Vernal keratoconjunctivitis in Down syndrome: a case report.

BACKGROUND: Down syndrome (DS) or Trisomy 21 is the most common chromosomal disease and is characterized by possible heart defects, cognitive impairment and visual disorders. CASE PRESENTATION: We describe for the first time a 17-year-old Caucasian girl suffering from Down syndrome associated with vernal keratoconjunctivitis (VKC), a rare disorder of the anterior segment of the eye, characterized by intense photophobia, redness, watering eyes and itching due to an inflammatory-allergic reaction of the cornea and conjunctiva. On slit-lamp examination, the girl showed conjunctival hyperemia, papillary hypertrophy, giant papillae and corneal leukoma in right eye as a result of a previous corneal ulcer. A successful topical immunosuppressant therapy with cyclosporin 1% was started. CONCLUSION: So far, to our knowledge, this is the first description of VKC in a patient with DS. Finding an inflammatory-allergic disease such as VKC in DS is unusual but it must be taken into account because keratoconus, one of the most frequent eye pathologies in DS, can be secondary to an unrecognized VKC.

Neurotrophic Keratitis Due to Congenital Corneal Anesthesia with Deafness, Hypotonia, Intellectual Disability, Face Abnormality and Metabolic Disorder: A New Syndrome?

Neurotrophic keratitis is a rare degenerative disease of the cornea that can lead to corneal ulceration, scarring, and significant visual impairment. It most commonly occurs in adults and is rarely diagnosed in children. Congenital corneal anesthesia is an extremely rare condition that requires appropriate ophthalmologists' attention in making diagnosis and treatment decisions. This condition usually presents in infancy or early childhood and is characterized by rare blinking rate, decreased tearing or a corneal ulcer that is unresponsive to treatment. In this case report, we describe a patient with multiple systemic and neurological disorders who presented to the ophthalmology department due to corneal erosion unresponsive to treatment. Brain magnetic resonance imaging confirmed bilateral trigeminal hypoplasia and the diagnosis of neurotrophic keratopathy due to bilateral congenital corneal anesthesia was made. The discrepancy between clinical signs and symptoms or treatment non-response in cases of corneal erosions should alert the ophthalmologists to suspect trigeminal dysfunction. MRI is the gold standard to confirm congenital corneal anesthesia and to differentiate from other possible neurotrophic keratitis causes.

Health-related quality of life in children at the diagnosis of Vernal Keratoconjunctivitis.

BACKGROUND: Vernal keratoconjunctivitis (VKC) is a bilateral, chronic, allergic condition mostly affecting children. Clinical evaluations may not necessarily reflect the impact of the disease on the patients' health-related quality of life (HRQoL). We aimed to evaluate HRQoL in children at VKC diagnosis and to analyze correlations between HRQoL and clinical and laboratory variables. METHODS: We studied 5- to 12-year-old patients with VKC. Data on clinical history, instrumental eye evaluations, blood examinations, and visual analog scale (VAS) for the subjective symptoms were collected. HRQoL was assessed through a disease-specific validated Quality of Life in Children with Vernal Keratoconjunctivitis (QUICK) questionnaire. RESULTS: Seventy subjects were included in the analysis (female/male: 10/60; tarsal/mixed VKC form: 36/34). Clinical severity of VKC according to the Bonini scale was as follows: 14, mild; 36, moderate; and 20, severe. No significant difference was found concerning the distribution of patient age, gender, and history of allergic manifestations between tarsal and mixed VKC. A significant positive correlation was found between all QUICK scores and VAS scores, including different VAS subscale, while no significant correlation was found between QUICK scores and total sign scores, Schirmer's test, and corneal thickness. The presence of active severe VKC was not associated with worse HRQoL. CONCLUSIONS: Our evidence shows that VKC patients experience impairment of HRQoL, especially in relation to the perception of symptoms independently of the ophthalmologic changes found, and that the QUICK questionnaire could be a useful tool to evaluate HRQoL in children with VKC, which may improve patients' classification and management.

Blue Cone Monochromatism with Foveal Hypoplasia Caused by the Concomitant Effect of Variants in OPN1LW/OPN1MW and GPR143 Genes.

