Sitosterolaemia in Switzerland: molecular genetics links the US Amish-Mennonites to their European roots.

Sitosterolaemia is a rare autosomal recessive disease characterized by increased intestinal absorption of plant sterols, decreased hepatic excretion into bile and elevated concentrations in plasma phytosterols. Homozygous or compound heterozygous loss of function mutations in either of the ATP-binding cassette (ABC) proteins ABCG5 and ABCG8 explain the increased absorption of plant sterols. Here we report a Swiss index patient with sitosterolaemia, who presented with the classical symptoms of xanthomas, but also had mitral and aortic valvular heart disease. Her management over the last 20 years included a novel therapeutic approach of high-dose cholesterol feeding that was semi-effective. Mutational and extended haplotype analyses showed that our patient shared this haplotype with that of the Amish-Mennonite sitosterolaemia patients, indicating they are related ancestrally.

Verruciform xanthoma--biological profile of 282 oral lesions based on a literature survey with nine new cases from Japan.

The biological profile of oral verruciform xanthoma (VX) is presented based on a world-wide literature survey of 282 cases. From 1979 onwards, extraoral cases have also been reported. This rare, harmless lesion with a sessile or pedunculated base is a red/pink, papillary/granular/verrucous mucosal growth, occurring in females (mean age, 54.9 yrs) and males (mean age, 44.2 yrs) in a female:male ratio of 1:1.1. The most common location is by far the gingival margin and other areas of the masticatory oral mucosa. Comparison between 173 non-Japanese and 109 Japanese patients with oral VX showed few discrepancies in epidemiological data, indicating only few significant ethnic differences between the two cohorts. Histomorphologically, the epithelium covering the lesion can be divided into three groups: (A) a verrucous, (B) a papillary and (C) a flat pattern. The hallmark of all VX, irrespective of the lesion being intra- or extraoral is, however, the presence of vacuolated, foam or xanthoma cells which ultimately replace the connective tissue between the epithelial ridges. The xanthoma cells have been shown to be cells of the monocyte/macrophage lineage. The present concept of the etiology and pathogenesis of VX, including the possible viral (HPV) association is revised, based on both intra- and some extraoral cases, and it is concluded that it is still far from being clarified.

Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics.

Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive lipid-storage disease caused by mutations in the sterol 27 hydroxylase gene (CYP27). Clinically, a multitude of neurological, skeletal, and vascular manifestations are usually present. Premature atherosclerosis has been reported in CTX and may be related to the metabolic derangement caused by the deficiency of the enzyme. A CYP27 nonsense mutation created by the deletion of cytosine376 has been identified in four Israeli Druze CTX patients residing in the same village. Molecular screening for this mutation in families of two probands revealed a total of 10 homozygotes and 28 heterozygotes whose clinical and biochemical characteristics are described. Overall, except for tendon xanthomas, most of the clinical manifestations progress with age. The CYP27 mutation was associated with modest differences in the levels of plasma total cholesterol (TC) and LDL cholesterol (LDL-C). The distribution of plasma concentrations of TC and LDL-C in the CTX families was consistent with a polygenic model. A similar model that includes also the effects of the CYP27 genotypes was not better supported by the data. It may be concluded that, in CTX, the presence of a CYP27 mutation does not significantly affect the plasma concentrations of lipids and lipoproteins. Therefore, the reported increased prevalence of atherosclerosis in this disease must be related to other factors.