Fig 2 from Fogo et al AJKD, © National Kidney Foundation.

Congenital (presenting before age 3 months) and infantile (presenting at age 4-12 months) nephrotic syndrome are commonly caused by genetic defects. Diffuse mesangial sclerosis (DMS) is a histopathologic finding in some children with congenital (CNS) or infantile nephrotic syndrome (INS). In DMS, there is an increase in mesangial matrix without mesangial cellular proliferation, leading to obliteration of glomerular capillaries and eventual glomerulosclerosis. DMS, being a genetic disease, is generally progressive and steroid-resistant. DMS can be an isolated finding, or it can be syndromic and associated with Denys-Drash Syndrome (CNS, pseudohermaphroditism in boys, and Wilms tumor) or Frasier Syndrome (CNS, pseudohermaphroditism in boys, and gonadoblastoma).

Three genes have been associated with DMS. The Wilms Tumor 1 (WT1) gene is a transcription factor important in kidney and gonadal embryogenesis. Mutations in WT1 are associated with isolated DMS, as well as Denys-Drash and Frasier Syndromes. Mutations in PLCE1 (which encodes phospholipase C epsilon-1, a podocyte protein) are associated with isolated DMS. A rare cause of DMS is Pierson Syndrome, caused by a mutation in LAMB2, and associated with CNS, microcoria and neurodevelopmental defects.

A genetic evaluation should be performed in all children with CNS or INS. Infants with DMS and obvious syndromic manifestations should have appropriately targeted testing (ie, WT1 testing in the presence of ambiguous male genitalia or pseudohermaphroditism, Wilms tumor, or gonadoblastoma; LAMB2 testing with ocular findings and CNS). Children with isolated, non-syndromic DMS should be tested for WT1 and PLCE1 mutations. Testing for these genes are available individually and as part of combined panels in a variety of commercial and research laboratories (links to these labs can be found at the Genetics Testing Registry: http://www.ncbi.nlm.nih.gov/gtr/).

Jerome C. Lane, MD
Associate Professor of Pediatrics
Division of Kidney Diseases
Feinberg School of Medicine, Northwestern University
Ann & Robert H. Lurie Children’s Hospital of Chicago

Please visit the Atlas of Renal Pathology II at AJKD.org to view the related installment on DMS (freely available).