A 28-year-old man presents with recurrent epistaxis since childhood (multiple episodes weekly) and a 2-year history of exertional dyspnea and platypnea. Examination reveals punctate telangiectasia on the lips, tongue, fingertips, and nasal mucosa, with digital clubbing. Resting SpO₂ is 88% on room air and does NOT fully correct with 100% oxygen. Contrast echocardiography shows early left-sided opacification within 3–6 cardiac cycles, and chest CT confirms a large pulmonary arteriovenous malformation in the right lower lobe. His father, paternal aunt, and one sibling are similarly affected. The pedigree pattern shown in **B** is most consistent with which inheritance pattern and genetic basis?
A. X-linked recessive; mutations in a gene on the X chromosome affecting vascular development
B. Autosomal recessive; mutations in SMAD4 causing combined HHT and juvenile polyposis
C. Autosomal dominant; mutations in ENG or ACVRL1/ALK1 affecting TGF-β/BMP9 signaling in endothelial cells
D. Mitochondrial inheritance; maternal transmission of mutations affecting oxidative phosphorylation
Explanation
Why "Autosomal dominant; mutations in ENG or ACVRL1/ALK1 affecting TGF-β/BMP9 signaling in endothelial cells" is right
The pedigree pattern shown in B demonstrates the father, paternal aunt, and one of two siblings affected—a classic autosomal dominant inheritance pattern with male-to-male transmission (father to son), which excludes X-linked inheritance. Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu syndrome) is an autosomal dominant disorder caused by mutations in ENG (endoglin, HHT1, chromosome 9) or ACVRL1/ALK1 (HHT2, chromosome 12). Both genes encode receptors in the TGF-β/BMP9 signaling pathway in endothelial cells, leading to defective vascular development and the characteristic triad of recurrent epistaxis, mucocutaneous telangiectasia, and visceral arteriovenous malformations. This patient meets Curaçao criteria (≥3 of 4: spontaneous recurrent epistaxis, characteristic mucocutaneous telangiectasia, visceral AVM, and first-degree relative with HHT) and demonstrates the pulmonary AVM phenotype typical of HHT1 (ENG mutations).
Why each distractor is wrong
Autosomal recessive; mutations in SMAD4 causing combined HHT and juvenile polyposis: SMAD4 mutations cause a rare syndromic form combining HHT features with juvenile polyposis syndrome, not classic HHT. The pedigree in B shows autosomal dominant inheritance (affected father transmitting to son), not recessive. Autosomal recessive inheritance would require two unaffected carrier parents and would not show paternal transmission to the son.
X-linked recessive; mutations in a gene on the X chromosome affecting vascular development: X-linked recessive inheritance would affect males predominantly and would NOT show male-to-male transmission (affected father cannot pass X chromosome to son). The pedigree in B clearly shows the father transmitting the condition to his son, ruling out X-linked inheritance.
Mitochondrial inheritance; maternal transmission of mutations affecting oxidative phosphorylation: Mitochondrial inheritance shows maternal transmission only—all children of affected mothers are affected, and affected fathers do not transmit to any offspring. The pedigree in B shows paternal transmission (father to son), which is incompatible with mitochondrial inheritance. Additionally, HHT is not a mitochondrial disorder.
High-YieldNEET PG
HHT is autosomal dominant (ENG or ACVRL1/ALK1 mutations); the presence of male-to-male transmission in the pedigree is the key diagnostic clue that excludes X-linked and mitochondrial inheritance.
