In vivo confocal microscopy of pre-Descemet corneal dystrophy associated with X-linked ichthyosis: a case report
© The Author(s). 2017
Received: 21 July 2016
Accepted: 7 March 2017
Published: 16 March 2017
Pre-Descemet corneal dystrophy (PDCD) is characterized by the presence of numerous, tiny, polymorphic opacities immediately anterior to Descemet membrane, which is a rare form of corneal stromal dystrophy and hard to be diagnosed. In vivo confocal microscopy (IVCM) is a useful tool to examine the minimal lesions of the cornea at the cellular level. In this article, we report a rare case of PDCD associated with X-linked ichthyosis and evaluate IVCM findings.
We present a 34-year-old male Chinese patient with PDCD associated with X-linked ichthyosis. Slit-lamp biomicroscopy showed the presence of tiny and pleomorphic opacities in the posterior stroma immediately anterior to Descemet membrane bilaterally. IVCM revealed regular distributed hyperreflective particles inside the enlarged and activated keratocytes in the posterior stroma. Hyperreflective particles were also observed dispersedly outside the keratocytes in the anterior stroma. Dermatological examination revealed that the skin over the patient’s entire body was dry and coarse, with thickening and scaling of the skin in the extensor side of the extremities. PCR results demonstrated that all ten exons and part flanking sequences of STS gene failed to produce any amplicons in the patient.
IVCM is useful for analyzing the living corneal structural changes in rare corneal dystrophies. We first reported the IVCM characteristics of PDCD associated with X-linked ichthyosis, which was caused by a deletion of the steroid sulfatase (STS) gene, confirmed by gene analysis.
KeywordsPre-Descemet corneal dystrophy X-linked ichthyosis In vivo confocal microscopy Steroid sulfatase
Pre-Descemet corneal dystrophy (PDCD) is a rare form of corneal dystrophy, characterized by the presence of numerous, tiny, polymorphic opacities in the posterior stroma immediately anterior to Descemet membrane. PDCD commonly occurs in adults aged 30–40 years, and the vision is not usually affected [1, 2]. According to the International Classification of Corneal Dystrophies (IC3D), PDCD is classified into two subtypes: (1) isolated PDCD, with unknown genetic locus; (2) PDCD associated with X-linked ichthyosis, a deletion of steroid sulfatase (STS) gene on chromosome Xp22.3 (MIM #308100) .
Ichthyosis is classified into four types: ichthyosis vulgaris (the most common), X-linked ichthyosis, lamellar ichthyosis, and bullous ichthyosiform erythrodermia. X-linked ichthyosis is the second most common form of ichthyosis that commonly affects males with an incidence of 1: 6000 . The disease is early-onset, usually occurring within the first year of the life, and presents with “fish scale” appearance of the skin [5, 6]. X-linked ichthyosis may cause various ocular diseases and PDCD is the most common ocular manifestation [7, 8].
The symptoms and ocular manifestations of PDCD are usually not obvious, therefore it’s difficult for the doctors to diagnose. The use of in vivo confocal microscope (IVCM) makes it possible to observe the different layers of the living cornea at the cellular level and discover the minimal lesions of the cornea. Previous reports have described the characteristics of isolated PDCD using IVCM [2, 9–13]. Here, we present a rare case of PDCD associated with X-linked ichthyosis and evaluate the characteristics of the corneal changes using IVCM.
As PDCD seldom affects visual acuity and it’s difficult to obtain the corneal tissue, the histopathological study of such corneal dystrophy is rare. Curran et al  first performed a histopathological analysis of the cornea from a case of PDCD and found that the keratocytes were enlarged with accumulation of vacuoles in the intracellular compartment containing lipofuscin-like lipoproteins. In an ultrastructural study of a corneal button from a patient with X-linked ichthyosis, Kempster et al  found electron-dense polymorphic and lamellated materials along the anterior aspect of Descemet membrane. By contrast, the corneal histopathological features of PDCD and X-linked ichthyosis were similar, and were consistent with the IVCM findings of enlarged keratocytes with intracellular hyperreflective particles in the present case.
