Marfan Syndrome

A 17-year-old boy presents to the cardiology clinic after a school screening detected a diastolic murmur. He is asymptomatic but has always been noted to be tall and thin. On examination, his arm span exceeds his height (ratio 1.08), and he has marked arachnodactyly with positive Steinberg and Walker-Murdoch signs. Ophthalmology reveals bilateral upward ectopia lentis. Echocardiography shows aortic root dilatation at the sinuses of Valsalva (Z-score +3.2) with mild aortic regurgitation. The clinical and imaging findings are consistent with the condition marked **B** in the diagram. Which of the following best explains the underlying pathophysiology of aortic root dilatation in this syndrome?

A 28-year-old Indian male presents to the outpatient clinic with a family history of sudden cardiac death. On examination, the structure marked **A** in the diagram is noted—the thumb crosses the palm when the hand is clenched, and the thumb and fifth finger overlap around the wrist. His arm span exceeds his height by 3 cm. Echocardiography reveals aortic root dilatation (Z-score 2.5) with normal lens position. Which of the following genetic mutations is most likely responsible for this patient's phenotype?

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**?