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{{WBRQuestion
{{WBRQuestion
|QuestionAuthor=Mahmoud Sakr (Reviewed by Will J Gibson and {{Rim}})
|QuestionAuthor=Mahmoud Sakr (Reviewed by Will J Gibson,  {{Rim}}, and {{YD}})
|ExamType=USMLE Step 1
|ExamType=USMLE Step 1
|MainCategory=Genetics
|MainCategory=Genetics
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|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Gastrointestinal
|SubCategory=Gastrointestinal
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
|MainCategory=Genetics
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|MainCategory=Genetics
|MainCategory=Genetics
|SubCategory=Gastrointestinal
|SubCategory=Gastrointestinal
|Prompt=A 33-year-old Caucasian female presents with diarrhea and foul-smelling bulky stools for the past 3 weeks. She has tried several over the counter medications with no relief. Yesterday, she noticed an eruption of intensely pruritic papules and vesicles on her elbows, dorsal forearms and back. She recalls that her older brother has suffered from a similar illness for approximately 5 years. Her vital signs and initial labs are unremarkable. Serologic testing revealed elevated levels of IgA tissue transglutaminase antibodies. Which of the following gene mutations most likely predisposed this patient's condition?
|Prompt=A 33-year-old woman presents with complaints of diarrhea and foul-smelling bulky stools for the past 3 weeks. She previously tried several over-the-counter medications with no relief. Yesterday, she noticed an eruption of intensely pruritic papules and vesicles on her elbows, dorsal forearms, and back. She recalls that her older brother has suffered from a similar illness for approximately 5 years. Her blood pressure is 120/80 mmHg, heart rate is 70/min, and temperature is 36.8 °C (98.24 °F). Serological testing reveals elevated levels of tissue transglutaminase IgA antibodies. Which of the following HLA haplotypes most likely predisposed this patient to develop his condition?
|Explanation=This patient suffers from [[celiac disease]] or gluten-sensitive enteropathy.  Celiac disease is an [[autoimmune disease]] of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward. Symptoms include pain and discomfort in the digestive tract, chronic [[diarrhea]], [[failure to thrive]] (in children), [[anemia]] and fatigue, but these may be absent, and symptoms in other organ systems have been described. [[Celiac disease]] is genetically predisposed by [[HLA-DQ2]] or [[HLA-DQ8]] HLA subtypes.
|Explanation=Celiac disease is an [[autoimmune disease]] that often affects the distal duodenum and proximal jejunum. It occurs among genetically predisposed individuals of all ages. The onset of symptoms is typically during late childhood or early adulthood. Symptoms include malabsorption, abdominal pain and discomfort, chronic [[diarrhea]], [[failure to thrive]] in children, [[anemia]], and fatigue. IgA antibodies against tissue transglutaminase are present almost all patients with celiac disease. Serology for anti-tTG IgA antibodies is a very sensitive (99%) and specific (>90%) for identifying celiac disease. Other serological tests, anti-endomysium, anti-gliadin, and anti-reticulin may also be used, but are less sensitive and less specific. On biopsy, blunting of villi is observed, with lymphocytes in the lamina propria. The greatest risk factor for celiac disease is a positive family history, followed by the presence of [[HLA-DQ2]] haplotype. [[Celiac disease]] is associated with HLA haplotypes [[HLA-DQ2]] or [[HLA-DQ8]] subtypes. While these HLA subtypes are present in approximately 30% of individuals of European descent, only 1% of the population develops celiac disease.
|AnswerA=HLA DQ2 gene
 
|AnswerAExp=This patient suffers from [[celiac disease]] or gluten-sensitive enteropathy, which is genetically predisposed by [[HLA DQ2]] or [[HLA DQ8]] gene mutations.
Common HLA subtypes and their associated diseases are shown in the table below.<br>
|AnswerB=IBD1 gene
[[Image:HLA subtypes and associated diseases.jpg|600px]]
|AnswerBExp=IBD1 encodes an intracellular pattern recognition receptor (NOD2).  IBD1 mutations are associated with inflammatory bowel diseases.
<br><br>
 
