Ocular findings in 22q11.2 deletion syndrome: A systematic literature review and results of a Dutch multicenter study.

The 22q11.2 deletion syndrome (22q11.2DS) is a multisystem disorder with an estimated prevalence of 1:3000 live births. Manifestations show a marked variability in expression and include speech- and language delay, intellectual disability, and neuropsychiatric disorders. We aim to provide an overview of ocular findings in 22q11.2DS in order to optimize recommendations for ophthalmic screening. We combined results from a systematic literature review with results from a multicenter cross-sectional study of patients with 22q11.2DS who were assessed by an ophthalmologist. Our systematic literature search yielded four articles, describing 270 patients. We included 132 patients in our cross-sectional study (median age 8.9 [range 0-56] years). Most reported ocular findings were retinal vascular tortuosity (32%-78%), posterior embryotoxon (22%-50%), eye lid hooding (20%-67%), strabismus (12%-36%), amblyopia (2%-11%), ptosis (4%-6%), and refractive errors, of which hyperopia (6%-48%) and astigmatism (3%-23%) were most common. Visual acuity was (near) normal in most patients (91%-94%). Refractive errors, strabismus, and amblyopia are treatable conditions that are frequently present in patients with 22q11.2DS and should be corrected at an early stage. Therefore, in 22q11.2DS, we recommend ophthalmic and orthoptic screening at the age of 3 years or at diagnosis, and a low-threshold referral in adults.

Ophthalmological Evaluation in Children Presenting With a Primary Brain Tumor.

BACKGROUND: Children with a brain tumor are prone to develop visual impairment, which to date is often underestimated and unrecognized. Our aim was to assess the prevalence of ophthalmological evaluation and abnormal ophthalmological findings, and investigate whether demographic and tumor-related characteristics are associated with abnormal ophthalmological findings in children presenting with a primary brain tumor. METHODS: Medical records of all 90 children diagnosed with a primary brain tumor between June 2018 and May 2019 and treated at the Princess Máxima Center for Pediatric Oncology, a tertiary referral center in the Netherlands, were retrospectively reviewed. Univariate regression analysis was used to investigate associations between demographic, tumor-related and clinical characteristics, and abnormal ophthalmological findings. RESULTS: Sixty children (34 male [56.7%]; median [range] age, 9.3 [0-16.9] years) underwent ophthalmological evaluation within 6 weeks before or after diagnosis, 11 children (5 male [45.5%]; median [range] age, 5.7 [0.1-17.2] years) were seen more than 6 weeks before or after diagnosis, and 19 children (7 male [36.8%]; median [range] age, 7.2 [1.9-16.6] years) did not receive ophthalmological evaluation within at least 6 months from diagnosis. A total of 19 children (21.1%) presented with visual symptoms as first sign leading to the diagnosis of a brain tumor. Children who presented with visual symptoms (odds ratio [OR], 22.52; 95% confidence interval [CI], 4.90-103.60) and/or hydrocephalus (OR, 3.60; 95% CI, 1.38-9.36) at diagnosis were more often seen for ophthalmological evaluation. The most common abnormal ophthalmological findings were eye movement disorders (66.0%), papilledema (44.1%), and visual field defects (58.1%). Eye movement disorders occurred more frequently in patients with an infratentorial tumor (OR, 4.71; 95% CI, 1.03-21.65). The risk of papilledema was associated with older age (OR, 1.19; 95% CI, 1.05-1.34), hydrocephalus (OR, 9.63; 95% CI, 2.68-34.61), and infratentorial (OR, 9.11; 95% CI, 1.77-46.78) and supratentorial (OR, 13.13; 95% CI, 1.92-89.52) tumors. CONCLUSIONS: In this study, most children with a primary brain tumor underwent ophthalmological evaluation around diagnosis, 21% of the children were not evaluated. The high prevalence of abnormal ophthalmological findings stresses the importance of early standardized ophthalmological evaluation to detect visual impairment and provide timely treatment to potentially prevent permanent visual loss.

Longitudinal Analysis of Ocular Disease in Children with Mucopolysaccharidosis I after Hematopoietic Cell Transplantation.