Blue cone monochromatism (BCM) is an X-linked recessive cone dysfunction disorder caused by mutations in the OPN1LW/OPN1MW gene cluster, encoding long (L)- and middle (M)-wavelength-sensitive cone opsins. Here, we report on the unusual clinical presentation of BCM caused by a novel mutation in the OPN1LW gene in a young man. We describe in detail the phenotype of the proband, and the subclinical morpho-functional anomalies shown by his carrier mother. At a clinical level, the extensive functional evaluation demonstrated in the proband the M/L cone affection and the sparing of S-cone function, distinctive findings of BCM. Interestingly, spectral-domain optical coherence tomography showed the presence of foveal hypoplasia with focal irregularities of the ellipsoid layer in the foveal area, reported to be associated with some cases of cone-rod dystrophy and achromatopsia. At a molecular level, we identified the novel mutation c.427T > C p.(Ser143Pro) in the OPN1LW gene and the common missense mutation c.607T > C (p.Cys203Arg) in the OPN1MW gene. In addition, we discovered the c.768-2_769delAGTT splicing variant in the GPR143 gene. To our knowledge, this is the first case of foveal hypoplasia in a BCM patient and of mild clinical affection in a female carrier caused by the concomitant effect of variants in OPN1LW/OPN1MW and GPR143 genes, thus as the result of the simultaneous action of two independent genetic defects.

Surgical treatment of severe congenital ptosis using deep temporal fascia.

Purpose: To evaluate the surgical outcome of a frontalis sling using deep temporal fascia in the treatment of severe congenital ptosis (SCP). Methods: A retrospective, interventional case series was performed. The study involved 25 patients with SCP (>4 mm). All patients underwent frontalis sling surgery with deep temporal fascia between 2004 and 2012 with a follow-up period of 12 months at a minimum. Data regarding eyelid position, eyelid symmetry, cosmetic outcomes, and postoperative complications were evaluated. Results: The mean age at surgery was 7.68 years (range 4-17 years) with an average follow-up of 60 months (range is 12-108 months). The functional success rate was 88% (22/25). Ptosis recurred in 8% (2/25) of patients, overcorrection was present in 4% (1/25) of patients. The patients with ptosis recurrence underwent reoperation. The preoperative margin-to-reflex distance (MRD1) was -0.85±0.87 mm (range, -2.5 to + 0.5 mm), while the postoperative MRD1 was + 2.1 ± 1.05 mm (range, -1.5 to + 4 mm) (p < .0001). Lid symmetry (asymmetry < of 1 mm of MRD1 between the two eyes) was present in all the successful cases. Postoperative complications included transient exposure keratopathy (32%) and inflammatory brow reaction (8%). Conclusions: Frontalis sling operation with deep fascia temporalis is very effective in the treatment of SCP with excellent long-term functional and cosmetic successes.

Four years of corneal keratoplasty in Italian paediatric patients: indications and clinical outcomes.

PURPOSE: The purpose was to evaluate indications and clinical outcomes in paediatric corneal keratoplasty. METHODS: Fifty-four eyes of 43 patients who underwent corneal keratoplasty from the 1st of January 2010 through the 31st of December 2013 at the Bambino Gesù Children's Hospital in Rome, Italy, were retrospectively evaluated. To assess the effect of age on graft failure rate, the recipient age was considered as a dichotomous variable (≤5 or >5 years) and a 2X2 table was developed, using the chi-square test for testing the statistical significance. Furthermore, two separate subgroup analyses were conducted on patients of ≤5 years and those of >5 years, to evaluate the effect of penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty (DALK) on the graft failure rate. The level of statistical significance was set at p < 0.05 RESULTS: Mean recipient age was 8.9 ± 5.7 [SD] years. Mean follow-up time was 22.8 months. Main preoperative diagnoses were keratoconus (37 %) and congenital glaucoma (20 %). Patients ≤5 years showed a higher percentage of graft failure (p = 0.0008). PK and DALK did not show statistically significant differences regarding the graft failure in both subgroups (p = 0.15 for ≤5 years group and p = 0.27 for >5 years group, respectively). However, across groups DALK provided a lower rate of graft failure. CONCLUSIONS: Our findings suggest that children older than 5 years show a significantly better graft outcome and that DALK seems to offer greatest benefits in terms of failure risk in paediatric patients.

