Chapter 473

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.

### Familial Hematurias: Alport Syndrome and Thin Basement Membrane Nephropathy

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.

#### Genetics

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.

#### Clinical Features

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.

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.

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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