Haplotype-based analysis resolves missing heritability in oculocutaneous albinism type 1B.

Oculocutaneous albinism (OCA) is a rare disorder of pigment production. Affected individuals have variably decreased global pigmentation and visual-developmental changes that lead to low vision. OCA is notable for significant missing heritability, particularly among individuals with residual pigmentation. Tyrosinase (TYR) is the rate-limiting enzyme in melanin pigment biosynthesis and mutations that decrease enzyme function are one of the most common causes of OCA. We present the analysis of high-depth short-read TYR sequencing data for a cohort of 352 OCA probands, ∼50% of whom were previously sequenced without yielding a definitive diagnostic result. Our analysis identified 66 TYR single-nucleotide variants (SNVs) and small insertion/deletions (indels), 3 structural variants, and a rare haplotype comprised of two common frequency variants (p.Ser192Tyr and p.Arg402Gln) in cis-orientation, present in 149/352 OCA probands. We further describe a detailed analysis of the disease-causing haplotype, p.[Ser192Tyr; Arg402Gln] ("cis-YQ"). Haplotype analysis suggests that the cis-YQ allele arose by recombination and that multiple cis-YQ haplotypes are segregating in OCA-affected individuals and control populations. The cis-YQ allele is the most common disease-causing allele in our cohort, representing 19.1% (57/298) of TYR pathogenic alleles in individuals with type 1 (TYR-associated) OCA. Finally, among the 66 TYR variants, we found several additional alleles defined by a cis-oriented combination of minor, potentially hypomorph-producing alleles at common variant sites plus a second, rare pathogenic variant. Together, these results suggest that identification of phased variants for the full TYR locus are required for an exhaustive assessment for potentially disease-causing alleles.

Crossed VEP asymmetry in a patient with AHR-linked infantile nystagmus and foveal hypoplasia.

INTRODUCTION: Infantile nystagmus and foveal hypoplasia associated with AHR gene defects is a newly recognized and rare disorder. Our aim was to present a patient with a novel biallelic AHR pathogenic variant with electrophysiological evidence of chiasmal misrouting. MATERIALS AND METHODS: Complete ocular examination, fundus imaging, visual evoked potentials (VEP) and full-field electroretinography were performed at initial presentation. Genetic testing was performed by whole exome sequencing. RESULTS: Female patient of 6 years old presented a reduced best corrected visual acuity, an infantile nystagmus and a grade III typical foveal hypoplasia without ocular hypopigmentation. A crossed asymmetry was discovered on pattern onset/offset VEP. Genetic testing put in evidence a novel homozygous variant in AHR: c.2242del, p. (Gln748Lysfs*5). During 11-years follow-up period, BCVA gradually improved. There was no evidence of retinal degeneration. CONCLUSION: AHR gene defects could be associated with infantile nystagmus, foveal hypoplasia and chiasmal misrouting.

A novel missense variant expands the phenotype and genotype of PAX6-associated foveal hypoplasia accompanied by various manifestations of anterior segment dysgenesis.

BACKGROUND: According to previous reports, PAX6-associated foveal hypoplasia (FH) could usually be accompanied by various anterior segment anomalies including variable iris changes. This study aims to exhibit unusual phenotypes of a novel missense variant of PAX6 from a Chinese pedigree. METHODS: Ophthalmic examinations including slit-lamp biomicroscopy, gonioscopy, ophthalmic ultrasound, ultrasonic biomicroscopy, optical coherence tomography, wide-field fundus imaging, and visual field test were performed to evaluate the clinical manifestations. Whole-exome sequencing (WES) and bioinformatics analysis were conducted in eight members from this pedigree to identify the causative mutation. RESULTS: WES revealed a novel heterozygous substitution of PAX6 (NM_000280.5:c.157G > A, p.(Val53Met) (chr11:31823309 C > T, hg19)), which cosegregated with the phenotype of this pedigree. All the three patients (a pair of fraternal twins and their mother) exhibited bilateral FH and anterior segment dysgenesis (ASD) including microcornea, sclerocornea, obvious symmetrical corectopia, iris stromal dysplasia, goniodysgenesis, and abnormal distribution of fundus blood vessels. The girl of the fraternal twins also demonstrated bilateral temporal deviation of lenses and abnormal tissue membrane connecting anterior chamber angle and lens anterior capsule in the right eye. The mother additionally showed apparent cataract bilaterally and cupping of the optic disc in her left eye. CONCLUSION: A novel missense variant in PAX6 gene was detected in a Chinese pedigree demonstrating bilateral FH and ASD. It is really distinctive that the ASD involves almost all parts of the anterior segment, and bilateral symmetrical corectopia is the most perceptible sign. This study expands the phenotypic and genotypic spectrum of PAX6-associated ocular diseases, and facilitates the understanding of the crucial role that PAX6 plays in the development of the eye. Meanwhile, PAX6 could be considered as a candidate pathogenic gene of bilateral symmetrical corectopia.

