Background/Objectives: Inherited retinal diseases (IRDs) are a heterogeneous group of rare eye disorders characterized by progressive photoreceptor degeneration, leading to severe visual impairment or even blindness. This study aims to investigate the prevalence, types, and clinical significance of ophthalmic comorbidities in Portuguese patients with IRDs. Methods: This nationwide Portuguese population-based retrospective study was based on the IRD-PT registry (retina.com.pt). Statistical analysis was conducted using Microsoft® Excel® for Microsoft 365 and IBM SPSS Statistics version 29.0.2.0. Informed consent was obtained from all participants. Results: A total of 1531 patients (1254 families) from six centers were enrolled. The cohort consisted of 51% males, with a mean age of 45.8 ± 19.3 years and a mean age at diagnosis of 39.4 ± 19.5 years. Overall, ocular comorbidities were reported in 644 patients (42.1%). In 176 individuals (11.5%), multiple concurrent comorbidities were found. Cataract was the most common comorbidity (21.3%), followed by amblyopia (6.3%) and high myopia (5.9%). Statistically significant associations with ocular comorbidities were observed in isolated progressive IRDs. Specifically, AR RP was associated with cataract (p < 0.001), and gene analysis revealed several significant associations. CRB1 was statistically linked to epiretinal membrane (ERM) (p = 0.003), EYS with cataract (p = 0.001), PROM1 with choroidal neovascularization (CNV) (p = 0.0026), and USH2A with macular hole (p = 0.01). Patients with the RPE65 mutation in Leber congenital amaurosis were associated with ERM (p = 0.019). There was also a significant association between X-linked RP and high myopia (p < 0.001) and CNV in Best disease (p < 0.001); in syndromic IRDs, cataract, cystoid macular edema, and ERM were observed in Usher syndrome, p = 0.002, p = 0.002, and p = 0.005, respectively, and the MYO7A gene was linked to cataract (p = 0.041) and strabismus (p = 0.013); pseudoxanthoma elasticum was significantly associated with CNV (p = 0.002); and foveal hypoplasia was associated with anterior segment dysgenesis (p < 0.001). Conclusions: This study enhances the current understanding of ocular comorbidities in IRDs in Portuguese patients. Common findings were cataract, refractive error, and CME. Stationary IRDs and pattern dystrophies showed fewer concomitant comorbidities, supporting their classification as non-progressive or benign conditions. The significance of registries like IRD-PT cannot be overstated, particularly in the context of rare diseases. These databases serve multiple crucial functions in enabling detailed documentation of disease characteristics and long-term monitoring of disease progression.

Myhre syndrome is an autosomal dominant condition caused by pathogenic variants in the transcriptional co-regulator SMAD4. Myhre syndrome is characterized by distinctive facial features, short stature, musculoskeletal abnormalities, and intellectual disability. Reported ocular abnormalities include refractive errors, corectopia, cataract, strabismus, and pseudo) papilledema. We describe an 8-year-old boy with Myhre syndrome due to a c.1498A > G; p.I500V pathogenic variant in SMAD4. Ocular examination revealed bilateral emmetropia, mild visual acuity reduction in the right eye (20/25), grade 1b foveal hypoplasia in both eyes and small optic discs with pseudopapilledema. This report marks the first reported case of foveal hypoplasia in Myhre syndrome, a potentially underreported finding, given the relative lack of OCT assessment in patients with Myhre syndrome. We discuss pathophysiological link between foveal hypoplasia and gain-of-function variants in SMAD4.

To understand the retina micropathology in a family with a novel variant in VCAN. Two sisters ages 16 (proband) and 18 years old and their 48-year-old father underwent comprehensive ophthalmic evaluations. Multimodal imaging was performed with spectral domain optical coherence tomography, ultrawide field short-wavelength fundus autofluorescence, and pseudocolor imaging. Cataracts were present in the sisters along with a penetrant retinal phenotype in all three patients with vitreoretinal ring opacities and traction, peripheral pigmentary clumps, lattice-like features, retinoschisis, foveal ectopia, and nasal displacement of vessels. There were regions with inner retinal thinning with spared outer retina, likely a consequence of vitreoretinal traction, that contrasted with large areas of profound photoreceptor degeneration, but with a rather normal or thickened inner retina. A previously unreported heterozygous variant in intron 7 of VCAN (c.4004-2A>C) segregated with the phenotype in the proband and her father. Segregation of a versican-associated vitreoretinopathy supports the pathogenicity of the VCAN variant. The patterns of structural abnormalities support classical mechanisms of disease that involve local vitreoretinal traction, as well as possible alternative developmental and/or degenerative changes of the retina, RPE, and/or choroid that result from the primary molecular defect.

