LAUSR

1. Alport syndrome, despite the negative results given by the genetic test, seemed the most likely diagnosis given the patient’s family history and the early onset of the symptoms both in the child and his mother [1]. Alport syndrome should be strongly considered in the event of persistent glomerular hematuria during the first years of life, particularly if the family history presents cases of chronic glomerulonephritis and/or renal failure without other causes or when the characteristic clinical features (hearing loss, lenticonus, or retinopathy) are present [2]. As reported in the latest guidelines by Savige and colleagues [3], the diagnosis is confirmed by the presence of lamellated glomerular basal membrane (GBM) in the examination of the renal biopsy under an electron microscope or by pathogenic mutations detected by genetic testing (one deleteriousmutation in the COL4A5 gene, two in the COL4A3 or COL4A4), which has been reported to be at least 90% sensitive for X-linked or automal recessive Alport syndrome. Furthermore, since the mother’s diagnosis of mesangial proliferative glomerulonephritis was obtained by examining renal biopsy tissue, Alport syndrome cannot be excluded as the actual diagnosis, especially if the biopsy examination was conducted without the use of an electron microscope. As a matter of fact, both mesangial proliferative glomerulonephritis (MsPGN) and focal and segmental glomerulosclerosis (FSGS) were shown to be the most commonly misdiagnosed glomerulonephritis (26.9% and 19.2% of cases, respectively) [4]. 2. We therefore decided to perform a cutaneous biopsy. Immunofluorescence performed on the skin sample showed the complete absence of the α5-chain of type IV collagen, as typically found in X-linked Alport syndrome patients (Fig. 1). Further genetic analysis performed with multiplex ligation-dependent probe amplification (MLPA) highlighted the presence of a pathogenic duplication of exons 48, 49, and 50 in the COL4A5 gene, therefore confirming X-linked Alport syndrome. Alport syndrome is an inherited disorder of type IV collagen, the major collagenous constituent of basal membranes [5]. The majority of Alport syndrome patients (approximately 85%) present a dominant X-linked hereditary pattern caused by mutations in the COL4A5 gene, found in the Xq22 region, which codes for the α5-chain of type IV collagen [3]. On top of all cases diagnosed by standard genetic testing, there are a few cases (due to duplications, insertions, and deletions which represent 5–10% of all pathogenic variants) which may evade detection during standard genetic testing due to insufficient sensitivity of the testing process, as in this case. The use of MLPA genetic testing is recommended in these cases [3]. Mutations in the COL4A5 gene lead to a loss of the α5-chain in basal membranes, and, generally, a complete lack of expression of α5 in male patients and a mosaic distribution in female patients is considered diagnostic of Alport syndrome. Theα5-chain is found in both normal glomerular basal membrane (GBM), and normal epidermal basal membrane and its absence result in the typical GBM ultrastructural lesions, widely recognized as diagnostic of the disease [6]. As reported by Wang and colleagues [7], using skin biopsy a negative or mosaic α5-chain staining in the epidermal basal membrane was detected in 86.2% ofmale and 93.5% of female X-Linked Alport syndrome patients. Immunohistochemical analysis of the α5-chain in the epidermal basal membrane (EBM) is therefore a clearly This refers to the article that can be found at https://doi.org/10.1007/ s00467-020-04548-w.