Penetrating Keratoplasty (PK)
Indication: Traditional gold standard
Features: Replaces the full thickness of the cornea
Challenges: High astigmatism, rejection, difficult suture management
Congenital Hereditary Endothelial Dystrophy (CHED)
1. What is Congenital Hereditary Endothelial Dystrophy (CHED)?
Section titled “1. What is Congenital Hereditary Endothelial Dystrophy (CHED)?”Congenital hereditary endothelial dystrophy (CHED) is a bilateral corneal endothelial dystrophy that presents at birth or in infancy 1)2). Dysfunction of corneal endothelial cells leads to diffuse corneal edema and opacity 1).
IC3D Classification and Evolution of Disease Concept
Section titled “IC3D Classification and Evolution of Disease Concept”Traditionally, CHED was classified into autosomal dominant CHED1 and autosomal recessive CHED2. However, with the 2015 revision by the International Committee for Classification of Corneal Dystrophies (IC3D), CHED1 was recognized as part of the spectrum of posterior polymorphous corneal dystrophy (PPCD) and was abolished 1)2). Currently, CHED2 is simply called “CHED” and is defined as an autosomal recessive disease 2). It is thought to be due to abnormal endothelial differentiation in late fetal life; because endothelial function is immature, diffuse corneal edema occurs at birth or within a few months after birth. Abnormalities are found only on the posterior surface of Descemet’s membrane, and endothelial cells are either absent or degenerated.
Epidemiology
Section titled “Epidemiology”The incidence of congenital corneal opacity (CCO) is about 6 per 100,000 births. The exact prevalence of CHED is unknown, but it is frequently reported from regions with high rates of consanguineous marriage, such as Saudi Arabia, India, Pakistan, Myanmar, and Ireland 2).
Q
How is CHED different from PPCD (posterior polymorphous corneal dystrophy)?
A
CHED is caused by autosomal recessive mutations in the SLC4A11 gene and presents with severe bilateral corneal edema from birth. In contrast, PPCD is an autosomal dominant disease in which corneal endothelial cells transform into epithelial-like cells. The mild form formerly called CHED1 is now reclassified as part of PPCD.
2. Main Symptoms and Clinical Findings
Section titled “2. Main Symptoms and Clinical Findings”Subjective Symptoms
Section titled “Subjective Symptoms”Reduced visual acuity from birth or early infancy is the main symptom. Deprivation amblyopia due to corneal opacity is common, and nystagmus is often associated 1). Photophobia and tearing are usually mild.
Clinical Findings
Section titled “Clinical Findings”Bilateral and symmetric diffuse corneal edema is characteristic. The cornea has a bluish-gray ground-glass appearance. Descemet’s membrane is thickened and may show a beaten copper appearance on retroillumination.
Corneal thickness is markedly increased. Bellucci et al. reported 660–680 μm 1), and Salman et al. reported 742–1310 μm 2). Intraocular pressure is usually normal, but may be falsely elevated due to increased corneal thickness 1)2).
3. Causes and Risk Factors
Section titled “3. Causes and Risk Factors”SLC4A11 Gene Mutation
Section titled “SLC4A11 Gene Mutation”The causative gene is SLC4A11 located on the short arm of chromosome 20 (20p13) 2). SLC4A11 encodes the transmembrane protein NaBC1, which is involved in ion transport on the surface of corneal endothelial cells 2). This gene was identified in 2006 as the cause of CHED in consanguineous families from Myanmar 2).
Mutation Diversity
Section titled “Mutation Diversity”Salman et al. studied Indian CHED families and sporadic cases, reporting various mutations including missense mutations (p.Ser489Trp, p.Ser480Ile), compound heterozygous mutations (p.Arg161Arg + p.Val805fs), and a splice site mutation (c.620-2A>G) 2). About 75% are single-base homozygous mutations 2). However, some cases without SLC4A11 mutations suggest involvement of other genetic factors such as the MPDZ gene 2).
