WBR0116

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 Caucasian female 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). Routine laboratory work-up is ordered and is unremarkable. Serologic testing revealed elevated levels of tissue transglutaminase IgA antibodies. Which of the following gene mutations most likely predisposed this patient to develop his condition?]]
Answer A	AnswerA::HLA DQ2 gene
Answer A Explanation	[[AnswerAExp::This patient suffers from celiac disease or gluten-sensitive enteropathy, which is genetically predisposed by HLA DQ2 or HLA DQ8 gene subtypes.]]
Answer B	AnswerB::IBD1 gene
Answer B Explanation	AnswerBExp::IBD1 encodes an intracellular pattern recognition receptor (NOD2). IBD1 mutations are associated with inflammatory bowel diseases.
Answer C	AnswerC::HLA-DR2
Answer C Explanation	[[AnswerCExp::The HLA-DR2 variant is associated with inflammatory bowel disease.]]
Answer D	AnswerD::APC gene
Answer D Explanation	[[AnswerDExp::APC gene mutations predispose to familial adenomatous polyposis. APC encodes a gene that functions to degrade the transcription factor beta-catenin.]]
Answer E	AnswerE::MSH2 gene
Answer E Explanation	[[AnswerEExp::MSH2 gene mutation is associated with Hereditary nonpolyposis colorectal cancer. MSH2 encodes a DNA mismatch repair enzyme.]]
Right Answer	RightAnswer::A
Explanation	[[Explanation::Celiac disease is an autoimmune disease of the small intestine that occurs among genetically predisposed individuals of all ages. The onset of symptoms is typically during late childhood or early adulthood. Symptoms include abdominal pain and discomfort, chronic diarrhea, failure to thrive in children, anemia and fatigue. Although abdominal symptoms may be absent, symptoms in other organ systems could also be present. Antibodies against tissue transglutaminase are present in nearly all individuals with celiac disease. Serology for anti-tTG antibodies has superseded older serological tests (anti-endomysium, anti-gliadin, and anti-reticulin) and has a strong sensitivity (99%) and specificity (>90%) for identifying celiac disease. The greatest risk factor for celiac disease is another family member with celiac disease. The second most influential risk factor is the presence of the HLA-DQ2 subtype. Celiac disease is genetically predisposed by HLA-DQ2 or HLA-DQ8 HLA subtypes. While these HLA subtypes are present in ~30% of individuals of European descent, only 1% of the population develops celiac disease (Hunt et al). HLA associations are commonly tested on the USMLE. One useful mnemonic for the HLA associations is DR = MD..AAH HLA Subtype Associated disease HLA-DR2 Multiple Sclerosis HLA-DR3 Diabetes mellitus type 1 HLA-DR4 Arthritis (Rheumatoid) HLA-DR5 Anemia (Pernicious), Hashimoto's thyroiditis Educational Objective: Celiac disease is genetically predisposed by HLA-DQ2 or HLA-DQ8 HLA subtypes. References: First Aid 2014 page 199 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.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Celiac disease; HLA-DQ2; HLA-DQ8; HLA; diarrhea; chronic diarrhea; HLA;
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