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| Year : 2019 | Volume
: 62
| Issue : 3 | Page : 457-460 |
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| Nephropathic cystinosis presenting with uveitis: Report of a “Can't See, Can't Pee” situation |
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Smita Mary Matthai1, Shibu Jacob2, Mandeep S Bindra3, Vinoi George David2, Santosh Varughese2
1 Central Electron Microscopy Facility, Wellcome Trust Research Laboratory, Vellore, Tamil Nadu, India
2 Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu, India
3 Department of General Pathology, Christian Medical College, Vellore, Tamil Nadu, India
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| Date of Web Publication | 26-Jul-2019 |
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 Abstract | | |
Nephropathic cystinosis is a rare autosomal recessive lysosomal disease characterized by accumulation of pathognomonic cystine crystals in renal and other tissues of the body. Cystinosis is caused by mutant cystinosin, the cystine transport protein located in lysosomal membranes, leading to systemic deposits of cystine and resultant end organ damage. Cystinosis is rarer in Asians than Caucasians with only a handful of cases reported from India to date. Due to its extreme rarity and clinically insidious presentation in contrast to the infantile form, the diagnosis of juvenile nephropathic cystinosis is frequently delayed or overlooked. Moreover, routine processing and sectioning of paraffin embedded tissues dissolves cystine crystals, making it difficult to diagnose this condition on light microscopic examination alone, mandating electron microscopic (EM) analysis of renal biopsies for an accurate diagnosis of this condition. We describe a case of juvenile nephropathic cystinosis presenting with uveitis and photophobia in a 17-year-old Indian male, diagnosed after EM examination of the patient's renal biopsy for evaluation of nephrotic syndrome. While highlighting the diagnostic utility of EM, we describe a few histopathologic clues which can prompt inclusion of EM analysis of renal biopsies in this setting.
Keywords: CTNS gene, cysteamine, cystinosis, lysosomal diseases, nephropathic cystinosis
How to cite this article:
Matthai SM, Jacob S, Bindra MS, David VG, Varughese S. Nephropathic cystinosis presenting with uveitis: Report of a “Can't See, Can't Pee” situation. Indian J Pathol Microbiol 2019;62:457-60 |
How to cite this URL:
Matthai SM, Jacob S, Bindra MS, David VG, Varughese S. Nephropathic cystinosis presenting with uveitis: Report of a “Can't See, Can't Pee” situation. Indian J Pathol Microbiol [serial online] 2019 [cited 2023 May 28];62:457-60. Available from: https://www.ijpmonline.org/text.asp?2019/62/3/457/263493 |
| Introduction | |  |
Cystinosis is a rare autosomal recessive lysosomal transport disorder characterized by systemic intracellular accumulation of the amino acid cystine due to mutations in the CTNS gene encoding for the carrier protein cystinosin which transports cystine out of the lysosomal compartment.[1] The pathological hallmark of cystinosis is identification of intralysosomal cystine crystals in all body cells and organs, prominently observed as “gold dust” in cornea and conjunctiva.[2]
Depending on the mutation affecting the CTNS gene, cystinosis has been categorized into three different forms, which differ in age at manifestation and severity of the symptoms: (i) infantile nephropathic cystinosis, which is the most common and severe form leading to end-stage renal disease (ESRD) in the first decade of life, if left untreated; (ii) juvenile nephropathic cystinosis, characterized by later onset of symptoms and slower disease progression; and (iii) non-nephropathic cystinosis, with a mainly ocular manifestation, also known as adult form.[1]
The annual incidence of cystinosis is 1 in 100,000–200,000 live births in the United States and Europe, of which the juvenile form accounts for only 5% of the cases.[1],[3] The incidence is lower in Asian populations and almost nil in the middle eastern countries.[3],[4] This low frequency of occurrence coupled with mildly progressive symptomatology of the juvenile form is responsible for the difficulties encountered in the diagnosis of juvenile nephropathic cystinosis which is often delayed resulting in irreversible kidney damage.