Risk Factors
Section titled “Risk Factors”Because it is an autosomal recessive disorder, consanguinity is the greatest risk factor 2).
Q
What is Harboyan syndrome?
A
Harboyan syndrome is a disorder associated with the same SLC4A11 gene mutation as CHED, characterized by corneal opacity and progressive sensorineural hearing loss. SLC4A11 is expressed not only in corneal endothelial cells but also in fibrocytes and the stria vascularis of the inner ear; both tissues share a common embryological origin from the neural crest. Hearing loss can develop as early as age 2 or as late as age 33.
4. Diagnosis and Examination Methods
Section titled “4. Diagnosis and Examination Methods”Slit-Lamp Microscopy
Section titled “Slit-Lamp Microscopy”From birth, bilateral diffuse corneal edema and Descemet membrane thickening are observed. The degree of corneal opacity varies from ground-glass to complete opacity. In children, examination under anesthesia may be necessary.
Imaging Tests
Section titled “Imaging Tests”Anterior segment optical coherence tomography (AS-OCT) is useful for measuring corneal thickness and evaluating edema 1)2). Specular microscopy is used to assess endothelial cells, but observation is difficult in cases of severe corneal opacity. Bellucci et al. clearly delineated the position of the donor lamella on AS-OCT 12 years after surgery 1)2).
Genetic Testing
Section titled “Genetic Testing”Definitive diagnosis is possible by sequencing all 19 exons and adjacent intronic regions of the SLC4A11 gene 2). However, in some cases, SLC4A11 mutations are not detected, and comprehensive analysis using next-generation sequencing (NGS) may be useful 2).
Differential Diagnosis
Section titled “Differential Diagnosis”| Differential Disease | Main Differences from CHED |
|---|---|
| Primary Congenital Glaucoma | Elevated intraocular pressure, increased corneal diameter |
| PPCD | AD inheritance, mild and slowly progressive |
| Peters Anomaly | Central opacity, iris adhesions |
5. Standard Treatment
Section titled “5. Standard Treatment”Medical Treatment
Section titled “Medical Treatment”For mild and stable corneal edema, symptomatic treatment with hypertonic saline eye drops may be used. Recently, NSAIDs have been reported to potentially restore function in SLC4A11 mutant cells, but clinical application is still in the research stage 2).
Surgical Treatment
Section titled “Surgical Treatment”The main treatment for CHED is surgery. If there is severe corneal opacity from birth, early intervention is necessary to prevent deprivation amblyopia 1).
Descemet Stripping Automated Endothelial Keratoplasty (DSAEK)
Indication: Current mainstream EK
Features: Transplants endothelium and posterior stromal lamella
Advantages: Minimally invasive, less astigmatism, faster recovery
Descemet Membrane Endothelial Keratoplasty (DMEK)
Indication: Technically feasible cases
Feature: Transplantation of Descemet’s membrane + endothelium only
Challenge: Technically difficult in children
Currently, endothelial keratoplasty (EK) is the first choice in many institutions 1). Bellucci et al. performed Descemet membrane non-stripping EK in a 3-month-old neonate with CHED and reported a 12-year follow-up 1).
At 12 years postoperatively, the corneas of both eyes remained clear, and corrected visual acuity was 0.4 LogMAR. Endothelial cell density was unexpectedly good: 2383 cells/mm² in the right eye and 2547 cells/mm² in the left eye, suggesting involvement of Descemet’s membrane in the pathology. 1)
In a study by Salman et al., all 10 cases underwent DSAEK, and DSAEK is becoming the standard procedure for CHED 2). Compared to PK, EK has shorter surgical time, lower risk of serious complications, and comparable long-term visual outcomes 1).
Q
When should corneal transplantation be performed for CHED in children?