Foveal Hypoplasia in CRB1-Related Retinopathies.

The CRB1 gene plays a role in retinal development and its maintenance. When disrupted, it gives a range of phenotypes such as early-onset severe retinal dystrophy/Leber congenital amaurosis (EOSRD/LCA), retinitis pigmentosa (RP), cone-rod dystrophy (CORD) and macular dystrophy (MD). Studies in CRB1 retinopathies have shown thickening and coarse lamination of retinal layers resembling an immature retina. Its role in foveal development has not yet been described; however, this retrospective study is the first to report foveal hypoplasia (FH) presence in a CRB1-related retinopathy cohort. Patients with pathogenic biallelic CRB1 variants from Moorfields Eye Hospital, London, UK, were collected. Demographic, clinical data and SD-OCT analyses with FH structural grading were performed. A total of 15 (48%) patients had EOSRD/LCA, 11 (35%) MD, 3 (9%) CORD and 2 (6%) RP. FH was observed in 20 (65%; CI: 0.47-0.79) patients, all of whom were grade 1. A significant difference in BCVA between patients with FH and without was found (p = 0.014). BCVA continued to worsen over time in both groups (p < 0.001), irrespective of FH. This study reports FH in a CRB1 cohort, supporting the role of CRB1 in foveal development. FH was associated with poorer BCVA and abnormal retinal morphology. Nonetheless, its presence did not alter the disease progression.

Genotypic and Phenotypic Spectrum of Foveal Hypoplasia: A Multicenter Study.

PURPOSE: To characterize the genotypic and phenotypic spectrum of foveal hypoplasia (FH). DESIGN: Multicenter, observational study. PARTICIPANTS: A total of 907 patients with a confirmed molecular diagnosis of albinism, PAX6, SLC38A8, FRMD7, AHR, or achromatopsia from 12 centers in 9 countries (n = 523) or extracted from publicly available datasets from previously reported literature (n = 384). METHODS: Individuals with a confirmed molecular diagnosis and availability of foveal OCT scans were identified from 12 centers or from the literature between January 2011 and March 2021. A genetic diagnosis was confirmed by sequence analysis. Grading of FH was derived from OCT scans. MAIN OUTCOME MEASURES: Grade of FH, presence or absence of photoreceptor specialization (PRS+ vs. PRS-), molecular diagnosis, and visual acuity (VA). RESULTS: The most common genetic etiology for typical FH in our cohort was albinism (67.5%), followed by PAX6 (21.8%), SLC38A8 (6.8%), and FRMD7 (3.5%) variants. AHR variants were rare (0.4%). Atypical FH was seen in 67.4% of achromatopsia cases. Atypical FH in achromatopsia had significantly worse VA than typical FH (P < 0.0001). There was a significant difference in the spectrum of FH grades based on the molecular diagnosis (chi-square = 60.4, P < 0.0001). All SLC38A8 cases were PRS- (P = 0.003), whereas all FRMD7 cases were PRS+ (P < 0.0001). Analysis of albinism subtypes revealed a significant difference in the grade of FH (chi-square = 31.4, P < 0.0001) and VA (P = 0.0003) between oculocutaneous albinism (OCA) compared with ocular albinism (OA) and Hermansky-Pudlak syndrome (HPS). Ocular albinism and HPS demonstrated higher grades of FH and worse VA than OCA. There was a significant difference (P < 0.0001) in VA between FRMD7 variants compared with other diagnoses associated with FH. CONCLUSIONS: We characterized the phenotypic and genotypic spectrum of FH. Atypical FH is associated with a worse prognosis than all other forms of FH. In typical FH, our data suggest that arrested retinal development occurs earlier in SLC38A8, OA, HPS, and AHR variants and later in FRMD7 variants. The defined time period of foveal developmental arrest for OCA and PAX6 variants seems to demonstrate more variability. Our findings provide mechanistic insight into disorders associated with FH and have significant prognostic and diagnostic value.

