X-Linked Endothelial Corneal Dystrophy
X-linked endothelial corneal dystrophy (ICD-10 # H18.51 - endothelial corneal dystrophies)
X-linked endothelial corneal dystrophy (XECD) is a very rare subtype of posterior corneal dystrophy characterized by diffuse corneal haze and congenital ground class corneal clouding. There are wide variations in the phenotypic features of XECD based on gender, in which males are more severely impacted by the condition than females. Changes in the corneal endothelium resembling “moon craters” are a common feature to both males and females. However, advanced cases in males have been associated with congenital ground glass corneal opacification, nystagmus, subepithelial band keratopathy, and worsened visual acuity. As an X-linked inherited disorder, XECD is passed down from affected males to females with an absence of male-to-male transmission. XECD is described as the least common dystrophy of the corneal dystrophies and was identified in numerous family members in a single Austrian pedigree.
The prevalence of this rare corneal dystrophy is unknown. A 2006 genealogical study of the North Tyrol region in Western Austria reported a seven-generation pedigree of a large family affected by a new corneal endothelial dystrophy. Nine family members from generations I to III were deemed affected based on family records. 88 other individuals were diagnosed via slit-lamp biomicroscopy. The proband was a 1-year-old male patient observed under general anesthesia. Pedigree analyses revealed evidence for X-linked transmission since affected fathers transmitted the disorder to all their daughters but never to any son.
Linkage analysis of the X chromosome using the 25 polymorphic markers across the whole X chromosome revealed linkage to a 14.79 megabase region on the long arm of Xp25. However, the causative gene of XECD is currently unidentified. The critical interval of XECD is composed of 72 genes, in which seven code for putative transcription factors. The locus of XECD contains 181 genes – 68 of which are protein coding and 113, which are either putative or noncoding.
XECD can present with various pathological changes, which may be more pronounced in affected males compared to females.
In addition to the pedigree analyses of the multi-generational Austrian family, the study also described exam observations of several patients. The mother of the infant proband presented with moon crater-like endothelial alterations that appeared as pits that resembled an abnormal corneal guttata in the center and mid-periphery of the cornea under direct illumination. These changes also resembled a moon-crater landscape under retroillumination.
A 63-year-old male patient with XECD underwent a penetrating keratoplasty (PKP) for moon-crater like endothelial changes with a late subepithelial band keratopathy on the right eye. Light microscopy (LM) of the corneal button identified thinning of the epithelium and Bowman’s layer, including thickening of Descemet’s membrane with small pits and excavations filled by cuboid and fibroblast-like cells with spindle-shaped nuclei. Atypically arranged collagen lamellae were seen directly under the epithelium in the anterior stroma while the posterior stroma appeared more regular. LM also revealed abnormal endothelial cells arranged in multilayers and a loss of endothelial cells in bare sites along Descemet’s membrane.
Transmission electron microscopy (TEM) of the same patient revealed thinning of Bowman’s lamellae with gaps containing irregularly arranged collagen fibrils with vacuoles and plaques. Descemet’s membrane was thickened with abnormal anterior (ABZ) and posterior banded zones (PBZ), including an absence of the posterior non-banded zone. The ABZ and PBZ of Descemet’s membrane both contained microfibrillar bundles and long-spacing collagen. Collagen type I-like and type VIII-like fibrils and plaques of amorphous material were also seen in the PBZ. A discontinuous endothelial layer with partially normal and degenerative cells of different electron densities were observed with cytoplasmic processes that formed several layers. Apical microvilli were seen in parts of endothelial cells, but there was no evidence of desmosome-like adherent junctions between the cells or tonofilament bundles. Finally, subepithelial amorphous-granular material accumulated in the central cornea, which was consistent with subepithelial band keratopathy.
There are no primary prevention strategies reported in the literature.
Physical examination of XECD is best visualized with pupillary dilation and direct and retroillumination. Although XECD physical features can vary in the degree of severity and type between different genders, males tend to experience poorer visual outcomes while females present with subtle corneal changes without significant visual impairment. For example, an 18-year-old male patient in the 2006 genealogical study presented with milky, bilateral, ground glass corneal opacification with additional nystagmus and severely decreased visual acuity. In comparison, the mother of this patient only presented with moon crater-like endothelial changes without visual complaints. It was suggested that clinical evaluation of parents of patients with histories of congenital corneal clouding may permit for an endothelial corneal dystrophy diagnosis.
Signs and Symptoms
In males, XECD signs include corneal opacification ranging from a milky, ground glass appearance to diffuse corneal haze, moon crater-like changes in the endothelium, and possible nystagmus and subepithelial band keratopathy. In contrast to males, females with XECD only present with moon crater-like endothelial abnormalities.  Males with XECD often present with a decrease in visual acuity, especially with additional ocular manifestations such as congenital haze, subepithelial band keratopathy, and nystagmus. Females remain asymptomatic.
Affected males are born with clouding ranging from a diffuse haze to a ground-glass, milky appearance, which commonly causes blurred vision, and possible nystagmus . Female patients are asymptomatic but have crater-like endothelial abnormalities. In advanced cases, a subepithelial band keratopathy associated with endothelial changes that resemble moon craters is observed.
