ABSTRACT
PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.
Subject(s)
Neurofibromatosis 1 , Neuropsychological Tests , Pyridones , Pyrimidinones , Humans , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Pyrimidinones/pharmacology , Pyrimidinones/administration & dosage , Male , Female , Adolescent , Child , Neurofibromatosis 1/drug therapy , Neurofibromatosis 1/complications , Neurofibromatosis 1/psychology , Young Adult , Child, Preschool , Glioma/drug therapy , Glioma/psychology , Glioma/complications , Brain Neoplasms/drug therapy , Brain Neoplasms/psychology , Brain Neoplasms/complications , Adult , Protein Kinase Inhibitors/therapeutic use , Antineoplastic Agents/adverse effectsABSTRACT
PURPOSE: Treatment of optic pathway gliomas is prompted by neuroradiological evidence of tumor growth, usually associated with progressive visual loss. Despite therapy, approximately 40% will show visual deterioration. Treatment outcome is largely based on the preservation of vision. However, current visual function assessment is often unreliable in children with optic pathway gliomas who have limited collaboration. Thus, there is a need for new clinical tools to evaluate visual functions in these children. The aim of the study was to assess the value of steady-state visual evoked potentials as a tool to assess function in the central and peripheral visual fields of children with optic pathway gliomas. METHOD: Ten patients with optic pathway gliomas and 33 healthy controls (ages 3 to 18 years) were tested using steady-state visual evoked potentials. The dartboard stimulus consisted of one central circle alternating at 16 reversals/s and one peripheral hoop alternating at 14.4 reversals/s, separated by a hoop of gray space. It was presented monocularly at 30% and 96% contrasts. RESULTS: Results indicated that central signal-to-noise ratios were significantly lower in children with optic pathway gliomas compared to controls. However, no significant group difference was detected in the peripheral visual field. CONCLUSION: Steady-state visual evoked potentials could eventually be implemented in the clinical assessment and follow-up of central visual field deficits in uncooperative or nonverbal children but seem to have limited usefulness for evaluation of peripheral visual field deficits. Additional studies are needed to identify testing parameters for full visual field assessment.
Subject(s)
Evoked Potentials, Visual/physiology , Optic Nerve Glioma/physiopathology , Optic Nerve Neoplasms/physiopathology , Visual Fields/physiology , Adolescent , Child , Child, Preschool , Electroretinography , Female , Humans , Male , Vision Disorders/physiopathologyABSTRACT
Methylphenidate- and amphetamine-based psychostimulants are the most common medications used to treat the symptoms of attention-deficit/hyperactivity disorder in children. Ocular side effects including dry eyes, mydriasis, accommodation disturbance, and blurry vision are listed in the product monograph but interestingly, are rarely reported in the paediatric literature. Our patient, a 9-year-old boy, presented a significant decrease in visual acuity secondary to accommodation disorder after being treated with methylphenidate hydrochloride controlled release (Biphentin) and lisdexamfetamine (Vyvanse). The unusual acute adverse effect, altered accommodation leading to a decline in visual acuity, emphasizes the importance of considering any change in vision following the introduction of psychostimulant medication as a potential adverse effect. This case highlights the importance of pharmacovigilance especially in paediatrics where data are lacking.
ABSTRACT
Joubert syndrome (JBTS) is a primarily autosomal-recessive disorder characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. JBTS is a genetically heterogeneous ciliopathy. We sought to characterize the genetic landscape associated with JBTS in the French Canadian (FC) population. We studied 43 FC JBTS subjects from 35 families by combining targeted and exome sequencing. We identified pathogenic (n = 32 families) or possibly pathogenic (n = 2 families) variants in genes previously associated with JBTS in all of these subjects, except for one. In the latter case, we found a homozygous splice-site mutation (c.735+2T>C) in CEP104. Interestingly, we identified two additional non-FC JBTS subjects with mutations in CEP104; one of these subjects harbors a maternally inherited nonsense mutation (c.496C>T [p.Arg166*]) and a de novo splice-site mutation (c.2572-2A>G), whereas the other bears a homozygous frameshift mutation (c.1328_1329insT [p.Tyr444fs*3]) in CEP104. Previous studies have shown that CEP104 moves from the mother centriole to the tip of the primary cilium during ciliogenesis. Knockdown of CEP104 in retinal pigment epithelial (RPE1) cells resulted in severe defects in ciliogenesis. These observations suggest that CEP104 acts early during cilia formation by regulating the conversion of the mother centriole into the cilia basal body. We conclude that disruption of CEP104 causes JBTS. Our study also reveals that the cause of JBTS has been elucidated in the great majority of our FC subjects (33/35 [94%] families), even though JBTS shows substantial locus and allelic heterogeneity in this population.
