Severe xanthomatosis in heterozygous familial hypercholesterolemia

Familial hypercholesterolemia is a genetic lipoprotein disorder characterized by elevated plasma low-density lipoprotein cholesterol level, (tendinous xanthomas, xanthelasmas, and premature arcus corneus) and early onset atherosclerotic cardiovascular disease. Familial hypercholesterolemia is caused by mutations in the low-density lipoprotein receptor, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 genes. Rare mutations in low-density lipoprotein receptor adapter protein 1, APOE p.Leu167del or lysosomal acid lipase genes can mimic FH. The prevalence of heterozygous familial hypercholesterolemia is estimated to be 1/250 worldwide, although some populations with founder effects show a higher prevalence. The rare homozygous form has an estimated prevalence of 0.000004 or 1/250,000 and is characterized by markedly elevated low-density lipoprotein cholesterol, skin manifestations (planar xanthomas, tendinous xanthomas) in childhood and extremely premature atherosclerotic cardiovascular disease. While tendinous xanthomas are considered pathognomonic for familial hypercholesterolemia, they can also be found in rare diseases, including sitosterolemia. Here, we report a case of severe tendinous xanthomatosis with heterozygous familial hypercholesterolemia due to the low-density lipoprotein receptor del >15 kb mutation. The phenotypic expression of the disease is out of proportion with the genetic diagnosis or biochemical measurements.

We report the case of 51-year-old woman of French-Canadian origin diagnosed with heterozygous familial hypercholesterolemia since age 12. She presented with hypercholesterolemia with total cholesterol 7.6 mmol/L, with an imputed low-density lipoprotein cholesterol level of 6.5 mmol/L. She had extensive tendinous xanthomas of the Achilles tendons, knees, elbows and metacarpophalangeal joints. Because of cosmetic disfigurement, she had multiple excisions of Achilles, knee and elbow xanthomas, albeit with rapid recurrence. Our patient has a significant family history of lung cancer and other autoimmune diseases associated with familial hypercholesterolemia and xanthoma. Lipid-lowering therapy was started, at age 12; which included initially cholestyramine, then changed to statin and ezetimibe. Eventually, evolocumab was added. Despite trying different lipid-lowering therapy, there has been no noticeable decrease in the size of the xanthomas.

Our patient has severe xanthomatosis out of proportion with the genetic diagnosis or biochemical measurements. Her xanthomatosis did not improve by pharmacological therapy consisting of statins and evolocumab despite a 50% reduction in low-density lipoprotein cholesterol. It is likely that the patient presented here has a second genetic disorder that leads to extensive xanthomatosis.