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Diagnosis: Diffuse mesangial sclerosis

The term diffuse mesangial sclerosis (DMS) indicates a characteristic glomerular histological alteration that occurs in childhood nephrotic syndrome and is associated with genetic alterations. Histopathological findings consist in glomeruli with mesangial expansion by increased mesangial matrix, with capillary walls that may be normal initially, but with hypertrophy and hyperplasia of podocytes. By advancing the process (usually in months or a few years), there is progressively greater mesangial expansion, capillary lumens are lost and the capillary walls are difficult to see clearly. In the terminal stages there is glomerular sclerosis, as can be seen in several of our case images.

DMS is a rare renal disease, first described histologically in 1973 by Habib and Bois (Habib R, Bois E. [Heterogeneity of early onset nephrotic syndromes in infants. Anatomical, clinical and genetic study of 37 cases]). Helv Paediatr Acta. 1973;28(2):91-107. [PubMed link]). It has a poor prognosis as this nephropathy is resistant to treatment with corticosteroids and rapidly progresses to end-stage renal failure. It can appear isolated or as part of the Denys-Drash syndrome, a rare disorder characterized by the triad of DMS, male pseudohermaphroditism, and Wilms’ tumor. Incomplete forms of the syndrome in which one of the components of the triad is missing have been described; nephropathy is the constant element, and DMS usually presents as a corticoresistant nephrotic syndrome with severe proteinuria. It is characterized by early onset, generally before 2 years of age, and progression to endstage renal failure occurs in a mean of 3 years. The most frequent karyotype in these patients is 46XY with ambiguous or female genitalia, but this can be an artefact due to the less frequent diagnosis in XX patients without pseudohermaphroditism.

The main differential diagnosis is Frasier syndrome. This is a rare disease defined by the presence of nephropathy secondary to focal and segmental glomerular sclerosis, with a slower progression to end-stage renal failure, male pseudohermaphroditism, and gonadoblastoma. It is generally not associated to Wilms’ tumor. Nevertheless, the two syndromes can overlap, so that patients have been described with Frasier’s clinical characteristics and Denys- rash’s typical mutation and vice versa.

The etiology and pathogenesis of DMS is not understood, but the three mutations described in this glomerular disease involve the genes WT1, LAMB2 or PLCE1. Mutations in PLCE1 have been associated to isolated DMS.

See the chapter Focal Segmental Glomerulosclerosis of our tutorial.

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References

• Nso Roca AP, Peña Carrión A, Benito Gutiérrez M, García Meseguer C, García Pose A, Navarro M. Evolutive study of children with diffuse mesangial sclerosis. Pediatr Nephrol. 2009 May;24(5):1013-9. [PubMed link]
• Gbadegesin R, Hinkes BG, Hoskins BE, Vlangos CN, Heeringa SF, Liu J, Loirat C, Ozaltin F, Hashmi S, Ulmer F, Cleper R, Ettenger R, Antignac C, Wiggins RC, Zenker M, Hildebrandt F. Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS). Nephrol Dial Transplant. 2008 Apr;23(4):1291-7. [PubMed link] [Free full text]
• Niaudet P, Gubler MC. WT1 and glomerular diseases. Pediatr Nephrol. 2006 Nov;21(11):1653-60. [PubMed link]
• Guo JK, Menke AL, Gubler MC, Clarke AR, Harrison D, Hammes A, Hastie ND, Schedl A. WT1 is a key regulator of podocyte function: reduced expression levels cause crescentic glomerulonephritis and mesangial sclerosis. Hum Mol Genet. 2002 Mar 15;11(6):651-9. [PubMed link] [Free full text]
• Yang Y, Zhang SY, Sich M, Béziau A, van den Heuvel LP, Gubler MC. Glomerular extracellular matrix and growth factors in diffuse mesangial sclerosis. Pediatr Nephrol. 2001 May;16(5):429-38. [PubMed link]

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