Clinical and pathohistological characteristics of Alport spectrum disorder caused by COL4A4 mutation c.193-2A>C: a case series

Abstract

Aim: To present the pathohistological and clinical characteristics of five Croatian families with Alport spectrum disorders caused by splice acceptor pathogenic variant c.193-2A>C in COL4A4 at the genomic position chr2:227985866.

Methods: The study enrolled five probands with kidney biopsy analysis and five family members. Mutation screening was performed with Illumina MiSeq platform. The pathogenic variant was confirmed with standard dye-terminator sequencing.

Results: The only homozygous patient, aged two, had proteinuria and hematuria with preserved kidney function and no extrarenal manifestations. This patient had changes characteristic for Alport syndrome observed on electron microscopy of the kidney biopsy. In the heterozygous group, six patients had hematuria, four biopsied probands had proteinuria, and only one had moderately reduced kidney function. Heterozygous probands had variable kidney biopsy findings. Three patients had thin glomerular basement membrane nephropathy visible on electron microscopy and focal segmental glomerulosclerosis on light microscopy, two of them with focal lamellation on electron microscopy. One heterozygous patient had changes characteristic for Alport syndrome on electron microscopy without focal segmental glomerulosclerosis.

Conclusion: The homozygous patient had hematuria and proteinuria with preserved kidney function. The heterozygous patients presented with reasonably mild clinical phenotype and variable pathohistological findings.

Figure 1

A kidney biopsy specimen of the proband HR 1.1. (A) The kidney cortex with an immature glomerulus (black arrow) and a small focus of interstitial fibrosis and tubular atrophy (red arrow). Periodic Acid-Schiff stain, magnification ×200. (B) Glomerular basement membrane with lamellation (arrow). E – erythrocyte. Transmission electron microscopy, magnification ×15,000.

Figure 2

Family pedigrees of the three included families. (A) Family HR1. Homozygous male proband and his heterozygous parents. (B) Family HR2. Heterozygous male proband and his two heterozygous sons. (C) Family HR5. Heterozygous female proband, her heterozygous son and a healthy daughter. Arrow – proband, circle – female, square – male, black – homozygous patient, white – healthy individual, black and white – heterozygous patient.

Figure 3

A kidney biopsy specimen of the proband HR 2.1. (A) A glomerulus with perihilar segmental sclerosis (arrow), Jones methamine silver stain, magnification ×400. (B) Marked arteriolar hyalinosis (black arrow) and mild arterial fibrointimal thickening (red arrow). Periodic Acid-Schiff stain, magnification ×200. (C) Glomerular capillary loop with thin glomerular basement membrane and focal lamellation (arrow). E – erythrocyte, P – podocyte. Transmission electron microscopy, magnification ×8000.

Figure 4

A kidney biopsy specimen of the proband HR 3.1. Glomerular capillary loop with glomerular basement membrane showing lamellation (arrows). EN – endothelium, P – podocyte. Transmission electron microscopy, magnification ×8000.

Figure 5

A kidney biopsy specimen of the proband HR 4.1. (A) The kidney cortex with a glomerulus, with segmental sclerosis (black arrow) and an area of interstitial fibrosis and tubular atrophy (red arrow). Periodic Acid-Schiff stain, magnification ×200. (B) A part of the glomerular capillary loop with focal lamellation of the glomerular basement membrane (arrow). EN – endothelium, P – podocyte. Transmission electron microscopy, magnification ×8000.

Figure 6

A kidney biopsy specimen of the proband HR 5.1. (A) A glomerulus with perihilar segmental sclerosis (arrow), Masson trichrome stain, magnification ×400. (B) Arteriolar hyalinosis (arrow). Masson trichrome stain, magnification ×200. (C) Glomerular capillary loops with thin glomerular basement membrane (arrow). EN – endothelium, P – podocyte. Transmission electron microscopy, magnification ×8000.