We report a case of a 17-year-old Indian male whose presenting manifestation was uveitis and visual disturbances along with nephrotic range proteinuria, in whom electron microscopic (EM) evaluation of renal biopsy revealed pathognomonic crystalline deposits of nephropathic cystinosis. The diagnosis was further confirmed by corneal slit lamp examination revealing corneal gold dust crystals.
| Case Report | | |
A 17-year-old Indian male presented with a history of blurring of vision and photophobia of 6 months' duration which had been initially diagnosed as uveitis at local hospital and treated with “eye drops” (further details of initial treatment were not available). Two months after onset of ocular symptoms, he started noticing gradually progressive pedal edema, and urine protein by dipstick method was found to be 3+. He was referred to our center for evaluation of proteinuria of unknown cause and persisting visual disturbances. He was born to nonconsanguineous healthy parents, and his childhood growth and development had been normal. Physical examination was unremarkable except for bilateral pitting pedal edema and increased lacrimation with photophobia. His laboratory findings were as follows: serum creatinine 1.26 mg% (normal range: 0.5–1.4 mg%), blood urea 43 mg% (normal range: 15–40 mg%), urine protein excretion in 24 h 6.7 g, and urine analysis showed protein 3+ with no active sediments. Serological tests for bloodborne viral infections (HIV, hepatitis B and C) were negative. Blood glucose levels were within normal range. Assays for serum complements (C3 and C4), antinuclear antibodies, and antineutrophil cytoplasmic antibody levels showed normal results. His serum uric acid levels were mildly decreased (3.3 mg/dL; normal range: 4–7 mg/dL).
An ultrasound-guided renal biopsy was performed to ascertain cause of nephrotic range proteinuria. Light microscopic (LM) examination of two cores of renal tissue received for evaluation showed 15 glomeruli, 4 of which were globally sclerosed. Three of the remaining 11 glomeruli showed focal segmental glomerulosclerosis (FSGS) with mild increase in mesangial cellularity. There was no thickening or double contouring of capillary walls. Many multinucleated visceral and parietal epithelial cells were noted [Figure 1]a and [Figure 1]b. The interstitium showed foci of fibrosis and tubular atrophy with an Interstitial fibrosis tubular atrophy score (IFTA score) of approximately 10%–15% of renal cortical tissue examined. Features of chronic tubulointerstitial nephritis were observed along with barely discernible cleft-like spaces in focal proximal tubular epithelial cells and interstitial histiocytes [Figure 1]c and [Figure 1]d. Immunofluorescence studies showed nonspecific trapping of IgM and C3 in sclerosed tufts and negative staining for IgG, IgA, IgM, C3, C4, kappa, and lambda. Examination of toluidine blue–stained epoxy resin–embedded tissue sections revealed rhomboid, hexagonal, and needle-shaped clefts within interstitial histiocytes and focal proximal convoluted tubular epithelium [Figure 2]a. EM evaluation confirmed the presence of membrane-bound, intracytoplasmic and intralysosomal, polygonal, needle-shaped, and rectangular clefts in interstitial histiocytes and lining epithelium of few adjoining proximal tubules, corresponding to dissolved cystine crystals [Figure 2]b, [Figure 2]c, [Figure 2]d. A diagnosis of crystalline nephropathy was rendered based on these findings, and ophthalmic assessment was requested to confirm the presence of corneal cystine crystals. Slit lamp examination of cornea demonstrated the presence of cystine crystals, confirming the diagnosis of juvenile nephropathic cystinosis with ocular involvement. | Figure 1: (a) Light microscopic examination of a glomerulus reveals a multinucleated podocyte (arrow) (H and E × 200). (b) Polykaryocytosis of glomerular visceral epithelial cells (arrows) clearly visible at higher magnification, providing a unique diagnostic clue (H and E × 400). (c) Small intraepithelial needle-shaped clefts in proximal tubular epithelium are difficult to appreciate on light microscopy even at higher magnification (H and E × 400). (d) Clefts within interstitial histiocytes are barely visualized on light microscopic examination of formalin-fixed sections (H and E × 400)
