OBJECTIVE: To describe three anterior segment dysgenesis disorders with infantile corneal opacities, namely, congenital hereditary endothelial dystrophy (CHED), primary congenital glaucoma (PCG), and Peters anomaly (PA) in terms of clinical characteristics, histopathology, genetic association, and diagnostic imaging profiles using imaging modalities such as ultrasound biomicroscopy (UBM) and microscope-integrated intraoperative optical coherence tomography (i-OCT).
METHODS: Seventy-four eyes with 22 eyes of CHED, 28 eyes of PA, and 24 eyes of PCG were clinically evaluated and underwent imaging using UBM and i-OCT. Corneal buttons of 16 operated patients underwent histopathological analysis, while genetic analysis was done in 23 patients using whole-exome sequencing.
RESULTS: Corneal diameters (CD) and UBM parameters like anterior chamber depth (ACD), iris thickness (IT), and ciliary body (CB) thickness revealed a statistically significant difference between the three categories. In PA, 9 eyes had a third rare phenotype with only a posterior corneal defect with no iris adhesions. Genetic mutations were seen in all tested patients with CHED, in 83.3% of patients with PCG, and in 80% of patients with the third type of PA. i-OCT helped in the characterization of corneal opacity, identification of posterior corneal defects, iridocorneal adhesions, and contour of Descemet\'s membrane.
CONCLUSIONS: Overlapping phenotypes of the above disorders cause a diagnostic dilemma and parameters like CDs, UBM ACD, IT, and CB thickness help differentiate between them. i-OCT can help in classifying the diseases in a high resolution, non-contact manner, and can better delineate corneal characteristics. The rare third type of PA phenotype may have a genetic association.

Congenital hereditary endothelial dystrophy (CHED) is a rare genetic corneal disorder causing progressive cornea clouding and significant visual impairment. CHED remains a leading indication for pediatric corneal transplantation despite its infrequency, particularly in regions with high consanguinity rates like Southeast Asia. Identifying the Solute Carrier Family 4 Member 11 (SLC4A11) gene as the genetic basis of CHED has led to the discovery of it\'s various genetic variations. However, a comprehensive understanding of its clinical-genetic correlation, pathophysiology, and optimal management is ongoing. This review aims to consolidate current knowledge about CHED, covering its genetic origins, pathophysiological mechanisms, clinical presentation, and management strategies. Surgical intervention, such as penetrating keratoplasty (PK), Descemet stripping automated endothelial keratoplasty (DSAEK), and Descemet membrane endothelial keratoplasty (DMEK), remains the primary treatment. DSAEK and DMEK offer advantages over PK, including quicker visual recovery, reduced complications, and longer graft survival, especially in the pediatric age group. The timing of surgical interventions depends on disease severity, age at presentation, comorbidities, and visual potential. Elevated oxidative stress in CHED corneal tissue suggests potential benefits from anti-inflammatory drugs to rescue mutated endothelial cells. Considering the limitations of corneal graft surgeries, exploring novel gene-based molecular therapies are essential for future management. Early diagnosis, appropriate surgical interventions, amblyopia control, and genetic counseling for predictive analysis are pivotal for optimizing CHED management. A multidisciplinary approach involving ophthalmologists, researchers, and genetic counselors is essential for precise diagnosis and optimal care for CHED patients.

BACKGROUND: Endothelial Keratoplasty (EK) is now considered as the standard treatment for Congenital Hereditary Endothelial Dystrophy (CHED) by many surgeons. We present the 12-year clinical outcome of the youngest operated patient with CHED in which we successfully performed a bilateral EK procedure without removing the recipient endothelium-Descemet complex.
METHODS: In November 2010 we performed EK without Descemet Stripping in a 3-month female newborn, thinking that the lower manipulation obtained by leaving the recipient endothelium-Descemet complex could be the key factor for the success of our surgery. Such a particular technique was new in newborns. The surgery was a success, but the long-term visual result was not predictable at that time. We followed the patient at 4 months, and then yearly. At the latest visit in October 2022 the visual, cognitive, and motorial developments were normal, with Best-corrected Distance Visual Acuity of 0.4 LogMAR with - 0.75 D sf + 2.75 D cyl @ 105° in the right eye (RE) and 0.4 LogMAR with + 1.50 D sf + 2.50 D cyl @ 60° in the left eye (LE). The endothelial microscope showed an unexpected healthy endothelium, with a cell count of 2383 cells/mm2 in the RE and of 2547 cells/mm2 in the LE from a starting donor count of 2900 cells/mm2. No secondary procedures were performed during the 12-year follow-up.
CONCLUSIONS: EK without Descemet stripping has proved to be a successful procedure over time in our newborn. The unexpected healthy endothelium suggests a role of the Descemet membrane in CHED.

