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Hereditary disorders of the glomerulus are categorized on the basis of the demonstrated or predicted function(s) of the affected proteins. These are somewhat arbitrary categorizations that likely simplify the cell-cell and cell-matrix interactions that produce disease phenotypes, as listed in Chapter 472, Table 472-1.

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Familial Hematurias: Alport Syndrome and Thin Basement Membrane Nephropathy

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Between 30% and 50% of children with persistent hematuria have an inherited disorder of glomerular basement membranes (GBM). Accurate diagnosis of familial hematuria is crucial for predicting prognosis and providing accurate reproductive counseling.

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Genetics

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Most children and adolescents with familial glomerular hematuria have either Alport syndrome (AS) or thin basement membrane nephropathy (TBMN). All patients with AS, and about 50% of those with TBMN, have mutations in genes that code for type IV collagen proteins, the major collagenous constituents of basement membranes. About 80% of AS patients have X-linked disease due to mutations in COL4A5, the gene encoding the a5 chain of type IV collagen (a5[IV]). Autosomal recessive AS accounts for about 15% of patients and arises from mutations in both alleles of COL4A3 or COL4A4, which encode the a3(IV) and a4(IV) chains, respectively. About 5% of AS patients have autosomal dominant disease, due to heterozygous COL4A3 or COL4A4 mutations. However, most people with heterozygous mutations of COL4A3 or COL4A4 have TBMN, a nonprogressive form of familial hematuria.

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Clinical Features

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Persistent microscopic hematuria is the hallmark of AS, occurring in 100% of X-linked AS males, 95% of X-linked AS females, and all patients with autosomal recessive AS. Episodic gross hematuria is common. The onset of hematuria in X-linked AS males occurs during infancy. Since only 10% to 15% of children with X-linked AS have de novo mutations, most children with X-linked AS have a parent with hematuria. However, normal parental urinalyses do not exclude a diagnosis of X-linked AS. Each parent of a child with autosomal recessive AS is a heterozygous carrier of a mutation in COL4A3 or COL4A4. Since about 50% of these carriers are symptomatic, hematuria may be found in both parents, one parent, or neither parent.

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Microscopic hematuria is also the cardinal clinical finding in children with TBMN, who may have episodic gross hematuria, often in association with acute infection. TBMN is a dominant disorder, so hematuria is frequently found in a parent.

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As TBMN is typically nonprogressive, a family history of kidney failure in a child with hematuria suggests a diagnosis of AS. A family history of deafness should also raise suspicion for AS. Sensorineural deafness develops in 80% of X-linked AS males and most patients with autosomal recessive AS. The onset of measurable hearing deficits typically occurs in late childhood. The hearing defect is bilateral and initially involves high-frequency wavelengths, gradually extending into conversational speech wavelengths over time. About 40% of X-linked AS males exhibit ocular anomalies, including maculopathy, anterior ...

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