Congenital isolated unilateral third nerve palsy in children: the diagnostic contribution of high-resolution MR imaging.

PURPOSE: To describe the neuroanatomical correlates of unilateral congenital isolated oculomotor palsy by means of high-resolution MRI. METHODS: Children with a clinical diagnosis of congenital isolated oculomotr palsy and with a high-resolution MRI acquisition targeted on the orbits and cranial nerves were selected and included in the study. An experienced pediatric neuroradiologist evaluated all the exams, assessing the integrity and morphology of extraocular muscles, oculomotor, trochlear and abducens nerves as well as optic nerves and globes. Clinical data and ophthalmologic evaluations were also collected. RESULTS: Six children (age range: 1-16 years; males: 3) were selected. All patients showed, on the affected side (left:right = 5:1), anomalies of the III nerve and extraocular muscles innervated by the pathological nerve. One patient had complete nerve agenesis, two patients showed a diffuse thinning of the nerve, from the brainstem to the orbit and 3 patients showed a distal thinning of the oculomotor nerve, starting at the level of the cavernous sinus. In all cases atrophy of corresponding muscles was noticed, but the involvement of the affected muscles varied with the nervous pattern of injury. CONCLUSIONS: High-resolution MRI represents a valuable tool for the diagnosis of III nerve anomalies in unilateral congenital IOP, showing different patterns of nerve involvement and muscular atrophy.

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort.

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5' tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher's exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni's correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype-phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

Propranolol eye drops in patients with corneal neovascularization.

RATIONALE: Studies performed in animal models of corneal neovascularization suggested the possible efficacy of a treatment with propranolol. Corneal neovascularization is one of the most feared complications of Stevens-Johnson syndrome that frequently involves ocular surface. We report the first 2 patients with severe ocular neo-vascularization treated with different degrees of success, with propranolol eye drops. PATIENT CONCERNS: Two patients with corneal neovascularization complicating the Stevens-Johnson syndrome, not responsive to steroids and cyclosporine, were treated with propranolol eye drops. DIAGNOSES: Corneal neovascularization was detected by ophthalmoscopic evaluation. INTERVENTIONS: Topical treatment with propranolol eye drops at different concentrations. OUTCOMES: Both patients reported dramatic subjective benefits (reduction of photophobia and discomfort) without adverse effects, and in the patient with a less advanced disease, an objective reduction of neovascularization and an improved visual acuity was observed. LESSONS: This experience suggests that propranolol might be an inexpensive, safe and effective treatment in counteracting the progression of corneal neovascularization.

Ocular features in mucopolysaccharidosis: diagnosis and treatment.

Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders characterized by the accumulation of glycosaminoglycans (GAGs) in different parts of the eye. Ocular problems are very common in MPS children, and the cornea, sclera, trabecular meshwork, retina, and optic nerve may all be involved. Early diagnosis is very important to preserve the visual function, and the diagnosis requires experience and different evaluations. Follow-up is mandatory to allow a correct pathway to consequent therapy. This article aims to provide a review of ocular alterations and treatment options in MPS. The ophthalmologist is sometimes the first physician who can suspect a metabolic disease and can help to make the correct diagnosis. It is important to stimulate awareness of MPS among ophthalmologists.

Therapeutic Algorithm for Congenital Ptosis Repair with Levator Resection and Frontalis Suspension: Results and Literature Review.