Optical coherence tomography and electrophysiological findings in torpedo maculopathy.

PURPOSE: To describe the morphofunctional findings in a 6-year-old child with a unilateral lesion of the temporal macula called "torpedo maculopathy" throughout a 1-year follow-up. METHODS: Evaluation of retinal morphology and function was assessed by means of spectral-domain OCT scans, best-corrected visual acuity, full-field flash electroretinogram (ERG), multifocal electroretinogram (mfERG) and pattern visual evoked potentials (VEP). Patient was examined every 4 months for a 1-year follow-up time. RESULTS: Torpedo maculopathy consisted in a sharply demarcated hypopigmented oval iuxta-macular lesion (1.5 DD wide × 0.7 DD high). The baseline visual acuity of the affected eye was 20/25. OCT showed a sensorial retinal detachment in correspondence with the torpedo lesion. Pattern VEPs revealed a reduced response in left eye, as compared to contralateral eye. Full-field flash ERGs amplitude was normal in both eyes. Multifocal ERG response was reduced at all sites, more significantly at the site of the lesion in the eye with torpedo maculopathy and normal in fellow eye. Visual acuity, fundoscopic evaluation, OCT scans and electrophysiological tests showed no changes from baseline throughout the follow-up time. CONCLUSIONS: Torpedo maculopathy, although known as benign, may affect visual function if macular involvement is associated with neuroretinal detachment.

Vernal keratoconjunctivitis and eosinophilic esophagitis: A rare combination?

Vernal keratoconjunctivitis (VKC) is a bilateral ocular inflammatory disease with a conjunctival and corneal involvement and typical onset during childhood. Eosinophilic esophagitis (EoE) is a chronic disease characterized by eosinophilic inflammation of the mucosa (≥15 eosinophils/HPF) and symptoms of esophageal dysfunction. EoE and VKC are both immune-mediated diseases sharing a similar pathogenetic mechanism and a high association with other allergic diseases. Nevertheless, no data are currently available about their clinical association. We present 4 cases of concomitant diagnosis of vernal keratoconjunctivitis and eosinophil esophagitis suggesting that these conditions may coexist in the same patient more frequently than expected. Health care providers should be aware of the possibility of co-occurrence in their daily practice.

Simultaneous transepithelial topographic-guided laser and cross-linking to correct irregular astigmatism in a pediatric patient.

PURPOSE: To evaluate an original approach for treating corneal ectasia and irregular astigmatism secondary to penetrating trauma in a pediatric patient. CASE REPORT: An 11 year old patient had a penetrating trauma in right eye when he was two and the refractive error was +1.50 diopters sphere -6.00 diopters cylinder axis 95°. To correct irregular astigmatism, the patient underwent simultaneous transepithelial topographic-guided laser Central Corneal Remodeling (CCR) and Corneal Cross-linking (CXL) in the attempt to regularize corneal ectasia and to improve the quality of vision. Uncorrected and Corrected Distance Visual Acuity were measured using Efficacy and Safety indexes; objective and subjective qualities of vision were evaluated using respectively corneal morphological irregularity index and National Eye Institute Visual Function questionnaires. CONCLUSIONS: Twelve month follow up suggests that simultaneous CCR and CXL could be effective to improve the quality of vision and to halt the progression of post-traumatic ectasia in pediatric patients.

Transepithelial corneal cross-linking in pediatric patients: early results.