In addition to slit lamp biomicroscopy, LM and TEM are additional tools that can be used to diagnose XECD. There are currently no studies in the literature of optical coherence tomography of XECD.
LM may reveal several features of XECD, including moon crater-like endothelial abnormalities, subepithelial band keratopathy, irregular thinning of the Bowman’s membrane and epithelium, irregularly arranged collagen lamellae in the anterior stroma, abnormal thickening of Descemet’s membrane with small pits and excavations, loss of endothelial cells, and atypical endothelial cells arranged in multilayers.
Additionally, TEM may show endothelial changes that resemble moon craters, subepithelial band keratopathy and amorphous-granular material accumulations, irregular Bowman’s layer thinning (up to 0.5 μm) with numerous interruptions and gaps, Descemet’s membrane thickening (20-35 μm) with irregular posterior and anterior banded zones, an absent posterior non-banded zone, discontinuous endothelial layer with partially normal and degenerative-appearing cells, and no evidence of cytoplasmic tonofilament bundles or desmosome-like adherent junctions.
There are no laboratory tests indicated for XECD.
Fuch’s endothelial dystrophy (FECD)
FECD is the most common posterior corneal dystrophy characterized by a loss of endothelial cells along with excrescences and thickening of Descemet's membrane. As FECD progresses, the guttae becomes confluent and increases in number. As a result, cornea edema and visual impairment occur due to the inability of the endothelium to keep the cornea dehydrated. FECD more commonly appears in females and exhibits an autosomal dominant mode of inheritance. Although the etiology is unknown, specific mutations have been identified in the COL8A2 gene. Symptoms of FECD may include halo perception, photophobia, foreign body sensation, visual impairment, and recurrent corneal erosions. Compared to the endothelial changes in XECD, the regular corneal guttata are a landmark of FECD.
Congenital Hereditary Endothelial Dystrophy (CHED)
Historically, CHED was divided into two forms: a less severe form characterized by an autosomal dominant mode of transmission (CHED type 1) and a more severe type described by an autosomal recessive inheritance (CHED type 2). CHED2 is caused by the SLC4A11 gene mutation which codes for a sodium borate cotransporter and is characterized by corneal opacification and edema, and abnormal collagen deposition at the Descemet’s membrane. Corneal clouding appears in the neonatal period and is often associated with nystagmus and occasionally associated with sensorineural deafness. Like XECD, congenital corneal clouding with a ground glass, milky appearance is a landmark of CHED. However, subepithelial band keratopathy is considered a secondary and late characteristic of CHED and has rarely been observed with CHED.
Posterior Polymorphous Corneal Dystrophy (PPCD)
PPCD is a rare type of posterior corneal dystrophy marked by endothelial overgrowth and metaplasia, in which vesicles at the level of Descemet’s membrane appear to be surrounded by a gray haze. Typically, PPCD develops in childhood and is often asymptomatic. In rare occurrences, PPCD may gradually progress and lead to cornea edema and visual impairment. Metaplastic cells in the corneal endothelium may spread over the trabecular meshwork and iris, leading to glaucoma in approximately 40% of patients. PPCD is characterized by an autosomal dominant mode of inheritance with genetic mutations in three genes: ZEBI, VSXI, and COL8A2. Like XECD, moon-like craters in the corneal endothelium can also be present in PPCD but are rarer. Like CHED, subepithelial band keratopathy is considered a late and secondary feature and is a rare finding of PPCD. In contrast to XECD, a correlation between degree of severity and gender has not been reported with PPCD.
Treatment of corneal dystrophies is variable, depending on the severity, clinical course, symptoms, age of the patient, and type of dystrophy. Management aims to lower recurrences of corneal erosions and improve vision. No medical therapy can slow the progression of corneal dystrophies and is limited to the treatment of corneal erosions. Patients who are asymptomatic should be routinely followed for the progression of disease but do not require treatment. Artificial tears, antibiotics, or therapeutic contact lenses should be used to treat recurrent erosions. Oral doxycycline or topical steroids have been suggested for frequent erosions. Anterior stromal puncture, corneal scraping, or phototherapeutic keratectomy are options if therapy fails to decrease the frequency of erosions.
Due to the rarity of XECD, the optimal therapy is uncertain. A penetrating keratoplasty (PKP) has been indicated for patients with XECD who experience severe visual impairment, in which the graft can remain clear for up to 30 years. A study that examined 60 members of a multi-generational Austrian family reported numerous individuals affected by XECD. One patient underwent PKP in the left eye in 1973 and demonstrated no recurrences of this transplant during the last examination in 2003. Another patient from this family exhibited moon crater-like endothelial changes with bilateral subepithelial band keratopathy and underwent PKP in the left eye in 1977 and 1994, and the right eye in 2003.