Congenital aniridia (CA) is a severe and complex disorder involving the entire eye, primarily characterized by iris anomalies alongside other clinical features that pose significant risks to vision. This study seeks to offer a comprehensive overview of CA by detailing its clinical presentations, genetic underpinnings, associated phenotypes, and differential diagnoses. Additionally, it proposes a diagnostic framework to distinguish CA from other conditions that present with similar iris abnormalities. We conducted a comprehensive literature review to compile and analyze clinical and genetic data related to CA and its differential diagnoses. We included all studies describing the clinical characteristics, pathogenic variants, and associated syndromes of congenital aniridia. CA presents a wide range of ocular symptoms. Pathogenic variants in the PAX6 gene are the primary genetic cause of CA, though variations in other genes, including FOXC1, PITX2, CYP1B1, FOXD3, PITX3, CPAMD8, ITPR1, TENM3, TRIM44, COL4A1, CRYAA, and PXDN may also be implicated. The differential diagnosis of CA requires careful consideration of conditions with overlapping symptoms, such as WAGR syndrome (which involves deletions affecting the PAX6 and WT1 genes on chromosome 11p13, and potentially BDNF on 11p14.1), Axenfeld-Rieger syndrome (FOXC1/PITX2), ring-chromosome 6 syndrome (which involves FOXC1 microdeletion), COL4A1-related anterior segment dysgenesis, Gillespie syndrome (ITPR1 gene) or Peters anomaly. Accurate diagnosis can be achieved by evaluating specific clinical features-including iris anomalies, aniridia-associated keratopathy, cataracts, glaucoma, foveal hypoplasia, nystagmus, and optic nerve head abnormalities-supplemented by genetic testing. Understanding the diverse clinical presentations and genetic basis of diseases associated with iris abnormalities is essential for accurate diagnosis and effective management. Integrating genetic diagnostics into the evaluation process enables the development of tailored treatment strategies, which can significantly improve patient outcomes.

Congenital optic disc dysplasia with coexistent macular abnormalities is seen in Morning-glory disc anomaly, optic disc pit, PAX6-related disc coloboma, and in the PAX2-related Papillo-renal syndrome. We report novel compound heterozygous variants in SIX6 causing optic disc dysplasia and macular abnormality without coexisting cataract or microphthalmia for the first time in Chinese ethnicity and also describe the macular OCT findings. A 4 year-8 months-old female child presented with poor vision, photophobia, and nystagmus noticed 4 months after her birth was diagnosed elsewhere to have isolated cone dystrophy. She was evaluated subsequently by an ocular geneticist. She underwent a complete ophthalmic evaluation including orthoptic evaluation, cycloplegic refraction, and a dilated fundus evaluation. She had fundus photography, macular OCT, and ERG. She had systemic evaluations, relevant systemic investigations, and molecular genetic testing. Whole Exome Sequencing (WES) revealed compound heterozygous variants both in the SIX6 and in the TULP1 gene. No pathogenic variants were identified in the PAX2, PAX6 or in any of the other developmental genes or in the genes currently known to cause cone dystrophy or cone-rod dystrophy. Parents were heterozygous for variants in both SIX6 and TULP1. Homozygous or compound heterozygous pathogenic variants in SIX6 can cause a dysplastic optic disc and coexistent macular abnormalities. This dysplastic disc may be clinically indistinguishable from that seen in the PAX2 related Papillo-renal syndrome. Careful optic disc evaluation of subtle disc dysplasia is critical in differentiating this extremely rare entity from other relatively common causes of isolated cone dystrophies or cone-rod dystrophies.