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

Differential Diagnosis of the Renal Biopsy

Glomerular deposition of fibrillar collagen may be seen to a minor degree in many chronic glomerular diseases but is the dominant finding in the nephropathy of nail-patella syndrome and collagen type III glomerulopathy. As in this case, the light microscopic changes in nail-patella syndrome are typically mild, and glomeruli may appear normal initially. By contrast, collagen type III glomerulopathy is always associated with obvious mesangial matrix expansion and thickening of capillary walls. At electron microscopy, in nail-patella syndrome, the glomerular basement membrane is primarily involved and expanded by fibrillar collagen, whereas in our case and in patients with collagen type III glomerulopathy, the lamina densa is preserved; fibrillar collagen accumulates in the subendothelial area and mesangium and may result in membrane duplication and mesangial cell interposition. The morphology, clinical presentation, and pathogenesis of these conditions are summarized in Table 1.

Renal Pathophysiology

These three conditions (nail-patella syndrome, collagen type III glomerulopathy, and the current case) are linked by a common morphologic lesion, the accumulation of fibrillar collagen within glomeruli, but the mechanisms by which this develops are likely to be diverse. Our understanding of the pathophysiology of the morphologic changes and proteinuria in these patients is far from complete and requires knowledge of the underlying genetic abnormalities.

Nail-patella Syndrome

Nail-patella syndrome results from mutations of the gene encoding LMX1B on chromosome 9.¹ LMX1B is a LIM-homeodomain transcription factor that plays a central role in limb development; hence, the skeletal abnormalities that result from mutations in this gene. It is also expressed by podocytes and regulates transcription of the genes for the α3 and α4 chains of type IV collagen, podocin, and CD2AP. How this relates to the development of the nephropathy, which is a variable feature of nail-patella syndrome, is uncertain.² There is, however, a link between genotype and phenotype; individuals with a mutation in the LMX1B homeodomain have a higher frequency of proteinuria than those with mutations in the LIM domains.³

Collagen Type III Glomerulopathy

Most cases of this rare condition show an autosomal recessive pattern of inheritance.⁴ It is a systemic disease; serum procollagen III peptide is invariably elevated, and extrarenal accumulation of type III collagen is reported.⁵ The nature of the genetic abnormality is unknown.

Hereditary Multiple Exostoses

The autosomal dominantly inherited condition hereditary multiple exostoses has been linked to two genes, EXT1 on chromosome 8 and EXT2 on chromosome 11, that account for 80% of affected individuals. The gene encoding EXT1 (8q24.11-q24.13) encodes a 86.3-kDa endoplasmic reticulum-localized type II transmembrane glycoprotein. EXT1 and EXT2 form a hetero-oligomeric complex that accumulates in the Golgi apparatus and has glycosyltransferase activity that is essential for the synthesis and expression of heparan sulfate glycosaminoglycans.⁶

The mRNA encoding EXT1 is expressed ubiquitously in many tissues including the kidney, although its renal protein expression has not been investigated. In patients with hereditary multiple exostoses, functional loss of EXT1 results in exostoses (osteochondromas), but inactivation of both copies of the gene (germline mutation plus loss of the remaining wild-type allele) is not required for development of the bone lesions.⁷ In these lesions, the cartilage matrix shows absence of heparan sulfate,⁸ is deficient in perlecan and decorin, and contains increased amounts of collagens I and X.⁹ Similar loss of heparan sulfate proteoglycans and increased fibrillar collagens in the glomerular capillary walls may account for the clinical presentation and biopsy findings in our patient (Figure 3).

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Figure 3.

Hypothetical pathophysiologic mechanisms in this patient and minimal change nephrotic syndrome.

Although the proteinuria in patients with nail-patella syndrome and collagen type III glomerulopathy is not steroid-sensitive, renal involvement in our patient manifest as steroid-sensitive nephrotic syndrome. The etiology of most cases of steroid-sensitive nephrotic syndrome is unknown. In contrast to steroid-resistant nephrotic focal segmental glomerulosclerosis, which appears to be primarily a podocyte disease, there is growing evidence that in steroid-sensitive nephrotic syndrome, abnormalities of the glomerular basement membrane play a central role. The normal glomerular basement membrane is rich in heparan sulfate proteoglycans, conferring a negative charge barrier to macromolecules, and there is both experimental and clinical evidence that loss of this anionic barrier, because of degradation of the heparan sulfate chains by the enzyme heparanase, results in proteinuria. In experimental models, enzymatic depletion of heparan sulfate in the glomerular basement membrane results in increased permeability,^10,11 and injection of animals with a monoclonal antibody against glomerular basement membrane heparan sulfate induces acute selective proteinuria.¹² In normal glomeruli, there is minimal expression of heparanase, but a marked increase in glomerular heparanase staining is observed in the acute puromycin aminonucleoside nephrosis model of nephrotic syndrome.¹³ Transgenic mice that overexpress heparanase in all tissues are proteinuric and show effacement of podocyte foot processes, similar to that seen in minimal change nephropathy.¹⁴ Renal biopsies from patients with minimal change nephropathy show absent or markedly reduced glomerular basement membrane staining with an antibody against heparan sulfate side chains but normal staining for the agrin core protein of heparan sulfate proteoglycans.¹⁵ Recently, it has been demonstrated that relapsing steroid-sensitive nephrotic syndrome in children is associated with elevated urinary heparanase activity,¹⁶ implicating loss of heparan sulfate in the pathogenesis of the nephrotic syndrome in these patients. Heparanase is expressed by peripheral T lymphocytes, providing a link between the immune abnormalities and glomerular basement membrane changes observed in minimal change nephropathy.

In our patient with steroid-sensitive nephrotic syndrome and glomerular fibrillar collagen deposition, a pathogenic role for the EXT1 mutation seems highly likely, although we cannot formally exclude a contribution from other inherited abnormalities. Furthermore, an impairment of heparan sulfate synthesis cannot be the sole explanation for the nephrotic syndrome, as our patient did not develop renal symptoms until adulthood. The genetic defect and deficiency in heparan sulfate proteoglycan may, however, render the basement membrane susceptible to further, heparanase-induced loss of heparan sulfate and the development of the nephrotic syndrome.

Familial steroid-sensitive nephrotic syndrome is rare and genetic studies have not found a linkage to any gene known to be associated with the nephrotic syndrome.^17,18 Our kindred demonstrate a novel association between hereditary multiple exostoses and glomerular disease. While hearing impairment, a feature in this family, is seen in Langer-Giedion syndrome,¹⁹ a syndrome caused by more extensive chromosomal deletions that encompass EXT1, there is no reported association between EXT1 abnormalities and renal disease. Our understanding of the genetic basis for this phenotype is incomplete, but the association of a primary defect in heparan sulfate synthesis and steroid-sensitive nephrotic syndrome may have important implications for the pathogenesis of the much commoner nonfamilial minimal change nephrotic syndrome. As is often the case in medicine, an understanding of common conditions may emerge from the study of rare genetic disorders.