A 22-year-old man presents for cardiac evaluation after his brother died of aortic dissection at age 35. He is 196 cm tall with arm span 208 cm and upper:lower segment ratio 0.82. Examination reveals arachnodactyly (positive wrist and thumb signs), pectus excavatum, scoliosis, and bilateral superior-temporal lens dislocation on slit-lamp examination. Echocardiography shows aortic root dilation at the sinuses of Valsalva (Z-score +3.5) with mitral valve prolapse. His mother, maternal grandmother, and two siblings show similar features. The pedigree marked **B** in the diagram demonstrates the inheritance pattern and clinical manifestations of this condition. Which of the following best describes the genetic basis and pathophysiology of the condition illustrated in pedigree **B**?
A. X-linked recessive inheritance due to dystrophin mutations, manifesting as progressive muscular dystrophy with secondary cardiac involvement
B. Autosomal dominant inheritance due to FBN1 mutations causing fibrillin-1 deficiency, leading to loss of TGF-β sequestration and tissue overgrowth
C. Autosomal recessive inheritance due to COL3A1 mutations affecting type III collagen, resulting in vascular fragility and aortic dissection
D. Autosomal dominant inheritance due to TGFBR1/2 mutations causing hypertelorism, bifid uvula, and more aggressive aortic disease than classic Marfan syndrome
Explanation
Why option 1 is correct
The pedigree marked B shows autosomal dominant inheritance with affected individuals across three generations (mother, maternal grandmother, and siblings affected), tall stature, arachnodactyly, lens dislocation, and aortic dissection—the cardinal features of Marfan syndrome. The condition is caused by heterozygous mutations in FBN1 (chromosome 15q21.1), which encodes fibrillin-1, a critical component of microfibrils in the extracellular matrix. Fibrillin-1 normally sequesters transforming growth factor-β (TGF-β); loss of fibrillin-1 function releases TGF-β, causing excessive tissue growth, weakening of elastic structures (aortic root dilation, lens zonule disruption), and skeletal overgrowth (tall stature, arachnodactyly). This directly matches the Ghent Nosology 2010 diagnostic criteria and the clinical presentation in pedigree B (Ghent Nosology 2010; Harrison's 21e).
Why each distractor is wrong
Option 2 (COL3A1, autosomal recessive): Vascular Ehlers-Danlos syndrome (caused by COL3A1 mutations) is autosomal dominant (not recessive) and presents with vascular fragility, thin translucent skin, and rupture of medium/small arteries—not the skeletal and ocular features seen in pedigree B. Also, it does not show the multi-generational dominant pattern illustrated.
Option 3 (X-linked dystrophin): Duchenne/Becker muscular dystrophy is X-linked recessive and presents with progressive muscle weakness, elevated CK, and cardiomyopathy—not the tall stature, arachnodactyly, lens dislocation, and aortic root dilation characteristic of pedigree B. The inheritance pattern is also inconsistent (mother and maternal grandmother affected).
Option 4 (TGFBR1/2, Loeys-Dietz): While Loeys-Dietz syndrome is autosomal dominant and involves TGF-β signaling, it is a distinct entity characterized by hypertelorism, bifid uvula, and more aggressive aortic disease. It does not explain the specific skeletal and ocular features (arachnodactyly, lens dislocation) or the fibrillin-1 deficiency mechanism shown in pedigree B.
High-YieldNEET PG
Marfan syndrome = FBN1 mutations → fibrillin-1 loss → TGF-β release → tissue overgrowth + elastic weakening; autosomal dominant inheritance; aortic root dilation is the leading cause of death.
Ghent Nosology 2010; Harrison's Principles of Internal Medicine, 21e; Loeys et al. 2010 revised criteria
Practice similar questions
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.
