Alport syndrome, also known as hereditary nephritis, is characterized by hematuria, proteinuria, and progressive renal failure. Some patients may suffer from extrarenal symptoms such as sensorineural hearing loss and vision loss [5]. The COL4A5 gene mutation leads to progressive and irregular thickening, thinning, or splitting of the glomerular basement membrane, which is the basis for the genetic and renal histopathological diagnosis of this disease. In this case, the child’s disease onset was at 4 months after birth, with persistent microscopic hematuria, intermittent proteinuria, gross hematuria, Upon inquiry, a family history of renal disease was discovered. The child’s maternal grandmother was diagnosed with uremia at the age of 50. His maternal aunt experienced proteinuria at the age of 20, with renal pathological diagnosis of focal segmental glomerulosclerosis. The child’s mother had a 5-year history of hematuria (see Fig. 4 for the Genogram). At the same time, renal tissue histopathology of the child under an electron microscope showed an uneven thickness of the glomerular basement membrane, and thickening of the stratum compactum with tear-like and cobweb-like morphology in areas, suggesting a high possibility of Alport syndrome. However, no abnormal changes in the vision and hearing systems were observed in this child. Unfortunately, the child did not undergo basal membrane IV collagen beta immunofluorescence test. In order to confirm the diagnosis, we performed whole-exome sequencing. The results revealed no mutation of the COL4An gene. Instead, site mutation of the fibronectin 1 (FN1) gene had occurred, i.e., heterozygous mutation at chr2:216270963 with c.2984 C > T (exon19) and p.T995I. Therefore, genetic finding appeared inconsistent with Alport syndrome and compatible with GFND.
First reported by Tuttle et al. in 1987, GFND is a rare hereditary glomerulopathy newly recognized in recent years [1]. The genetic disease is autosomal dominant, but the exact pathogenesis of the disease remains unclear. Proteinuria and hematuria are the primary clinical manifestations and symptoms can persist for decades. At present, however, there are still few reports on it in the literature from China and the rest of the world [6,7,8]. As a result, diagnosis and treatment remain challenging. Some patients present with hypertension and slow-progressing glomerular filtration rate decline, and even progress to renal failure. Among the reported cases, the youngest was aged 3 years and the eldest was 88 years [9, 10]. The child reported here was only 2 years and 2 months, which may be the youngest confirmed case reported so far, suggesting that the disease may occur in any age group.
The typical histopathological changes of GFND are glomerular lobular pattern, mesangial and GBM expansion, double contour and strongly positive fibronectin, and deposition of a large amount of fine fibrous materials can be observed under electron microscope. The child in this case had not shown the above-mentioned typical pathological changes yet. Considering that the child mainly manifested and proteinuria only occurred intermittently, the onset age of the child was young, the duration of the medical history was short, and typical pathological changes might not have occurred, it was suggested that long-term follow-up should be conducted for the child, and renal biopsy should be performed again as necessary to confirm the pathological diagnosis.
The key pathogenesis of GFND is the deposition of fibronectin (FN) in glomeruli. At present, it is believed that the impaired ability of glomeruli to process deposits due to the FN1 gene defect is an important cause of GFND. The FN1 gene is located on chromosome 2 and the main mutation point. The abnormality of FN1 gene in this child was manifested by the substitution of cytosine by thymine in the base pair at position 2,984 of exon 19 [c.2984 C > T(exon19)] in the gene coding sequence of chromosome 2 (position: chr2:216270963); this caused the missense mutation of the amino acid at position 995 of the transcribed mRNA from threonine to isoleucine (p.T995I). This mutation simultaneously affects the interaction of the heparin-binding domain among fibronectin cells on the one hand and while promoting the formation of fibronectin on the other hand. In 2016, Ohstubo et al. [3] conducted the largest pedigree analysis to date for patients with GFND, showing that 6 types of FN1 gene mutations were found in 12 GFND pedigrees, and more mutant genes have continuously been found. In addition to the gene reported in this case, pathogenic FN1 gene mutations found in China and other countries also include p.T973C, p.1T925A, p.T1925C, p.L1974A, p.P969L, and p.1P974D. In this case, the genetic diagnosis was made before the typical renal pathological changes appeared, suggesting the advantages of early-stage genetic diagnosis and providing conditions for early intervention.
Currently, there is no effective or specific treatment for GFND, and only symptomatic treatment is available, in which hormonal and immunosuppressive therapies have no significant efficacy, with poor prognosis. Literature shows that even after kidney transplantation, the disease can still relapse [11]. The child did not receive special treatment after discharge from the hospital. Follow-up was conducted for 3 years and 4 months, which showed that he still had persistent microscopic hematuria and intermittent proteinuria, while no abnormality in renal function was found. We suggested he return to the hospital for reexamination and another kidney biopsy, but his family refused.
The limitation of this study is that, on the one hand, fibronectin and collagen were not stained in the biopsies of the children and their aunt, which affects the diagnosis of this disease to a certain extent. On the other hand, the impact of the disease on the children cannot be assessed without functional analysis of the detected mutations.