Comparison of OCT imaging in children with foveal hypoplasia born full term versus preterm.

PURPOSE: It is unknown if foveal hypoplasia in full-term born children differs in structure and function from that observed in children born preterm. We compared macular structure and visual function in children with history of prematurity and full-term children diagnosed with foveal hypoplasia. METHODS: We compared three groups of subjects (3-18 years old): (1) full-term hypoplasia (FH, n = 56, gestational age ≥ 36 weeks); (2) preterm hypoplasia (n = 57, gestational age ≤ 31 weeks, birth weight ≤ 1500 g); (3) control (n = 54), full-term normal. Using spectral-domain optical coherence tomography volume-scan images, macular structure within 3 mm of Early-Treatment-Diabetic-Retinopathy-Study circle was segmented. Total, inner, and outer foveal thickness of right eyes were compared. Foveal hypoplasia was graded according to the Leicester Grading System. RESULTS: The mean total foveal thickness in micrometers was 263 ± 19 for the control, 299 ± 30 for the full-term hypoplasia, and 294 ± 28 for the preterm hypoplasia groups (F = 33, p < 0.001). Foveal inner retinal layer thickness differed among groups (p < 0.001), but not in the outer layers (p = 0.10). The full-term hypoplasia group had significantly thicker foveal inner layers (p < 0.05) and greater frequency of higher-grade hypoplasia than the preterm hypoplasia group. LogMAR visual acuity was worse in the full-term hypoplasia group (0.35 ± 0.36) than in the preterm hypoplasia group (0.19 ± 0.27, p < 0.001). CONCLUSION: Fovea was thicker in both hypoplasia groups. The full-term hypoplasia group is associated with more severe structure changes and poorer visual function than the preterm hypoplasia group.

Expanding the Spectrum of Oculocutaneous Albinism: Does Isolated Foveal Hypoplasia Really Exist?

Oculocutaneous albinism is an autosomal recessive disorder characterized by the presence of typical ocular features, such as foveal hypoplasia, iris translucency, hypopigmented fundus oculi and reduced pigmentation of skin and hair. Albino patients can show significant clinical variability; some individuals can present with only mild depigmentation and subtle ocular changes. Here, we provide a retrospective review of the standardized clinical charts of patients firstly addressed for evaluation of foveal hypoplasia and slightly subnormal visual acuity, whose diagnosis of albinism was achieved only after extensive phenotypic and genotypic characterization. Our report corroborates the pathogenicity of the two common TYR polymorphisms p.(Arg402Gln) and p.(Ser192Tyr) when both are located in trans with a pathogenic TYR variant and aims to expand the phenotypic spectrum of albinism in order to increase the detection rate of the albino phenotype. Our data also suggest that isolated foveal hypoplasia should be considered a clinical sign instead of a definitive diagnosis of an isolated clinical entity, and we recommend deep phenotypic and molecular characterization in such patients to achieve a proper diagnosis.

Disease Progression in CNGA3 and CNGB3 Retinopathy; Characteristics of Slovenian Cohort and Proposed OCT Staging Based on Pooled Data from 126 Patients from 7 Studies.

Achromatopsia has been proposed to be a morphologically predominately stable retinopathy with rare reports of progression of structural changes in the macula. A five-grade system of optical coherence tomography (OCT) features has been used for the classification of structural macular changes. However, their association with age remains questionable. We characterized the Slovenian cohort of 12 patients with pathogenic variants in CNGA3 or CNGB3 who had been followed up with OCT for up to 9 years. Based on observed structural changes in association with age, the following four-stage classification of retinal morphological changes was proposed: (I) preserved inner segment ellipsoid band (Ise), (II) disrupted ISe, (III) ISe loss and (IV) ISe and RPE loss. Data from six previously published studies reporting OCT morphology in CNGA3 and CNGB3 patients were additionally collected, forming the largest CNGA3/CNGB3 cohort to date, comprising 126 patients aged 1-71 years. Multiple regression analysis showed a significant correlation of OCT stage with age (p < 0.001) and no correlation with gene (p > 0.05). The median ages of patients with stages I-IV were 12 years, 23 years, 27 years and 48 years, respectively, and no patient older than 50 years had continuous ISe. Our findings suggest that achromatopsia presents with slowly but steadily progressive structural changes of the macular outer retinal layers. However, whether morphological changes in time follow the proposed four-stage linear pattern needs to be confirmed in a long-term study.