A
If there is severe corneal opacity from birth, early surgical intervention is desirable to prevent deprivation amblyopia. Bellucci et al. performed surgery at 3 months of age and reported good results after 12 years. However, nystagmus and amblyopia may persist after surgery, so long-term visual function follow-up is necessary.
6. Pathophysiology and Detailed Pathogenesis
Section titled “6. Pathophysiology and Detailed Pathogenesis”Corneal Endothelial Pump Function and SLC4A11
Section titled “Corneal Endothelial Pump Function and SLC4A11”Corneal deturgescence is maintained by the pump function of the corneal endothelium. This pump system is centered on active transport by Na⁺-K⁺ ATPase and consists of secondary membrane ion transporters such as SLC4A11, pNBCe1, NKCC1, AE2, NHE1, and MCT 1/2/4 2). In normal corneal endothelial cells, SLC4A11 is the most abundantly expressed ion transporter 2).
Molecular Mechanism of SLC4A11 Mutation
Section titled “Molecular Mechanism of SLC4A11 Mutation”SLC4A11 mutations cause corneal edema through multiple pathways.
In SLC4A11 knockout mice, sodium and chloride ions accumulate in the corneal stroma, leading to corneal edema 2). Recent studies have shown that changes in H⁺ flux properties, rather than protein trafficking defects, are involved in the phenotype of SLC4A11 mutants 2).
In SLC4A11-deficient corneal endothelial cells, the NH₃:H⁺ cotransporter activity is lost2). This severely impairs glutaminolysis, affecting cellular energy production2).
In silico analysis by Salman et al. showed that the identified mutations (p.Ser489Trp, p.Ser480Ile, p.Arg869Cys) all lead to decreased protein stability and reduced number of hydrogen bonds2). These structural changes are thought to affect protein folding and flexibility, leading to loss of ion transport function2).
7. Latest Research and Future Perspectives
Section titled “7. Latest Research and Future Perspectives”Gene Therapy and Genome Editing
Section titled “Gene Therapy and Genome Editing”Slc4a11 gene replacement therapy using adeno-associated virus (AAV) has been successful in mouse models, potentially opening the way for a curative treatment for CHED2). CRISPR/Cas9-based gene editing approaches are also being explored2).
Potential for Pharmacotherapy
Section titled “Potential for Pharmacotherapy”Certain NSAIDs have been shown in vitro to correct the function of mutant SLC4A11 protein, and clinical trials are ongoing2).
Advances in Surgical Techniques
Section titled “Advances in Surgical Techniques”Improvements in EK techniques are making Descemet membrane non-stripping corneal endothelial transplantation safe even in neonates and infants1). The 12-year follow-up by Bellucci et al. is the longest report demonstrating the long-term efficacy of this procedure1). Application of DMEK in children is also being attempted, but technical challenges remain1).
Unexplained Genetic Factors
Section titled “Unexplained Genetic Factors”The existence of CHED cases without detectable SLC4A11 mutations suggests involvement of other genetic mechanisms, such as the MPDZ gene2). Comprehensive analysis using NGS is expected to contribute to future elucidation2).
8. References
Section titled “8. References”- Bellucci C, Mora P, Tedesco SA, Gandolfi S, Chierego C, Bellucci R. 12-year follow-up of the first endothelial keratoplasty without Descemet stripping in a 3-month newborn with Congenital Hereditary Endothelial Dystrophy (CHED). BMC Ophthalmol. 2023;23:433.
- Salman M, Verma A, Chaurasia S, Prasad D, Kannabiran C, Singh V, Ramappa M. Identification and in silico analysis of a spectrum of SLC4A11 variations in Indian familial and sporadic cases of congenital hereditary endothelial dystrophy. Orphanet J Rare Dis. 2022;17(1):361.
- Mehta N, Verma A, Achanta DS, Kannabiran C, Roy S, Mishra DK, et al. Updates on congenital hereditary endothelial dystrophy. Taiwan J Ophthalmol. 2023;13(4):405-416. PMID: 38249503.