Numerous yellowish maculopapular lesions on the palms. Note the pathognomonic macular yellowish discoloration of the palms which is limited to the creases.
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Rothschild M, Duhon G, Riaz R, et al. Pathognomonic Palmar Crease Xanthomas of Apolipoprotein E2 Homozygosity-Familial Dysbetalipoproteinemia. JAMA Dermatol. 2016;152(11):1275–1276. doi:10.1001/jamadermatol.2016.2223
It is important for all clinicians, especially dermatologists, to recognize the rare diagnostic physical sign of familial dysbetalipoproteinemia (FD), palmar crease xanthoma (PCX),1 because it is an early warning sign to initiate diagnostic tests (apolipoprotein [apoE] genotyping, lipid profiling, documentation of dysbetalipoproteinemia by ultracentrifugation or nuclear magnetic resonance lipid profiling), and thus enables treatment. Familial dysbetalipoproteinemia, a rare familial hyperlipidemia, is very sensitive to treatment with fibrates and/or statins,2 with lipid normalization and reduction in risk of atherosclerotic cardiovascular disease (ASCVD).3 Approximately 20% of patients with FD have characteristic palmar xanthomas.1 Our specific aim was to assess dermatologic manifestations of FD (type 3 hyperlipoproteinemia) with the mutant apoE2/2 genotype, and emphasize the centrality of the dermatologist in a diagnostic-therapeutic role in identifying unique palmar xanthomas.
A total of 2055 patients sequentially referred to us for the diagnosis and treatment of combined hyperlipidemia had examination for palmar xanthomas and apoE genotyping. The study followed a protocol (#12-03) approved by the Jewish Hospital institutional review board. Signed informed consent was obtained in 39 patients with combined hyperlipidemia and apoE2/2 genotype, where a diagnosis of FD was confirmed by ultracentrifugation.
Of the 2055 patients evaluated, 39 (25 men, 14 women; 1.9% of the 2055 examined) were found to have FD with the apoE2/2 genotype; 7 of the 39 (18%) had PCXs accompanied by severe combined hyperlipidemia (total [SD] cholesterol [TC] level, 8.77 mmol/L [4.27 mmol/L]; triglyceride [TG] level, 5.28 mmol/L [4.53 mmol/L]). Neither the 216 patients with the apo E2/3 genotype nor the 45 with apoE2/4 (Table) had PCX, which were also not observed in the remaining 1755 patients without the apoE2 allele. One of the 7 apoE2 homozygotes, a man in his 20s with palmar crease planar xanthomas, tuberous xanthomas, high TC levels (11.97 mmol/L), and high TG levels (14.51 mmol/L), was referred only after biopsy of palmar lesions revealed xanthoma (Figure). In this case, after 4 weeks of receiving dietary gemfibrozil, 1.2 g/d, TC levels fell to 10.37 mmol/L, TG levels to 1.98 mmol/L, and xanthomas regressed with complete resolution in 8 weeks, paralleling regression of palmar xanthomas in the other 6 FD patients on treatment with fibrates, fibrates plus a statin, or statin alone.
By virtue of systematic evaluation for xanthomas in all 2055 patients at their initial visit to our center, before lipid profile and apoE genotyping data were completed, our study uniquely focused on the rare diagnostic physical finding of PCXs in a large population referred for diagnosis and therapy of hyperlipidemia, and the association of the diagnosis of palmar xanthomas with lipid profiles and apoE genotypes. Of the 2055 patients examined for PCXs, and having apoE genotyping, 39 (1.9%) had FD, and 7 (18% of the 39) had PCXs, comparable with a prevalence of 20% found in a review1 of 105 South African FD patients. The prevalence of PCXs, however, is likely a function of how intensively the diagnosis is sought and how many patients are investigated, given their usually subtle presentation of yellow-orange macules involving the palm creases. These are considered pathognomonic of FD, but may be confused with planar xanthoma seen in cholestasis diseases, which are usually white plaques that extend beyond the palmar creases.4 Since FD has important cardiac5 and dermatologic manifestations that respond well to treatment,3 identification of FD is critical.
Recognition by all physicians, especially dermatologists, of the rare diagnostic and pathognomonic physical sign of PCXs of apoE2/2 dysbetalipoproteinemia, opens the door to early diagnosis, documentation, and therapy; all focused on resolution of both cutaneous xanthomas and atherosclerotic lesions. The dermatologist is the gatekeeper for early diagnosis and treatment.
Corresponding Author: Matan Rothschild, MD, Cholesterol, Metabolism, and Thrombosis Center, MMA-Jewish Hospital, 2135 Dana Ave, Suite 430, Cincinnati, OH 45207 (email@example.com).
Accepted for Publication: May 22, 2016.
Published Online: September 7, 2016. doi:10.1001/jamadermatol.2016.2223.
Author Contributions: Drs Rothschild and Glueck had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Rothschild, Glueck, Wang.
Acquisition, analysis, or interpretation of data: Rothschild, Duhon, Riaz, Jetty, Goldenberg Glueck, Wang.
Drafting of the manuscript: Rothschild, Duhon, Riaz, Jetty, Glueck, Wang.
Critical revision of the manuscript for important intellectual content: Rothschild, Duhon, Riaz, Jetty, Glueck, Wang, Goldenberg.
Statistical analysis: Wang.
Obtained funding: Glueck.
Administrative, technical, or material support: Glueck, Goldenberg.
Study supervision: Glueck.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported in part by the Lipoprotein Research Fund (this is a fund of the Jewish Hospital-Mercy Health which provides support for The Cholesterol, Metabolism, and Thrombosis Center).
Role of the Funder/Sponsor: The Jewish Hospital-Mercy Health had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.