Identification of a novel GPR143 mutation in a large Chinese family with isolated foveal hypoplasia.

BACKGROUND: Pathogenic variants of G-protein coupled receptor 143 (GPR143) gene often leads to ocular albinism type I (OA1) characterized by nystagmus, iris and fundus hypopigmentation, and foveal hypoplasia. In this study, we identified a novel hemizygous nonsense mutation in GPR143 that caused an atypical manifestation of OA1. CASE PRESENTATION: We reported a large Chinese family in which all affected individuals are afflicted with poor visual acuity and foveal hypoplasia without signs of nystagmus. Fundus examination of patients showed an absent foveal reflex and mild hypopigmentation. The fourth grade of foveal hypoplasia and the reduced area of blocked fluorescence at foveal region was detected in OCT. OCTA imaging showed the absence of foveal avascular zone. In addition, the amplitude of multifocal ERG was reduced in the central ring. Gene sequencing results revealed a novel hemizygous mutation (c.939G > A) in GPR143 gene, which triggered p.W313X. However, no iris depigmentation and nystagmus were observed among both patients and carriers. CONCLUSIONS: In this study, we reported a novel nonsense mutation of GPR143 in a large family with poor visual acuity and isolated foveal hypoplasia without nystagmus, which further expanded the genetic mutation spectrum of GPR143.

Axenfeld-Rieger syndrome combined with a foveal anomaly in a three-generation family: a case report.

BACKGROUND: Axenfeld-Rieger syndrome (ARS) is a rare autosomal dominant eye disorder that can also affect other organs of the human body. The condition is primarily characterized by the anterior segmental abnormalities of the eye. Here, we present an observational case series of a three-generation family with ARS and unexpected foveal anomaly. CASE PRESENTATION: A 33-year-old woman was admitted to an Ophthalmology Clinic in Bialystok for left eye congenital cataract surgery. The patient (proband) was diagnosed with visual deterioration, multiple defects of iris, corectopia, displacement of the Schwalbe's line, and phenotypic characteristics of ARS. A perimetric examination indicated peripheral visual field loss and signs typical for glaucoma. Based on the phenotypic symptoms and genetic test, the patient was diagnosed with Axenfeld Rieger Syndrome. However, the optical coherence tomography of the macula showed foveal anomaly (absence of the physiological pit), which is not typically associated with this genetic disorder. The patient's family history revealed that her two daughters were undergoing treatment for congenital glaucoma, and one of the daughters also had foveal anomaly the same as her mother. Interestingly, an examination of the patient's mother showed typical phenotypic features of ARS such as a defect of the iris, posterior embryotoxon, and coloboma, as well as foveal anomaly. A genetic test confirmed PITX2 mutation in both, proband's two daughters and mother. CONCLUSIONS: This study highlights the occurrence of ARS with unusual ophthalmic features such as foveal anomaly (absence of the physiological pit) in a three-generation family. Although ARS is known to represent the developmental defects of the anterior segment of the eye, it is very important to perform fundus evaluation to identify associated posterior segment anomalies that may affect visual acuity. The presence of ocular defects not typically associated with ARS suggests a wide spectrum of mutations within PITX2 gene which are required to identify in order to determine genotype- phenotype correlation in ARS affected individuals.

Novel Biallelic Variants and Phenotypic Features in Patients with SLC38A8-Related Foveal Hypoplasia.

