WBR0144
| Author | [[PageAuthor::Yazan Daaboul, M.D. (Reviewed by by Will Gibson and Alison Leibowitz [1])]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Musculoskeletal/Rheumatology |
| Prompt | [[Prompt::A 37-year-old man presents to the emergency department (ED) for a severe sudden "tearing" chest pain that radiates to his back. The patient is tall, has abnormal laxity of his joints, and long extremities. A medical student suggests that this patient has Marfan syndrome, whereas the resident in the ED contends that long extremities and joint laxity may be features of other inherited conditions. Which of the following mechanism's explains the resident’s argument?]] |
| Answer A | AnswerA::Mosaicism |
| Answer A Explanation | [[AnswerAExp::Mosaicism is the presence of two or more populations of cells with different genotypes in one individual who has developed from a single fertilized egg.
Different types of mosaicism exist, such as gonadal mosaicism (restricted to the gametes), tissue mosaicism, or somatic mosaicism.]] |
| Answer B | AnswerB::Heteroplasmy |
| Answer B Explanation | [[AnswerBExp::Heteroplasmy is the presence of more than one type of an organelle genes (mitochondrial DNA or plastid DNA) within a cell or individual. Heteroplasmy is a factor for severity of mitochondrial diseases.]] |
| Answer C | AnswerC::Pleiotropy |
| Answer C Explanation | [[AnswerCExp::Pleiotropy occurs when one gene influences multiple phenotypic traits. Consequently, a mutation in a pleiotropic gene may have an effect on some or all traits simultaneously. While the Fibrillin mutations of Marfan syndrome are illustrations of pleiotropy, pleiotropy is not the most accurate descriptor of the resident's argument.]] |
| Answer D | AnswerD::Locus heterogeneity |
| Answer D Explanation | [[AnswerDExp::Locus heterogeneity is defined as mutations at different chromosomal loci that cause similar phenotypes. Although this patient’s marfanoid habitus may be result from Marfan syndrome, other diseases such as homocysteinuria or MEN 2 B syndrome, should also be considered in the differential diagnosis.]] |
| Answer E | AnswerE::Variable expressivity |
| Answer E Explanation | [[AnswerEExp::Variable expressivity occurs when a phenotype varies among individuals who have the same genotype. Although MFS is characterized by variable expressivity, whereby some patients patients have dissimilar manifestations, locus heterogeneity better explains the resident's argument in the vignette.]] |
| Right Answer | RightAnswer::D |
| Explanation | [[Explanation::Marfan syndrome (MFS) is an autosomal dominant genetic disorder of the connective tissue caused by a mutation of the Fibrillin (FBN1) gene. It is characterized by complete penetrance with a variable expression and significant variation across individuals. The hallmark features of MFS are cardiovascular, ocular, and skeletal, which might lead to life-threatening complications. The most common cardiovascular complication is aortic root enlargement that requires frequent monitoring. The most concerning complication among patients with MFS is aortic dissection and/or rupture, which typically presents as a acute severe "tearing" chest pain that radiates to the back as observed in this patient. Ocular manifestations associated with MS include ectopia lentis, myopia, and retinal detachment. Skeletal malformations are also common, they include tall stature, increased arm span, anterior chest abnormalities such as pectus excavatum or carinatum, arachnodactyly, joint laxity, narrow and high-arched palate, scoliosis, and lordosis.
The patient in this vignette has most likely suffered aortic dissection, which is classically associated with MS. Patients with marfanoid habitus are usually tall, have abnormal joints laxity, and long extremities, fingers, and toes. Although marfanoid habitus may be caused by Marfan syndrome, patients with other inherited diseases, such as homocystinuria or MEN 2 B syndrome, may also have marfanoid habitus and appear phenotypically similar to patients with MFS. This may be thus explained by locus heterogeneity, which is defined as mutations at different chromosomal loci that cause similar phenotypes. |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Marfan, WBRKeyword::Marfan syndrome, WBRKeyword::Marfan's syndrome, WBRKeyword::Pleiotropy, WBRKeyword::Locus, WBRKeyword::Heterogeneity, WBRKeyword::Locus heterogeneity, WBRKeyword::Phenotype, WBRKeyword::Genotype, WBRKeyword::Aortic dissection |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |