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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 21: Line 21:
|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 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?  
|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.
|Explanation={| border="1" style="border-collapse:collapse; text-align:left;" cellpadding="5" align="center"
|AnswerA=Serum Creatinine
|+ '''''Clinical Manifestations of Alport's Syndrome'''''
|AnswerAExp=Alport syndrome is a familial cause of deafness, ocular disturbances and nephritis.
|  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. 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.
 
{| border="1" style="border-collapse:collapse; text-align:center;" cellpadding="5" align="center"
|+ '''''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
|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.  
|AnswerB=Electrocardiogram
|AnswerB=Electrocardiogram
|AnswerBExp=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=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=Alanine aminotransferase
|AnswerDExp=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=Platelet counts
|AnswerEExp=Alport syndrome is not associated with hematologic disturbances.
|AnswerEExp=Alport's syndrome is not primarily associated with quantitative platelet disturbances.
|EducationalObjectives=Alport 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.
|References=First Aid 2014 page 538
|References=McCarthy PA, Maino DM. Clin Eye Vis Care. 2000; 12(3-4):139-50.<br>
|RightAnswer=A
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>
|WBRKeyword=Alport syndrome, Alport, Nephritis, Deafness, Hearing loss, Genetics,  
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
}}
}}

Revision as of 16:16, 7 November 2014
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 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?]]
Answer A AnswerA::Serum creatinine
Answer A Explanation [[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.]]
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::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::Platelet counts
Answer E Explanation AnswerEExp::Alport's syndrome is not primarily associated with quantitative platelet disturbances.
Right Answer RightAnswer::C
Explanation [[Explanation::{

Educational Objective: Alport's syndrome is a familial cause of deafness, ocular disturbances, and nephritis.
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
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