Biallelic pathogenic variants in solute carrier family 38 member 8, SLC38A8, cause a pan-ocular autosomal recessive condition known as foveal hypoplasia 2, FVH2, characterised by foveal hypoplasia, nystagmus and optic nerve chiasmal misrouting. Patients are often clinically diagnosed with ocular albinism, but foveal hypoplasia can occur in several other ocular disorders. Here we describe nine patients from seven families who had molecularly confirmed biallelic recessive variants in SLC38A8 identified through whole genome sequencing or targeted gene panel testing. We identified four novel sequence variants (p.(Tyr88*), p.(Trp145*), p.(Glu233Gly) and c.632+1G>A). All patients presented with foveal hypoplasia, nystagmus and reduced visual acuity; however, one patient did not exhibit any signs of chiasmal misrouting, and three patients had features of anterior segment dysgenesis. We highlight these findings in the context of 30 other families reported to date. This study reinforces the importance of obtaining a molecular diagnosis in patients whose phenotype overlap with other inherited ocular conditions, in order to support genetic counselling, clinical prognosis and family planning. We expand the spectrum of SLC38A8 mutations which will be relevant for treatment through future genetic-based therapies.

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.

The pathogenicity of SLC38A8 in five families with foveal hypoplasia and congenital nystagmus.

PURPOSE: A recently described subtype of foveal hypoplasia with congenital nystagmus and optic-nerve-decussation defects was found to be associated with mutations in the SLC38A8 gene. The aim of this study is to advance the clinical and molecular knowledge of SLC38A8 gene mutations. METHODS: Five Israeli families with congenital foveal hypoplasia were studied, two of Karait Jewish origins and three of Indian Jewish origins. Subjects underwent a comprehensive ophthalmic examination including retinal photography and ocular coherence tomography. Molecular analysis including whole exome sequencing and screening of the SLC38A8 gene for specific disease-causing variants was performed. RESULTS: Eight affected individuals were identified, all had congenital nystagmus and all but one had hypoplastic foveal pits. Anterior segment dysgenesis was observed in only one patient, one had evidence of developmental delay and another displayed early age-related macular degeneration (AMD). Molecular analysis revealed a recently described homozygous mutation, c.95T > G; p.Ile32Ser, in two families of Jewish Indian descent, and the same mutation in two families of Karaite Jewish descent. In a patient with only one pathogenic mutation (c.95T > G; p.Ile32Ser), a possible partial clinical expression of the disorder was seen. One patient of Jewish Indian descent was found to be compound heterozygous for c.95T > G; p.Ile32Ser and a novel mutation c.490_491delCT; p.L164Vfs*41. CONCLUSIONS: In five unrelated families with congenital nystagmus and foveal hypoplasia, mutations in the SLC38A8 gene were identified. Possible partial expression in a heterozygous patient was observed and novel potential disease-related phenotypes were identified including early-onset AMD and developmental delay. A novel mutation was also identified and a similar mutation in both Indian and Karaite Jewish ethnicities could be suggestive for common ancestry.

Homozygous stop mutation in AHR causes autosomal recessive foveal hypoplasia and infantile nystagmus.

Herein we present a consanguineous family with three children affected by foveal hypoplasia with infantile nystagmus, following an autosomal recessive mode of inheritance. The patients showed normal electroretinography responses, no signs of albinism, and no anterior segment or brain abnormalities. Upon whole exome sequencing, we identified a homozygous mutation (c.1861C>T;p.Q621*) in the aryl hydrocarbon receptor (AHR) gene that perfectly co-segregated with the disease in the larger family. AHR is a ligand-activated transcription factor that has been intensively studied in xenobiotic-induced toxicity. Further, it has been shown to play a physiological role under normal cellular conditions, such as in immunity, inflammatory response and neurogenesis. Notably, knockout of the Ahr gene in mouse impairs optic nerve myelin sheath formation and results in oculomotor deficits sharing many features with our patients: the eye movement disorder in Ahr-/- mice appears early in development and presents as conjugate horizontal pendular nystagmus. We therefore propose AHR to be a novel disease gene for a new, recessively inherited disorder in humans, characterized by infantile nystagmus and foveal hypoplasia.

Novel clinical findings in autosomal recessive NR2E3-related retinal dystrophy.

