Abstract
BackgroundPathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy.MethodsWe used nested case–control study to investigate 52 patients previously misdiagnosed and 52 patients initially diagnosed in the China Alport Syndrome Treatments and Outcomes Registry e-system.ResultsWe found mesangial proliferative glomerulonephritis (MsPGN, 26.9%) and focal and segmental glomerulosclerosis (FSGS, 19.2%) were the most common misdiagnosis. FSGS was the most frequent misdiagnosis in female X-linked AS (fXLAS) patients (34.8%), and MsPGN in male X-linked AS (mXLAS) patients (41.2%). Previous misdiagnosed mXLAS patients (13/17, 76.5%) and autosomal recessive AS (ARAS) patients (8/12, 66.7%) were corrected after a second renal biopsy. While misdiagnosed fXLAS patients (18/23, 78.3%) were corrected after a family member diagnosed (34.8%) or after rechecking electronic microscopy and/or collagen-IV alpha-chains immunofluresence study (COL-IF) (43.5%) during follow-up. With COL-IF as an additional criterion for AS diagnosis, we found that patients with less than 3 criteria reached have increased risk of misdiagnosis (3.29-fold for all misdiagnosed AS patients and 3.90-fold for fXLAS patients).ConclusionWe emphasize timely and careful study of electronic microscopy and COL-IF in pathologic evaluation of AS patients. With renal and/or skin COL-IF as additional criterion, 3 diagnosis criteria reached are the cutoff for diagnosing AS pathologically.
Highlights
Pathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping
The fundamental abnormalities lie in the linear and/or the conformational structures of the subchains of collagen IV molecules (COL-IV-α3:α4:α5 or COL-IV-α5:α6:α5), caused by different individual genotypes involving a monogenic mutation in COL4A3, or COL4A4, or COL4A5 genes [4,5,6]
The characteristic ophthalmologic changes found in 1950s [7,8], the widespread ultra-structural changes of glomerular basement membrane (GBM) described in 1970s [9,10], and collagen-IV α-chain immunofluorescence (COL-IF) defects discovered in 1980s [11,12] made histological diagnosis of the disease more accurate, and the modes of inheritance discernable
Summary
Pathologic studies play an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy. Phenotypes of Alport syndrome (AS) exhibit a wide spectrum of this systemic disorder of collagen IV molecules, from mild clinical forms living to old ages to severe forms developed into end stage renal disease early in life [1,2,3]. The characteristic ophthalmologic changes found in 1950s [7,8], the widespread ultra-structural changes of glomerular basement membrane (GBM) described in 1970s [9,10], and collagen-IV α-chain immunofluorescence (COL-IF) defects discovered in 1980s [11,12] made histological diagnosis of the disease more accurate, and the modes of inheritance discernable. After 1990s, genotyping added still more accuracy to the diagnosis and family counseling of AS, and nowadays, genotyping has been accepted as the gold standard for diagnosis of Alport syndrome [13,14]
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