A 22-year-old man presents to the clinic for a routine physical examination. He has no significant past medical history and doesn’t take any medications. He is 195 cm (6 ft 5 in) tall and weighs 75 kg (165 lb). On physical examination, he is noted to have remarkably long, slender fingers and an arm span that is significantly greater than his height. He has a mild inward deformity of his sternum. Slit-lamp examination reveals a superior and temporal displacement of the crystalline lens in both eyes. Auscultation of the heart reveals a high-pitched, blowing diastolic murmur heard best at the right upper sternal border.
Which of the following is the most likely underlying genetic defect in this patient?
The correct answer is:
D) Mutation in the FBN1 gene
This patient presents with the classic constellation of findings for Marfan syndrome, an autosomal dominant disorder of connective tissue. Key features include a marfanoid habitus (tall stature, long extremities, arachnodactyly), pectus excavatum (inward chest deformity), and ectopia lentis (specifically superior/upward subluxation of the lens). The diastolic murmur at the right upper sternal border is characteristic of aortic regurgitation, often resulting from aortic root dilation. Marfan syndrome is caused by a mutation in the FBN1 gene on chromosome 15, which encodes fibrillin-1, a glycoprotein that serves as a scaffold for elastin and regulates TGF-β signaling.
Answer choice A: Cystic medial necrosis, is incorrect. While cystic medial necrosis is the classic histological finding in the aorta of patients with Marfan syndrome (characterized by the loss of smooth muscle cells and fragmentation of elastic fibers), it is a pathological consequence of the disease rather than the underlying genetic defect.
Answer choice B: Defect in collagen type I, is incorrect. Mutations in the COL1A1 or COL1A2 genes, which lead to defects in type I collagen, result in osteogenesis imperfecta. This condition typically presents with multiple fractures, blue sclerae, and hearing loss, rather than the skeletal and ocular findings seen here.
Answer choice C: Defect in collagen type III, is incorrect. This is the underlying defect in the vascular type of Ehlers-Danlos syndrome. While these patients can have joint hypermobility and are at risk for arterial rupture, including aortic dissection, they do not typically exhibit a marfanoid habitus or ectopia lentis.
Answer choice E: Mutation in the FGFR3 gene, is incorrect. A gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene leads to achondroplasia, which is the most common cause of dwarfism. This presents with short-limbed stature, not the tall stature and long extremities seen in Marfan syndrome.
Key Learning Point
Marfan syndrome is an autosomal dominant connective tissue disorder caused by a mutation in the FBN1 gene on chromosome 15 encoding fibrillin-1. It is characterized by a marfanoid habitus, superior ectopia lentis, and life-threatening cardiovascular complications such as aortic root dilation and dissection due to cystic medial necrosis.