Corneal clouding, causing visual impairment, is seen in nearly all patients with mucopolysaccharidosis type 1 (MPS-1). Hematopoietic cell transplantation (HCT) is able to stabilize disease in many organs. Residual disease in several tissues is being increasingly recognized, however. Data on the effect of HCT on ocular disease in patients with MPS-1 are contradictory. With this study, we aim to clarify the long-term effects of HCT on ocular disease in these patients. Best corrected visual acuity (BCVA), refraction, intraocular pressure (IOP), and slit-lamp biomicroscopic and fundoscopic examinations, including corneal clouding, were collected prospectively from 24 patients with MPS-1 who underwent HCT successfully between 2003 and 2018 (92% with >95% chimerism and normal enzyme activity after HCT). The course of corneal clouding and BCVA after HCT were analyzed using a linear mixed model. Other parameters studied were clinical phenotype, age at time of transplantation, and hematologic enzyme activity after transplantation. Outcomes of additional ophthalmologic tests were described. In addition, IDUA and α-galactosidase A (AGAL) enzyme activity and glycosaminoglycan (GAG) concentration in tear fluid were determined. Corneal clouding stabilized in the first years after HCT but increased rapidly beyond 3 years (P < .0001). BCVA and IOP also worsened over time (P = .01 and P < .0001, respectively). IDUA activity in tear fluid remained very low (P < .0001). After initial stabilization in the cornea, ongoing ocular disease and low IDUA activity in tear fluid is seen in patients with MPS-1 despite treatment with HCT, unveiling a weak spot of current standard therapy. New therapies that overcome these shortcomings are needed to improve the late outcomes of patients.

Ophthalmological Findings in Youths With a Newly Diagnosed Brain Tumor.

Importance: Visual impairment is an irreversible adverse effect in individuals who experienced a childhood brain tumor. Ophthalmological evaluation at diagnosis enables early detection of vision loss, decision-making about treatment, and when applicable, the timely use of visual interventions. However, awareness of visual impairment in clinical practice is suboptimal, and adherence to ophthalmological evaluation needs to be improved. Objective: To assess the prevalence and types of abnormal ophthalmological findings in youths with a newly diagnosed brain tumor. Design, Setting, and Participants: In this nationwide, prospective cohort study, youths aged 0 to 18 years with a newly diagnosed brain tumor between May 15, 2019, and August 11, 2021, were consecutively enrolled in 4 hospitals in the Netherlands, including the dedicated tertiary referral center for pediatric oncology care. Exposures: A standardized and comprehensive ophthalmological examination, including orthoptic evaluation, visual acuity testing, visual field examination, and ophthalmoscopy, was performed within 4 weeks from brain tumor diagnosis. Main Outcomes and Measures: The main outcomes were prevalence and types of visual symptoms and abnormal ophthalmological findings at brain tumor diagnosis. Results: Of 170 youths included in the study (96 [56.5%] male; median age, 8.3 years [range, 0.2-17.8 years]), 82 (48.2%) had infratentorial tumors; 53 (31.2%), supratentorial midline tumors; and 35 (20.6%), cerebral hemisphere tumors. A total of 161 patients (94.7%) underwent orthoptic evaluation (67 [41.6%] preoperatively; 94 [58.4%] postoperatively); 152 (89.4%), visual acuity testing (63 [41.4%] preoperatively; 89 [58.6%] postoperatively); 121 (71.2%), visual field examination (49 [40.4%] preoperatively; 72 [59.6%] postoperatively); and 164 (96.5%), ophthalmoscopy (82 [50.0%] preoperatively; 82 [50.0%] postoperatively). Overall, 101 youths (59.4%) presented with visual symptoms at diagnosis. Abnormal findings were found in 134 patients (78.8%) during ophthalmological examination. The most common abnormal findings were papilledema in 86 of 164 patients (52.4%) who underwent ophthalmoscopy, gaze deficits in 54 of 161 (33.5%) who underwent orthoptic evaluation, visual field defects in 32 of 114 (28.1%) with reliable visual field examination, nystagmus in 40 (24.8%) and strabismus in 32 (19.9%) of 161 who underwent orthoptic evaluation, and decreased visual acuity in 13 of 152 (8.6%) with reliable visual acuity testing. Forty-five of 69 youths (65.2%) without visual symptoms at diagnosis had ophthalmological abnormalities on examination. Conclusions and Relevance: The results of this study suggest that there is a high prevalence of abnormal ophthalmological findings in youths at brain tumor diagnosis regardless of the presence of visual symptoms. These findings support the need of standardized ophthalmological examination and the awareness of ophthalmologists and referring oncologists, neurologists, and neurosurgeons for ophthalmological abnormalities in this patient group.

Visual outcome in Sturge-Weber syndrome: a systematic review and Dutch multicentre cohort.

