Cutaneous Xanthomas Research Articles

Novel Therapeutic Strategies for the Homozygous Familial Hypercholesterolemia

HoFH is an autosomal co-dominant disease with a prevalence of one in 1,000,000. Mutations of LDL-R gene are responsible for this disease. HoFH needs to be distinguished from autosomal recessive hypercholesterolemia protein (ARH) that causes a similar clinical phenotype. HoFH induces aggressive cardiovascular disease that can develop from birth. These patients possess high LDL-C levels, cutaneous and tendon xanthomas, and accelerated atherosclerosis shown in the first 2 decades of life. Current treatment modalities include life-style modifications, lipid-lowering therapy and LDL-apheresis. However, the treatment goal cannot be achieved only by statin therapy. New therapeutic strategies to lower LDL-C have been developed over recent years. These include monoclonal antibodies binding to PCSK9, inhibition of ApoB production and MTP-inhibitors. This review is focused on new treatments for HoFH and their patents. It is known to be an important contribution in this rare disease, which is difficult to manage.

Homozygous familial hypercholesterolemia: development and a case illustration

Familial hypercholesterolemia (FH) is a genetic disease caused by a mutation of the gene encoding for the low density lipoproteins (LDL) membrane receptor. The mutation is transmitted in an autosomal dominant mode and is manifested by permanent elevation of the plasma LDL-cholesterol concentration; such elevation is responsible for the early onset of cardiovascular complications. The other clinical manifestation is the existence of extravascular cholesterol deposits: xanthomas and corneal arcus. There are two forms of familial hypercholesterolemia: homozygous FH and heterozygous FH which is generally less severe biologically and clinically. We report in this work, a case of FH diagnosed at the laboratory of clinical chemistry of Rabat children's hospital. The lipid profile revealed a dramatic LDL-cholesterol elevation (24 mmol/L) with normal triglycerides concentration (0.84 mmol/L). The physical examination revealed cutaneous xanthomas. The diagnosis of homozygous FH was strongly suggested by family study.

Treatment of Mycosis Fungoides with Bexarotene Results in Remission of Diffuse Plane Xanthomas

Cutaneous xanthomas develop as a result of intracellular and dermal deposition of lipids in either hyper- or normolipidemic patients. Plane xanthomas may signal the presence of an underlying monoclonal gammopathy, chronic myelomonocytic leukemia, or cutaneous T-cell lymphoma. Investigators have suggested that xanthomatized T cells may result in induction of plane xanthomas. We report the case of a patient with mycosis fungoides (MF) and plane xanthomas who was treated with bexarotene for his MF. Significant improvement in the clinical signs of MF was observed within 3 months. We also observed a substantial regression of the xanthomas after 5 months of treatment. Complete clinical remission of both the MF and xanthomas was obtained after 6 months. The patient was still free of xanthomas after 3 years of follow-up. Bexarotene led to the clearing of the cutaneous lesions of cutaneous T-cell lymphoma and plane xanthomas. This may be due to an effect of bexarotene on the aberrant T cells that may cause xanthomatization.

Scrotal cutaneous verruciform xanthoma with monocyte chemoattractant protein-1 immunohistochemical study: a case report

IntroductionVerruciform xanthoma is a rare, benign lesion characterized by hyperkeratosis and aggregates of foam cell macrophages. Here, we describe a case of verruciform xanthoma on the scrotum, in which the immunohistochemical localization of monocyte chemoattractant protein-1, a chemokine of the C-C or beta family that has been shown to induce the recruitment of monocytes for injured tissue, was analyzed to determine which cells release chemoattractants for macrophages.Case presentationA 75-year-old Japanese man with a well-defined nodule on the left scrotum was admitted to the hospital. An excision biopsy revealed epidermal papillary proliferation with parakeratosis, hyperkeratosis, and infiltration of foam cell macrophages, whereby a pathological diagnosis of benign cutaneous verruciform xanthoma was made. Immunohistochemically, monocyte chemoattractant protein-1 was observed predominantly on cytokeratin AE1/AE3-positive differentiating keratinocytes in the prickle cell layer. However, while infiltrating macrophages were densely stained for monocyte chemoattractant protein-1, keratinocytes in the basal and parabasal layers were almost negative.ConclusionsWe demonstrated that keratinocyte-derived monocyte chemoattractant protein-1 plays an important role in the establishment of particular histological features of verruciform xanthoma. However, in the present case, unlike in previous reports, monocyte chemoattractant protein-1 immunostaining in keratinocytes in the basal and parabasal layers was not prominent. We speculate that in the active phase of verruciform xanthoma, when continuous stimuli that release monocyte chemoattractant protein-1 from keratinocytes to the surrounding stromal area are present, the apparent immunostaining of monocyte chemoattractant protein-1 can be underestimated because of the void created by accelerated keratinocyte release from the cytoplasmic fraction.

