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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson
|QuestionAuthor=William J Gibson (Reviewed by  {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
Line 8: Line 8:
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|SubCategory=Head and Neck, Renal
|SubCategory=Head and Neck, Renal
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
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|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|SubCategory=Head and Neck, Renal
|SubCategory=Head and Neck, Renal
|Prompt=A 26 year old man presents to his primary care physician with progressive deafness. Family history is significant for a maternal uncle who suffered a similar condition. On ophthalmic exam, the physician notes bulging of the patient’s lens capsule. The clinician orders sequencing of the Type IV Collagen Genes, which demonstrates a frameshift mutation in COL4A5.   Which of the following tests should the clinician also order?
|Prompt=A 7-year-old boy is brought to his pediatrician's office for progressive bilateral deafness. Family history is significant for a similar condition among multiple family members. Physical examination is remarkable for subcapsular posterior lens opacities, peripheral coalescing retinopathy, and high-tone sensorineural deafness. The physician suspects the patient's condition is caused by a genetic disease. Genetic testing results demonstrate a mutation in the ''COL4A5'' gene. Which test is most likely to reveal abnormal findings during further work-up of this patient?
 
|Explanation=[[Image:Clinical manifestations of Alport's syndrome.png|900px]]
|Explanation=Alport syndrome is a familial cause of deafness, ocular disturbances and nephritis.  Kidney function should be assessed and tracked in a patient with Alport syndrome. Serum creatinine is a measure of kidney function.  Alport syndrome is inherited in a variety of ways depending on which gene has been mutated.  The most common inheritance is X-linked recessive.


'''Educational Objective:''' Alport syndrome is a familial cause of deafness, ocular disturbances and nephritis.
Alport’s syndrome (hereditary nephritis) is a familial nephropathy characterized by renal impairment, auditory manifestations, and ocular defects. It has an X-linked form, which is characterized by the mutation of ''COL4A5'' gene on the long arm of the X-chromosome, and another much less common autosomal recessive form characterized by the homogeneous mutation of ''COL4A3'' or ''COL4A4'' on chromosome 2. Notably, the 2 forms may also be distinguished by identification of a patient's pedigree. The mutation leads to abnormal alpha chain of type IV collagen, which is normally responsible for the structure and function of basement membranes in the body. Histopathological analysis of the kidneys demonstrates a lamellated glomerular basement membrane (GBM) with the appearance of false layers, along with glomerular focal sclerosis. Renal molecular analysis reveals absence of collagen network of the GBM.


'''References:''' First Aid 2012 page 84.
Alport’s syndrome commonly presents in childhood with persistent hematuria. Prognosis of Alport’s syndrome is generally poor with inevitable progression to end-stage renal disease (ESRD) at varying rates. Alport's syndrome should always be considered among children with any of auditory, ocular, and/or urinary findings. Nonetheless, it should be distinguished from other diseases that may present with similar symptoms (table below). Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome. Hematuria is usually present before patients experience symptoms of renal failure (eg. hypertension) and before either proteinuria or an elevation in serum creatinine is observed. Management of renal disease in Alport's syndrome is usually by ACE-inhibitors that may delay disease progression to ESRD. ESRD requires renal replacement modalities, such as dialysis and renal transplantation. Genetic counseling is recommended for families and patients with Alport's syndrome.


|AnswerA=Serum Creatinine
[[Image:Differential diagnosis of Alport's syndrome.png|1300px]]
|AnswerAExp='''Correct''' – Alport syndrome is a familial cause of deafness, ocular disturbances and nephritis.
|AnswerA=Serum creatinine
|AnswerAExp=Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Although patients usually develop end stage renal disease (ESRD), serum creatinine is often normal early in the course of the disease or among patients with mild disease.
|AnswerB=Electrocardiogram
|AnswerB=Electrocardiogram
|AnswerBExp='''Incorrect''' – Alport syndrome is not associated with cardiovascular complications
|AnswerBExp=Alport's syndrome is not primarily associated with cardiac disease or changes on electrocardiogram (ECG).
|AnswerC=Head MRI
|AnswerC=Urinalysis
|AnswerCExp='''Incorrect''' – Alport syndrome is not associated with macroscopic structural disturbances or soft tissue tumors of the head.
|AnswerCExp=Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome. Hematuria is usually present before patients experience symptoms of renal failure (eg. hypertension) and before an elevation in serum creatinine is observed.
|AnswerD=Liver Enzymes (ALT, AST)
|AnswerD=Serum alanine aminotransferase
|AnswerDExp='''Incorrect''' – Alport syndrome is not associated with liver abnormalities.
|AnswerDExp=Alport syndrome is not primarily associated with abnormal values of alanine aminotransferase (ALT) or liver abnormalities.
|AnswerE=Complete blood count
|AnswerE=Serum platelet count
|AnswerEExp='''Incorrect''' – Alport syndrome is not associated with hematologic disturbances.
|AnswerEExp=Alport's syndrome is not primarily associated with quantitative platelet disturbances.
|RightAnswer=A
|EducationalObjectives=Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome.
|References=McCarthy PA, Maino DM. Clin Eye Vis Care. 2000; 12(3-4):139-50.<br>
Savige J, Gregory M, Gross O, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013; 24(3):364-75.<br>
First Aid 2014 page 538
|RightAnswer=C
|WBRKeyword=Alport's syndrome, Alport, Nephritis, Deafness, Hearing loss, Hematuria, Creatinine, Work-up, COL4A5, Hereditary nephritis
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:48, 27 October 2020