Visual functions in Sturge-Weber syndrome (SWS) may be impaired by glaucoma, diffuse choroidal haemangioma (DCH) or leptomeningeal angioma. The aim of this study was to gain better insight in the visual deficits of SWS patients. A systematic literature search using PubMed and Embase medical databases was performed to identify articles describing visual acuity (VA) and/or visual field (VF) findings in SWS patients. In addition, a Dutch multicentre cohort with 33 SWS patients was collected and the combined results of VA and VF findings are presented. Visual acuity results of 25 studies and VF results of 12 studies were suitable for data extraction. Description of the combination of both VA and VF findings was scarce. Homonymous hemianopia (HH) was present in 42% of SWS patients. Seventy per cent of eyes had a (near) normal vision, while VA of eyes with glaucoma or DCH was severely impaired in 28% and 67%, respectively. In the Dutch cohort, only 18% (6/33) of patients had (near) normal findings of both visual parameters. In addition, half of the patients with glaucoma suffered from a combination of a HH and VA impairment. In conclusion, although SWS patients are exposed to severe functional visual impairment due to the possible cumulative consequences of glaucoma, DCH and cerebral injury, description of the combination of both VA and VF results is scarce in the literature. Particularly, the combination of visual impairment due to glaucoma or DCH, and HH might be invalidating.

Compound heterozygous NEK1 variants in two siblings with oral-facial-digital syndrome type II (Mohr syndrome).

The oral-facial-digital (OFD) syndromes comprise a group of related disorders with a combination of oral, facial and digital anomalies. Variants in several ciliary genes have been associated with subtypes of OFD syndrome, yet in most OFD patients the underlying cause remains unknown. We investigated the molecular basis of disease in two brothers with OFD type II, Mohr syndrome, by performing single-nucleotide polymorphism (SNP)-array analysis on the brothers and their healthy parents to identify homozygous regions and candidate genes. Subsequently, we performed whole-exome sequencing (WES) on the family. Using WES, we identified compound heterozygous variants c.[464G>C];[1226G>A] in NIMA (Never in Mitosis Gene A)-Related Kinase 1 (NEK1). The novel variant c.464G>C disturbs normal splicing in an essential region of the kinase domain. The nonsense variant c.1226G>A, p.(Trp409*), results in nonsense-associated alternative splicing, removing the first coiled-coil domain of NEK1. Candidate variants were confirmed with Sanger sequencing and alternative splicing assessed with cDNA analysis. Immunocytochemistry was used to assess cilia number and length. Patient-derived fibroblasts showed severely reduced ciliation compared with control fibroblasts (18.0 vs 48.9%, P<0.0001), but showed no significant difference in cilia length. In conclusion, we identified compound heterozygous deleterious variants in NEK1 in two brothers with Mohr syndrome. Ciliation in patient fibroblasts is drastically reduced, consistent with a ciliary defect pathogenesis. Our results establish NEK1 variants involved in the etiology of a subset of patients with OFD syndrome type II and support the consideration of including (routine) NEK1 analysis in patients suspected of OFD.

Neurochemical characterization of pterygopalatine ganglion branches in humans.

BACKGROUND: Pterygopalatine ganglion (PPG) branches, seem to be involved in the pathophysiology of facial pain. The functions of these branches, including a recently discovered orbital branch, are not completely known but could be of clinical significance. This study was designed to characterize PPG branches through immunohistochemical stain and study their anatomy, specifically the orbital branches. METHODS: In a cadaver study of four specimens, the pterygopalatine fossa (PPF) was dissected out of its bony surroundings as a tissue block. Subsequently, cryostat sectioning of these blocks was performed. In one specimen the PPF was microscopically dissected. Recently discovered neural structures were identified, dissected out of the tissue block, and cryosectioned. All cryostat sectionings were immunohistochemically stained for protein gene product (PGP) 9.5, nitric oxide synthase (NOS), and tyrosine hydroxylase (TH). RESULTS: A recently discovered neural connection between the PPG and the ophthalmic nerve could be confirmed and classified as an orbital PPG branch. The connection stained throughout for PGP 9.5 and partially stained for NOS. In other orbital branches, both NOS and TH(+) nerve fibers were found. The PPG contained NOS(+) cells. TH labeling was also found in nerve fibers running through the PPG and the vidian nerve. CONCLUSION: The recently discovered orbital PPG branch is of a mixed parasympathetic and sensory nature. In the other orbital branches, sympathetic fibers were shown as well. This knowledge may add to understanding the symptomatology and therapies of headache syndromes such as nerve block.