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. TGFBR1 or TGFBR2 gene mutation causing Loeys-Dietz syndrome
B. COL3A1 gene mutation causing Ehlers-Danlos syndrome type IV
C. FBN1 gene mutation on chromosome 15q21 encoding fibrillin-1
D. Cystathionine β-synthase deficiency causing homocystinuria
Explanation
Why FBN1 gene mutation on chromosome 15q21 encoding fibrillin-1 is right
The clinical presentation—arachnodactyly with positive Steinberg sign (thumb crosses palm) and Walker-Murdoch sign (thumb-fifth finger overlap around wrist), tall stature with arm span > height, and aortic root dilatation—is pathognomonic for Marfan syndrome. Per the Revised Ghent Nosology 2010, aortic root dilatation (Z-score ≥2) combined with a systemic score ≥7 (the wrist and thumb sign alone contributes 3 points) confirms the diagnosis. Marfan syndrome is an autosomal dominant connective tissue disorder caused by FBN1 mutations encoding fibrillin-1, a critical component of microfibrils in elastic fibers. Fibrillin-1 normally sequesters latent TGF-β; mutations cause both structural weakness and dysregulated TGF-β signaling, explaining both skeletal features and cardiovascular complications.
Why each distractor is wrong
TGFBR1 or TGFBR2 gene mutation causing Loeys-Dietz syndrome: While Loeys-Dietz also presents with arachnodactyly and aortic disease, it is distinguished by bifid uvula, cleft palate, and hypertelorism—features absent in this patient. Additionally, Loeys-Dietz is more aggressive and typically presents earlier with more severe aortic pathology.
Cystathionine β-synthase deficiency causing homocystinuria: Homocystinuria does cause arachnodactyly and aortic disease, but the lens dislocation is characteristically inferonasal (downward), not normal as in this patient. Homocystinuria is autosomal recessive and presents with intellectual disability and thrombotic complications—not present here.
COL3A1 gene mutation causing Ehlers-Danlos syndrome type IV: Ehlers-Danlos syndrome presents with skin hyperextensibility and severe joint hypermobility as primary features, with minimal aortic involvement. The skeletal phenotype and cardiovascular manifestations do not match this diagnosis.
High-YieldNEET PG
The Steinberg sign (thumb crosses palm) and Walker-Murdoch sign (thumb-fifth finger overlap) are cardinal features of Marfan syndrome and score 3 points on the systemic score; combined with aortic root dilatation, they confirm FBN1-related Marfan syndrome per Revised Ghent Nosology 2010.