Bilateral Circular Xanthelasma Palpebrarum

Bilateral Circular Xanthelasma Palpebrarum

Multicenter Study to Determine the Diagnosis Criteria of Heterozygous Familial Hypercholesterolemia in Japan

Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria. A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed. Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL-C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied. We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan.

Localized Xanthomas Associated with Primary Lymphedema

Cutaneous xanthomas arising in chronic lymphedema are rare. We present a case of verruciform xanthoma involving the left foot and toes of a 10-year-old boy who had developed a primary lymphedema (lymphedema praecox) in the left lower extremity. Laboratory studies demonstrated a normal lipid profile.

Coexistent cutaneous tuberous and tendinous xanthomas in traumatic regions: a case report

Xanthomas are tumors containing lipid-filled cells thatcan be seen on various regions of the body and areimportant clinical manifestations of disordered lipidmetabolism [1, 2]. They are generally classified accordingto their locations and appearances. Tuberous xanthomasare nodular, firm, painless subcutaneous swellings thatdevelop in those areas which are subjected to repeatedtrauma such as the elbows, knees, and buttocks. They mayoccur as single or multiple swellings and may vary in size,sometimes coalescing to form large tumorous swellings asshowninthiscase[3–6]. Tuberous xanthomas are usuallyassociated with raised low density lipoprotein levels [3, 5,6]. Tendinous xanthomas involve tendons or fascia mostlyseen on hands, feet, elbows, or knees and, although rare,are frequently seen in type-II hyperlipoproteinemia [7–9].Planar xanthomas, on the other hand, are yellow papularplaques seen on the head and neck region, the trunk, andextremities and occur mostly in type-II hyperlipoproteine-mia. Eruptive xanthomas, in contrast, are small, inflam-matory, red to yellow papules that appear suddenlyassociated with high serum rates of triglyceride mostlyseen in types III and IV hyperlipoproteinemia [10, 11].Xanthelasmas are plane xanthomas seen on the uppereyelids due to elevated cholesterol levels as seen in type-IIhyperlipoproteinemia.Patient and methodsThis case is a 21-year-old man who was referred to ourclinic complaining of multiple tuberous xanthomas overextensor surfaces and joints of the hands, arms, and legswith tendinous xanthomas of the extensor digits and theAchilles tendon, simultaneously. The history of thepatient revealed a diagnosis of familial hyperlipidemiatype IIa for which the patient was using medication. Hehad undergone an attack of acute rheumatic fever forwhich he was still using monthly prophylactic penicillininjections. On physical examination, he had oily skin andmultiple ulcerated xanthomas all over his body presenting asyellow pigmented and infected subcutaneousmasses over thethird metacarpophalangeal (MCP) joint of the right hand andover the extensor surface of the right and left elbows (Figs. 1,2). There was a tendinous lesion without any ulceration overthe third MCP of the left hand extending onto the proximalphalanx that was mobile with flexion and extension of thefinger and over the patella of both knees (Fig. 3). Atendinous mass was also palpated in the Achilles tendon ofthe right foot (Fig. 4).