BACKGROUND: Several treatments have been described for the treatment of congenital ptosis, but there are few studies that analyze the effectiveness of a therapeutic approach rather than a single technique. AIMS: In this study, we aim to evaluate the effectiveness of our therapeutic algorithm, which relies on levator muscle resection and frontalis suspension with silicone rods, polytetrafluoroethylene (PTFE), or autologous fascia lata. METHODS: We retrospectively analyzed all patients affected by congenital ptosis who underwent corrective surgery at a single department between January 1998 and January 2016. RESULTS: A total of 116 procedures were performed in 86 patients, accounting for 35 levator resections, 67 frontalis suspensions, and 14 revisions. A satisfactory result was observed in 65 cases after one procedure (75.6%). Complications occurred in 13 cases after primary surgery (15.1%). Ptosis relapse was observed in 25 cases after primary procedure (21.5%). Frontalis suspension displayed a higher number of complications than levator resection (22.2% vs 3.1%, p=0.02). CONCLUSION: Our therapeutic algorithm was effective in 75.6% after one procedure. Frontalis suspension procedures encountered a higher rate of complication than levator resection. Fascia lata should be preferred to silicon rods whenever possible due to the lower recurrence rate. These issues confirm the therapeutic algorithm, although larger prospective studies are necessary to validate our approach.

Carbonic Anhydrase Inhibitor with Topical NSAID Therapy to Manage Cystoid Macular Edema in a Case of Gyrate Atrophy.

PURPOSE: Gyrate atrophy of the choroid and retina (GACR) is a rare chorioretinal dystrophy characterized by a deficiency of the enzyme ornithine aminotransferase, inherited in an autosomal recessive pattern. CASE REPORT: We report a case of a 17-year-old girl with GACR, for whom the level of serum ornithine had been reduced by an arginine-restricted diet. The patient was responsive to an association of topical nonsteroidal anti-inflammatory drugs (NSAIDs) and a carbonic anhydrase inhibitor (CAI) to reduce cystoid macular edema (CME). CONCLUSIONS: The efficacy of topical NSAIDs and systemic CAI association indicates that the imbalance in the distribution of retinal pigment epithelium membrane-bound carbonic anhydrase could play a major role in CME pathogenesis in GACR. To our knowledge, this is the first case of therapy with CAI treatment for GACR-related CME.

Transient Esotropia in the Child: Case Report and Review of the Literature.

The aim of this report is to investigate the possible causes of acute acquired onset of transient esotropia (AATE) in children and to help to differentiate ophthalmoplegic migraine (OM) from accommodative spasm (AS). A case of an 8-year-old Caucasian female affected by AATE and diplopia is described. The day before AATE onset, the patient complained of slight headache without nausea and vomiting, with spontaneous resolution. AATE diagnosis is challenging. The most likely ophthalmological causes of AATE are AS and OM. In these cases it is important to evaluate the presence of both a familial history of recurrent headaches and an AATE associated with migraine, ptosis, nausea, and vomiting. A full ophthalmological evaluation and a thorough refractive examination in cycloplegia are mandatory to exclude ophthalmological causes.

Clinical evaluation and molecular screening of a large consecutive series of albino patients.

Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. In this study we recruited 321 albino patients and screened them for the genes known to cause oculocutaneous albinism (OCA1-4 and OCA6) and ocular albinism (OA1). Our purpose was to detect mutations and genetic frequencies of the main causative genes, offering to albino patients an exhaustive diagnostic assessment within a multidisciplinary approach including ophthalmological, dermatological, audiological and genetic evaluations. We report 70 novel mutations and the frequencies of the major causative OCA genes that are as follows: TYR (44%), OCA2 (17%), TYRP1 (1%), SLC45A2 (7%) and SLC24A5 (<0.5%). An additional 5% of patients had GPR143 mutations. In 19% of cases, a second reliable mutation was not detected, whereas 7% of our patients remain still molecularly undiagnosed. This comprehensive study of a consecutive series of OCA/OA1 patients allowed us to perform a clinical evaluation of the different OCA forms.

Pediatric Idiopathic Orbital Inflammation: Clinical Features of 30 Cases.

