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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=William J Gibson (Reviewed by {{YD}})
|QuestionAuthor=William J Gibson (Reviewed by {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
Line 21: Line 21:
|MainCategory=Genetics, Pathophysiology
|MainCategory=Genetics, Pathophysiology
|SubCategory=Head and Neck, Renal
|SubCategory=Head and Neck, Renal
|Prompt=A 7-year-old boy is brought to his primary care physician for progressive bilateral deafness. Family history is significant for multiple family members who suffered from a similar condition at childhood. Physical examination is remarkable for subcapsular posterior lens opacities and sensorineural deafness. The physician suspects the patient's condition is caused by a genetic disease. Genetic testing results demonstrate a frameshift mutation in the ''COL4A5'' gene. Further work-up will most likely be remarkable for abnormalities in which of the following tests?  
|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={| border="1" style="border-collapse:collapse; text-align:left;" cellpadding="5" align="center"
|Explanation=[[Image:Clinical manifestations of Alport's syndrome.png|900px]]
|+ '''''Clinical Manifestations of Alport's Syndrome'''''
|  bgcolor="#d9ff54"|'''Renal'''|| bgcolor="#d9ff54"|'''Auditory'''|| bgcolor="#d9ff54"|'''Ocular'''
|-valign="top"
|
*Hematuria
*Hypertension
*Reduced Creatinine Clearance
||
*Early Tinnitus
*Vertigo
*High-Frequency Progressive Bilateral Hearing Loss
||
*Refractory Error
*Posterior Polymorphous Dystrophy
*Arcus
*Glaucoma
*Vogt’s White Limbal Girdle
*Band Keratopathy
*Lenticonus
*Spherophakia
*Cataracts
*Lens Coloboma
*Anterior Lenticonus
*Flecked Retinopathy of the Macula or Periphery
|}


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 (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. 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. Alport’s syndrome most 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). Management is by multidisciplinary approach, involving established and promising pharmacologic therapy along with renal replacement methods, such as dialysis and renal transplantation.
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. 


{| border="1" style="border-collapse:collapse; text-align:center;" cellpadding="5" align="center"
[[Image:Differential diagnosis of Alport's syndrome.png|1300px]]
|+ '''''Common Differential Diagnoses of Alport's Syndrome'''''
| bgcolor="#d9ff54"|'''Differential Diagnosis''' || bgcolor="#d9ff54"|'''Distinguishing Features''' || bgcolor="#d9ff54"|'''Comments'''
|-
| bgcolor="#ececec"|'''Polycystic Kidney Disease''' || Generally, absence of auditory or ocular manifestations||Ocular manifestations such as retinal dystrophy might be present   
|-
| bgcolor="#ececec"|'''Medullary Cystic Disease''' || Absence of auditory or ocular manifestations ||  Ocular manifestations such as congenital cataracts may be present   
|-
| bgcolor="#ececec"|'''Epstein Syndrome''' ||Renal, auditory, and hematological manifestations || Type V AS variant
|-
| bgcolor="#ececec"|'''Fechtner Syndrome''' || Renal, auditory, and hematological manifestations || Type III AS variant   
|-
| bgcolor="#ececec"| '''Leiomyomatosis''' || Cataract, auditory manifestations, and glomerulonephritis with multiple benign lesions made of smooth muscle cells || May be present with Alport’s syndrome due to involvement of adjacent gene, COL4A6
|}
|AnswerA=Serum creatinine
|AnswerA=Serum creatinine
|AnswerAExp=Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis. Although patients eventually develop end stage renal disease (ESRD), serum creatinine is often normal early in the course of the disease, and the diagnosis may be missed.  
|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=Alport's syndrome is not primarily associated with cardiac disease or changes on electrocardiogram (ECG).
|AnswerBExp=Alport's syndrome is not primarily associated with cardiac disease or changes on electrocardiogram (ECG).
|AnswerC=Urinalysis
|AnswerC=Urinalysis
|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.  
|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=Alanine aminotransferase
|AnswerD=Serum alanine aminotransferase
|AnswerDExp=Alport syndrome is not primarily associated with abnormal values of alanine aminotransferase (ALT) or liver abnormalities.
|AnswerDExp=Alport syndrome is not primarily associated with abnormal values of alanine aminotransferase (ALT) or liver abnormalities.
|AnswerE=Platelet counts
|AnswerE=Serum platelet count
|AnswerEExp=Alport's syndrome is not primarily associated with quantitative platelet disturbances.
|AnswerEExp=Alport's syndrome is not primarily associated with quantitative platelet disturbances.
|EducationalObjectives=Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis.
|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>
|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>
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>

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::