Subject(s)
Cerebellum/abnormalities , Cilia/pathology , Microtubule-Associated Proteins/genetics , Mutation/genetics , Retina/abnormalities , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/pathology , Adolescent , Adult , Canada/epidemiology , Cerebellum/pathology , Child , Child, Preschool , Cilia/metabolism , Exome/genetics , Eye Abnormalities/epidemiology , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Female , Follow-Up Studies , High-Throughput Nucleotide Sequencing , Homozygote , Humans , Infant , Infant, Newborn , Kidney Diseases, Cystic/epidemiology , Kidney Diseases, Cystic/genetics , Kidney Diseases, Cystic/pathology , Male , Pedigree , Prognosis , Retina/pathology , Young AdultABSTRACT
Mitochondrial protein synthesis is initiated by formylated tRNA-methionine, which requires the activity of MTFMT, a methionyl-tRNA formyltransferase. Mutations in MTFMT have been associated with Leigh syndrome, early-onset mitochondrial leukoencephalopathy, microcephaly, ataxia, and cardiomyopathy. We identified compound heterozygous MTFMT mutations in a patient with a mild neurological phenotype and late-onset progressive visual impairment. MRI studies documented a progressive and selective involvement of the retrochiasmatic visual pathway. MTFMT was undetectable by immunoblot analysis of patient fibroblasts, resulting in specific defects in mitochondrial protein synthesis and assembly of the oxidative phosphorylation complexes. This report expands the clinical and MRI phenotypes associated with MTFMT mutations, illustrating the complexity of genotype-phenotype relationships in mitochondrial translation disorders.
Subject(s)
Cognitive Dysfunction/genetics , Hydroxymethyl and Formyl Transferases/genetics , Mitochondrial Diseases/genetics , Vision Disorders/genetics , Cognitive Dysfunction/complications , DNA Mutational Analysis , Female , Humans , Mitochondrial Diseases/complications , Phenotype , Visual Pathways/metabolism , Visual Pathways/pathology , Young AdultABSTRACT
Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs*31], c.4804C>T [p.Arg1602*], and c.7477C>T [p.Arg2493*]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.
Subject(s)
Cerebellar Diseases/genetics , Eye Abnormalities/genetics , Kidney Diseases, Cystic/genetics , Membrane Proteins/genetics , Mutation , Abnormalities, Multiple , Adult , Base Sequence , Canada , Cerebellum/abnormalities , Child , Child, Preschool , Exome , Female , Heterozygote , Homozygote , Humans , Male , Molecular Sequence Data , Polymorphism, Single Nucleotide , Retina/abnormalitiesABSTRACT
OBJECTIVE: To describe the long-term ophthalmologic outcomes of patients with methylmalonic aciduria and homocystinuria, cobalamin C type (cblC). DESIGN: Retrospective case series. PARTICIPANTS: All patients with cblC referred to the Department of Ophthalmology of the Centre Hospitalier Universitaire Sainte-Justine from 1984 through 2012 were studied. Twelve such patients were identified. METHODS: Clinical ophthalmic examinations, neuroimaging, electroretinography, and the results of MMACHC mutation analysis were reviewed retrospectively. MAIN OUTCOME MEASURES: We examined visual acuity, ocular alignment, presence of maculopathy and peripheral retinopathy, optic atrophy, and nystagmus. Photopic and scotopic electroretinograms were reviewed. We examined and compared mutations in the MMACHC gene. Neuroimaging abnormalities were compiled when available. RESULTS: Twelve cblC patients were followed up from 2 to 23 years (average, 10 years). Eleven of 12 patients were diagnosed before the age of 1 year (range, birth-2 years). An initial ophthalmic examination was performed within the first year of age in 9 of 12 patients. Visual acuity at the time of presentation was variable, ranging from light perception to 20/20. Visual acuity was worse than 20/100 in 75% (9/12) of patients at last follow-up. Eight patients (67%) had obvious maculopathy on fundus examination. Other findings included peripheral retinopathy (8/12 [67%]), nystagmus (8/12 [67%]), strabismus (5/12 [42%]), and optic atrophy (6/12 [50%]). Funduscopic deterioration was documented in 1 patient, whereas electrophysiologic changes occurred in 4 patients. Neuroimaging results were available in 7 of the patients, revealing corpus callosum atrophy (7/7 [100%]) and periventricular white matter loss (6/7 [85%]). CONCLUSIONS: Most children in our series had early-onset disease with neurologic manifestations and abnormal ophthalmologic examination results. Despite early treatment, many early-onset cblC patients have poor visual function.