PURPOSE: Pediatric idiopathic orbital inflammation (IOI) is a rare entity with little known about the clinical presentation and natural history. The authors report the demographics, clinical presentations, radiographic and histopathologic characteristics, and treatment outcome of 30 children with IOI. METHODS: Retrospective chart review of 30 patients 18 years and younger diagnosed with IOI and statistical analysis using analysis of variance and Fisher's exact test. This study was reviewed and approved by the Institutional Review Board of SUNY Downstate Medical Center. RESULTS: There were 9 males (30%) and 21 females (70%) with pediatric IOI who presented at a median age of 11 years (range 2-18 years). Primary IOI was found in 19 patients (63%) and recurrent IOI in 11 patients (37%). Overall, 26 patients (87%) had unilateral IOI while 4 patients (13%) had bilateral disease at presentation. There were 12 patients (40%) with systemic constitutional signs. The most common ophthalmic findings included periorbital edema (n = 20, 67%) and blepharoptosis (n = 17, 57%). All patients had orbital radiography with common findings of dacryoadenitis (n = 12, 40%), orbital mass (n = 12, 40%), or myositis (n=10, 33%). The presence of a radiographic orbital mass was significantly related to the clinical presence of blepharoptosis (p = 0.03). The most common treatment was oral glucocorticoids in 24 patients (80%). Over mean follow up of 19 months (range 6-64 months), females were more likely to display recurrent disease (p = 0.01). CONCLUSIONS: Idiopathic orbital inflammation is an uncommon but important cause of acute orbital syndrome in children, manifesting as a bilateral condition in 13% and with constitutional symptoms in 40%. Posttreatment recurrence is found in 37% of cases.

Screening of PAX6 gene in Italian congenital aniridia patients revealed four novel mutations.

PURPOSE: To uncover underlying mutations in a cohort of Italian patients with aniridia, a rare congenital panocular condition with an incidence ranging from 1:64,000 to 1:100,000. The disease may be found isolated or in association with other syndromes characterized by partial or complete absence of the iris and iris hypoplasia. METHODS: We analyzed the PAX6 gene in 11 patients with aniridia fulfilling the following inclusion criteria: partial or complete absence of the iris and age < 18 years at the time of diagnosis. DNA sequence analysis was integrated with Multiple Ligation Probe Assay (MLPA) analysis. RESULTS: We identified seven PAX6 mutations, including four novel ones. The majority of mutations lie in the DNA-binding domain and all produce a truncated protein. All tested patients did not have WT1 gene deletions thus excluding the WAGR syndrome. We present the clinical findings in the four cases harboring novel mutations. We were unable to identify mutations in four cases with complete aniridia thus indicating that other gene/s could be involved in the disease. CONCLUSIONS: It is important to establish the molecular diagnosis early to avoid repeated and long-term screening for Wilms tumor. Our work further emphasizes that a wide range of ocular phenotypes are associated with loss of function PAX6 mutations. In addition to the possibility of stochastic variations, other genetic variations could play a role as modifier genes, thus giving rise to the observed different ocular phenotypes.

Pediatric keratoconus and iontophoretic corneal crosslinking: refractive and topographic evidence in patients underwent general and topical anesthesia, 18 months of follow-up.

To evaluate the efficiency and safety of iontophoretic transepithelial corneal crosslinking in pediatric patients with progressive keratoconus underwent general or topical anesthesia in 18 months follow-up. 13 patients (13 eyes) diagnosed with progressive keratoconus underwent corneal CXL with iontophoresis (I-CXL). Riboflavin solution was administered by iontophoresis for 5 min, and then UV-A irradiation (10 mW/cm) was performed for 9 min. Preoperative and post-operative visits at 1, 6, 12, and 18 months assessed the following parameters: uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), slit-lamp biomicroscopy, corneal topography, optical tomography, and pachymetry with Pentacam (Oculus Optikgeräte GmbH, Wetzlar, Germany), endothelial biomicroscopy (Konan Specular Microscope; Konan Medical, Inc., Hyogo, Japan). The paired Student t test was used to compare data during the follow-up. 10 males and 3 females with a mean age of 15.4 ± 1.7 years (range 11-18 years) were included. The results showed a stabilization of the refractive UCVA and BCVA as early as the first post-operative month, with a slight improvement over time. The Kmax remained stable throughout follow-up (p = 0.04). Transepithelial collagen crosslinking by iontophoresis, unlike other transepithelial techniques seems to halt pediatric keratoconus progression over 18 months. This is the second study evaluating CXL with iontophoresis in pediatric patients with progressive keratoconus with 18 months of follow-up using two different ways of anesthesia.