PURPOSE: To report 18-month follow-up after transepithelial cross-linking (CXL) in young patients. METHODS: Thirteen eyes with keratoconus were evaluated (mean patient age: 14.4 ± 3.7 years [range: 8 to 18 years]). Corrected distance visual acuity (CDVA); spherical equivalent refraction; keratometry (K); coma, spherical aberration, and higher order aberrations (HOAs) for a 5.0-mm pupil; and thinnest point were measured preoperatively and 1, 3, 6, 9, 12, and 18 months postoperatively by Scheimplflug camera. Endothelial cell density and anterior segment optical coherence tomography were also evaluated. Paired Student t test was used to compare preoperative and 12- and 18-month postoperative data. P<.05 was considered significant. RESULTS: Eighteen months after treatment, CDVA improved significantly, whereas K readings and HOAs showed statistically significant worsening (P<.05). Spherical equivalent refraction, sphere and cylinder, coma, spherical aberration, thinnest point, and endothelial cell density did not show statistically significant changes (P>.05). The mean demarcation line depth was 105 µm. No side effects were observed. CONCLUSIONS: Transepithelial CXL appears to be a safe treatment in children. Although improved CDVA was noted 18 months after treatment, this technique does not effectively halt keratoconus progression in children compared to standard CXL.

Effectiveness of hyaluronic acid and arnica extract ophthalmic solution in reducing dry eye symptoms in pediatric population.

AIM: to assess the effectiveness of a new combination of topical solution with Hyaluronic Acid 0.2% and arnica extract 0.1% in reducing dry eye symptoms in a population of pediatric patients. METHODS: 52 pediatric patients (aged 9 to 14 years) with signs and symptoms of dry eyes and allergic conjunctivitis were included in the study. Twenty-six patients were assigned to the Hyaluronic Acid 0.2%/ Arnica extract 0.1% group (Study Group) while 26 patients to the Hyaluronic Acid 0.2% group (Control Group). Clinical signs and symptoms were assessed at baseline and at week 4. The assessment plan included: slit-lamp examination, tear film break up time (TBUT), Schirmer's test and conjunctival hyperemia score. Ocular surface disease index (OSDI) score was used to evaluate subjective symptoms of dry eye disease. RESULTS: Both treatment groups showed improvements in the estimated clinical parameters after treatment. OSDI score was significantly lower in both treatment groups (Study group p = 0.02; Control group p = 0.04) at the end of the follow up period. Improvements in TBUT, Schirmer's test results and conjunctival hyperemia were statistically significant only in the Study group (p = 0.021; p = 0.03; p < 0.01 respectively). CONCLUSIONS: Preliminary findings suggest that combined topical Hyaluronic Acid 0.2% and arnica extract 0.1% can be effective in reducing symptoms and signs of dry eye disease in children.

Superficial and Deep Capillary Plexuses: Potential Biomarkers of Focal Retinal Defects in Eyes Affected by Macular Idiopatic Epiretinal Membranes? A Pilot Study.

Inner macular layers are the most involved in the retinal distortion caused by idiopathic epiretinal membrane (iERM). They represent the anatomical structures in which the superficial (SCP) and deep (DCP) capillary plexus are embedded. We quantified flow signal (FS) in these capillary plexuses using Swept Source OCT angiography to identify possible markers for postoperative outcome. The software ImageJ was used to quantify the FS in a 150 µm radius area around each point analyzed by MAIA microperimeter. In 16 patients with unilateral iERM, focal light sensitivity (FLS) in the para- and perimacular areas was measured to evaluate macular function in 24 points overlapping macular plexuses and compared with normal fellow eyes (FEs). t-Test for independent samples iERM eyes (iERMEs) vs. fellow eyes (FEs) and Pearson correlation coefficient of FS vs. FLS in each point were calculated. A level of p < 0.05 was accepted as statistically significant. As a whole, FLS was significantly higher in FEs vs. ERMEs (p < 0.001); FS in both SCP and DCP was not significantly different between ERMEs and FEs (p = 0.827, p = 0.791). Correlation in focal retinal areas between FLS and FS in ERMEs was significant in SCP (p = 0.002) and not significant in DCP (p = 0.205); in FEs was significant in both SCP (p < 0.001) and DCP (p = 0.022). As previously described, these defective areas were located mainly in sites of distortion of retinal layers; therefore, it can be hypothesized that a focal change in FS, occurring mostly in SCP, could be involved in the onset of the functional defect.

Dexamethasone Intravitreal Implant (Ozurdex) in Paediatric Patients with Non-infectious Intermediate Uveitis and Related Cystoid Macular Oedema: Evaluation of Macular Morphology and Function with Six-month Follow-up; a Deeper Role of MfERG?