 
Author [[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Genetics, MainCategory::Pathophysiology
Sub Category SubCategory::Head and Neck, SubCategory::Renal
Prompt [[Prompt::A 7-year-old boy is brought to his pediatrician's office for progressive bilateral deafness. Family history is significant for a similar condition among multiple family members. Physical examination is remarkable for subcapsular posterior lens opacities, peripheral coalescing retinopathy, and high-tone sensorineural deafness. The physician suspects the patient's condition is caused by a genetic disease. Genetic testing results demonstrate a mutation in the COL4A5 gene. Which test is most likely to reveal abnormal findings during further work-up of this patient?]]
Answer A AnswerA::Serum creatinine
Answer A Explanation [[AnswerAExp::Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Although patients usually develop end stage renal disease (ESRD), serum creatinine is often normal early in the course of the disease or among patients with mild disease.]]
Answer B AnswerB::Electrocardiogram
Answer B Explanation AnswerBExp::Alport's syndrome is not primarily associated with cardiac disease or changes on electrocardiogram (ECG).
Answer C AnswerC::Urinalysis
Answer C Explanation [[AnswerCExp::Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome. Hematuria is usually present before patients experience symptoms of renal failure (eg. hypertension) and before an elevation in serum creatinine is observed.]]
Answer D AnswerD::Serum alanine aminotransferase
Answer D Explanation AnswerDExp::Alport syndrome is not primarily associated with abnormal values of alanine aminotransferase (ALT) or liver abnormalities.
Answer E AnswerE::Serum platelet count
Answer E Explanation AnswerEExp::Alport's syndrome is not primarily associated with quantitative platelet disturbances.
Right Answer RightAnswer::C
Explanation [[Explanation::

Alport’s syndrome (hereditary nephritis) is a familial nephropathy characterized by renal impairment, auditory manifestations, and ocular defects. It has an X-linked form, which is characterized by the mutation of COL4A5 gene on the long arm of the X-chromosome, and another much less common autosomal recessive form characterized by the homogeneous mutation of COL4A3 or COL4A4 on chromosome 2. Notably, the 2 forms may also be distinguished by identification of a patient's pedigree. The mutation leads to abnormal alpha chain of type IV collagen, which is normally responsible for the structure and function of basement membranes in the body. Histopathological analysis of the kidneys demonstrates a lamellated glomerular basement membrane (GBM) with the appearance of false layers, along with glomerular focal sclerosis. Renal molecular analysis reveals absence of collagen network of the GBM.

Alport’s syndrome commonly presents in childhood with persistent hematuria. Prognosis of Alport’s syndrome is generally poor with inevitable progression to end-stage renal disease (ESRD) at varying rates. Alport's syndrome should always be considered among children with any of auditory, ocular, and/or urinary findings. Nonetheless, it should be distinguished from other diseases that may present with similar symptoms (table below). Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome. Hematuria is usually present before patients experience symptoms of renal failure (eg. hypertension) and before either proteinuria or an elevation in serum creatinine is observed. Management of renal disease in Alport's syndrome is usually by ACE-inhibitors that may delay disease progression to ESRD. ESRD requires renal replacement modalities, such as dialysis and renal transplantation. Genetic counseling is recommended for families and patients with Alport's syndrome.


Educational Objective: Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Microscopic hematuria is the most common presenting sign of patients with Alport's syndrome.
References: McCarthy PA, Maino DM. Clin Eye Vis Care. 2000; 12(3-4):139-50.
Savige J, Gregory M, Gross O, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013; 24(3):364-75.
First Aid 2014 page 538]]

Approved Approved::Yes
Keyword WBRKeyword::Alport's syndrome, WBRKeyword::Alport, WBRKeyword::Nephritis, WBRKeyword::Deafness, WBRKeyword::Hearing loss, WBRKeyword::Hematuria, WBRKeyword::Creatinine, WBRKeyword::Work-up, WBRKeyword::COL4A5, WBRKeyword::Hereditary nephritis
Linked Question Linked::
Order in Linked Questions LinkedOrder::