PURPOSE: To evaluate the clinical phenotype of autosomal recessive NR2E3-related retinal dystrophy. METHODS: We retrospectively studied 11 patients carrying out at least 2 NR2E3 mutations; they had undergone comprehensive ophthalmological examination, fundus photography, optical coherence tomography, electrophysiological testing, and visual field at the Regional Reference Center for Hereditary Retinal Degenerations of the Eye Clinic in Florence. RESULTS: Five females and six males with a diagnosis of NR2E3-related retinal dystrophy were included in the study. All patients complained of nyctalopia. Visual acuity ranged from 0.00 logMAR to hand motion. Two patients presented bull's eye maculopathy, and one of these was characterized by a triple hyper-autofluorescent ring at the fundus autofluorescence examination. Three patients showed small yellowish dots and spots at the mid-periphery. One patient was characterized by widespread subretinal drusenoid deposits (SDD) at the posterior pole. Four patients showed vitreous abnormalities. Optical coherence tomography (OCT) examinations detected variable degrees of abnormal retinal lamination and schitic changes. Seven patients were compound heterozygous and four were homozygous for mutations in NR2E3. CONCLUSIONS: Our study confirmed high variable phenotype in autosomal recessive NR2E3-related retinal dystrophy. Bull's eye maculopathy, subretinal drusenoid deposits, and foveal hypoplasia represent novel clinical findings in NR2E3-related retinal dystrophy. Macular involvement was detectable in all the patients, and the abnormal foveal avascular zone (FAZ) supports the role of NR2E3 in retinal development.

Evidence of macular pigment in the central macula in albinism.

PURPOSE: Albinism represents a spectrum of disorders with diminished to absent amounts of melanin pigmentation including the posterior segment of the eye. Macular pigment (MP) consists of two main carotenoids, lutein and zeaxanthin, concentrated in the macula. MP serves as blue light absorbent, antioxidant, and may reduce chromatic aberration and glare. It remains unclear if albinos have detectable MP. The purpose was to investigate the distribution of MP in albino patients with psychophysical and imaging techniques. METHODS: MP was measured at the eccentricity of 0.5° by heterochromatic flicker perimetry (QuantifEye(®); Tinsley Precision Instruments Ltd.) or by scanning laser ophthalmoscopy (MPOD module, MultiColor Spectralis(®), Heidelberg Engineering, Heidelberg, Germany) in four albino patients, who were also investigated with multimodal ophthalmic imaging. RESULTS: Visual acuity ranged from 20/32 to 20/125, nystagmus was present in three patients, and all patients showed typical foveal hypoplasia on fundus exam and optical coherence tomography. Fundus autofluorescence (FAF) demonstrated various degrees of central FAF signal attenuation. Genetic testing was available in three patients and confirmed the diagnosis. Measurable amounts of MP were detected in all four patients and ranged from 0.05 to 0.24, which is below the normal range. CONCLUSIONS: We conclude that MP can be demonstrated and measured in albinos. Further studies are needed to investigate MP accumulation following carotenoid supplementation and its impact on visual performance.

Outer retinal deformity detected by optical coherence tomography in eyes with foveal hypoplasia.

PURPOSE: To investigate the relationship between vision and foveal maturity, especially in foveal hypoplasia exhibiting severe structural immaturity. METHODS: This retrospective observational case series included 42 eyes of 23 patients (mean age, 7.0 ± 5.0 years; 9 patients with foveal hypoplasia as an isolated entity and 14 patients with aniridia). A complete ophthalmic examination included measurement of best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography (SD-OCT). The sensory retina, ganglion cell complex (GCC), and outer retinal layers, including Henle's fiber layer (HFL), were measured and analyzed. RESULTS: Using SD-OCT images, eyes were classified as having a differentiated (6 eyes), diffuse (19 eyes), or no HFL (17 eyes), based on the appearance of the HFL around the foveal region. The logMAR BCVA was significantly worse (p < 0.0001) in eyes with diffuse HFL and those with no HFL than in those with differentiated HFL. Outer retinal thickness (outer plexiform layer + HFL + outer nuclear layer) was less (p = 0.0051) in eyes with no HFL than in those with differentiated HFL. The logMAR BCVA, GCC thickness, and outer retinal thickness in eyes with foveal hypoplasia with aniridia were significantly worse (p = 0.0083), thicker (p = 0.0039), and thinner (p = 0.0001), respectively, than in eyes with foveal hypoplasia as an isolated entity. CONCLUSIONS: In eyes with foveal hypoplasia with severe structural immaturity, diffuse HFL or no HFL was associated with worse vision. There was greater foveal immaturity in eyes with foveal hypoplasia with aniridia compared with foveal hypoplasia as an isolated entity.