In this study, we, for the first time, reported the characteristics of PDCD associated with X-linked ichthyosis using IVCM. We found that the activated keratocytes in the posterior stroma had enlarged cell bodies with a regular arrangement of hyperreflective particles inside. These IVCM findings were similar to the previous reports of isolated PDCD in the literatures [2, 11, 12]. In some other previous studies, the size and morphology of keratocytes in the posterior stroma were reported to be normal in isolated PDCD, although hyperreflective particles were also found in the intracellular and extracellular compartments [9, 10, 13]. The involved corneal layers in PDCD has been reported to be mainly limited within the posterior stroma immediately anterior to Descement membrane as observed by slit-lamp biomicroscopy, and confirmed by Malhotra et al  using anterior segment optical coherence tomography. Similarly, some IVCM studies have revealed that the lesion of PDCD was restricted within the posterior stroma [9–13]. However, other IVCM studies have found that the lesion of PDCD was involved in the whole thickness of the corneal stroma [9, 10, 13]. The involvement of corneal endothelial layer was also reported in some PDCD patients [2, 12]. In our present case, using IVCM, we found that the enlarged keratocytes with hyperreflective particles in the posterior stroma were consistent with the histopathological study. We also found hyperreflective particles outside the anterior stroma, which has not been reported previously.
X-linked ichthyosis is a genetic disorder of the skin caused by mutation or deletion of the STS gene on chromosome Xp22.3. The STS gene is composed of 10 exons that span a region of about 140 kb. Up to 90% X-linked ichthyosis patients exhibit large deletions of the entire STS gene and flanking sequences, while a minority show a point mutation or partial deletion of the STS gene [17, 18]. In our case, we demonstrated that the patient had a deletion of the entire STS gene and flanking sequences DXS1139-DXS22S1 using PCR. He had no immediate family history of X-linked ichthyosis, but similar ichthyotic skin was found in his maternal grandmother’s brother. So we speculated that his mother and his maternal mother were heterozygous females, and the STS gene deletion of our patient was hesitated from them. Hung et al  also demonstrated that the corneal changes in PDCD and X-linked ichthyosis were associated with deletion of the STS detected with microarray-based comparative genomic hybridization. STS is found throughout the body, including the epidermis, where it is thought to play a role in the steroid production and lipid regulation of the stratum corneum . As STS deficiency leads to elevated plasma levels of cholesterol sulfate, the characteristic feature of posterior stromal opacities in PDCD has been postulated to represent focal accumulations of cholesterol sulfate [7, 16]. Therefore, we propose that STS deficiency may lead to lysosomal dysfunction and lipid metabolism disorder, thus leading to accumulation of undigested substances in the intracellular and extracellular compartments of keratocytes. This may explain the hyperreflective particles in the anterior and posterior stroma identified in our patient by IVCM.
In summary, we first reported the IVCM characteristics of PDCD associated with X-linked ichthyosis. These IVCM findings of PDCD may be associated with STS deficiency, caused by X-linked ichthyosis. Gene analysis demonstrated that there was complete a deletion of all ten exons and part flanking sequences of STS gene in the patient. Therefore, IVCM is useful for analyzing the corneal structural changes in rare corneal dystrophies where availability of corneal tissues is limited for examination.
The International classification of corneal dystrophies
In vivo confocal microscopy
Pre-descemet corneal dystrophy
The authors would like to thank Dr. Xian-jun Liu and Dr. Dan Shao for their great support of gene analysis. We thank Comate Bioscience Co., Ltd. and BGI TechSolutions Co., Ltd. for technical assistance. We are grateful to the patient, his family and the healthy volunteers for their enthusiastic participation.
This research was funded by research grants from the National Natural Science Foundation of China (Grant No. 81400403).
Availability of data and materials
All the data supporting the findings is contained within the manuscript.
ZHC and QH carried out the design of the study and critical revision of manuscript. HS and LLL drafted the manuscript and carried on gene analysis. XFQ and TTL evaluated IVCM and anterior segment photography. XHL and YMW reviewed the literature. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the editor of this journal.
Ethics approval and consent to participate
The ethics committee of the First Hospital of Jilin University approved this study, and the patient gave written informed consent.