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) may be misdiagnosed as primary congenital glaucoma (PCG) due to similar clinical phenotypes during early infancy. In this study, we identified a family with CHED2, which was previously misdiagnosed as having PCG, and followed up for 9 years. Linkage analysis was first completed in eight PCG-affected families, followed by whole-exome sequencing (WES) in family PKGM3. The following in silico tools were used to predict the pathogenic effects of identified variants: I-Mutant 2.0, SIFT, Polyphen-2, PROVEAN, mutation taster and PhD-SNP. After detecting an SLC4A11 variant in one family, detailed ophthalmic examinations were performed again to confirm the diagnosis. Six out of eight families had CYP1B1 gene variants responsible for PCG. However, in family PKGM3, no variants in the known PCG genes were identified. WES identified a homozygous missense variant c.2024A>C, p.(Glu675Ala) in SLC4A11. Based on the WES findings, the affected individuals underwent detailed ophthalmic examinations and were re-diagnosed with CHED2 leading to secondary glaucoma. Our results expand the genetic spectrum of CHED2. This is the first report from Pakistan of a Glu675Ala variant with CHED2 leading to secondary glaucoma. The p.Glu675Ala variant is likely a founder mutation in the Pakistani population. Our findings suggest that genome-wide neonatal screening is worthwhile to avoid the misdiagnosis of phenotypically similar diseases such as CHED2 and PCG.

Congenital hereditary endothelial dystrophy affects the Descemet membrane and endothelium, resulting in corneal decompensation. Penetrating keratoplasty (PKP) has been the gold-standard surgical management until recently; however, at present, endothelial keratoplasty (DSEK/DSAEK/n-DSEK: Descemet-stripping or non-Descemet stripping endothelial keratoplasty and DMEK/n-DMEK: Descemet membrane endothelial keratoplasty) is being preferred due to lesser intraoperative and postoperative complications, early visual recovery, and comparable visual outcomes. Endothelial keratoplasty (EK) can be challenging, especially in pediatric eyes with CHED due to smaller eyeballs, shallow anterior chambers, phakic status, and poor intraoperative visibility due to thick and hazy corneas. A total of 198 articles matched our search strategy. After screening for duplication and going through the titles and abstracts, 12 relevant original articles, one case series, and six case reports were included in this review. Various surgical modifications have to be adopted in comparison to adult eyes to overcome the aforementioned difficulties. Regardless, studies have shown favorable visual outcomes with better graft survival and fewer complications in eyes that underwent EK compared to PKP. Hence, timely surgical intervention and strict amblyopia management can result in better final visual outcomes. The purpose of this review is to summarize various intraoperative difficulties and the surgical modifications required, different surgical techniques, visual and graft-related outcomes, and various complications of EK in CHED eyes.

UNASSIGNED: Congenital hereditary endothelial dystrophy (CHED) is a rare condition that manifests at an early age showing corneal edema, increased oxidative stress, mitochondrial dysfunction, and eventually apoptosis of the endothelium due to loss of function of the membrane transport protein SLC4A11. This project tested whether replacing Slc4a11 into the Slc4a11 -/- CHED mouse model can reverse the disease-associated phenotypes.
UNASSIGNED: Experimental study.
UNASSIGNED: Five-week-old or 11-week-old Slc4a11 -/- mice. Age- and gender-matched Slc4a11 +/+ animals were used as controls. A total of 124 animals (62 female, and 62 male) were used in this study. Fifty-three animals of the genotype Slc4a11 +/+ were used as age- and gender-matched noninjected controls. Seventy-one Slc4a11 -/- mice were administered anterior chamber injections of adeno-associated virus (AAV).
UNASSIGNED: Anterior chambers of young (5 weeks old) or older (11 weeks old) Slc4a11 -/- mice were injected once with adeno-associated virus serotype 9 (AAV9) mouse Slc4a11 or AAV9-Null vectors. Corneal thickness was measured using OCT. End point analysis included corneal endothelial cell density, mitochondrial oxidative stress, and corneal lactate concentration.
UNASSIGNED: Corneal thickness, endothelial cell loss, lactate levels, and mitochondrial oxidative stress.
UNASSIGNED: In the young animals, AAV9-Slc4a11 reversed corneal edema, endothelial cell loss, mitochondrial oxidative stress, lactate transporter expression, and corneal lactate concentration to the levels observed in wild-type animals. In the older animals, gene replacement did not reverse the phenotype but prevented progression.
UNASSIGNED: Functional rescue of CHED phenotypes in the Slc4a11 -/- mouse is possible; however, early intervention is critical.