PURPOSE: To evaluate the efficacy of Ozurdex implant by analyzing macular morphology and function in pediatric uveitis and related cystoid macular edema (CMO). METHODS: Main outcomes were visual acuity, mfERG and photopic ERG response, and central macular thickness. Mean values recorded at each time-point were compared to baseline and correlations between functional and anatomical parameters were evaluated. RESULTS: Resolution of intraocular inflammation and CMO was achieved in all eyes 1 month after implant without procedure or drug-related complications. Mean visual acuity and mfERG amplitude improved showing a statistically significant difference to baseline values for the first 4 months. Mean central macular thickness showed a statistically significant reduction for all follow-up time. Photopic ERG did not vary significantly. Statistically significant correlation was found between trends of visual acuity, central macular thickness, and mfERG responses. CONCLUSION: Correlation found between macular morphology and function confirms the efficacy of Ozurdex in pediatric uveitis.

Comparative analysis of visual outcomes of multifocal and monofocal intraocular lenses in congenital cataract surgery.

PURPOSE: To assess the impact on visual development of multifocal vs monofocal intraocular lenses (IOLs) implantation in children after congenital cataract surgery. SETTING: Ophthalmology Department, Bambino Gesù Children's Hospital, Rome, Italy. DESIGN: Retrospective interventional consecutive case series. METHODS: Records of 56 eyes of 43 pediatric patients who underwent congenital cataract surgery with phacoaspiration and simultaneous implantation of the IOL younger than 1 year were reviewed. Corrected distance visual acuity (CDVA), refractive error, and ocular motility disorders were evaluated at follow-up of greater than 4 years. RESULTS: 32 multifocal (18 unilateral, Group A and 14 bilateral, Group B) and 24 monofocal (12 unilateral, Group C and 12 bilateral, Group D) IOLs were implanted. Mean follow-up was 6.67 years. Mean CDVA of the eyes with multifocal IOLs was 0.75 ± 0.46 logMAR in unilateral cataract surgery and 0.34 ± 0.25 logMAR in bilateral ones; with monofocal IOLs was 0.71 ± 0.52 logMAR in unilateral and 0.53 ± 0.43 logMAR in bilateral ones. No statistically significant difference in the CDVA between Groups A and B and Groups C and D were recorded. Final mean spherical equivalent was -3.88 ± 4.73 diopters (D); in Group A, it was -2.74 ± 4.22 D, in Group C was -1.08 ± 1.45 D, in Group B was -4.82 ± 4.64 D, and in Group D was -6.81 ± 4.61 D. The difference was statistically significant between Groups B and D (P = .01), but not between Groups A and C (P = .14). 26 patients (60.4%) showed postoperative strabismus. Surgical correction occurred more in patients with multifocal IOLs implanted (P = .038). CONCLUSIONS: Multifocal IOLs did not show significant advantages in visual development in children after congenital cataract extraction younger than 1 year when compared with monofocal IOLs.

Treatment of Advanced Coats' Disease With Combination Therapy of Laser Photocoagulation, Intravitreal Ranibizumab, and Sub-Tenon Methylprednisolone Acetate.

PURPOSE: To investigate the efficacy of combination therapy with laser photocoagulation, intravitreal ranibizumab, and sub-Tenon methylprednisolone acetate in patients presenting with advanced Coats' disease. METHODS: This was a retrospective analysis of 16 patients who underwent laser photocoagulation combined with intravitreal ranibizumab and sub-Tenon methylprednisolone acetate between 2008 and 2017. The primary outcome was anatomic success and the secondary outcomes were globe preservation and final visual acuity. RESULTS: The average age at surgery was 5.12 ± 2.7 years (range: 3 to 10 years). The mean follow-up time was 45.43 ± 29.01 months (range: 12 to 108 months). Of the 16 patients (16 eyes) reviewed, 6 patients had stage 3A and 10 patients had stage 3B Coats' disease. The mean number of applications was 10 (range: 4 to 18). Globe preservation was achieved in all patients. Final visual acuity outcomes were satisfactory: 20/20 to 20/50 in 2 patients, 20/60 to 20/100 in 1 patient, and 20/200 or worse in 13 patients. CONCLUSIONS: Intravitreal ranibizumab used in combination with laser photocoagulation and sub-Tenon methylprednisolone acetate could be an effective treatment option for patients with advanced Coats' disease. The combined therapy achieved anatomical success, globe preservation, and reasonable visual acuity outcomes. [J Pediatr Ophthalmol Strabismus. 2022;59(3):187-191.].