Idiopathic solitary cutaneous xanthoma in a dog

A 6-year-old female spayed Boxer mix dog was presented with multiple cutaneous masses, one of which was determined to be a xanthoma. Fine-needle aspirates of this mass revealed large round cells that were consistent with macrophages. These macrophages had lightly basophilic cytoplasm that was filled with many clear circular spaces that varied in size. The nuclei of these cells displayed mild anisokaryosis with condensed chromatin and lacked prominent nucleoli. The cytologic interpretation was lipid-laden histiocytic inflammation most consistent with a cutaneous xanthoma, which was confirmed histologically. Mild hypertriglyceridemia and persistent moderate hypercholesterolemia were present. After ruling out other causes of hyperlipidemia, we concluded that the dog likely had idiopathic hyperlipidemia with secondary xanthoma formation.

Homozygous Familial Hypercholesterolemia: Case Series and Review of the Literature

Introduction. Familial hypercholesterolemia (FH) is caused by nonfunctioning low-density lipoprotein (LDL) receptors, resulting in high serum cholesterol. Two types of FH are described: the heterozygous form is diagnosed in adults and responds well to medical therapy; the homozygous form is rare, diagnosed in children, and often requires multiple treatments to prevent complications. Cholesterol accumulation in tissues produces common clinical manifestations including cutaneous xanthomas, coronary artery disease, and aortic stenosis. Treatment options consist of lifestyle modifications, lipid-lowering medications, LDL aphaeresis, and orthotopic liver transplantation (OLT). Case Presentation. Two patients with FH presented at young ages due to characteristic cutaneous xanthomas. The patients underwent cardiac testing that revealed atherosclerotic changes. The patients received maximal medical therapy, but only experienced a small decrease in serum cholesterol and LDL levels. After several years of medical treatment without improvement of symptoms, the patients were listed for OLT. The transplantations were successful, and only one patient had a postoperative complication of acute rejection, treated successfully. Currently, both patients are doing well with regression of the cutaneous xanthomas and atherosclerotic changes. Conclusion. OLT is a safe and effective option for patients with homozygous FH refractory to maximal medical therapy and may represent the optimal treatment for these patients.

Platelet Activation In Sitosterolemia Mice

AbstractAbstract 2022 Introduction:Sitosterolemia is a rare, autosomal recessive disorder characterized by the accumulation of plant sterols in blood and tissues, and is caused by mutations in one of the adenosine triphosphate-binding cassette (ABC) transporter ABCG5 or ABCG8 genes. Patients with mutations in either of these sterol transport proteins, which normally form a heterodimer sterol egress channel, frequently develop tendon and cutaneous xanthomas and, most importantly, are at risk of developing premature coronary atherosclerosis. Other clinical manifestations include hematological abnormalities such as hemolytic anemia, macrothrombocytopenia, and loss of ristocetin-induced platelet agglutination – a measure of the ability of platelet glycoprotein (GP) Ib to function as a adhesion receptor for von Willebrand factor (VWF). Mice genetically deficient in ABCG5 or ABCG8 fully recapitulate the macrothrombocytopenia and loss of platelet function seen in human sitosterolemia, a condition that can be corrected by treatment with the sterol-absorption inhibitor, ezetimibe. Because the mechanism by which accumulated plant sterols affects platelet size, production, and function is incompletely understood, we further analyzed these traits in Abcg5- and Abcg8-deficient mice in an animal model of sitosterolemia. Methods:Blood was collected every 1–2 weeks and CBC monitored in Abcg5- and Abcg8-deficient mice that had been fed either a high or low plant sterol diet. Expression of platelet receptors was analyzed by both flow cytometry and Western blotting. GPIbα null mice were used as controls since they have similarly enlarged platelets. Platelet microparticles were analyzed by labeling with a mAb specific for GPIIb and Annexin V. Plasma samples were analyzed for von Willebrand factor (VWF) antigen and multimer patterns. Results:Following onset of a high sterol diet, the platelet count decreased over a two week period to less than 30% of that of normal controls in both Abcg5-/- and Abcg8-/- mice. At the same time, the mean platelet volume gradually increased over a 4 week period from a normal value of approximately 7 fl to approximately 10 fl. In addition, an increased number of platelet-derived microparticles were detected in Abcg5-/- and Abcg8-/- mice kept on high sterol diet over a 9 week period, suggesting that low-grade platelet activation was occurring in these mice. Unexpectedly, the surface expression of the GPIIb integrin subunit was decreased in both Abcg5-/- and Abcg8-/- mouse platelets compared to that of similarly large platelets derived from GPIbα-null (Bernard-Soulier) platelets. Intracellular staining revealed that the GPIIb in Abcg8-/- platelets was being internalized and retained within the cell. Both surface-bound and total platelet fibrinogen was increased in Abcg5-/- and Abcg8-/- mice fed a high sterol diet. Finally, plasma VWF antigen levels decreased by approximately 50% within two weeks following switching Abcg5-/- mice from a low-fat to a high-fat diet. Multimer analysis showed loss of high molecular weight multimers in some of the plasma samples. Conclusions:This study demonstrates a heightened state of platelet activation in a murine model of sitosterolemia, leading to VWF and fibrinogen binding, with concomitant internalization of GPIIb. This might explain, at least in part, the cause of macrothorombocytopenia and absence of ristocetin-induced platelet aggregation in sitosterolemia patients. Platelet activation may also lead to calpain activation, resulting filamin A and talin degradation and microparticle production. Future studies aims at identifying the mechanism by which plant sterols or their metabolites elicit these effects on platelets may provide important clues to the ability of dietary lipids to affect platelet activation and the development of atherosclerosis. Disclosures:Newman:New York Blood Center: Membership on an entity's Board of Directors or advisory committees; Children's Hospital of Boston: Membership on an entity's Board of Directors or advisory committees.