Subject(s)
Amino Acid Metabolism, Inborn Errors/physiopathology , Homocystinuria/physiopathology , Retinal Diseases/physiopathology , Vision Disorders/physiopathology , Visual Acuity/physiology , Adolescent , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/genetics , Carrier Proteins/genetics , Child , Child, Preschool , Chromosomes, Human, Pair 1/genetics , Color Vision/physiology , DNA Mutational Analysis , Diagnostic Imaging , Electroretinography , Female , Follow-Up Studies , Homocystinuria/diagnosis , Homocystinuria/genetics , Humans , Male , Mutation/genetics , Night Vision/physiology , Nystagmus, Pathologic/diagnosis , Nystagmus, Pathologic/genetics , Nystagmus, Pathologic/physiopathology , Optic Atrophy/diagnosis , Optic Atrophy/genetics , Optic Atrophy/physiopathology , Oxidoreductases , Retinal Diseases/diagnosis , Retinal Diseases/genetics , Retrospective Studies , Strabismus/diagnosis , Strabismus/genetics , Strabismus/physiopathology , Vision Disorders/diagnosis , Vision Disorders/genetics , Vitamin B 12 Deficiency/congenital , Young AdultABSTRACT
BACKGROUND: Chemotherapy is the most common primary treatment modality for pediatric optic pathway gliomas (OPGs). Due to the risk of severe visual impairment, visual acuity (VA) has become a clinical parameter of fundamental importance for children with OPGs. Despite this reality, most studies omit crucial information necessary for analysis of the effect of chemotherapy on VA in patients with cerebral gliomas. The principal goal of this study was to determine the immediate and long-term visual outcome of children treated first with chemotherapy for OPGs. PROCEDURE: Retrospective, non-comparative, case series of children with OPGs treated initially with chemotherapy. VA was measured prior to chemotherapy, directly following chemotherapy, as well as at last follow-up. RESULTS: Seven children (14 eyes) were positive for the neurofibromatosis type-1 (NF1) mutation and 10 children (20 eyes) were without the NF1 mutation (sporadic). Three deaths, all in the sporadic cohort, occurred as a result of their OPG. Median follow-up time of survivors was 10.54 ± 4.36 (SD) years. Both NF1 mutation positive and sporadic cohorts had deterioration in VA over time; however, deterioration was only statistically significant in the sporadic population. The percentage of eyes with vision weaker than 20/200 prior to chemotherapy, directly following chemotherapy and at last follow-up grew from 18% to 24% to 38%, respectively. CONCLUSIONS: In both NF1 mutant and sporadic OPGs, VA deteriorated directly following chemotherapy as well as at long-term follow-up. Despite chemotherapy, eyes with severe functional impairment gradually increased over time.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mutation/genetics , Neurofibromatosis 1/genetics , Optic Nerve Glioma/drug therapy , Vision Disorders/etiology , Visual Acuity , Child , Child, Preschool , Combined Modality Therapy , Disease Progression , Female , Follow-Up Studies , Genes, Neurofibromatosis 1 , Humans , Infant , Infant, Newborn , Male , Neoplasm Staging , Optic Nerve Glioma/complications , Optic Nerve Glioma/genetics , Prognosis , Retrospective Studies , Vision Disorders/chemically induced , Vision Disorders/pathologyABSTRACT
