A Thirteen-Year-Old Boy with Rashes and Bumps on Arms and Legs

A 13-year-old boy developed a raised, yellow bumpy rash on his arm. His primary care physician (PCP) thought the rash was secondary to ingrown hair. The rash became more profuse despite 4 weeks of antibiotic treatment. The patient was referred to a pediatric dermatologist who identified diffuse yellow-orange waxy papules over arms, legs, and trunk (Fig. 1A). Microscopic examination of a shave biopsy of one of the papules demonstrated histopathologic findings consistent with eruptive xanthomas (Fig. 1B). The patient was subsequently admitted to the hospital and referred to a pediatric cardiologist and a pediatric endocrinologist. Admission history and physical examination findings revealed an obese male with a body weight of 87 kg, height of 166 cm, and elevated BMI of 31 (BMI: 95%--99% percentile for age and sex). Family history showed that the father had a history of borderline elevated triglycerides that had been treated with diet. There is no family history of cardiac disease on his father’s side. The biological mother had a history of prediabetes and gestational diabetes. A. Rashes and waxy papules in arm. B. Eruptive xanthoma: dermal foamy histiocytes with admixed neutrophils and extravascular lipid. C. Milky serum as arrived in the laboratory. D. Standing plasma test overnight showing presence of chylomicrons and turbid plasma. A. Rashes and waxy papules in arm. B. Eruptive xanthoma: dermal foamy histiocytes with admixed neutrophils and extravascular lipid. C. Milky serum as arrived in the laboratory. D. Standing plasma test overnight showing presence of chylomicrons and turbid plasma. Multiple fasting blood specimens were sent to the clinical laboratory and initial inspection of one of the specimen’s revealed milky serum (Fig. 1C). Standing plasma test (1) was also performed by cooling the sample overnight at 4 °C, revealing an upper layer of fat (chylomicrons) overlying turbid plasma (VLDL) (Fig. 1D). A complete summary of laboratory test results is shown in Table 1. Notable findings included elevated glucose 395 mg/dL, HbA1c 11.1%, total cholesterol 778 mg/dL, and total triglyceride >4425 mg/dL. Fractionation of lipoprotein subclasses revealed lipoprotein (a), and lipoprotein-X (Lp-X, a lipoprotein rich in phospholipid and free cholesterol)-cholesterol and LDL-cholesterol and -triglycerides within corresponding reference limits, with undetectable beta-VLDL-cholesterol and -triglycerides. Apolipoprotein B (Apo B) was mildly elevated at 124 mg/dL. The most striking findings were marked elevation of both VLDL- and chylomicron-cholesterol and triglycerides as predicted based on the results of the standing plasma test. Laboratory results. Lipid metabolism profile is measured in a reference lab by a combination of electrophoresis, ultracentrifugation, enzymatic quantitation of cholesterol and triglycerides, and immunoturbidimetric measurement of apolipoproteins. Laboratory results. Lipid metabolism profile is measured in a reference lab by a combination of electrophoresis, ultracentrifugation, enzymatic quantitation of cholesterol and triglycerides, and immunoturbidimetric measurement of apolipoproteins. Xanthomas appear as soft waxy papules or firm nodules with yellow hue, most commonly found in the upper and lower extremities but sometimes occur on the chest and abdomen. Microscopically, these lesions show characteristically abundant lipid-laden macrophages (histiocytes) referred to as “foam cells” admixed with neutrophils, extravascular lipid, and varying degrees of lymphocyte infiltration and edema. Eruptive xanthomas arise in patients with profound hypertriglyceridemia. The size, number, and location of these lesions change over time in conjunction with changes in total triglyceride levels (2). Our patient presented to his PCP with papules on his upper forearm (Fig. 1A). They did not cause any discomfort, so no further evaluation was pursue. However, the skin findings progressively worsened 5 months later and a shave biopsy of the papules confirmed the presence of eruptive xanthomas. Xanthoma is usually caused by high levels of blood lipids. This may be a symptom of an underlying medical condition, such as hyperlipidemia, diabetes, hypothyroidism, primary biliary cirrhosis, or cholestasis. In our patient who presented with eruptive xanthomas and profoundly elevated triglyceride and cholesterol levels, the presence of chylomicrons in the top layer, and turbid plasma indicating high VLDL in the standing plasma test/refrigerator test (Fig. 1D) provided strong supportive evidence for mixed hyperlipidemia (Fredrickson Classification type V) that was further confirmed by fasting studies of cholesterol and triglyceride content of chylomicrons, VLDL, beta-VLDL, and LDL. In subjects who have high fasting triglycerides (>500 mg/dL), the standing plasma test/refrigerator test has utility in differentiating presence and absence of chylomicrons and VLDL. A visibly milky specimen stored overnight at 4 °C would help differentiate between Type I (a clear infranate with a creamy layer on the top), Type IV (an even turbidity throughout the sample without a creamy layer), and Type V dyslipidemias (a turbid infranate with a creamy layer on the top) (3). Mixed hyperlipidemia (Fredrickson Classification type V) is characterized by an increase in both chylomicrons and VLDL and has an incidence of about 1 in 500. It is