case_images: PMC11766185_01
case_images: PMC11766185_02
case_images: Renal biopsy findings in early childhood-onset fibronectin glomerulopathy. (A) Light microscopy revealed markedly enlarged hypercellular glomeruli; the tubules and interstitium appear normal. The diameter of the lower glomerulus: 204 mum (red line). The glomerular size was in the range of that in non-obese adult patients. Periodic acid-Schiff (PAS) reaction. The mesangium was widened by proliferated cells and an expanded matrix area, shown in (B-D,G,I). (B) The mesangial areas were slightly eosinophilic in hematoxylin and eosin, (C) blue in Masson's trichrome, (D) positive in Jones' methenamine silver, and (I) weakly positive in PAS. (E) The mesangial area at low magnification with electron microscopy. The expanded matrix is finely granular, and it is surrounded by nuclei and cytoplasmic cell processes of mesangial cells. The area around the asterisk is shown at higher magnification in (F). (F) Vague fibrils and ill-defined denser areas alternate with lighter areas. (G) The strong fibronectin positivity of mesangial areas. (H) The strong positivity of mesangial cells with smooth muscle-specific actin (SMA). (I) Ki-67 positivity in nuclei of mesangial cells (arrows). The reaction was counterstained with PAS. Original magnification: x200 for (A), 630x for (B-D,G), 5000x for (E), 22,000x for (F), 400x for (H), and 1000x for (I).
case_images: ijms-26-00641-g001.jpg
case_images: PMC11766185_02_ijms-26-00641-g001.jpg
case_images: ijms-26-00641-f001
case_images: Patent glomeruli were observed, which were markedly enlarged, and their size was comparable to that encountered in non-obese adults (Figure 1A). The mesangium was diffusely widened by an increase in mesangial cells (2 to 6 nuclei/area) and a mild expansion of the mesangial matrix-area (Figure 1B). The mesangial areas were slightly eosinophilic (Figure 1B), blue in Masson's trichrome staining (Figure 1C), positive in methenamine silver (Figure 1D), and weakly to moderately positive with the PAS-reaction (Figure 1I). The mesangial areas were widened by mesangial cell processes and nuclei (Figure 1E). At high magnification, the matrix focally exhibited a fibrillary background (Figure 1F). The FN immunostaining performed in the light of an FN1 mutation revealed massive positivity in the mesangial areas (Figure 1G), and early childhood-onset FG was diagnosed.
case_images: (a) A sequenogram of the FN1 gene exon 9 of the investigated family members. The genetic analysis identified a heterozygous likely pathogenic mutation (NM_212482.4):c.1250G>T/p.Gly417Val) in the FN1 gene in the index patient. (b) Family lineage analyses indicated a de novo mutation since the identified heterozygous FN1 variant was absent in the blood DNA samples of the family members without clinical symptoms. Red arrow indicates the proband.
case_images: ijms-26-00641-g002.jpg
case_images: PMC11766185_02_ijms-26-00641-g002.jpg
case_images: ijms-26-00641-f002
case_images: Next-generation sequencing confirmed by Sanger sequencing identified a single nucleotide change (NM_212482.4:c.1250G>T/p.Gly417Val) in exon 9 in the FN1 (2q35) gene in a heterozygous state in the patient (Figure 2 and Figure 3). AlphaMissense; and a tolerated prediction obtained from Fathmm. A segregation analysis of the variant in the family revealed that only the symptomatic index patient had this variant in the FN1 gene, while asymptomatic relatives did not, suggesting a potential de novo mutation; although, the rare possibility of parental gamete mosaicism cannot be excluded (Figure 2).
case_images: The fibronectin (FN) monomer molecule consists of type I (blue), II (red), and III (white) domains. Extra domains A and B, and variant region (V) are alternative splice sites, differently expressed in both adult and fetal tissues. The binding sites for different proteins are indicated. Pathogenic mutations in fibronectin glomerulopathy affect the heparin-binding domains II/III or only rarely the cell surface binding integrin domain. The single nucleotide change NM_212482.4:c.1250G>T/p.Gly417Val in exon 9 identified in our patient is located in the FN II-2 domain which binds collagen. Abbreviations: MMP 26:metalloprotease 26, GF:growth factor, Hep:heparin, FN:fibronectin.
case_images: ijms-26-00641-g003.jpg
case_images: PMC11766185_02_ijms-26-00641-g003.jpg
case_images: ijms-26-00641-f003
case_images: Next-generation sequencing confirmed by Sanger sequencing identified a single nucleotide change (NM_212482.4:c.1250G>T/p.Gly417Val) in exon 9 in the FN1 (2q35) gene in a heterozygous state in the patient (Figure 2 and Figure 3).
case_images: PMC11766185_03
case_images: Differences in the histopathological appearance of early vs advanced fibronectin glomerulopathy at-a-glance. (A) Mesangial proliferative pattern from early fibronectin glomerulopathy. The mesangial areas did not react intensely with the PAS reaction. PAS, x200. (B-F) show the advanced state of fibronectin glomerulopathy diagnosed in an adult patient. (B) A lobulated pattern due to a massive mesangial expansion that stained strongly with PAS (x400), (C) red with acid fuchsine-orange G stain (x400), and (D) negative with Jones' silver methenamine stain (x400). (E) Expanded mesangium due to an abundance of electron-dense granular material, admixed focally with membranous and filamentous structures. Electron microscopy, original magnification, x8000. (F) The strong fibronectin positivity of expanded mesangium, x400.
case_images: ijms-26-00641-g004.jpg
case_images: PMC11766185_03_ijms-26-00641-g004.jpg
case_images: ijms-26-00641-f004
case_images: H. Hopfer concluded the case (Figure 4).