BACKGROUND: Joubert syndrome (JBTS) is a predominantly autosomal recessive disorder characterised by a distinctive midhindbrain malformation, oculomotor apraxia, breathing abnormalities and developmental delay. JBTS is genetically heterogeneous, involving genes required for formation and function of non-motile cilia. Here we investigate the genetic basis of JBTS in 12 French-Canadian (FC) individuals. METHODS AND RESULTS: Exome sequencing in all subjects showed that six of them carried rare compound heterozygous mutations in CC2D2A or C5ORF42, known JBTS genes. In addition, three individuals (two families) were compound heterozygous for the same rare mutations in TMEM231(c.12T>A[p.Tyr4*]; c.625G>A[p.Asp209Asn]). All three subjects showed a severe neurological phenotype and variable presence of polydactyly, retinopathy and renal cysts. These mutations were not detected among 385 FC controls. TMEM231 has been previously shown to localise to the ciliary transition zone, and to interact with several JBTS gene products in a complex involved in the formation of the diffusion barrier between the cilia and plasma membrane. siRNA knockdown of TMEM231 was also shown to affect barrier integrity, resulting in a reduction of cilia formation and ciliary localisation of signalling receptors. CONCLUSIONS: Our data suggest that mutations in TMEM231 cause JBTS, reinforcing the relationship between this condition and the disruption of the barrier at the ciliary transition zone.
Subject(s)
Cerebellar Diseases/genetics , Eye Abnormalities/genetics , Kidney Diseases, Cystic/genetics , Membrane Proteins/genetics , Mutation , Abnormalities, Multiple , Adolescent , Adult , Amino Acid Sequence , Brain/pathology , Canada/ethnology , Cerebellar Diseases/diagnosis , Cerebellum/abnormalities , Child , Child, Preschool , Exome , Eye Abnormalities/diagnosis , Female , Gene Order , Humans , Infant , Kidney Diseases, Cystic/diagnosis , Male , Middle Aged , Molecular Sequence Data , Pedigree , Retina/abnormalities , Sequence Alignment , Young AdultABSTRACT
OBJECTIVE: To report long-term structural, visual, and refractive outcomes after monotherapy with intravitreal bevacizumab injection. DESIGN: Cohort retrospective chart review. PARTICIPANTS: A total of 56 premature infants with type 1 retinopathy of prematurity. METHODS: This is a chart review at 2 Canadian institutions. Inclusion criteria were single injection of 0.625 mg⯠intravitreal bevacizumab and minimum age at last follow-up of 3 years. Primary outcome was retinal structure. Secondary outcomes were refractive error in spherical equivalent, monocular visual acuity, strabismus, and amblyopia. RESULTS: Fifty-six infants (101 eyes) met inclusion criteria. Mean birth weight was 707 ± 178 g (range, 420-1520 g). Mean gestational age was 25.0 ± 1.3 weeks (range, 22.9-29.7 weeks). Twenty-four eyes were in zone I (24%) and 77 in zone II (76%). Mean postmenstrual age at treatment was 36.9 ± 2.1 weeks (range, 32.8-42.0 weeks). At a mean age of 5.4 ± 1.6 years (range, 3.0-8.0 years), all eyes had a favourable structural outcome with no reactivation requiring treatment. Mean monocular visual acuity was 0.29 ± 0.27 logMAR (range, 0.0-1.3 logMAR; 89 of 101 eyes). Mean spherical equivalent was -1.98 ± 4.91 D (range, -16.63 to +5.38 D; 101 of 101 eyes). Prevalence of emmetropia (>-1.0 to ≤1 D) was 43.6%; low myopia (≥1.0 to <5 D) was 17.8%; high myopia (≥5 to <8 D) was 8.9 %; very high myopia (≥8.0 D) was 12.9%; and hyperopia (>1 D) was 16.8%. Twelve children (23%) had amblyopia, and 17 (32%) developed strabismus. CONCLUSIONS: All patients demonstrated a favourable structural outcome with a single bevacizumab injection without the need for additional laser. We suggest regular monitoring following regression of acute retinopathy of prematurity as an alternative to universal, preplanned delayed prophylactic laser treatment. Future studies to evaluate other aspects of visual function are needed.