An epidemiologic analysis of the association between eyelid disorders and ocular motility disorders in pediatric age.

Aim of the study was to assess: (a) the prevalence and type of strabismus, ptosis and eyelid dynamic disorders features, (b) the prevalence of refractive errors, amblyopia and, (c) their association with ocular/systemic syndromes in a cohort of patients. This is a retrospective observational multicenter cohort study. Patients with coexisting ocular motility disorders, comitant and incomitant strabismus, ptosis and dynamic eyelid disorders who have never undergone surgery were enrolled throughout a 3-years a study period. 137 out of 19,089 patients were enrolled, of which 97 with uniocular and 40 with binocular disease. Isolated congenital ptosis was observed in 84 patients. A polymalformative syndrome was present in almost one third of cases, whilst among strabismus type, esotropia was slightly more prevalent. Most patients were hypermetropic. In monocular disease, myopia mainly affected older patients, who were characterized by a worse ptosis margin reflex distance and levator function, and significantly higher astigmatism. Amblyopia occurred in 67.4% of the study sub-population. Of note, in monocular disease this was mild in 25.8%, moderate in 24.2% and severe in 11.3% of cases, whilst in binocular disease it was mild in 25%, moderate in 41.7% and severe in 16.7%. All patients with coexisting eyelid and ocular motility dysfunctions in pediatric age need ophthalmologic and systemic evaluation to accurately assess amblyopia, refractive errors and systemic/ocular disorders.

The effect of COVID-19 imposed lockdown on Italian children with Vernal Keratoconjunctivitis.

Background: Vernal keratoconjunctivitis (VKC) is a chronic, inflammatory-allergic disease of the cornea and conjunctiva. Environmental factors, such as light exposure, have been supposed to play a role in the pathogenesis of ocular inflammation and in the worsening of VKC. Objective: The aim of this study was to estimate the impact of reduced sunlight exposure in patients with VKC during the imposed lockdown period for the SARS-CoV-2 pandemic emergency. Methods: We retrospectively reviewed data of patients with VKC visited during spring season in 2020 and 2019 at Vernal Keratoconjunctivitis Multidisciplinar Outpatient of our Hospital.Subjective symptoms were evaluated by Visual analogue scale (VAS) and VKC severity was graded by Bonini scale. Quality of life was evaluated by Correlations of Quality of Life in Children with Vernal Keratoconjunctivitis (QUICK) questionnaire. The number of hours of e-learning as well as of hours spent in front of a bright screen (PC, TV, mobile, tablet play station, and so on) was also investigated. Results: Twenty-nine male subjects (mean ± SD age: 8.74 ± 2.40 years) with VKC were included in the study. Most of the patients (17/29) were sensitized individuals.No significant changes in Bonini severity score and in VAS evaluation were observed comparing 2020 to 2019 values. Ten (34.4%) patients did benefit from the reduced sunlight exposure. The increased use of bright screens was associated with worsening of VKC severity. Conclusions: Sunlight exposure plays a role in VKC exacerbation in about one third of patients. The number of hours spent in front of bright screens may influence severity of VKC symptoms.

Genetics of Inherited Retinal Diseases in Understudied Ethnic Groups in Italian Hospitals.

