A 42-year-old man presents with a pulsatile mass in the neck and tinnitus. Imaging reveals a carotid body paraganglioma. Genetic testing identifies a germline mutation in the gene marked **A** in the diagram. His father had a similar tumor at age 38, but his mother, who carries the same mutation, remains asymptomatic. Which of the following best explains the inheritance pattern and clinical presentation associated with mutations in the structure marked **A**?
A. X-linked dominant; affected males pass the mutation to all daughters but no sons
B. Autosomal recessive; both parents must be carriers for the disease to manifest in offspring
C. Autosomal dominant with maternal imprinting; disease manifests only when inherited paternally, causing parasympathetic head-neck paragangliomas
D. Autosomal dominant with paternal imprinting; disease manifests only when inherited maternally, causing sympathetic abdominal paragangliomas
Explanation
Why option 1 is correct
The structure marked A is SDHD (chromosome 11q23), which causes hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC). SDHD mutations exhibit maternal imprinting, meaning the maternal allele is epigenetically silenced. Therefore, disease manifests only when the mutation is inherited from the father—the paternal allele is expressed while the maternal allele is silenced. SDHD-associated paragangliomas are characteristically parasympathetic in location (head and neck sites: carotid body, jugulotympanic, vagal), typically nonfunctional but causing symptoms like pulsatile tinnitus, neck masses, and cranial nerve palsies—exactly as presented in this case. The father's affected status and the mother's asymptomatic carrier status confirm paternal inheritance of the expressed mutation (Sabiston Surgery 21e, Ch 39).
Why each distractor is wrong
Option 2 (Autosomal recessive): SDHD mutations are autosomal dominant, not recessive. Only one mutated allele is needed to cause disease (when inherited paternally). The patient's mother carries the mutation but is unaffected, ruling out recessive inheritance.
Option 3 (X-linked dominant): SDHD is located on chromosome 11q23, not the X chromosome. X-linked inheritance would show a different pattern (affected males passing to all daughters, no sons), which does not match this pedigree.
Option 4 (Paternal imprinting with maternal inheritance): This reverses the imprinting pattern. SDHD shows maternal imprinting (maternal allele silenced), not paternal imprinting. Additionally, SDHD causes parasympathetic head-neck paragangliomas, not sympathetic abdominal tumors (which are characteristic of SDHB mutations on 1p36).