most commonly seen as a transient phenotype and is frequently found in association with diabetes mellitus. Although the exact molecular cause of this disorder is not known, the metabolic defect appears to be increased production or decreased clearance of VLDL, or a combination of both. The activity of lipoprotein lipase (LPL) in these patients may be normal or low, and the plasma concentration of apo C-II is normal, but they were not measured for our patient. Although this phenotype is not usually expressed in childhood, several affected preadolescents have been described (4). The LPL deficiency can be tested by measuring LPL activity in post heparin plasma. The decrease in post heparin lipolytic activity is corrected to normal with addition of apoC protein. There are molecular workups that may also help differentials of familial origin of the dyslipidemia that were not carried out on this patient (5). Patients with hyperglyceridemia may develop acute pancreatitis (6), but this patient had normal amylase and lipase activities. Further evaluation for concomitant diabetes mellitus was undertaken, given the high blood glucose and HbA1C. Type 1 diabetes mellitus was excluded based on normal insulin levels and low islet cell and glutamic acid decarboxylase antibody levels in serum. C-peptide was within corresponding reference limits, making primary insulin resistance unlikely. Thyroid function testing was performed, since hyperlipidemia is exacerbated in patients with hypothyroidism. Thus, the final diagnosis in our patient was mixed hyperlipidemia (Fredrickson Classification type V) with type-II diabetes mellitus based on obesity and elevated glucose and HbA1c. Although patients with type 2 diabetes and hyperlipidemia most often have the type IV variety, they can also have other types, including type V (7). The primary treatment goals were to control blood glucose and lipid levels through insulin administration and fat-free diet (8). The use of statins to lower cholesterol and reduce cardiovascular disease risk in this case is unlikely to be beneficial as LDL cholesterol is normal in our patient, and the primary role of statin therapy is to upregulate LDL receptors on hepatocytes to selectively accelerate LDL clearance and reduce circulating concentrations of this primary atherogenic lipoprotein. Nevertheless, lowering chylomicron and VLDL cholesterol and triglycerides is of benefit in mixed hyperlipidemia (Fredrickson classification type V). Additional medications to achieve this in our patient include Lovaza, ezetimibe, and fenofibrate. Topical lidocaine is also of benefit to reduce any discomfort associated with cutaneous eruptive xanthomas. The patient responded well to the treatment. Ten days later, his plasma triglyceride, cholesterol, non-HDL-cholesterol, and glucose concentrations decreased to 2050 mg/dL, 448 mg/dL, 429 mg/dL, and 152 mg/dL, respectively. His HDL-cholesterol increased to 19 mg/dL. At follow-up 2 months later, his plasma triglyceride, cholesterol, and non-HDL-cholesterol concentrations were 278 mg/dL, 201 mg/dL, and 168 mg/dL, respectively, and HDL-cholesterol was 33 mg/dL. His HbA1c reduced to 7.8% after 4-month treatment. It is worthwhile to note that the milky specimens from our patient may interfere with some assays arising from multiple mechanisms. One mechanism is based on volume displacement errors which affect results of any test where analyte concentration is measured following sample dilution. A classic example is pseudohyponatremia when ion selective electrode (ISE) measurements of sodium are made following sample dilution (“indirect” ISE measurements). A second mechanism of interference arises in spectrophotometric methods due to light scattering by lipoproteins suspended in the plasma phase of blood. The magnitude of interference in these assays is a complex function of lipoprotein particle size and concentration and assay wavelength. And finally, lipid soluble analytes (including therapeutic drugs) may partition in the lipid phase where they are not available to interact with antibodies in immunoassay techniques (9). Ultracentrifugation, high speed centrifugation, and lipids removal agents can be used to eliminate or reduce the interference (10). However, for patients such as ours with so high triglyceride in chylomicron and VLDL, the above techniques may not be able to completely eliminate the interference. For instance, our patient demonstrated falsely low plasma sodium ranging 128–136 mmol/L, presumably due to volume displacement, and falsely increased alanine transaminase, total protein, albumin, and calcium, presumably because of light scattering by lipoproteins. Xanthoma is usually caused by high levels of blood lipids. This may be a symptom of an underlying medical condition, such as hyperlipidemia, diabetes, hypothyroidism, primary biliary cirrhosis, or cholestasis. A simple and easy standing plasma refrigerator test can provide important information about differential diagnosis of dyslipidemia. Hypertriglyceridemia and associated lipemia in serum and plasma causes interference with many common laboratory tests. Ultracentrifugation, high speed centrifugation, and lipid removal agents can be used to eliminate or reduce the interference. Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. M.A. Barbhuiya, statistical analysis, provision of study material or patients. Authors’ Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.