasia: a case report.

INTRODUCTION: Pseudo-Foster Kennedy Syndrome is described as unilateral optic disc swelling with contralateral optic atrophy in the absence of an intracranial mass causing compression of the optic nerve. This occurs typically due to bilateral sequential optic neuritis or ischaemic optic neuropathy. CASE PRESENTATION: We describe a case of pseudo-Foster Kennedy Syndrome in a two year old boy with unilateral papilloedema due to a congenital optic disc anomaly in one eye preventing transmission of raised intracranial pressure to the optic nerve. CONCLUSION: From our findings we conclude that congenital optic nerve hypoplasia is a cause of pseudo-Foster Kennedy Syndrome.