In addition to its association with some malignancies like T-cell lymphoma, celiac disease is also associated with cutaneous manifestations, classically dermatitis herpetiformis (Duhring's disease) as observed in this patient. Dermatitis herpetiformis is a pruritic papulovesicular eruption that symmetrically affects the scalp, buttocks, posterior nuchal area, and extensor surfaces, such as the elbows, knees. Microscopically, dermatitis herpetiformis has speckled IgA deposits in the dermal papillae and few deposits under the epidermal rete ridges and the basement membrane zone.
|AnswerA=HLA-DQ2
|AnswerAExp=This patient in the vignette suffers from [[celiac disease]] or gluten-sensitive enteropathy, which is associated with [[HLA-DQ2]] and [[HLA-DQ8]] haplotypes.
|AnswerB=HLA-A3
|AnswerBExp=HLA-A3 haplotype is associated with [[Hemochromatosis]].
|AnswerC=HLA-DR2
|AnswerC=HLA-DR2
|AnswerCExp=HLA-DR2 is associated with [[inflammatory bowel disease]]s.
|AnswerCExp=HLA-DR2 haplotype is associated with [[multiple sclerosis]], [[hay fever]], [[SLE]], and [[Goodpasture syndrome]].
|AnswerD=APC gene
|AnswerD=HLA-DR5
|AnswerDExp=APC gene mutation predisposes to [[familial adenomatous polyposis]].
|AnswerDExp=HLA-DR5 haplotype is associated with [[pernicious anemia]] and [[Hashimoto's thyroiditis]].
|AnswerE=MSH2 gene
|AnswerE=HLA-DR3
|AnswerEExp=MSH2 gene mutation is associated with [[Hereditary nonpolyposis colorectal cancer]].
|AnswerEExp=HLA-DR3 haplotype is associated with development of [[diabetes mellitus type 1]], [[SLE]], and [[Graves' disease]].
|EducationalObjectives=Celiac disease or gluten-sensitive enteropathy, which is genetically predisposed by [[HLA-DQ2]] or [[HLA-DQ8]] HLA subtypes.
|EducationalObjectives=Celiac disease is an autoimmune disease that is associated with HLA haplotypes [[HLA-DQ2]] and [[HLA-DQ8]].
|References=First Aid 2014 page 199
|References=Hunt KA, Zhernakova A, Turner G, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40(4):395-402.<br>Katz SI, Strober W. The pathogenesis of dermatitis herpetiformis. J Invest Dermatol. 1978;70(2):63-75.<br> Gough SCL, Simmonds MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics. 2007;8(7):453-65.<br>First Aid 2014 page 199
|RightAnswer=A
|RightAnswer=A
|WBRKeyword=Celiac disease; HLA-DQ2; HLA-DQ8; HLA; diarrhea; chronic diarrhea
|WBRKeyword=Celiac disease, Autoimmune, Diarrhea, Chronic diarrhea, Chronic, Abdominal pain, Pain, Abdominal, HLA, Subtype, HLA subtype, HLA-DQ, HLA-DQ2, HLA-DQ8, HLA DQ2, HLA DQ8, Genetic mutation, Gene, Mutation, Predispose, Predisposition, Gluten, Insensitive, Insensitivity
|Approved=Yes
|Approved=Yes
}}
}}