Subject(s)
Amblyopia , Myopia , Retinopathy of Prematurity , Strabismus , Infant, Newborn , Infant , Child , Humans , Child, Preschool , Bevacizumab , Angiogenesis Inhibitors , Retinopathy of Prematurity/diagnosis , Retinopathy of Prematurity/drug therapy , Amblyopia/therapy , Retrospective Studies , Vascular Endothelial Growth Factor A , Canada/epidemiology , Infant, Premature , Retina , Gestational Age , Intravitreal InjectionsABSTRACT
Colobomas of the globe and microphthalmia are congenital conditions that can strongly affect vision. Etiologies are varied and include embryonic and hereditary origins. We report what is, to the best of our knowledge, the first case of a SIX6 gene pathogenic variant associated with a phenotype of both bilateral microphthalmia and extensive colobomas of the globes. A 3-week-old boy presented with bilateral microphthalmia and iris, optic nerve, and chorioretinal colobomas. Genetic analysis was performed on a panel of 78 genes (microphthalmia, anophthalmia, and coloboma panel), and a homozygous likely pathogenic variant was identified in the SIX6 gene, resulting in the loss of the initiator methionine. Thus, our report expands the phenotypic spectrum of SIX6-related disorders.
ABSTRACT
PURPOSE: To study the efficacy of propranolol in the treatment of periocular infantile hemangiomas (IHs). DESIGN: Retrospective interventional case series. PARTICIPANTS: Eighteen children presenting periocular IH with occlusion of the pupil, anisometropic astigmatism, proliferating eyelid IH, or cosmetically disfiguring periocular IH. METHODS: All patients received treatment with propranolol started at 0.5 mg/kg/day with an incremental increase by 0.5 mg/kg/day every 4 days, up to a maximum of 2 to 3 mg/kg/day. Complete eye examinations and serial photographs were obtained before, during, and after treatment. Doppler ultrasound and magnetic resonance imaging performed pre- and post-treatment were compared when available. MAIN OUTCOME MEASURES: Evolution of the treated IH was evaluated with respect to astigmatism, amblyopia, and size of the lesion. RESULTS: The IH size decreased in 17 of 18 patients. We noted a greater reduction when treatment was administered during the proliferative phase of growth of IHs. At the conclusion of treatment, none of our patients had amblyopia. The mean value of amblyogenic astigmatism (n = 7) decreased from 2.71 diopters (D) pretreatment to 1.03 D post-treatment. On radiology, 8 patients had significant regression of the lesion size of their IH and 1 patient had a limited progression. Propranolol had to be temporarily discontinued in only 1 patient because of symptomatic hypotension. CONCLUSIONS: Propranolol seems to be an effective modality of treatment for periocular IH. It seems to be most efficacious when initiated in the proliferative phase of IH but may be beneficial even in the later stage. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Subject(s)
Eyelid Neoplasms/drug therapy , Hemangioma, Capillary/drug therapy , Propranolol/administration & dosage , Administration, Oral , Dose-Response Relationship, Drug , Eyelid Neoplasms/diagnosis , Female , Follow-Up Studies , Hemangioma, Capillary/diagnosis , Humans , Infant , Magnetic Resonance Imaging , Male , Neoplasm Recurrence, Local/prevention & control , Retrospective Studies , Treatment Outcome , Ultrasonography, Doppler, Color , Vasodilator Agents/administration & dosageABSTRACT
PURPOSE: Androgens given for gender affirmation have been implicated in the pathophysiology of idiopathic intracranial hypertension (IIH) in transgender patients. 10 cases of transgender adults with IIH have been published but this association has not been described in younger patients. Herein we describe the first case of IIH in an adolescent transgender patient. OBSERVATIONS: A 17-year-old non-obese female-to-male transgender patient on subcutaneous testosterone since age 13 presented with a two-month history of transient visual obscuration and frontal headaches. Ophthalmological examination revealed Frisen grade 2 papilledema with preserved visual function. Lumbar puncture confirmed elevated opening pressure. Papilledema resolved with oral acetazolamide and reduction of testosterone therapy. CONCLUSIONS AND IMPORTANCE: The use of cross-sex hormone therapy (CSH) for gender affirmation may increase the risk of IIH. Awareness of this association is important as the number of younger transgender patients seeking CSH is increasing significantly.
