Abstract

Cystinosis is a rare autosomal recessive lysosomal storage disease associated with high mortality and morbidity rates. The most distinctive ocular manifestations of cystinosis are photophobia, tearing, and blurred vision. Herein, we assessed the ocular involvement of four patients from two families diagnosed with infantile nephropathic cystinosis using optical coherence tomography (OCT) and in vivo confocal microscopy (IVCM). Anterior segment OCT demonstrated multiple hyperreflective punctate deposits, and IVCM revealed needle-shaped bright crystal deposits in the corneal stroma in all patients. Three patients also had crystal deposits in the epithelium, where epithelial cell disruption was observed. Crystal deposits around the subepithelial nerve plexus were noted in some sections. In one patient, round and needle-shaped bright deposits along with inflammatory cells were observed in the limbal region of the conjunctiva. Infrared fundus images of two female siblings revealed hyperreflective crystal-like deposits around the optic disc, macula, and peripheral retina, and enhanced depth imaging OCT showed accumulation of crystals in all layers of the retina.

Introduction

Cystinosis is a rare lysosomal storage disease with autosomal recessive inheritance and high mortality and morbidity.^{1, 2} It is caused by a mutation in the CTNS gene, which is located on chromosome 17p13.2 and encodes cystinosin, a membrane transport protein that transports cystine from lysosomes to the extracellular space.^{1, 3}

Cystinosis has three clinical forms: infantile (early-onset) nephropathic cystinosis, juvenile (late-onset) nephropathic cystinosis, and adult (ocular) cystinosis. Infantile nephropathic cystinosis accounts for approximately 95% of cases and is the most severe form.¹ Cystine crystals can accumulate in various organs, including primarily the eyes and kidneys, as well as the nervous system, thyroid gland, bones, muscles, bone marrow, pancreas, liver, lungs, and gonads.⁴ These deposits can lead to numerous problems such as Fanconi syndrome, renal failure, rickets, retarded growth and development, learning disabilities, muscle atrophy, gastrointestinal symptoms, dysphagia, and hypothyroidism.^{5, 6}

In the eye, deposition can be seen in the cornea, conjunctiva, limbus, iris, anterior chamber, iridocorneal angle, lens capsule, ciliary body, choroid, and rarely in the retinal pigment epithelium and optic disc.¹ Clinically, it causes symptoms such as photophobia, tearing, and blurred vision.^{7, 8} Corneal deposition starts in the periphery and superficial layers and later progresses centrally and into the deeper corneal layers.⁹ Gahl et al.¹ defined a scoring system to objectively evaluate the density of cystine deposits in the cornea. This corneal cystine crystal score (CCCS) ranges from 0 (no deposits) to 3 (full of deposits) with 0.25-unit intervals. In advanced cases, pathologies such as recurrent corneal epithelial erosions, corneal thinning, band keratopathy, filamentary keratitis, peripheral corneal neovascularization, posterior synechia, secondary pupillary block, glaucoma, papilledema, and reduced color and night vision may occur.^{1, 2, 3}

In this case report, we discuss the ocular involvement of four patients from two families diagnosed with infantile nephropathic cystinosis and present their in vivo laser confocal microscopy (IVCM) and anterior segment optical coherence tomography (OCT) findings.

Discussion

Ocular involvement is among the most common causes of symptoms and morbidity in patients with cystinosis.¹ The most prominent feature of ocular involvement in cystinosis is diffuse crystal deposition in the cornea. IVCM and OCT enable a detailed assessment of the depth and morphology of these crystals.^{10, 11} Ozdemir et al.¹⁰ demonstrated the presence of needle- and fusiform-shaped crystal structures in the anterior and posterior stroma using anterior segment OCT and IVCM imaging in a 36-year-old male patient diagnosed with cystinosis. No cystine deposits were detected in the corneal epithelial and endothelial layers. Keidel et al.¹¹ revealed widespread crystal deposition in all levels of the stroma using anterior segment OCT in 88 eyes of 45 patients. We also observed diffuse stromal deposits in all 4 patients in this study, but there were also deposits in the epithelium in 3 patients. Disruptions in the epithelial cells were noted in areas of dense crystal deposition.

In addition to the cornea, cystine crystals may also accumulate in the retina and choroid in cystinosis. Al Abdulsalam¹² reported OCT findings of dome-shaped crystal deposits in the outer retinal layers in the subfoveal region in a 19-year-old female patient with cystinosis. Keidel et al.¹³ detected cystine crystals in the fovea on fundus examination and stated that on OCT imaging, these deposits were densest in the choriocapillaris, followed by the GCL, INL, IPL, and choroid. Among our patients, no significant retinal pathology was observed in the boys, while the girls had widespread cystine crystals in the GCL, IPL, INL, and OPL on posterior segment OCT sections and fundus autofluorescence.

Cystinosis is treated with cysteamine, which is available in oral and topical form. Oral cysteamine therapy may slow the progression of renal and retinal findings, but its effect on the cornea is limited because of its avascular structure. In contrast, topical cysteamine both relieves symptoms and helps dissolve crystals in the cornea.^{1, 14} Early-onset, long-term cysteamine therapy delays end-stage renal failure, reduces the risk of extrarenal complications, and improves survival rates.¹⁵ Among our cases, we believe the diagnosis of the boys at age 2 and 5 and the resulting early initiation of treatment prevented the occurrence of renal complications.

Calculations based on IVCM and OCT deposit analysis have been shown in the literature to offer a more objective and accurate assessment during disease progression and may serve as biomarkers in the future.^{11, 16} Vercauteren et al.¹⁷compared corneal thickness measurements taken by anterior segment OCT and corneal tomography in patients with cystinosis and found that corneal tomography measurements were much higher. Therefore, they suggested that anterior segment OCT should be taken as a basis for prognosis and evaluation of treatment response. In our patients, CCT measurements performed with anterior segment OCT did not show a marked deviation from corneal tomography measurements.

In the literature, studies of cystinosis patients consist of limited cases series. Our study demonstrated for the first time with IVCM that crystals accumulated in the corneal epithelium. In conclusion, cystinosis is a rare lysosomal storage disease with autosomal recessive inheritance, and the morphology, extent, and depth of cystine crystals deposited in the cornea and retina can be objectively demonstrated at the tissue and cellular level with IVCM and OCT.