Foveal Hypoplasia in Presumed Xeroderma Pigmentosum: A Case Report.

We present a case of presumed xeroderma pigmentosum (XP) with concomitant foveal hypoplasia. A 50-year-old male patient with extensive bilateral symblepharon-like pseudopterygia was referred for visual rehabilitation. After dermatology consultation and ophthalmologic examination, presumed XP was diagnosed. Optical coherence tomography revealed grade 2 foveal hypoplasia. The patient was referred for genetic testing because concomitant XP and foveal hypoplasia are rare. The genetic test results revealed mutations in some genes, including the hemochromatosis genes HFE, COL1A2, Lysosome Trafficking Regulator (LYST), NF1, and HMBS. The LYST gene is known to be associated with foveal hypoplasia. Since the association of foveal hypoplasia and XP has been reported in another case in the literature, we present our case to share this rare association.

Multimodal phenotyping of foveal hypoplasia in albinism and albino-like conditions: a pediatric case series with adaptive optics insights.

Aim of the present study is to evaluate the relationship between genetic and phenotypic data in a series of patients affected by grade I and II of foveal hypoplasia with stable fixation and good visual acuity using multimodal imaging techniques. All patients underwent complete clinical and instrumental assessment including structural Optical Coherence Tomography (OCT), OCT Angiography and Adaptive Optics (AO) imaging. Central macular thickness (CMT), inner nuclear layer (INL), vessel density in superficial capillary plexus were the main variables evaluated with OCT technology. Cone density, cone spacing, cone regularity, cone dispersion and angular density were the parameters evaluated with AO. Genetic evaluation and trio exome sequencing were performed in all affected individuals. Eight patients (3 males and 5 females) with a mean age of 12.62 years (range 8-18) were enrolled. The mean best corrected visual acuity (BCVA) was 0.18 ± 0.13 logMAR, mean CMT was 291.9 ± 16.6 µm and INL was 26.2 ± 4.6 µm. The absence of a foveal avascular zone (FAZ) was documented by examination of OCT-A in seven patients in the superficial capillary plexus. However, there was a partial FAZ in the deep plexus in patients P5 and P8. Of note, all the patients presented with major retinal vessels clearly crossing the foveal center. All individuals exhibited a grade I or II of foveal hypoplasia. In 5 patients molecular analyses showed an extremely mild form of albinism caused by compound heterozygosity of a TYR pathogenic variant and the hypomorphic p.[Ser192Tyr;Arg402Gln] haplotype. One patient had Waardenburg syndrome type 2A caused by a de novo variant in MITF. Two patients had inconclusive molecular analyses. All the patients displayed abnormalities on OCT-A. Photoreceptor count did not differ from normal subjects according to the current literature, but qualitative analysis of AO imaging showed distinctive features likely related to an abnormal pigment distribution in this subset of individuals. In patients with foveal hypoplasia, genetic and multimodal imaging data, including AO findings, can help understand the physiopathology of the foveal hypoplasia phenotype. This study confirms that cone density and visual function can both be preserved despite the absence of a pit.

Novel LOXL3-associated stickler syndrome-like phenotype: a case report.

PURPOSE: To report the case of a young boy with early onset high myopia (eoHM), foveal hypoplasia and skeletal dysplasia due to a homozygous LOXL3 pathogenic variant. Atypically, this was from a paternal uniparental isodisomy (UPiD) of chromosome 2. CLINICAL CASE: Four-year-old boy with several months history of holding items close to his face was found to have reduced visual acuity 6/30 in both eyes, bilateral vitreous syneresis, foveal hypoplasia and bilateral high myopia (-8.50D). A skeletal survey showed spondylo-epi-metaphyseal dysplasia. Whole-exome sequencing (WES) revealed a homozygous LOXL3 variant c.1448_1449del, p.(Thr483Argfs*13), inherited through paternal UPiD of chromosome 2. CONCLUSION: To our knowledge, this is the first reported case of LOXL3-associated eoHM, foveal hypoplasia and mild skeletal dysplasia due to the rare phenomenon of paternal UPiD of chromosome 2. This case further delineates the phenotype associated with LOXL3 pathogenic variants and supports truncating LOXL3 pathogenic variants being associated with a phenotypic spectrum; from isolated eoHM through to a Stickler syndrome-like phenotype.