Guest Editorial: Tuberous and Tendon Xanthomas: Don’t Overlook Sitosterolemia or Cerebrotendinous Xanthomatosis

Some inherited lipid disorders can be recognized by the deposition of cholesterol and other lipids in lesions on the body termed xanthomas. Lipid deposition can occur in cutaneous and subcutaneous structures, including tendons, with the pattern of deposition characteristic of the underlying genetic disorder. Tuberous xanthomas are nodules frequently localized to the extensor surfaces of elbows, knees, knuckles, and buttocks. Tendon xanthomas are subcutaneous nodules found in fascia, ligaments, and tendons, which can occur particularly in the Achilles tendon and extensor tendons of the hands (Figure 1). The focus of this article is to highlight less common genetic disorders that cause tuberous and tendon xanthomas to promote better diagnosis of these disorders.

The most common hyperlipidemia underlying tuberous and tendon xanthomas is familial hypercholesterolemia (FH), caused by defects in the genes encoding the low-density lipoprotein (LDL) receptor, apolipoprotein B (apoB)-100, PCSK9, and LDLRAP1,^1-7 although a number of other genetic disorders can cause these types of xanthoma (Table 1). Tuberous xanthomas also can occur in type III hyperlipidemia (familial dysbetalipoproteinemia) and sitosterolemia (phytosterolemia). Tendon xanthomas can occur in sitosterolemia and cerebrotendinous xanthomatosis (CTX). Outside of xanthomas in children with Alagille syndrome, finding xanthomas in children is extremely suggestive of homozygous familial hypercholestrolemia, sitosterolemia or CTX. For CTX especially, the appearance of xanthomas often occurs early in the course of disease and prompt diagnosis and early treatment is crucial in preventing disease progression and development of severe neurological disease.

Sitosterolemia (along with autosomal recessive FH because of mutations in LDL receptor adaptor protein 1 [LDLRAP1] and ARH) should be considered as the underlying cause of xanthomas when hypercholesterolemia is present and in the absence of a family history of FH.

CTX should be considered as the underlying cause of xanthomas in the absence of marked hypercholesterolemia and when persistent diarrhea, juvenile cataracts, and cognitive impairment may be present.

Biochemical diagnosis of sitosterolemia and CTX cannot be accomplished using standard laboratory methods of cholesterol measurement. Specialized analyses of cholestanol and plant sterols are required, typically using gas chromatography mass spectrometry (GC-MS). In sitosterolemia concentrations of the plant sterol sitosterol can be as high as 10-65 mg/dL.⁸ Typical plant sterol concentrations in healthy individuals are 100-fold lower than cholesterol (for sitosterol 0.21 ± 0.7 mg/dL⁸; see also Table 2). A plasma sitosterol concentration > 1mg/dL is considered diagnostic for sitosterolemia. A diagnostic threshold of 1 mg/dL helps avoid false positive results, although ezetimibe treatment may result in a false negative result. Identification of pathogenic mutations in ABCG5 and ABCG8 by molecular genetic testing also can be useful to confirm sitosterolemia. In untreated CTX patients, concentrations of cholestanol can range from 0.84 mg/dL to 6.6 mg/dL.¹² The range of the mean cholestanol concentration in healthy individuals is around 0.13 mg/dL (Table 2).¹² A plasma cholestanol concentration > 1mg/ dL is considered diagnostic for CTX. Because cholestanol can be elevated in liver disease and concentrations of up to 0.7 and 1.1 mg/dL have been reported in healthy individuals,^13,14 a diagnostic threshold of 1mg/dL helps avoid false positive results. Bile acid intermediates that accumulate in CTX also may be useful for biochemical diagnosis of this disorder.¹² Identification of pathogenic mutations in CYP27A1 by molecular genetic testing also can be useful in confirming CTX. The plasma concentration ranges for sitosterol and cholestanol in unaffected and affected individuals as historically determined by the Oregon Health and Science University (OHSU) Sterol Analysis Laboratory are provided in Table 2.

Sitosterolemia and CTX should not be overlooked when evaluating the cause of tuberous and tendon xanthomas, because correct diagnosis and appropriate treatment of these rare underlying genetic disorders are critical to ensure the best outcome for patients affected by these disorders.

Disclosure statement: Dr. DeBarber received a research grant from Retrophin Inc. to perform a screening pilot study to screen for cerebrotendinous xanthomatosis in newborns. Dr. Duell has received research grants from Genzyme, Regeneron, Retrophin, and Amgen. He has received honoraria from Genzyme, Sanofi, Regeneron, Retrophin, Lilly, and Kaneka.

References are listed on page 35 of the PDF.