A 45-year-old man of Northern European descent presents with fatigue, arthralgia in the second and third metacarpophalangeal joints, and hepatomegaly. Serum transferrin saturation is 68% and ferritin is 1200 ng/mL. HFE genotyping reveals the genotype marked **B** in the diagram. Which of the following best describes the expected phenotype and clinical course in this patient?
A. Simple heterozygote (C282Y/wild-type) with normal iron studies; clinical features are not expected in this genotype despite carrier status
B. Homozygous C282Y/C282Y with the highest risk of progressive iron overload; this genotype accounts for 80-90% of clinically affected patients and has the most severe phenotype
C. Homozygous H63D/H63D with mild iron overload; this genotype rarely develops clinical hemochromatosis due to very low penetrance of the H63D allele
D. Compound heterozygote (C282Y/H63D) with intermediate iron overload and variable expression; clinical manifestations often require cofactors such as alcohol or hepatitis C to become apparent
Explanation
Why option 1 is right
The genotype marked B in the diagram is explicitly defined as "Autosomal recessive — compound heterozygote (C282Y/H63D) with variable expression." According to Harrison's Principles of Internal Medicine 21e, compound heterozygotes (C282Y/H63D) account for 3–5% of clinical cases and have an intermediate phenotype with variable iron overload, generally less severe than C282Y homozygotes. Importantly, these individuals often manifest clinical features only when cofactors such as alcohol use, hepatitis C, or metabolic syndrome are present. The clinical anchor emphasizes that this genotype exhibits variable expression — varying severity among individuals with the same genotype — and incomplete penetrance, meaning not all carriers develop clinical disease. This patient's presentation with fatigue, arthralgia, hepatomegaly, and elevated iron markers is consistent with a compound heterozygote who has developed clinical hemochromatosis, likely with contributing factors.
Why each distractor is wrong
Option 2 (Homozygous C282Y/C282Y): While this is the most common genotype in clinically affected patients (80–90% of cases) and carries the highest risk of iron overload, the diagram explicitly marks B as a compound heterozygote, not a homozygote. C282Y homozygotes have a more uniform and severe phenotype compared to the variable expression seen in compound heterozygotes.
Option 3 (Homozygous H63D/H63D): H63D is a mild allele with very low penetrance; H63D homozygotes rarely develop clinical iron overload. This patient has clear clinical and biochemical evidence of hemochromatosis, which is inconsistent with this genotype. Additionally, B is defined as a compound heterozygote, not an H63D homozygote.
Option 4 (Simple heterozygote C282Y/wild-type): Simple heterozygotes generally have normal iron studies and do not develop clinical hemochromatosis. This patient's markedly elevated transferrin saturation and ferritin contradict this genotype. B is defined as a compound heterozygote with two mutant alleles, not a simple heterozygote.
High-YieldNEET PG
Compound heterozygotes (C282Y/H63D) have intermediate phenotype and often require cofactors (alcohol, hepatitis C) to manifest clinical hemochromatosis; they account for only 3–5% of clinical HH cases, whereas C282Y homozygotes account for 80–90%.
Harrison's Principles of Internal Medicine 21e — Hereditary Hemochromatosis chapter
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