WBR0255

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Genetics
Sub Category	SubCategory::Hematology
Prompt	[[Prompt::A newborn boy is born to a gravida-1 para-1 33-year-old woman by normal vaginal delivery. Following delivery, the child appears normal and has a normal physical examination. The next day, the child undergoes circumcision, but he bleeds excessively. The woman states that she received adequate prenatal care and had regular follow-ups with her obstetrician. The physician orders a blood work-up to investigate the boy's bleeding. His labs are remarkable for a prolonged aPTT, normal PT, and platelet count of 235 x 109/L. Further evaluation reveals factor VIII activity at less than 1% of normal. What is the mode of inheritance of this patient's condition?]]
Answer A	AnswerA::Autosomal recessive
Answer A Explanation	[[AnswerAExp::An example of an autosomal recessive disease is phenylketonuria.]]
Answer B	AnswerB::Autosomal dominant
Answer B Explanation	[[AnswerBExp::An example of an autosomal dominant disorder is von Willebrand disease (vWD).]]
Answer C	AnswerC::X-linked dominant
Answer C Explanation	[[AnswerCExp::An example of an X-linked dominant disorder is Rett syndrome.]]
Answer D	AnswerD::X-linked recessive
Answer D Explanation	AnswerDExp::Hemophilia A is an X-linked recessive disorder.
Answer E	AnswerE::Mitochondrial
Answer E Explanation	[[AnswerEExp::An example of a mitochondrial disorder is Leber’s hereditary optic neuropathy (LHON).]]
Right Answer	RightAnswer::D
Explanation	[[Explanation::Hemophilia A is an an X-linked recessive bleeding disorder caused by a deficiency of clotting factor VIII. Given its mode of inheritance, hemophilia generally affects males only. Factor VIII normally promotes the function of the intrinsic coagulation cascade and enhances thrombin generation and fibrin formation. Factor VIII is bound to von-Willebrand factor (vWF), which protects factor VIII against degradation. Hemophilia A may be clinically classified according to severity into 3 groups: Severe: Factor VIII < 1 % of normal. Patients often have spontaneous excessive bleeding. Moderate: Factor VIII % ranges between 2 to 5 % of normal. Patients bleed excessively with minor trauma, dental procedures, or surgery. Mild: Factor VIII % ranges between 5 to 40 % of normal. Excessive and prolonged bleeding following circumcision may be the first sign of hemophilia. Other clinical features of hemophilia include hemarthrosis (bleeding within synovial joints), intracranial bleeding, and unexplained bruising when infants start to crawl. Patients typically have an abnormal bleeding profile that demonstrates a prolonged aPTT with normal PT and bleeding time. The diagnosis of hemophilia is made when plasma levels of factors demonstrate severe deficiency. Nonetheless, hemophilia needs to be distinguished from other diseases that might also cause bleeding and factor VIII deficiency, such as Normandy-type (2N) von Willebrand disease that is characterized by bleeding in both males and females due to a binding defect between factor VIII and vWF. Patients with hemophilia are recommended to prophylactically receive recombinant clotting factors. In regions with no capacity to provide prophylactic management to hemophiliacs, on-demand therapy should be administered as soon as possible to prevent major bleeding events and irreversible sequelae. Bleeding can be controlled with infusions of the deficient clotting factor, i.e. factor VIII in hemophilia A and factor IX in hemophilia B. For patients with mild disease, intranasal or intravenous infusion of desmopressin has demonstrated efficacy by increasing the plasma concentration of factor VIII. Accordingly, desmopressin may be administered in hemophilia A but not hemophilia B. Educational Objective: Hemophilia A is an an X-linked recessive bleeding disorder caused by a deficiency of clotting factor VIII. References: Fijnvandraat K, Cnossen MH, Leebeek FW, et al. Diagnosis and management of haemophilia. BMJ. 2012;344:e2707. First Aid 2014 page 88, 389]]
Approved	Approved::Yes
Keyword	WBRKeyword::X-linked recessive, WBRKeyword::Hemophilia, WBRKeyword::Hemophilia A, WBRKeyword::Factor VIII, WBRKeyword::Bleeding disorder, WBRKeyword::Hemarthrosis, WBRKeyword::Circumcision
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