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Familial Nephropathy and Multiple Exostoses with Exostosin-1 (EXT1) Gene Mutation

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Familial Nephropathy and Multiple Exostoses with Exostosin-1 (EXT1) Gene Mutation PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org Familial Nephropathy and Multiple Exostoses With Exostosin-1 (EXT1) Gene Mutation Ian S. D. Roberts* and Jonathan M. Gleadle† *Department of Cellular Pathology, John Radcliffe Hospital, Headley Way, Headington, Oxford, United Kingdom; and †Renal Unit, Level 6, Flinders Medical Centre, Bedford Park, South Australia, Australia ABSTRACT Glomerular deposition of fibrillar collagen is a characteristic finding of genetically mained in remission with trace protein- distinct conditions, including nail-patella syndrome and collagen type III glomeru- uria until cyclosporine was stopped 3.5 lopathy. A case of familial nephropathy in which steroid-sensitive nephrotic syn- yr later. Six months after this, she suf- drome and glomerular deposits of fibrillar collagen are associated with multiple fered another relapse of nephrotic exostoses due to mutation of the EXT1 gene is described. This gene encodes a syndrome that responded to 60 mg pred- glycosyltransferase required for synthesis of heparan sulfate glycosaminoglycans. nisolone and reintroduction of cyclo- There is deficiency of heparan sulfate and perlecan, together with accumulation of sporine. After a further relapse 18 mo collagens, in the matrix of EXT1-associated osteochondromas. Similar glomerular later and because of the development of basement membrane abnormalities could offer an explanation for both the renal adverse corticosteroid effects, she was ultrastructural changes and steroid-sensitive nephrotic syndrome. treated with a 2-mo course of cyclophos- phamide (2.5 mg/kg, orally). Ten years J Am Soc Nephrol 19: 450–453, 2008. doi: 10.1681/ASN.2007080842 after her initial presentation, she remains in full remission and off steroids. Renal function has remained normal through- A 37-yr-old woman presented with the history of renal disease and hearing im- out with a current serum creatinine of nephrotic syndrome. Previously, she had pairment, which is illustrated in Figure 1. 1.1 mg/dl. had several episodes of skin infection re- One brother had steroid-sensitive ne- To investigate the cause of her multi- sponding to antibiotics, impaired hear- phrotic syndrome at the age of 4 yr but ple exostoses she underwent sequencing ing since birth and had been diagnosed did not have a renal biopsy. Her father of the gene encoding exostosin-1 (EXT1) with multiple exostoses in childhood. had acute renal failure at the age of 69 yr, on chromosome 8, which demonstrated These included symptomatic lesions in for which a renal biopsy had been per- a frameshift type 2 mutation 238 del A. the upper medial tibiae, left humerus and formed. Review of his biopsy revealed a radius, and neck of the right femur. At pauci-immune focal segmental prolifer- presentation, there was marked periph- ative glomerulonephritis with crescents. RENAL BIOPSY eral edema, and investigations revealed Electron microscopy showed largely nor- The renal biopsy contained 13 glomeruli, 24 g/d proteinuria, albumin 23 g/L, and mal capillary walls but with abundant one of which was globally sclerosed. The serum creatinine 1.1 mg/dl. She was fibrillar collagen within an expanded remaining glomeruli showed only subtle found to be hypothyroid and was com- mesangium. She also reported that two changes at light microscopy (Figure 2a) menced on thyroxine. nephews had childhood nephrotic syn- with a mild increase in mesangial cellu- Importantly, there was a strong family drome and a cousin had “kidney disease” larity and matrix, and focal thickening of and exostoses. A renal biopsy was performed. Fol- lowing this, the patient was treated with Published online ahead of print. Publication date 60 mg/d of prednisolone, resulting in a available at www.jasn.org. prompt remission of her nephrotic syn- Correspondence: Dr. Ian S. D. Roberts, Department drome. She suffered a relapse 3 mo later of Cellular Pathology, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, on discontinuation of steroids, which re- United Kingdom. Phone: ϩ44 (0)1865 222889; Fax: sponded to reintroduction of 40 mg ϩ44 (0)1865 220519; E-mail: [email protected] Figure 1. First-degree relatives of pro- prednisolone. Steroids were replaced Copyright © 2008 by the American Society of band (in red). with cyclosporine after 4 mo and she re- Nephrology 450 ISSN : 1046-6673/1903-450 J Am Soc Nephrol 19: 450–453, 2008 www.jasn.org PATHOPHYSIOLOGY of the RENAL BIOPSY hematuria hematuria Ϯ Ϯ (nephrotic syndrome unusual); chronic renal failure in 30% (nephrotic syndrome unusual); chronic renal failure, particularly in early-onset disease syndrome Persistent proteinuria Persistent proteinuria Steroid-sensitive