ABSTRACT
PURPOSE: To identify risk factors for ocular graft-versus-host disease (oGVHD) in children with graft-versus-host disease (GVHD). METHODS: This retrospective cohort study identified 38 children diagnosed with GVHD who underwent an ophthalmological examination. Survival to onset of oGVHD after transplant was analyzed using Kaplan-Meier analyses with log-rank tests. A multivariable Cox proportional hazards model was run for time to oGVHD using univariate risk factors. RESULTS: The average age was 10.0 ± 5.4 years at the time of transplant. Underlying illness was acute lymphoblastic leukemia in 19 (50%) and acute myeloid leukemia in 8 (21%). Nonocular GVHD organ involvement included skin (84%), lungs (16%), intestines (50%), liver (24%), and bone marrow (3%). Fifteen children (39%) had oGVHD, of which 47% were asymptomatic. oGVHD was diagnosed 601 ± 878 days after GVHD. A significant association between risk of oGVHD and diagnosis of acute lymphoblastic leukemia (P = 0.10) or acute myeloid leukemia (P = 0.08) was not found. Organ involvement associated with oGVHD included skin (P = 0.03) and lungs (P = 0.02). Survival curves were significantly influenced by GVHD organ involvement (P = 0.02), but not underlying disease (P = 0.51). The adjusted Cox regression model yielded an independent hazard ratio of 8.82 (95% CI: 1.51-51.49; P = 0.016) for the presence of concomitant GVHD involvement of skin, lungs, and another organ. CONCLUSIONS: Children with multiorgan GVHD involvement including skin and lung disease are at increased risk for oGVHD. Given the proportion of asymptomatic cases found in this series, regular eye examinations are warranted in this population.
Subject(s)
Eye Diseases/epidemiology , Graft vs Host Disease/epidemiology , Hematopoietic Stem Cell Transplantation/adverse effects , Leukemia, Myeloid, Acute/therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Bone Marrow Diseases/diagnosis , Bone Marrow Diseases/epidemiology , Child , Child, Preschool , Chronic Disease , Eye Diseases/diagnosis , Female , Follow-Up Studies , Graft vs Host Disease/diagnosis , Humans , Infant , Intestinal Diseases/diagnosis , Intestinal Diseases/epidemiology , Liver Diseases/diagnosis , Liver Diseases/epidemiology , Lung Diseases/diagnosis , Lung Diseases/epidemiology , Male , Multivariate Analysis , Proportional Hazards Models , Retrospective Studies , Risk Factors , Skin Diseases/diagnosis , Skin Diseases/epidemiologyABSTRACT
PURPOSE: To report 2 novel variants in the AAAS gene consistent with the diagnosis of Allgrove syndrome. METHODS: A 12-year-old girl was referred to our clinic for progressive bilateral decrease in visual acuity. She was known for achalasia that had been surgically treated at a very early age. On examination, she was found to have dry eye disease secondary to lacrimal insufficiency. She also had anisocoria, light-near dissociation, and bilateral optic nerve atrophy. RESULTS: Neurological examination and brain magnetic resonance imaging were within normal limits. Genetic workup revealed compound heterozygosity for 2 novel variants in the AAAS gene, confirming the diagnosis of Allgrove syndrome. The patient was referred to endocrinology to screen for adrenocorticotropic hormone insufficiency. She was started on topical lubricating therapy that improved her symptoms. CONCLUSIONS: Allgrove syndrome is a rare genetic disease that is characterized by the triad of achalasia, alacrima, and adrenal insufficiency. Early diagnosis, confirmed with genetic testing, is essential to initiate an appropriate follow-up and prevent a life-threatening addisonian crisis. Report of novel mutations is important to further characterize this disease.