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 | Figure 2: (a) Cleft-like spaces left behind by dissolved cystine crystals are evident within interstitial histiocytes andproximal tubular epithelium on epoxy resin–embedded scout sections (toluidine blue × 400). (b) Membrane-bound rectangular, rhomboid, and hexagonal clefts corresponding to dissolved cystine crystals within neck region of proximal tubular epithelial lining cells (transmission electron microscopy × 4200). (c) Interstitial histiocytes demonstrate characteristic crystal clefts of cystinosis (transmission electron microscopy × 4200).(d) Intralysosomal accumulation of needle-shaped and polygonal cystine crystal clefts (arrow) along with intracytoplasmic crystal clefts within a proximal tubular epithelial cell and an adjacent interstitial histiocyte (transmission electron microscopy × 6000)
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The treatment modalities for nephropathic cystinosis were discussed with the patient and family who deferred cysteamine therapy, possibly due to financial constraints. On follow-up after 5 months, his serum creatinine remained stable at 1.29 mg% while proteinuria had increased to 8.08 g in 24 h. The patient was repeatedly counseled regarding management options, including information about “The Cystinosis Foundation of India” which is helping several children affected by cystinosis,[5] but was lost to follow-up after 5 months.
| Discussion | | |
Among the three forms of cystinosis, diagnosis of the juvenile nephropathic form is the most difficult due to its rarity, indolent nature of disease, and less prominent corneal crystals than the infantile form. Juvenile nephropathic cystinosis is usually diagnosed in the second decade of life when the onset of photophobia leads to ocular examination which reveals the characteristic crystalline corneal deposits.[4],[6] Diagnosis by renal biopsy as occurred in our case is not the usual paradigm because visual complaints usually precede the slowly manifesting renal symptoms and mild urinary abnormalities.
Cystinosis was first described in 1903 by Swiss biochemist Emil Abderhalden as “familial cystine accumulation disease” based on the postmortem findings in a 21-month-old child who had multiorgan massive cystine deposition.[7] Over the years, the pathogenetic mutation was localized to the CTNS gene located on the short arm of chromosome 17 p13, coding for cystinosin, a lysosomal cystine proton symporter. To date, more than 100 different mutations have been identified in the CTNS gene,[8] most frequent of which is the 57-kb base pair deletion of the first 10 exons of CTNS gene, a 5' upstream region with the CARKL-gene-encoding sedoheptulokinase, and two non-coding exons of the TRPV1 gene.[9] The prototype disease of this mutation, commonly encountered in North Europeans, is the infantile nephropathic cystinosis. Absence of this European founder deletion in CTNS gene in East Asian and middle eastern populations accounts for the rarity of this disease in these geographical locations.[9]
Cystine is a disulfide of the amino acid cysteine, generated by lysosomal protein hydrolysis. Mutations affecting cystinosin result in defective transport of cystine across lysosomal membranes leading to accumulation and crystallization of cystine in the lysosomal compartment. Lysosomal cystine overload causes mitochondrial dysfunction, oxidative stress, and inflammation in the protagonist cells which ultimately undergo apoptosis. Since lysosomes are ubiquitous in the human cells, cystine accumulation occurs throughout the whole body, making cystinosis a systemic disease. However, susceptibility to cystine accumulation varies between organs, with renal and ocular cells leading the fray.[3],[9]
In the kidney, proximal convoluted tubules (PCTs) exhibit maximum susceptibility, manifesting as Fanconi syndrome in the infantile form of cystinosis. The “swan neck deformity,” identified by nephron microdissection studies, is difficult to appreciate on routine LM examination and is due to the atrophy of the first portion of PCT, possibly preceded by intraepithelial cystine crystal accumulation.[10] In addition, water solubility of cystine crystals makes them difficult to appreciate in formalin-fixed sections, whereas they are better visualized on toluidine blue–stained glutaraldehyde-fixed semi-thin sections as clefts and polygonal spaces. EM analysis is therefore essential for accurate pickup and characterization of cystine crystals in tissues. Glomerular lesions in cystinosis are confined to polykaryocytosis, that is, multinucleation of visceral and parietal epithelial cells and secondary FSGS, particularly in patients with proteinuria.[11]