nephrotic Figure 2. Renal biopsy: Light microscopy (a; Jones silver, original magnification ϫ60) shows increased mesangial matrix and focal thickening of capillary walls (arrows). Electron densa of glomerular basement membrane microscopy shows accumulation of fibrillar collagen in mesangium (b) and capillary walls subendothelial collagen fibrils subendothelial collagen fibrils Collagen fibrils in lamina (c). High power demonstrates the characteristic cross-striated fibrils of collagen (d). Mesangial and Mesangial and capillary walls evident on silver stain. thickening of capillary walls. At electron There was no segmental sclerosis or microscopy, in nail-patella syndrome, membrane spikes. Immunohistochemis- the glomerular basement membrane is try was negative for immunoglobulin G primarily involved and expanded by (IgG), IgA, IgM, C3, and C1q. fibrillar collagen, whereas in our case and Electron microscopy showed wide- in patients with collagen type III glo- spread mesangial expansion by fibrillar merulopathy, the lamina densa is pre- collagen (Figure 2b). Glomerular capil- served; fibrillar collagen accumulates in lary walls appeared normal in many the subendothelial area and mesangium membrane thickening and mesangial matrix expansion expansion, focal mild basement membrane thickening Normal or focal mild basement loops, other than moderate effacement and may result in membrane duplication Basement membrane thickening Mild mesangial matrix of podocyte foot processes. However, and mesangial cell interposition. The others showed expansion of capillary morphology, clinical presentation, and walls by subendothelial electron dense pathogenesis of these conditions are material within, which were abundant summarized in Table 1. collagen fibrils (Figure 2, c and d). The lamina densa in these capillaries showed Renal Pathophysiology expressed by podocytes areas of duplication with focal mesangial These three conditions (nail-patella syn- is systemic stimulation of type III collagen synthesis required for heparan sulfate synthesis Function of Gene Glomerular Changes Electron Microscopy Renal Presentation Transcription factor, cell interposition. drome, collagen type III glomerulopa- Unknown, but there Glycosyltransferase thy, and the current case) are linked by a Differential Diagnosis of the Renal common morphologic lesion, the accu- Biopsy mulation of fibrillar collagen within glo- Glomerular deposition of fibrillar colla- meruli, but the mechanisms by which gen may be seen to a minor degree in this develops are likely to be diverse. Our (autosomal many chronic glomerular diseases but is understanding of the pathophysiology of (autosomal (inheritance) the dominant finding in the nephropa- the morphologic changes and protein- Gene Involved dominant) recessive) dominant) LMX1B thy of nail-patella syndrome and colla- uria in these patients is far from complete Unknown (autosomal EXT1/2 gen type III glomerulopathy. As in this and requires knowledge of the underly- case, the light microscopic changes in ing genetic abnormalities. nail-patella syndrome are typically mild, and glomeruli may appear normal ini- Nail-patella Syndrome Comparison of this case with other conditions associated with glomerular deposition of fibrillar collagens tially. By contrast, collagen type III glo- Nail-patella syndrome results from mu- . merulopathy is always associated with tations of the gene encoding LMX1B on Condition syndrome glomerulopathy multiple exostoses 1 Nail-patella Collagen type III Hereditary obvious mesangial matrix expansion and chromosome 9. LMX1B is a LIM-home- Table 1 J Am Soc Nephrol 19: 450–453, 2008 EXT1 Nephropathy 451 PATHOPHYSIOLOGY of the RENAL BIOPSY www.jasn.org odomain transcription factor that plays a that accumulates in the Golgi apparatus cyte disease, there is growing evidence central role in limb development; hence, and has glycosyltransferase activity that that in steroid-sensitive nephrotic syn- the skeletal abnormalities that result is essential for the synthesis and expres- drome, abnormalities of the glomeru- from mutations in this gene. It is also ex- sion of heparan sulfate glycosaminogly- lar basement membrane play a central pressed by podocytes and regulates tran- cans.6 role. The normal glomerular basement scription of the genes for the ␣3 and ␣4 The mRNA encoding EXT1 is ex- membrane is rich in heparan sulfate chains of type IV collagen, podocin, and pressed ubiquitously in many tissues in- proteoglycans, conferring a negative CD2AP. How this relates to the develop- cluding the kidney, although its renal charge barrier to macromolecules, and ment of the nephropathy, which is a vari- protein expression has not been investi- there is both experimental and clinical able feature of nail-patella syndrome, is gated. In patients with hereditary multi- evidence that loss of this anionic bar- uncertain.2
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