Subject(s)
Adrenal Insufficiency/genetics , DNA/genetics , Esophageal Achalasia/genetics , Mutation , Nerve Tissue Proteins/genetics , Nuclear Pore Complex Proteins/genetics , Adrenal Insufficiency/diagnosis , Adrenal Insufficiency/metabolism , Child , DNA Mutational Analysis , Diagnosis, Differential , Esophageal Achalasia/diagnosis , Esophageal Achalasia/metabolism , Female , Humans , Nerve Tissue Proteins/metabolism , Nuclear Pore Complex Proteins/metabolismABSTRACT
Gaucher disease (GD) results from a deficiency of glucocerebrosidase activity and the subsequent accumulation of the enzyme's metabolites, principally glucosylsphingosine and glucosylceramide. There are three principal forms: Type I, which is the most common, is usually considered non-neuronopathic. Type II, III and IIIc manifest earlier and have neurological sequelae due to markedly reduced enzyme activity. Gaucher's can be associated with ophthalmological sequelae but these have not been systematically reviewed. We therefore performed a comprehensive literature review of all such ophthalmic abnormalities associated with the different types of Gaucher disease. We systematically searched the literature (1950 - present) for functional and structural ocular abnormalities arising in patients with Gaucher disease and found that all subtypes can be associated with ophthalmic abnormalities; these range from recently described intraocular lesions to disease involving the adnexae, peripheral nerves and brain. In summary, Gaucher can affect most parts of the eye. Rarely is it sight-threatening; some but not all manifestations are amenable to treatment, including with enzyme replacement and substrate reduction therapy. Retinal involvement is rare but patients with ocular manifestations should be monitored and treated early to reduce the risk of progression and further complications. As Gaucher disease is also associated with Parkinsons disease and may also confer an increased risk of malignancy (particularly haematological forms and melanoma), any ocular abnormalities should be fully investigated to exclude these potential underlying conditions.
Subject(s)
Eye Diseases/diagnosis , Gaucher Disease/diagnosis , Lysosomal Storage Diseases/diagnosis , Eye Diseases/classification , Eye Diseases/etiology , Gaucher Disease/classification , Gaucher Disease/etiology , Glucosylceramides/blood , Humans , Lysosomal Storage Diseases/classification , Lysosomal Storage Diseases/etiology , Phenotype , Psychosine/analogs & derivatives , Psychosine/bloodABSTRACT
Nystagmus has a profound impact on patients visual function and social life. Infantile nystagmus (IN) is much more common than neurological nystagmus, and establishing the correct diagnosis is key in guiding the appropriate treatment paradigm. This paper attempts to demonstrate a stepwise approach in investigation and clinical evaluation, that is (often) sufficient in differentiating IN from nystagmus of neurological origin, and to uncover underlying sensory etiologies of IN. Targeted and rational uses of paraclinical exams are emphasized when they deemed necessary to complement the clinical assessment. The author's preferred surgical and non-surgical strategies to optimize vision, and improve the head posture and strabismus that can accompany nystagmus, are discussed (although without the goal of writing a complete revision on the topic).