Purpose: Describing the clinical and genetic features of an ethnically heterogeneous group of (inherited retinal diseases) IRD patients from different underrepresented countries, referring to specialized Italian Hospitals, and expanding the epidemiological spectrum of the IRD in understudied populations. Methods: The patients' phenotypes underwent were characterized by exhaustive ophthalmological examinations, including morpho-functional testing. Genetic testing was performed using next-generation sequencing (NGS) and gene sequencing panels targeting a specific set of genes, Sanger sequencing and-when necessary-multiplex ligation-dependent probe amplification (MLPA) to better identify the genotype. When possible, segregation analysis was performed in order to confirm unsolved cases. Results: The article reports the results of the phenotypes and genotypes of 123 IRD probands, 69 males and 54 females, mean age 41 (IQR, 54-30) years, disease onset at 13 (IQR, 27.25-5) years. Thirty-three patients out of 123 (26.8%) were Africans (North/Northwest Africa), 21 (17.1%) Asians, 19 (15.4%) Americans (South/Central America) and 50 (40.7%) Europeans (Eastern Europe). Retinitis pigmentosa was the most represented phenotype (56%), followed by cone dystrophy (11%) and Leber congenital amaurosis (7%), while ABCA4 was the most frequently mutated gene (18%), followed by USH2A (9%) and RPGR (5%). About ABCA4 variants found in Stargardt disease, macular and cone dystrophies were predominant in Asian (42%) and European (21%) patients. The most represented inheritance pattern was autosomal recessive, while a higher frequency of homozygous patients versus compound heterozygotes as compared to previous studies on Italian IRD patients was evidenced, reflecting a possible higher frequency of inbreeding marriages. Conclusion: Though limited by the relatively low number of patients, the present paper paints a picture of the clinical and genetic features of IRD patients from understudied ethnic groups referred to Italian specialized hospitals and extended the epidemiological studies on underrepresented world regional areas.

A Novel Autosomal Recessive Variant of the NRL Gene Causing Enhanced S-Cone Syndrome: A Morpho-Functional Analysis of Two Unrelated Pediatric Patients.

Enhanced S-cone syndrome (ESCS) is a rare autosomal recessive retinal degeneration mainly associated with pathogenic variations in the NR2E3 gene. Only a few pathogenic variations in the NRL gene associated with ESCS have been reported to date. Here, we describe the clinical and genetic findings of two unrelated pediatric patients with a novel frameshift homozygous variant in the NRL gene. Fundus examinations showed signs of peripheral degeneration in both patients, more severe in Proband 2, with relative sparing of the macular area. Spectral domain optical coherence tomography (SD-OCT) revealed a significant macular involvement with cysts in Proband 1, and minimal foveal alteration with peripheral retina involvement in Proband 2. Visual acuity was abnormal in both patients, but more severely affected in Proband 1 than Proband 2. The electroretinogram recordings showed reduced scotopic, mixed and single flash cone responses, with a typical supernormal S-cone response, meeting the criteria for a clinical diagnosis of ESCS in both patients. The present report expands the clinical and genetic spectrum of NRL-associated ESCS, and confirms the age-independent variability of phenotypic presentation already described in the NR2E3-associated ESCS.

RPE65-Associated Retinopathies in the Italian Population: A Longitudinal Natural History Study.

Purpose: To investigate the course of inherited retinal degenerations (IRD) due to mutations in the RPE65 gene. Methods: This longitudinal multicentric retrospective chart-review study was designed to collect best corrected visual acuity (BCVA), Goldman visual field, optical coherence tomography (OCT), and electroretinography (ERG) measurements. The data, including imaging, were collected using an electronic clinical research form and were reviewed at a single center to improve consistency. Results: From an overall cohort of 60 Italian patients with RPE65-associated IRD, 43 patients (mean age, 27.8 ± 19.7 years) were included and showed a mean BCVA of 2.0 ± 1.0 logMAR. Time-to-event analysis revealed a median age of 33.8 years and 41.4 years to reach low vision and blindness based on BCVA, respectively. ERG (available for 34 patients) showed undetectable responses in most patients (26; 76.5%). OCT (available for 31 patients) revealed epiretinal membranes in five patients (16.1%). Central foveal thickness significantly decreased with age at a mean annual rate of -0.6%/y (P = 0.044). We identified 43 different variants in the RPE65 gene in the entire cohort. Nine variants were novel. Finally, to assess genotype-phenotype correlations, patients were stratified according to the number of RPE65 loss-of-function (LoF) alleles. Patients without LoF variants showed significantly (P < 0.05) better BCVA compared to patients with one or two LoF alleles. Conclusions: We described the natural course of RPE65-associated IRD in an Italian cohort showing for the first time a specific genotype-phenotype association. Our findings can contribute to a better management of RPE65-associated IRD patients.