Lens opacities in glycogenoses type I and III.

OBJECTIVE: The glycogen storage diseases (GSD) or glycogenoses comprise several inherited diseases caused by abnormalities of the enzymes that regulate the synthesis or degradation of glycogen. This report presents lens opacities not previously described in patients with type I or III GSD. PARTICIPANTS: Eleven patients with type I and III GSD. METHODS: We examined a series of 11 consecutive patients (aged 13-40 years) with type I and III GSD by full ophthalmologic examination. RESULTS: We found changes of the lens on 7 of 11 patients (aged 23-40 years) with glycogenoses I and III. In 6 patients, the lens showed multiple, bilateral, punctate, and peripheral opacities; only 1 patient showed a posterior subcapsular opacity in both eyes. We did not observe changes in the cornea and the posterior pole correlated to the accumulation of glycogen and lipids. CONCLUSIONS: In this series, we found that 60% of patients with type I and III GSD show lens opacities. These opacities are bilateral, peripheral, multiple, and small; they do not give any visual disturbance. Considering that subjects with age ranging from 13 to 23 years had no lens opacities, we postulate that they could progressively develop over time because of exposure to recurrent attacks of hypoglycemia, which lead to a progressive depletion of hexokinase.

Two novel splicing mutations in the SLC45A2 gene cause Oculocutaneous Albinism Type IV by unmasking cryptic splice sites.

Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type IV (OCA4) is one of the four commonly recognized forms of albinism, and is determined by mutation in the SLC45A2 gene. Here, we investigated the genetic basis of OCA4 in an Italian child. The mutational screening of the SLC45A2 gene identified two novel potentially pathogenic splicing mutations: a synonymous transition (c.888G>A) involving the last nucleotide of exon 3 and a single-nucleotide insertion (c.1156+2dupT) within the consensus sequence of the donor splice site of intron 5. As computer-assisted analysis for mutant splice-site prediction was not conclusive, we investigated the effects on pre-mRNA splicing of these two variants by using an in vitro minigene approach. Production of mutant transcripts in HeLa cells demonstrated that both mutations cause the almost complete abolishment of the physiologic donor splice site, with the concomitant unmasking of cryptic donor splice sites. To our knowledge, this work represents the first in-depth molecular characterization of splicing defects in a OCA4 patient.

SOX2, OTX2 and PAX6 analysis in subjects with anophthalmia and microphthalmia.

Anophthalmia (A) and microphthalmia (M) are rare developmental anomalies that have significant effects on visual activity. In fraction of A/M subjects, single genetic defects have been identified as causative. In this study we analysed 65 Italian A/M patients, 21 of whom are syndromic, for mutations in SOX2, OTX2 and PAX6 genes. In syndromic patients the presence of genome imbalances through array CGH was also investigated. No mutations were found for OTX2 and PAX6 genes. Three causative SOX2 mutations were found in subjects with syndromic A. In a subject with syndromic signs and monolateral M, two de novo 6.26 Mb and 1.37 Mb deletions in 4q13.2q13.3 have been identified. A SOX2 missense (p.Ala161Ser) mutation was found in 1 out of 39 a subject with non-syndromic monolateral M. Alanine at position 161 is conserved along phylogeny and the p.Ala161Ser mutation is estimated pathogenic by in silico analysis. However, this mutation was also present in the unaffected patient's daughter.