Subject(s)
Nystagmus, Congenital/diagnosis , Nystagmus, Congenital/therapy , Eye Movements/physiology , Eyeglasses , Head/physiopathology , Humans , Infant , Nystagmus, Congenital/etiology , Nystagmus, Pathologic/diagnosis , Nystagmus, Pathologic/etiology , Nystagmus, Pathologic/therapy , Oculomotor Muscles/surgery , Ophthalmologic Surgical Procedures , Posture/physiology , Strabismus/complicationsABSTRACT
PURPOSE: To compile international data on the risk factors, diagnosis, and treatment of endophthalmitis following pediatric cataract surgery. METHODS: An e-mail containing a link to an online survey was sent to all members of the American Association for Pediatric Ophthalmology and Strabismus. The questionnaire examined the incidence, risk factors, treatment, outcomes, and prophylaxis of endophthalmitis following pediatric cataract surgery around the world. RESULTS: Two hundred thirty-seven ophthalmologists answered the questionnaire. Eight ophthalmologists (3.4%) encountered 22 cases of endophthalmitis following pediatric cataract surgery during their practice. Most patients with endophthalmitis following pediatric cataract surgery were 2 to 4 years of age (36.4%). An intraocular lens was implanted in 59.1% of cases, most of which were acrylic intraocular lenses (53.8%). The main presenting symptoms were photophobia (50%) and pain (40.9%). The most common signs were conjunctival injection (36.4%) and hypopyon (31.8%). The final visual acuity was counting fingers or worse in 86% of cases. The most common cultured organism was Staphylococcus aureus (31.8%). The most common management of endophthalmitis following pediatric cataract surgery was a combination of intravitreal, systemic, and topical antibiotics (36.4%). Most ophthalmologists (68.2%) administered prophylactic intracameral antibiotic treatment during surgery and 50% used vancomycin. CONCLUSIONS: Endophthalmitis following pediatric cataract surgery is an uncommon, multifactorial complication with poor visual prognosis. Efforts directed at minimizing its risk, such as treating potential predisposing systemic conditions, improving sterilization techniques, optimizing operative conditions to reduce complications and surgery duration, and using subconjunctival and intracameral antibiotics, decrease its incidence. Early postoperative evaluation, subsequent follow-up visits, and keeping a high index of suspicion should facilitate the recognition of endophthalmitis following pediatric cataract surgery to avoid delaying treatment. [J Pediatr Ophthalmol Strabismus. 2018;55(1):23-29.].
Subject(s)
Anti-Bacterial Agents/therapeutic use , Antibiotic Prophylaxis/methods , Cataract Extraction/adverse effects , Endophthalmitis/etiology , Eye Infections, Bacterial/etiology , Surgical Wound Infection/etiology , Child , Child, Preschool , Endophthalmitis/epidemiology , Endophthalmitis/prevention & control , Eye Infections, Bacterial/epidemiology , Eye Infections, Bacterial/prevention & control , Female , Follow-Up Studies , Global Health , Humans , Incidence , Infant , Male , Ophthalmology , Retrospective Studies , Societies, Medical , Surgical Wound Infection/epidemiology , Surgical Wound Infection/prevention & control , Surveys and Questionnaires , Visual AcuityABSTRACT
BACKGROUND: Optic pathway gliomas (OPGs) occur sporadically or in patients with neurofibromatosis type 1 (NF1). The purpose of this study was to evaluate the clinical presentation at diagnosis and at progression of patients with OPGs. METHODS: We conducted a chart review of patients with OPGs diagnosed in a single center over a period of 15 years. Demographic data including age, sex, NF1 status, clinical presentation, and outcome were collected. RESULTS: Of the 40 patients who were identified, 23 had sporadic tumors (57.5%) and 17 had NF1-related tumors (42.5%). Among the children with NF1, there was a significant overrepresentation of girls (82.3%) (P = 0.02), while among the children without NF1, there were slightly more boys (56.5%) than girls (43.5%). The presence of nystagmus was strongly associated with sporadic optic pathway gliomas. Poor visual outcome was related to tumor affecting both optic pathways, hydrocephalus at diagnosis, and optic nerve atrophy. Of the 40 patients, five died of OPG complications (12.5%) and all had sporadic tumors. CONCLUSIONS: Our cohort is one of the largest with OPGs and a detailed description of the clinical presentation both at diagnosis and at progression. We observed a significant difference between sporadic and NF1 optic pathway gliomas in terms of demographics, clinical presentation, and outcome.