Sly syndrome

A 10-year-old boy with a diagnosis of infantile cystinosis and progressive renal failure underwent bilateral nephrectomy in preparation for renal transplantation. The native right kidney weighed 42.1 g (expected weight, 82 g), and the native left kidney weighed 36.1 g (expected weight, 83 g). Multiple sections from both the kidneys were fixed in 10% neutral buffered formalin and processed routinely for light microscopy. The sections showed global sclerosis of 30% to 40% of the glomeruli (Figure 1, hematoxylin-eosin, original magnification X40). The remaining glomeruli showed varying degrees of segmental sclerosis and capillary basement membrane thickening. Occasional giant cell transformation of the glomerular visceral epithelial cells was seen. We did not identify the "dark" cells, which are considered to be unique to cystinotic kidneys. The tubules showed moderate-to-severe atrophy with scattered dilated tubules. Some tubular lumens contained hyaline casts. A few tubular epithelial cells showed protein resorption droplets in their cytoplasm. Interstitial fibrosis and multiple foci of chronic inflammation predominantly composed of lymphocytes were seen. Occasional tubular and interstitial calcification was seen. With the help of a polarizer attachment to the light microscope, birefringent rectangular to polygonal crystals of cystine were seen in the tubular and interstitial cells (Figure 2, hematoxylin-eosin, original magnification ×100).

Cystinosis is an inherited, autosomal recessive disorder of lysosomal storage caused by a defective lysosomal integral membrane protein, cystinosin, which transports cystine (a disulfide of the amino acid cysteine) out of the lysosomes. A defect in cystinosin leads to abnormal lysosomal accumulation of soluble and crystalline cystine in various organs of the body. Cystinosin is encoded by the gene CTNS, which has been mapped to chromosome 17p13. The most common mutation that leads to cystinosis is a 57-kb deletion upstream of and including exon 10. This mutation is found in more than three quarters of the patients of European descent. A genotype-phenotype correlation occurs, with the more severe mutations leading to the nephropathic infantile form of the disease (OMIM 219800). Less severe mutations lead to the nephropathic late-onset (OMIM 219900) and the nonnephropathic ocular (OMIM 219750) forms of cystinosis. The infantile form of the disease occurs with an incidence of 1 in 100000 to 200000 live births and a carrier frequency of 1 in 200 in the North American population. The incidence is higher in parts of Western Europe, including France, the United Kingdom, and Germany. The untreated infantile form is the most common inherited form of renal Fanconi syndrome, but it also causes glomerular disease, leading to progressive renal failure that requires dialysis or renal transplantation by the age of 10 years. Although normal at birth, these children fail to grow and gain weight appropriately and develop electrolyte imbalances, renal tubular acidosis, hypophosphatemic rickets, photophobia, hypothyroidism, and heat intolerance due to diminished sweat production. The transplanted donor kidney does not develop abnormal accumulations of cystine, but the patients continue to store large amounts of cystine in other organs, leading to the late-onset manifestations of retinal blindness, corneal erosions, type 1 diabetes mellitus, pancreatic insufficiency, primary testicular failure, and neurologic symptoms. Skeletal myopathy leads to weakness, hypophonia, dysphagia, and diminished pulmonary function. The patients with late-onset variants of nephropathic cystinosis have slower progression of their renal and extrarenal disease and do not manifest growth retardation. The disease in the nonnephropathic ocular form of cystinosis is limited to the eyes. Further studies are under way to explain the exact mechanisms of organ damage in cystinosis.

The diagnosis of cystinosis does not require tissue biopsies and histologic evaluation but can be made by slitlamp examination of the cornea, revealing crystalline keratopathy. However, cystine crystals in the cornea are not usually detectable in the first year. Patchy deposition is seen at 12 to 24 months, and the untreated cornea is packed with crystals by 3 to 4 years of age. The diagnosis can be confirmed by measuring cystine content of peripheral white blood cells. Besides symptomatic therapy, the key to an improved quality of life and prolonged survival in patients with infantile cystinosis lies in early diagnosis and initiation of treatment with cysteamine bitartrate before the age of 2 years. Cysteamine enters the lysosomes by a specific transporter and converts cystine to cysteine and cysteine-cysteamine mixed disulfide. Cysteine and cysteine-cysteamine then exit the lysosome by their respective carrier proteins. Oral cysteamine therapy reduces the accumulation of lysosomal cystine in all body cells except for the epithelial cells of the avascular cornea. Topical cysteamine eyedrops clear cystine accumulations in the cornea.1,2

References

1. Gahl WA, Thoene JG, Schneider JA. Cystinosis: a disorder of lysosomal membrane transport. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic & Molecular Bases of Inherited Disease. 8th ed. New York, NY: McCrawHill; 2001:5085-5108.

2. Kalatzis V, Antignac C. New aspects of the pathogenesis of cystinosis. Pediatr Nephrol. 2003;18:207-215.

Dinesh Rakheja, MD; Dennis C. Wooten, MD, PhD; Ana M. Cornez, MD, PhD

Accepted for publication August 20, 2004.

From the Departments of Pathology, Children's Medical Center of Dallas (Drs Rakheja and Comez), and University of Texas Southwestern Medical Center (Drs Rakheja, Wooten, and Gomez), Dallas, Tex.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Dinesh Rakheja, MD, Department of Pathology, Mail Code 9073, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 (e-mail: dinesh.rakheja@ utsouthwestern.edu).

Copyright College of American Pathologists Jan 2005
Provided by ProQuest Information and Learning Company. All rights Reserved