Congenital Disorders

This chapter is devoted to specific diseases presenting usually in early infancy or childhood as a result of disruption in the normal development of the cornea and its associated structures. These disorders may develop due to one or a combination of various genetic, infectious, inflammatory, toxic, metabolic, traumatic, or mechanical processes and may occur at any time during tissue induction, differentiation, and maturation. Adjacent structures (anterior chamber angle, iris, and lens) can be impacted too. Congenital limbal stem cell deficiency is usually associated with aniridia and ectodermal dysplasia. Aniridia can occur in a sporadic or familial form. The familial inheritance pattern of aniridia is predominantly autosomal dominant. The aniridia phenotype varies depending on the mutation present. Interesting ocular congenital disorders associated with Neurofibromatosis, Axenfeld-Rieger syndrome, Icthyosis are shown in this chapter. It presents a rare case of porphyria-associated sclerocorneal melting with before and after treatment photos.

Axenfeld-Rieger Syndrome: A Case Report with Literature Review

Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant disorder that has both systemic and ocular anterior segment dysgenesis. The ocular manifestations include posterior embryotoxon, iris and anterior angle abnomalies with a high risk of glaucoma and blindness. The systemic manifestations can include craniofacial abnomalies such as maxillary hypoplasia, hypodontia, oligodontia and microdont.

Hyperproliferative embryotoxon simulating double cornea

Posterior embryotoxon, an anteriorly displaced Schwalbe’s line, is the most common feature of Axenfeld Rieger syndrome. We report a case of Axenfeld anomaly with unusual corneal manifestation, that is, a fairly symmetric, hyperproliferated posterior embryotoxon mimicking double cornea as well as a double pupil.

The Clinical Outcomes of Keratoplasty in Irreversible Corneal Decompensation Secondary to Axenfeld-Rieger Syndrome

Porpose To evaluate the clinical outcomes of penetrating keratoplasty (PK) and Descemet’s stripping automated endothelial keratoplasty (DSAEK) in eyes with irreversible corneal decompensation secondary to Axenfeld-Rieger syndrome (ARS).Methods In this retrospective case series, a total of 4 eyes undergoing PK and 7 eyes undergoing DSAEK, including 1 eye requiring 1 repeat DEASK, between 2014 and 2021 were enrolled. Postoperative complications, graft survival, glaucoma treatment before and after keratoplasty, visual outcomes, and endothelial cell density were recorded.Results The mean follow-up duration was 33.4 ± 16.8 months. Before keratoplasty, the mean BCVA was 2.0 ± 0.4 LogMAR, and the mean IOP was 21.6 ± 8.1 mmHg. 63.6% of eyes (7/11) received glaucoma treatment, including 5 eyes with glaucoma surgeries. After keratoplasty, 27.3% of eyes (3/11) exhibited secondary graft failure. The mean BCVA reached a maximum of 0.7 ± 0.5 LogMAR at 8.9 ± 7.5 months, with no significant difference between the PK and DSAEK groups (P1=1.00, P2=0.12). Four eyes with previous glaucoma surgeries exhibited markedly high IOP. 72.7% of eyes (8/11) required additional glaucoma treatments. The mean endothelial cell loss (ECL) rates at 1, 6, 12 and 24 months were 43%, 49%, 63% and 54%, respectively, with no significant difference between the PK and DSAEK groups (P1=0.64, P2=1.00, P3=0.57, and P4=0.44).Conclusion Both PK and DSAEK can successfully treat corneal decompensation secondary to ARS, resulting in similar outcomes with regard to IOP control, BCVA and ECL. IOP control is essential for postoperative management, especially for eyes with previous glaucoma surgeries.

A novel variant in FOXC1 associated with atypical Axenfeld-Rieger syndrome

Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, clinical diagnosis presents a huge challenge. In this study, we described a pathogenic in-frame variant in FOXC1 in one 5-year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3 bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Furthermore, Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linke to the FOXC1 variant and is coincidental. Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

A novel missense mutation of FOXC1 in an Axenfeld–Rieger syndrome patient with a congenital atrial septal defect and sublingual cyst: a case report and literature review

Background Axenfeld–Rieger syndrome (ARS) is a rare autosomal dominant hereditary disease characterized primarily by maldevelopment of the anterior segment of both eyes, accompanied by developmental glaucoma, and other congenital anomalies. FOXC1 and PITX2 genes play important roles in the development of ARS. Case presentation The present report describes a 7-year-old boy with iris dysplasia, displaced pupils, and congenital glaucoma in both eyes. The patient presented with a congenital atrial septal defect and sublingual cyst. The patient’s family has no clinical manifestations. Next generation sequencing identified a pathogenic heterozygous missense variant in FOXC1 gene (NM_001453:c. 246C>A, p. S82R) in the patient. Sanger sequencing confirmed this result, and this mutation was not detected in the other three family members. Conclusion To the best of our knowledge, the results of our study reveal a novel mutation in the FOXC1 gene associated with ARS.

A Novel Variant in FOXC1 Associated With Atypical Axenfeld-Rieger Syndrome

Background Mutations in the Forkhead Box C1 (FOXC1) are known to cause autosomal dominant hereditary Axenfeld-Rieger syndrome, which is a genetic disorder characterized by ocular and systemic features including glaucoma, variable dental defects, craniofacial dysmorphism and hearing loss. Due to late-onset of ocular disorders and lack of typical presentation, therefore, clinical diagnosis present a huge challenge. Results In this study, we described a pathogenic variant in FOXC1 in one 5 year-old boy who is presented with hypertelorism, pupil deformation in both eyes, conductive hearing loss, and dental defects. By whole exome sequencing, we identified a 3bp deletion in FOXC1, c.516_518delGCG (p.Arg173del) as the disease-causing variant, which was de novo and not detected in the parents, and could be classified as a “pathogenic variant” according to the American College of Medical Genetics and Genomics guidelines. After confirmation of this FOXC1 variant, clinical data on Axenfeld-Rieger syndrome-associated clinical features were collected and analyzed. Although the affected individual present hearing loss, however, the hearing loss is conductive and is reversible during the follow-up, which might not linked to the FOXC1 variant and is coincidental. Conclusions Routine examination of FOXC1 is necessary for the genetic diagnosis of hypertelorism-associated syndrome. These findings may assist clinicians in reaching correct clinical and molecular diagnoses, and providing appropriate genetic counseling.

Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants

Axenfeld–Rieger syndrome (ARS) encompasses a group of developmental disorders that affect the anterior segment of the eye, as well as systemic developmental defects in some patients. Malformation of the ocular anterior segment often leads to secondary glaucoma, while some patients also present with cardiovascular malformations, craniofacial and dental abnormalities and additional periumbilical skin. Genes that encode two transcription factors, FOXC1 and PITX2, account for almost half of known cases, while the genetic lesions in the remaining cases remain unresolved. Given the genetic similarity between zebrafish and humans, as well as robust antisense inhibition and gene editing technologies available for use in these animals, loss of function zebrafish models for ARS have been created and shed light on the mechanism(s) whereby mutations in these two transcription factors cause such a wide array of developmental phenotypes. This review summarizes the published phenotypes in zebrafish foxc1 and pitx2 loss of function models and discusses possible mechanisms that may be used to target pharmaceutical development and therapeutic interventions.