X-linked endothelial corneal dystrophy (XECD) is a subtype of posterior corneal dystrophy in the IC3D classification. It shows an X-chromosomal dominant inheritance pattern. It is characterized by diffuse ground-glass corneal opacity, and the phenotype differs greatly by sex.
In 2006, a family study in North Tyrol, western Austria, reported a single large family spanning seven generations. This remains the only reported case to date. Based on family records, 9 individuals from generations I–III were considered affected, and 88 individuals from generation IV onward were diagnosed by slit-lamp microscopy. The proband was a 1-year-old boy examined under general anesthesia.
Pedigree analysis confirmed that affected fathers transmit the disease to all daughters and never to sons. This father-to-son non-transmission pattern is evidence of X-linked inheritance. The prevalence is unknown, and no other families have been reported.
The subjective symptoms of XECD differ greatly by sex.
Male Phenotype
Ground-glass corneal opacity: Milky white diffuse corneal opacity. Congenital and bilateral.
Moon crater-like endothelial changes: Observed as pit-like depressions under direct illumination.
Nystagmus: Associated with visual deprivation due to congenital corneal opacity.
Subepithelial band keratopathy: Late finding that progresses from the peripheral cornea in adulthood.
Female Phenotype
Moon crater-like endothelial changes: Pit-like depressions in the central to mid-peripheral cornea. Also observed by retroillumination.
No visual impairment: Corneal transparency is maintained, and visual function is not affected.
In a reported case of an 18-year-old male, bilateral milky ground-glass corneal opacity was accompanied by nystagmus and marked visual loss. In contrast, the patient’s mother exhibited only moon crater-like endothelial changes and had no visual complaints. Clinical evaluation of parents of patients with congenital corneal opacity may enable diagnosis of corneal endothelial dystrophy.
Because XECD is X-linked dominant, men have only one X chromosome and are fully affected by the mutation. Women have a second normal X chromosome that partially compensates, so endothelial changes remain mild.
The cause of XECD is a gene mutation on the X chromosome. Linkage analysis using 25 polymorphic markers across the X chromosome confirmed linkage to the Xq25 region (14.79 megabases).
This region contains 181 genes. The breakdown is as follows.
However, the causative gene has not been identified at present. The inheritance pattern is X-linked dominant, and transmission from an affected male to his son does not occur.
Direct illumination and retroillumination under dilated pupils are the basic examination methods. Moon crater-like endothelial changes are observed as pits or small depressions on the corneal endothelial surface. In males, the presence of ground-glass corneal opacity and band keratopathy is also evaluated.
LM examination of the corneal button reveals the following:
TEM reveals more detailed structural abnormalities.
Endothelial dystrophies that require differentiation from XECD are listed below.
| Disease | Inheritance Pattern | Characteristic Findings |
|---|---|---|
| FECD | Autosomal dominant | Corneal guttae, female predominance |
| CHED | Autosomal recessive | Neonatal corneal opacity, SLC4A11 mutation |
| PPCD | Autosomal dominant | Endothelial metaplasia, Descemet membrane vesicles |
FECD is autosomal dominant, more common in women, and characterized by regular central corneal guttae. XECD is X-linked dominant with more severe disease in men, presenting with moon crater-like pits rather than guttae. Family history is useful for differentiation.
Because XECD is extremely rare, no optimal treatment has been established. There is no drug therapy to slow the progression of corneal dystrophy.
Asymptomatic cases such as female carriers require only regular follow-up and no treatment.
When recurrent corneal erosion occurs, the following symptomatic treatments are selected.
Penetrating keratoplasty is indicated for males with severe visual impairment. In an Austrian family, a 63-year-old man who underwent penetrating keratoplasty of the left eye in 1973 maintained graft clarity until the last examination in 2003, i.e., no recurrence for 30 years.
There have been no reports of recurrence after full-thickness corneal transplantation for XECD itself, and there are cases that have maintained transparency for 30 years. However, recurrence has been reported in PPCD, a similar disease, so long-term follow-up is important.
The corneal endothelium is located on the innermost surface of the cornea and maintains a constant hydration level of the corneal stroma through selective barrier function and ion pump function (dehydration maintenance function) 1). When this function fails, the corneal stroma becomes edematous and opacification occurs.
The most characteristic pathological finding of XECD is structural abnormality of Descemet’s membrane. Normal Descemet’s membrane consists of two layers: the anterior banded layer (ABL) and the posterior non-banded layer (PNBL) 2).
In XECD, the following structural changes are confirmed by TEM.
For comparison, Descemet’s membrane in FECD is characterized by thinning or loss of PNBL, appearance of a posterior banded layer (PBL) and guttae, in addition to normal ABL 2). Both XECD and FECD exhibit abnormal layering of Descemet’s membrane, but the patterns differ.
In XECD, the endothelial cell layer becomes discontinuous, with partially normal and degenerated cells intermixed forming several layers. Cells have cytoplasmic processes, and some cells show apical microvilli, but desmosome-like junctions and tonofilament bundles are not observed. This finding differs from the epithelial-like metaplasia seen in PPCD.
In adulthood, subepithelial band keratopathy starting from the peripheral cornea is caused by accumulation of amorphous granular material beneath the epithelium. Thinning and irregularity of Bowman’s layer progress, accompanied by disorganization of the collagen lamellar arrangement in the anterior stroma. This change is slowly progressive and intermittently exacerbates corneal opacity.
The biggest research challenge for XECD is the identification of the causative gene. The candidate region (Xq25, 14.79 Mb) contains 72 genes, of which 7 encode transcription factors. Advances in next-generation sequencing are expected to narrow down the candidate genes.
In other corneal endothelial dystrophies, gene identification has progressed. In FECD, CTG trinucleotide repeat expansion in the TCF4 gene has been identified as the most common causative mutation 2). In CHED, SLC4A11, and in PPCD, ZEB1 and COL8A2 have been identified as responsible genes. These findings also serve as references for gene discovery in XECD.
Currently, the standard surgical procedure for XECD is penetrating keratoplasty, but there have been remarkable technological advances in corneal endothelial transplantation (DSAEK, DMEK). For FECD, DMEK has shown good visual outcomes 2). In the future, these procedures may be applied to XECD as well. However, since surgical indications in young children are an issue for XECD, further consideration of the application of these procedures to children is necessary.