Congenital hereditary endothelial dystrophy (CHED) is a rare genetic disease of the corneal endothelium with a very early onset of bilateral corneal edema due to degeneration and dysfunction of the corneal endothelium. Currently SLC4A11 is the only established causative gene for CHED, but not all these reported CHED patients could be explained by SLC4A11 deficiency, indicating that the genetic predisposition of CHED still requires further exploration.
Trio-based whole-exome sequencing was performed on a CHED patient and his unaffected parents. The GATK2 and an in-house bioinformatics pipeline were applied for variant analyses, following the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Potential pathogenic variants were further validated by Sanger sequencing. The expression profiles of FAM149A in cell line, murine tissues or human corneal endothelia were determined by RT-qPCR. Small interfering RNA was used to knock down the expression of FAM149A in vitro. Cell viability was detected by a CCK-8 assay. ROS and 8-OHdG were examined by fluorometric analysis. The nuclear translocation of NRF2 was determined by western blotting.
We identified a homozygous mutation (NM_015398.3: c.991A > G; p.R331G) in the FAM149A gene that related to the phenotype of CHED. FAM149A was found to be highly expressed in corneal endothelium, and up-regulated upon oxidative stress. Further functional investigations demonstrated that deficiency in FAM149A impaired Nrf2-antioxidant signaling, rendering cells more vulnerable to oxidative stress. Consistently, the expression of FAM149A was significantly reduced in patients with corneal endothelium dysfunction.
This study demonstrated, for the first time, FAM149A as a plausible causative gene for CHED etiology, offering new insight for future investigation targeting CHED.

Objective: To explore the clinical characteristics and in vivo confocal microscopic (IVCM) findings of varicella zoster virus (VZV)-related corneal endotheliitis.Methods: Retrospectively reviewed 20 eyes with corneal edema which were diagnosed by real-time polymerase chain reaction.Results: one had VZV infection. Three had epithelial lesions. Six had mydriasis. Four had loss of iris pigment. Keratic precipitates (KPs) were mixed. Subbasal nerves had disappeared in 12 eyes. Langerhans cells were observed in seven eyes. The deviations in endothelial cell layers consisted of guttate (n = 1), enlarged intercellular gaps (n = 11), infiltration of inflammatory cells (n = 8), loss of defined cell boundaries (n = 1) and anomalous nucleus (n = 9). The shape of KPs in IVCM included type I (n = 6), type III (n = 3) and type IV (n = 4).Conclusion: VZV-related corneal endotheliitis is remarkably difficult to detect clinically. Most cases have no typical skin lesions. The typical clinical feature is that of segmental iris atrophy and mixed KPs.

SLC4A11 mutations cause cases of congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (HS), and Fuchs endothelial corneal dystrophy (FECD). Defective water reabsorption from corneal stroma by corneal endothelial cells (CECs) leads to these corneal dystrophies. SLC4A11, in the CEC basolateral membrane, facilitates transmembrane movement of H2 O, NH3 , and H+ -equivalents. Some SLC4A11 disease mutants have impaired folding, leading to a failure to move to the cell surface, which in some cases can be corrected by the drug, glafenine. To identify SLC4A11 mutants that are targets for folding-correction therapy, we examined 54 SLC4A11 missense mutants. Cell-surface trafficking was assessed on immunoblots, by the level of mature, high molecular weight, cell surface-associated form, and using a bioluminescence resonance energy transfer assay. Low level of cell surface trafficking was found in four out of 18 (20%) of FECD mutants, 19/ out of 31 (61%) of CHED mutants, and three out of five (60%) of HS mutants. Amongst ER-retained mutants, 16 showed increased plasma membrane trafficking when grown at 30°C, suggesting that their defect has potential for rescue. CHED-causing point mutations mostly resulted in folding defects, whereas the majority of FECD missense mutations did not affect trafficking, implying functional impairment. We identified mutations that make patients candidates for folding correction of their corneal dystrophy.

Congenital hereditary endothelial dystrophy (CHED) is a genetic disorder of corneal endothelial cells resulting in corneal clouding and visual impairment. Autosomal dominant (CHED1) and autosomal recessive (CHED2) forms have been reported and map to distinct loci on chromosome 20. CHED2 is caused by mutations in the SLC4A11 gene which encodes a membrane transporter protein.
Members of a large CHED2 family were recruited for clinical and genetic studies. Genomic DNA was sequenced for the exons and intron-exon boundaries of the SLC4A11 gene.
Twelve family members were recruited, of which eight were diagnosed with CHED. A homozygous SLC4A11 mutation (Leu843Pro) was detected in the eight patients; a single copy of the mutation was present in three unaffected carriers.
A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state.