A 15-year-old male came to clinic for his health supervision visit and clearance to play high school sports. He had recently moved to the area. He reported no problems other than a sprained ankle 2 years previously because of a soccer injury that healed without problems. When reviewing the family history the mother said, “I really haven’t thought about this for a long time, but he has had hematuria a couple of times when he was younger. My father was diagnosed with Alport syndrome after he had kidney failure just before my son was born. He was worked up and they said he had Alport syndrome.” The mother related that she didn’t have any problems she was aware of but she had never been tested for Alport. She did say she had some urinary problem when she had been pregnant but didn’t know more and she had never had her hearing tested. As her father had been a machinist, he and his doctor had always thought his hearing problems were because of his occupation but he found out later it was Alport. Her father’s mother also had hearing problems but the mother didn’t know more about it. Her son had seen a nephrologist after he had the hematuria, “but they told our doctor to just monitor him and if he had more problems to come back. They also said that he was so little at the time that with more time better testing would be available.” “My daughter saw the nephrologist too who said she was okay,” stated the mother. She said that she didn’t think her own brother or sister or their children had any problems and denied any kidney or hearing problems in the paternal family. The review of systems was negative.
The pertinent physical exam showed a healthy appearing teenager at 75% for height/weight and with a 90% blood pressure at 128/82. Repeated readings were consistent. 4-point blood pressures did not reveal differences in upper extremities and lower extremities. The rest of his examination was normal. The diagnosis of a healthy male with an elevated blood pressure, personal history of hematuria and family history of Alport syndrome was made. The laboratory evaluation showed a normal complete blood count, lipid panel, thyroid functions and a urinalysis that had a specific gravity of 1.015 with +1 blood and protein. Audiometry showed some minor sensory neuronal hearing loss. He was referred to a nephrologist and genetic testing for Alport was pending.
Alport Syndrome is a genetic disease classically associated with progressive renal disease often leading to end stage renal disease, variable sensory neuronal deafness and ocular findings (perimacular retinopathy).
A. Cecil Alport built on the work of others evaluating families with nephritis and/or hematuria. However he very clearly describes the third generation of a family with an X-linked dominant pattern and also emphasizes the syndrome’s associated deafness.
“It will be seen from this that nearly all the children of three generations of one family suffer from hematuria or nephritis associated with deafness. The deafness, which has not been stressed in the literature on the subject, is one of the most distressing features of this extraordinary disease.”
“This nerve deafness is apparently the type of defective hearing to which members of his family are subject. It occurs not only in the individuals who have nephritis or haematuria, but also in those who are otherwise perfectly healthy.”
His summary comments include:
“1. Hereditary familiar or congenital nephritis is a definite entity, and the kidneys in these patients are more susceptible to damage by the toxin of an unknown organism that is the cause and the normal person….
5. Deafness is a marked feature in nearly all cases.
6. The male members of a family tend to develop nephritis and deafness and do not as a rule survive. The females have deafness and haematuria and lead to an old age.”
Alport syndrome is genetically heterogeneous. The genetic mutations result in changes to Type VI collagen, the kidney’s basement membrane’s major structural protein. The change is described as a having a laminated basket-weave appearance to the basement membrane.
The majority of cases are X-linked (85%) with variable but highly penetrant. The affected gene is COL4A5 gene on Xq22.3 which codes for the type IV collagen α5 chain.
About 15% are autosomal recessive affecting the COL4A4 or COL4A3 genes on 2q36.3 which code for the Type VI collagen α4 or α3 chains respectively.
Autosomal dominant cases are rare and affect the COL4A3 genes on 2q36.3. Interestingly benign family hematuria (sometimes known as thin basement membrane nephropathy) is an autosomal dominant disorder affecting the COL4A3 genes on 2q36.3 also. It has a thin basement membrane and hematuria, but does not have progressive nephropathy.
From the family history in the case above, X-linked recessive Alport syndrome may be the cause of the teenager’s symptoms. Testing of the family members will also be important to understand who else in the family may be affected. Benign familial hematuria is a possibility but the teenager has evidence of progressive renal abnormalities as well as hearing loss which are not features of this entity.
Questions for Further Discussion
1. What other diseases have a classic X-linked recessive genetic pattern?
2. What are common causes of hematuria? Causes of gross hematuria can be reviewed here
3. What are the most common causes of nephritis?
4. What are causes of proteinuria? The differential diagnosis can be reviewed here
- Age: Teenager
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Alport AC. Hereditary Familial Congenital Haemorrhagic Nephritis. Br Med J. 1927 Mar 19; 1(3454):504-506.
Alport Syndrome, Autosomal Dominant #104200. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/104200?search=alport%20syndrome&highlight=syndromic%20alport%20syndrome (rev. 7/10/2015, cited 7/20/2017).
Alport Syndrome, Autosomal Recessive #203780. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/203780 (rev. 7/13/2015, cited 7/20/2017).
Alport Syndrome, X-Linked; ATS #301050. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/301050?search=alport%20syndrome&highlight=syndromic%20alport%20syndrome (rev. 7/10/2015, cited 7/20/2017).
Hematuria, Benign Familial #141200. Online Mendelian Inheritance in Man. Available from the Internet at http://www.omim.org/entry/141200 (rev. 7/21/2015, cited 7/20/2017).
Oka M, Nozu K, Kaito H, Fu XJ, Nakanishi K, Hashimura Y, Morisada N, Yan K, Matsuo M, Yoshikawa N, Vorechovsky I, Iijima K. Natural history of genetically proven autosomal recessive Alport syndrome.
Pediatr Nephrol. 2014 Sep;29(9):1535-44.
Fernandez-Rosado F, Campos A, Alvarez-Cubero MJ, Ruiz A, Entrala-Bernal C. Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene.
Nephrology (Carlton). 2015 Jul;20(7):502-5.
Weber S, Strasser K, Rath S, Kittke A, Beicht S, Alberer M, Lange-Sperandio B, Hoyer PF, Benz MR, Ponsel S, Weber LT, Klein HG, Hoefele J. Identification of 47 novel mutations in patients with Alport syndrome and thin basement membrane nephropathy. Pediatr Nephrol. 2016 Jun;31(6):941-55.
Donna M. D’Alessandro, MD
Professor of Pediatrics, University of Iowa