Latest revision as of 23:24, 27 October 2020
Author [[PageAuthor::Mahmoud Sakr (Reviewed by Will J Gibson, Rim Halaby, M.D. [1], and Yazan Daaboul, M.D.)]]
Exam Type ExamType::USMLE Step 1
Main Category MainCategory::Genetics
Sub Category SubCategory::Gastrointestinal
Prompt [[Prompt::A 33-year-old woman presents with complaints of diarrhea and foul-smelling bulky stools for the past 3 weeks. She previously tried several over-the-counter medications with no relief. Yesterday, she noticed an eruption of intensely pruritic papules and vesicles on her elbows, dorsal forearms, and back. She recalls that her older brother has suffered from a similar illness for approximately 5 years. Her blood pressure is 120/80 mmHg, heart rate is 70/min, and temperature is 36.8 °C (98.24 °F). Serological testing reveals elevated levels of tissue transglutaminase IgA antibodies. Which of the following HLA haplotypes most likely predisposed this patient to develop his condition?]]
Answer A AnswerA::HLA-DQ2
Answer A Explanation [[AnswerAExp::This patient in the vignette suffers from celiac disease or gluten-sensitive enteropathy, which is associated with HLA-DQ2 and HLA-DQ8 haplotypes.]]
Answer B AnswerB::HLA-A3
Answer B Explanation [[AnswerBExp::HLA-A3 haplotype is associated with Hemochromatosis.]]
Answer C AnswerC::HLA-DR2
Answer C Explanation [[AnswerCExp::HLA-DR2 haplotype is associated with multiple sclerosis, hay fever, SLE, and Goodpasture syndrome.]]
Answer D AnswerD::HLA-DR5
Answer D Explanation [[AnswerDExp::HLA-DR5 haplotype is associated with pernicious anemia and Hashimoto's thyroiditis.]]
Answer E AnswerE::HLA-DR3
Answer E Explanation [[AnswerEExp::HLA-DR3 haplotype is associated with development of diabetes mellitus type 1, SLE, and Graves' disease.]]
Right Answer RightAnswer::A
Explanation [[Explanation::Celiac disease is an autoimmune disease that often affects the distal duodenum and proximal jejunum. It occurs among genetically predisposed individuals of all ages. The onset of symptoms is typically during late childhood or early adulthood. Symptoms include malabsorption, abdominal pain and discomfort, chronic diarrhea, failure to thrive in children, anemia, and fatigue. IgA antibodies against tissue transglutaminase are present almost all patients with celiac disease. Serology for anti-tTG IgA antibodies is a very sensitive (99%) and specific (>90%) for identifying celiac disease. Other serological tests, anti-endomysium, anti-gliadin, and anti-reticulin may also be used, but are less sensitive and less specific. On biopsy, blunting of villi is observed, with lymphocytes in the lamina propria. The greatest risk factor for celiac disease is a positive family history, followed by the presence of HLA-DQ2 haplotype. Celiac disease is associated with HLA haplotypes HLA-DQ2 or HLA-DQ8 subtypes. While these HLA subtypes are present in approximately 30% of individuals of European descent, only 1% of the population develops celiac disease.

Common HLA subtypes and their associated diseases are shown in the table below.


In addition to its association with some malignancies like T-cell lymphoma, celiac disease is also associated with cutaneous manifestations, classically dermatitis herpetiformis (Duhring's disease) as observed in this patient. Dermatitis herpetiformis is a pruritic papulovesicular eruption that symmetrically affects the scalp, buttocks, posterior nuchal area, and extensor surfaces, such as the elbows, knees. Microscopically, dermatitis herpetiformis has speckled IgA deposits in the dermal papillae and few deposits under the epidermal rete ridges and the basement membrane zone.
Educational Objective: Celiac disease is an autoimmune disease that is associated with HLA haplotypes HLA-DQ2 and HLA-DQ8.
References: Hunt KA, Zhernakova A, Turner G, et al. Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet. 2008;40(4):395-402.
Katz SI, Strober W. The pathogenesis of dermatitis herpetiformis. J Invest Dermatol. 1978;70(2):63-75.
Gough SCL, Simmonds MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics. 2007;8(7):453-65.
First Aid 2014 page 199]]

Approved Approved::Yes
Keyword WBRKeyword::Celiac disease, WBRKeyword::Autoimmune, WBRKeyword::Diarrhea, WBRKeyword::Chronic diarrhea, WBRKeyword::Chronic, WBRKeyword::Abdominal pain, WBRKeyword::Pain, WBRKeyword::Abdominal, WBRKeyword::HLA, WBRKeyword::Subtype, WBRKeyword::HLA subtype, WBRKeyword::HLA-DQ, WBRKeyword::HLA-DQ2, WBRKeyword::HLA-DQ8, WBRKeyword::HLA DQ2, WBRKeyword::HLA DQ8, WBRKeyword::Genetic mutation, WBRKeyword::Gene, WBRKeyword::Mutation, WBRKeyword::Predispose, WBRKeyword::Predisposition, WBRKeyword::Gluten, WBRKeyword::Insensitive, WBRKeyword::Insensitivity
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