A 42-year-old man presents to the clinic because his wife is concerned about the coloring of his skin, stating “he looks like he just spent a week on the beach.” He reports that he was recently diagnosed with type 2 diabetes and is taking metformin. He denies having had any blood transfusions. Physical examination reveals hyperpigmentation of the skin diffusely. The sclera are noted to be yellow and there is pitting edema in the legs bilaterally. Abdominal examination reveals a distended abdomen with a fluid wave. An ultrasound of the liver is ordered and reveals the presence of cirrhosis. The patient declines a biopsy of the liver, but a blood test is ordered to evaluate for genetic conditions.
Which of the following genetic mutations will most likely be present in this patient?
B) C282Y HFE gene on chromosome 6p
This patient likely has hemochromatosis. The presence of diabetes, cirrhosis, and hyperpigmentation of the skin ("bronze diabetes") are highly suggestive of hemochromatosis. The mutation that causes hemochromatosis is C282Y HFE gene on chromosome 6p.
Answer A, ATP7B is seen in Wilson disease: ATP7B gene (copper binding membrane bound ATPase) which presents with Mallory bodies, macrovesicular steatosis, vacuolated hepatocyte nuclei, compound heterozygotes, and increased hepatic copper on Rhodanine stain.
Answer C, CFTR gene mutation, results in cystic fibrosis due to a dysfunctional cystic fibrosis transmembrane conductance receptor
Answer D, KRAS mutation, is a common cancer-related gene occurring in 17%-25% of all cancers. Approximately 30%-40% of colon cancers carry a KRAS mutation which is associated with a poorer survival and increased tumor aggressiveness.
Answer E, PiZZ genotype on chromosome 14, is associated with alpha 1-antitrypsin deficiency which manifests with chronic obstructive lung disease and liver disease.
Key Learning Point
Hemochromatosis is a disorder of iron overload. The iron deposits in the liver, pancreas, myocardium, pituitary, skin, and other tissues. The genetic form is due to autosomal recessive inheritance of the HFE gene on chromosome 6p, usually C282Y. The classic triad includes cirrhosis, skin pigmentation, and diabetes.
