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Chapter 46: Familial Hematurias: Alport Syndrome and Hematuria with Thin Glomerular Basement Membranes

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A 3-year-old boy is referred to you for evaluation of microscopic hematuria. Evaluation shows normal blood pressure, renal function, urinary protein, and calcium excretion. Renal ultrasound is normal. Mother has a history of microscopic hematuria for many years and thinks her kidney function is normal. Father says he does not have hematuria. There is no family history of kidney failure or deafness.

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Which of the following statements about the child is true?

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A. Since there is no family history of kidney failure he does not have Alport syndrome.

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B. Since the father does not have hematuria this child does not have autosomal recessive Alport syndrome.

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C. The information provided by this pedigree is insufficient for establishing a diagnosis or inheritance pattern.

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D. None of the above statements is true.

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The answer is C. First, pedigree information provided by families is not always accurate. Second, the mother may have a spontaneous rather than inherited mutation. Last, the child may have autosomal recessive Alport syndrome, in which case a family history of ESRD would typically be negative. The pedigree is consistent with any of the three genetic forms of Alport syndrome: X-linked, autosomal recessive or autosomal dominant. The information provided by this pedigree however, is insufficient for establishing a diagnosis or inheritance pattern.

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About 50% of people who are heterozygous for a mutation in the COL4A3 or COL4A4 gene are asymptomatic.

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Which of the following tests is most likely to establish a diagnosis and inheritance pattern in this family?

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A. Hearing evaluation of the child

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B. Kidney biopsy of the child’s mother

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C. Kidney biopsy of the child

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D. Next generation sequencing of the child

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The answer is D. In boys with X-linked Alport syndrome and in boys and girls with autosomal recessive Alport syndrome, sensorineural deafness typically becomes detectable by audiogram after the age of 5–6 years. A 3-year-old boy with Alport syndrome is likely to have a normal audiogram.

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The kidney biopsy of the mother may show mixed thinning and lamellation of glomerular basement membranes (GBM), thinning of GBM only or no pathological changes; whereas the kidney biopsy of a 3-year-old boy with Alport syndrome is likely to show GBM thinning. Distinguishing between Alport syndrome and other causes of GBM thinning may be possible if immunostaining of the biopsy specimen for collagen IV chains is available.

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Next generation sequencing ...

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