SLC45A2 mutation frequency in Oculocutaneous Albinism Italian patients doesn't differ from other European studies.

BACKGROUND: Oculocutaneous Albinism (OCA) is a heterogeneous group of inherited diseases involving hair, skin and eyes. To date, six forms are recognized on the effects of different melanogenesis genes. OCA4 is caused by mutations in SLC45A2 showing a heterogeneous phenotype ranging from white hair, blue irides and nystagmus to brown/black hair, brown irides and no nystagmus. The high clinic variety often leads to misdiagnosis. Our aim is to contribute to OCA4 diagnosis defining SLC45A2 genetic variants in Italian patients with OCA without any TYR, OCA2 and TYRP1 gene defects. MATERIALS AND METHODS: After the clinical diagnosis of OCA, all patients received genetic counseling and genetic test. Automatic sequencing of TYR, OCA2, and TYRP1 genes was performed on DNA of 117 albino patients. Multiplex Ligation-dependent Probe Amplification (MLPA) was carried out on TYR and OCA2 genes to increase the mutation rate. SLC45A2 gene sequencing was then executed in the patients with a single mutation in one of the TYR, OCA2, TYRP1 genes and in the patients, which resulted negative at the screening of these genes. RESULTS: SLC45A2 gene analysis was performed in 41 patients and gene alterations were found in 5 patients. Four previously reported SLC45A2 mutations were found: p.G100S, p.W202C, p.A511E and c.986delC, and three novel variants were identified: p.M265L, p.H94D, and c.1156+1G>A. All the alterations have been detected in the group of patients without mutations in the other OCA genes. CONCLUSIONS: Three new variants were identified in OCA4 gene; the analysis allowed the classification of a patient previously misdiagnosed as OA1 because of skin and hair pigmentation presence. The molecular defects in SLC45A2 gene represent the 3.4% in this cohort of Italian patients, similar to other Caucasian populations; our data differ from those previously published by an Italian researcher group, obtained on a smaller cohort of patients.

Functional characterization of two novel splicing mutations in the OCA2 gene associated with oculocutaneous albinism type II.

Oculocutaneous albinism (OCA) is characterized by hypopigmentation of the skin, hair and eye, and by ophthalmologic abnormalities caused by a deficiency in melanin biosynthesis. OCA type II (OCA2) is one of the four commonly-recognized forms of albinism, and is determined by mutation in the OCA2 gene. In the present study, we investigated the molecular basis of OCA2 in two siblings and one unrelated patient. The mutational screening of the OCA2 gene identified two hitherto-unknown putative splicing mutations. The first one (c.1503+5G>A), identified in an Italian proband and her affected sibling, lies in the consensus sequence of the donor splice site of OCA2 intron 14 (IVS14+5G>A), in compound heterozygosity with a frameshift mutation, c.1450_1451insCTGCCCTGACA, which is predicted to determine the premature termination of the polypeptide chain (p.I484Tfs*19). In-silico prediction of the effect of the IVS14+5G>A mutation on splicing showed a score reduction for the mutant splice site and indicated the possible activation of a newly-created deep-intronic acceptor splice site. The second mutation is a synonymous transition (c.2139G>A, p.K713K) involving the last nucleotide of exon 20. This mutation was found in a young African albino patient in compound heterozygosity with a previously-reported OCA2 missense mutation (p.T404M). In-silico analysis predicted that the mutant c.2139G>A allele would result in the abolition of the splice donor site. The effects on splicing of these two novel mutations were investigated using an in-vitro hybrid-minigene approach that led to the demonstration of the causal role of the two mutations and to the identification of aberrant transcript variants.

Epithelium-off corneal collagen cross-linking versus transepithelial cross-linking for pediatric keratoconus.