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- Chen PL, Tang KP, Liang JB. Pre-Descemet's corneal dystrophy associated with ichthyosis. Chinese Medical Journal (Taipei). 2002;65:407–9.Google Scholar
- Malhotra C, Jain AK, Dwivedi S, Chakma P, Rohilla V, Sachdeva K. Characteristics of Pre-Descemet Membrane Corneal Dystrophy by Three Different Imaging Modalities-In Vivo Confocal Microscopy, Anterior Segment Optical Coherence Tomography, and Scheimpflug Corneal Densitometry Analysis. Cornea. 2015;34:829–32.View ArticlePubMedGoogle Scholar
- Weiss JS, Moller HU, Aldave AJ, Seitz B, Bredrup C, Kivela T, et al. IC3D classification of corneal dystrophies--edition 2. Cornea. 2015;34:117–59.View ArticlePubMedGoogle Scholar
- Shapiro LJ, Weiss R, Buxman MM, Vidgoff J, Dimond RL, Roller JA, et al. Enzymatic basis of typical X-linked icthyosis. Lancet (London, England). 1978;2:756–7.View ArticleGoogle Scholar
- Bale SJ, Doyle SZ. The genetics of ichthyosis: a primer for epidemiologists. J Invest Dermatol. 1994;102:49S–50S.View ArticlePubMedGoogle Scholar
- Wells RS, Kerr CB. Genetic classification of ichthyosis. Arch Dermatol. 1965;92:1–6.View ArticlePubMedGoogle Scholar
- Jay B, Blach RK, Wells RS. Ocular manifestations of ichthyosis. Br J Ophthalmol. 1968;52:217–26.View ArticlePubMedPubMed CentralGoogle Scholar
- Costagliola C, Fabbrocini G, Illiano GM, Scibelli G, Delfino M. Ocular findings in X-linked ichthyosis: a survey on 38 cases. Ophthalmologica. 1991;202:152–5.View ArticlePubMedGoogle Scholar
- Grupcheva CN, Malik TY, Craig JP, Sherwin T, McGhee CN. Microstructural assessment of rare corneal dystrophies using real-time in vivo confocal microscopy. Clin Experiment Ophthalmol. 2001;29:281–5.View ArticlePubMedGoogle Scholar
- Holopainen JM, Moilanen JA, Tervo TM. In vivo confocal microscopy of Fleck dystrophy and pre-Descemet's membrane corneal dystrophy. Cornea. 2003;22:160–3.View ArticlePubMedGoogle Scholar
- Ye Y-F, Zhang H-C, Xie Y-N, Yao Y-F. Pre-Descemet's membrane corneal dystrophy: a case report. Chin Ophthalmic Res. 2009;27:39.Google Scholar
- Yeh SI, Liu TS, Ho CC, Cheng HC. In vivo confocal microscopy of combined pre-descemet membrane corneal dystrophy and fuchs endothelial dystrophy. Cornea. 2011;30:222–4.View ArticlePubMedGoogle Scholar
- Kontadakis GA, Kymionis GD, Kankariya VP, Papadiamantis AG, Pallikaris AI. Corneal confocal microscopy findings in sporadic cases of pre-descemet corneal dystrophy. Eye Contact Lens. 2014;40:e8–e12.View ArticlePubMedGoogle Scholar
- Shang DD, Zhang X, Liu A, Du L, Jiang WY, Xiao SX. Xp22.3 microdeletions in three Chinese families with X-linked ichthyosis. J Dermatol Sci. 2009;55:193–5.View ArticlePubMedGoogle Scholar
- Curran RE, Kenyon KR, Green WR. Pre-Descemet's membrane corneal dystrophy. Am J Ophthalmol. 1974;77:711–6.View ArticlePubMedGoogle Scholar
- Kempster RC, Hirst LW, de la Cruz Z, Green WR. Clinicopathologic study of the cornea in X-linked ichthyosis. Arch Ophthalmol. 1997;115:409–15.View ArticlePubMedGoogle Scholar
- Hernandez-Martin A, Gonzalez-Sarmiento R, De Unamuno P. X-linked ichthyosis: an update. Br J Dermatol. 1999;141:617–27.View ArticlePubMedGoogle Scholar
- Valdes-Flores M, Kofman-Alfaro SH, Vaca AL, Cuevas-Covarrubias SA. Deletion of exons 1-5 of the STS gene causing X-linked ichthyosis. J Invest Dermatol. 2001;116:456–8.View ArticlePubMedGoogle Scholar
- Hung C, Ayabe RI, Wang C, Frausto RF, Aldave AJ. Pre-Descemet corneal dystrophy and X-linked ichthyosis associated with deletion of Xp22.31 containing the STS gene. Cornea. 2013;32:1283–7.View ArticlePubMedPubMed CentralGoogle Scholar
- Reed MJ, Purohit A, Woo LW, Newman SP, Potter BV. Steroid sulfatase: molecular biology, regulation, and inhibition. Endocr Rev. 2005;26:171–202.View ArticlePubMedGoogle Scholar