It is currently unknown if recurrences of graft rejection specifically occur with XECD, but there have been reports of recurrences after PKP for a related posterior corneal dystrophy, PPCD. A 35-year-old male patient underwent two PKP procedures in the left eye in 1975 after a failed corneal transplant for a dystrophy in 1963. The patient developed a graft rejection in June 1975, in addition to edema and a retro-corneal membrane spanning the whole cornea after a repeat PKP in March 1976. Although newer studies are needed to confirm if recurrences occur after XECD treatment with PKP, it may be helpful to understand the PKP outcomes of a similar corneal dystrophy that can also appear with moon crater-like endothelial changes and subepithelial band keratopathy.
Procedures for repairing the posterior surface of the cornea, such as a deep lamellar endothelial keratoplasty (DLEK), Descemet stripping endothelial keratoplasty (DSEK), or Descemet stripping automated endothelial keratoplasty (DSAEK) are technically difficult in young children.
As an extremely rare condition, the prognosis of XECD has not been thoroughly reported in the literature. The condition is progressive in males and non-progressive in females. The course in XECD is slowly progressive with intermittent corneal clouding and a subepithelial band keratopathy develops in adulthood starting in the peripheral cornea. 
- ↑ Aldave AJ, Han J, Frausto RF. Genetics of the corneal endothelial dystrophies: an evidence-based review. Clin Genet. 2013 Aug;84(2):109-19. doi: 10.1111/cge.12191. Epub 2013 Jun 10. PMID: 23662738; PMCID: PMC3885339.
- ↑ Kannabiran C. Genetics of corneal endothelial dystrophies. J Genet. 2009 Dec;88(4):487-94. doi: 10.1007/s12041-009-0067-1. PMID: 20090209.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Schmid E, Lisch W, Philipp W, Lechner S, Göttinger W, Schlötzer-Schrehardt U, Müller T, Utermann G, Janecke AR. A new, X-linked endothelial corneal dystrophy. Am J Ophthalmol. 2006 Mar;141(3):478-487. doi: 10.1016/j.ajo.2005.10.020. PMID: 16490493.
- ↑ 4.0 4.1 4.2 4.3 Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009 Feb 23;4:7. doi: 10.1186/1750-1172-4-7. PMID: 19236704; PMCID: PMC2695576.
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Sacchetti M, Macchi I, Tiezzi A, La Cava M, Massaro-Giordano G, Lambiase A. Pathophysiology of Corneal Dystrophies: From Cellular Genetic Alteration to Clinical Findings. J Cell Physiol. 2016 Feb;231(2):261-9. doi: 10.1002/jcp.25082. PMID: 26104822.
- ↑ Nischal KK. Genetics of Congenital Corneal Opacification--Impact on Diagnosis and Treatment. Cornea. 2015 Oct;34 Suppl 10:S24-34. doi: 10.1097/ICO.0000000000000552. PMID: 26352876.
- ↑ Frausto RF, Wang C, Aldave AJ. Transcriptome analysis of the human corneal endothelium. Invest Ophthalmol Vis Sci. 2014 Nov 6;55(12):7821-30. doi: 10.1167/iovs.14-15021. PMID: 25377225; PMCID: PMC4258927.
- ↑ Kannabiran C, Chaurasia S, Ramappa M, Mootha VV. Update on the genetics of corneal endothelial dystrophies. Indian J Ophthalmol. 2022 Jul;70(7):2239-2248. doi: 10.4103/ijo.IJO_992_22. PMID: 35791103; PMCID: PMC9426112.
- ↑ 9.0 9.1 9.2 Siebelmann S, Scholz P, Sonnenschein S, Bachmann B, Matthaei M, Cursiefen C, Heindl LM. Anterior segment optical coherence tomography for the diagnosis of corneal dystrophies according to the IC3D classification. Surv Ophthalmol. 2018 May-Jun;63(3):365-380. doi: 10.1016/j.survophthal.2017.08.001. Epub 2017 Aug 9. PMID: 28801092.
- ↑ 10.0 10.1 10.2 10.3 10.4 Weiss JS, Møller HU, Aldave AJ, Seitz B, Bredrup C, Kivelä T, Munier FL, Rapuano CJ, Nischal KK, Kim EK, Sutphin J, Busin M, Labbé A, Kenyon KR, Kinoshita S, Lisch W. IC3D classification of corneal dystrophies--edition 2. Cornea. 2015 Feb;34(2):117-59. doi: 10.1097/ICO.0000000000000307. Erratum in: Cornea. 2015 Oct;34(10):e32. Erratum in: Cornea. 2022 Dec 1;41(12):e23. PMID: 25564336.
- ↑ Lisch W, Weiss JS. Early and late clinical landmarks of corneal dystrophies. Exp Eye Res. 2020 Sep;198:108139. doi: 10.1016/j.exer.2020.108139. Epub 2020 Jul 26. PMID: 32726603.
- ↑ Kwan JT, Dalton K, Weissman BA. Contact Lens Applications and the Corneal Dystrophies: A Review. Eye Contact Lens. 2016 May;42(3):177-84. doi: 10.1097/ICL.0000000000000170. PMID: 26309025.
- ↑ Krachmer JH. Posterior polymorphous corneal dystrophy: a disease characterized by epithelial-like endothelial cells which influence management and prognosis. Trans Am Ophthalmol Soc. 1985;83:413-75. PMID: 3914130; PMCID: PMC1298709.