PURPOSE: To compare efficiency and safety of epithelium-off corneal cross-linking (CXL) and transepithelial cross-linking (TE-CXL) in pediatric patients with progressive keratoconus. METHODS: Uncorrected and corrected visual acuity, corneal topography and pachymetry (Pentacam; Oculus Pentacam), and in vivo confocal microscopy (HRT II, Rostock Cornea Module, Heidelberg Engineering, Heidelberg, Germany) were evaluated at baseline and at 3, 6, and 12 months. RESULTS: In the epithelium-off CXL group (19 patients, 23 eyes; mean age, 14.75 ± 2.1 years), a significant improvement at month 12 was present for Kmax [-1.11 diopters (D), P = 0.01], Kmin (-3.2 D, P = 0.001), mean K (-1.47 D, P = 0.01), surface asymmetry index (-0.64 D, P = 0.001), inferior-superior symmetry index (-0.54 D, P = 0.01), index of height asymmetry (-2.97, P = 0.03), and anterior elevation at the thinnest location (-2.82 D, P = 0.01) and at the apex (-2.27 D, P = 0.01). Postoperative corneal edema lasted 3 months in 16 eyes (69.5%) and more than 6 months in 2 eyes (8.7%). In the TE-CXL group (10 patients, 14 eyes; mean age, 15 ± 4.2 years), a significant improvement at month 12 was present for Kmax (-1.14 D, P = 0.02), Kmin (-2.04 D, P = 0.01), mean K (-1.63 D, P = 0.01), surface asymmetry index (-0.86 D, P = 0.001), inferior-superior symmetry index (-0.55 D, P = 0.001), index of height asymmetry (-2.95, P = 0.01), and anterior elevation at the thinnest location (-2.96 D, P = 0.01) and at the apex (-2.19 D, P = 0.01). No postoperative corneal edema after TE-CXL was observed. Changes at month 12 from baseline were not significantly different between the 2 groups (P > 0.05). TE-CXE was significantly less painful than epithelium-off CXL. CONCLUSIONS: In pediatric patients with progressive keratoconus, TE-CXL was less painful, provided similar effectiveness and fewer complications than epithelium-off CXL at 12-month follow-up.

13q deletion syndrome and retinoblastoma in identical dichorionic diamniotic monozygotic twins.

PURPOSE: To report the case of identical dichorionic diamniotic female twins with unilateral retinoblastoma in 13q deletion syndrome. METHODS: Clinical and ophthalmoscopic evaluation, combination of multiple ligation-dependent probe amplification, array-comparative genomic hybridization analyses, and magnetic resonance imaging were performed. RESULTS: Peculiar facial features, marked hypotonia, gastroesophageal reflux, interatrial septal defect with left to right shunt and light dilatation of right chambers, 5th finger hypoplasia, 3rd-5th toes clinodactyly, 2nd toe overlapped to 3rd toe, and cutis marmorata were found. Ophthalmoscopic evaluation revealed unilateral retinoblastoma in both girls. Magnetic resonance imaging detected corpus callosum hypoplasia in both twins. A 34.4-Mb deletion involving bands 13q13.2-q21.33 and including the RB1 gene was identified in both twins. The deletion was not present in the DNA of their parents and older brother. CONCLUSIONS: Dysmorphic features in children must be always suspicious of 13q deletion syndrome and a short ophthalmoscopic follow-up is necessary to detect the presence of a retinoblastoma.

Surgical approach in a rare case of coloboma-choristoma.

Embryogenic eyelid defects can be isolated or associated with malformative diseases, such as Tessier craniofacial clefts. We describe the exceptional coexistence of upper eyelid coloboma and lower eyelid dermolipoma in a 45-day-old infant with a Tessier no. 0-1 cleft. The surgical intervention carried out on this patient, which used a flap of subconjunctival choristoma and grafting of reshaped cutaneous and tarsal portions of a preauricular anlage, is presented as a technique for correcting congenital palpebral coloboma. Adoption of this technique allowed virtually complete repair of the defect and gave an acceptable functional and cosmetic result.