Extrarenal complications of cystinosis include corneal crystals causing blepharospasm, photophobia, band keratopathy and retinal blindness in the eye, vacuolar myopathy, hypophosphatemic rickets, pancreatic exocrine insufficiency, hypothyroidism, male hypogonadism, benign intracranial hypertension, neurocognitive impairment, cystine encephalopathy, dysphagia, pulmonary dysfunction, vascular calcifications, and nodular regenerative hyperplasia of the liver.[1],[3],[9]
Diagnosis of cystinosis rests on three main modalities which are (i) detection of elevated cystine levels in white blood cells by high-performance liquid chromatography or liquid chromatography-tandem mass spectrometry methods, (ii) molecular testing for pathogenetic mutations by gene sequencing of CTNS gene, and (iii) visualization of corneal cystine crystals by slit lamp examination.[3],[9] The last modality is the main diagnostic method in developing countries because of its relative inexpensive and reliable outcomes.
Investigations for detecting long-term extrarenal complications include modified barium videofluoroscopy and oral sensorimotor evaluation for assessment of feeding difficulties and swallowing dysfunction, electromyography for documentation of cystinotic myopathy, computed tomography (CT) or magnetic resonance imaging of the brain to detect cerebral atrophy or calcifications in basal ganglia and/or periventricular region, CT of the chest to detect coronary artery and other vascular calcifications, and ophthalmologic examination with electroretinography to provide surveillance for late eye complications.
Cystinosis is one of the rare metabolic disorders for which treatment is available in the form of cysteamine supplementation which lowers intracellular levels of cystine by enabling its transportation. The advent of cystine depletion therapy has dramatically altered the prognosis of this disease in developed countries with postponement of ESRD onset by decades. However, renal survival in developing countries still lags behind dismally due to limited access to cysteamine and late initiation of therapy owing to delayed or missed diagnosis.[12] While nephropathic cystinosis remains an orphan disease which is mostly underdiagnosed and undertreated in developing countries, it is hoped that new emerging approaches to treatment such as administering cysteamine in gelatine capsules with 0.2% silicic acid acting as a dessicator (which is currently the preferred galenic form compared with suppositories or syrup), novel compounds, and hematopoietic stem-cell transplantation may delay the onset of ESRD and thus improve the global survival of patients by facilitating more equitable healthcare provisions.[13]
In conclusion, early diagnosis of nephropathic cystinosis and timely initiation of cysteamine therapy can have a major impact on the quality of life of the patient, for which a high index of clinical suspicion along with availability of routine EM services for diagnostic evaluation of renal biopsies is required. This would call for a focused reinforcement of clinical phenotypes and early recognition of tubulopathies in the training programs of pediatricians and nephrologists. From the view point of pathologists, it is noteworthy to reiterate that water solubility of cystine crystals commonly abnegates diagnosis by routine LM examination of formalin-fixed sections, resulting in earliest recognition of crystals on epoxy resin–embedded toluidine blue sections, as seen in our case, highlighting the role of EM analysis in diagnosis of nephropathic cystinosis on renal biopsies.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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Correspondence Address:
Shibu Jacob
Department of Nephrology, Christian Medical College, Vellore, Tamil Nadu - 632 004
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/IJPM.IJPM_623_18
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