805 Familial Lipoprotein Lipase Deficiency

Background: Mutations in the LPL gene cause familial lipoprotein lipase deficiency. Symptoms of familial LPL deficiency usually begin in childhood and include abdominal pain, acute and recurrent inflammation of the pancreas, skin lesions called eruptive cutaneous xanthoma and an enlargement of the liver and spleen. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy.Aims: Early diagnosis, routine surveillance and treatment of familial LPL deficiency may help to manage some of the symptoms and sometimes prevent related problems.Methods: Clinical genetic testing for familial lipoprotein lipase deficiency may be available through an in person genetic consultation for children who are considered at risk. Triglycerides and total cholesterol were measured using commercially available kits (Boehringer Mannheim).Results: Episodes of abdominal pain are common. Intensity, duration, and localization of episodes are variable. Enlargement of the liver and spleen occurs particularly among affected infants and children. The enlargement of these organs may vary, often in parallel with the fat content of the diet. The risk is the same for boys and girls.Conclusions: Familial lipoprotein lipase deficiency is an inherited condition that disrupts the normal breakdown of fats in the body. It is characterized by absence of lipoprotein lipase activity and a massive accumulation of chylomicrons in plasma and a corresponding increase of plasma triglyceride concentration. Higher levels of plasma LPL activity are associated with decreased TG and increased HDL cholesterol levels in children.

Late Evolution of Giant Verruciform Xanthoma in the Setting of CHILD Syndrome

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome is a rare X-linked dominant disorder that is characterized by peculiar cutaneous features commonly associated with skeletal and internal organ involvement. Cutaneous verruciform xanthoma is an uncommon cutaneous manifestation of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome. We present a case presenting with a late onset of a large verruciform xanthoma of the right foot, in addition to the more typical cutaneous features of congenital hemidysplasia with ichthyosiform erythroderma and limb defects syndrome.

Eruptive neutrophilic xanthomas

Cutaneous eruptive xanthomas are characteristics lesions of hyperlipidemia. Rarely,these lesions may present with prominent leukocytoclasis as seen in papular neutrophilic xanthomas, which have been described in HIV positive and immunocompromised patients. Herein we describe a patient with eruptive neutrophilic xanthomas with neither hyperlipidemia nor immunocompromise. Moreover, these lesions improved with sun and UV light exposure.

The challenge produced by familial homozygous hypercholesterolemia when treating premature coronary arterial disease in the young

Familial hypercholesterolemia is a monogenic, autosomal dominant disorder caused by mutations in the LDL receptor gene. Familial homozygous hypercholesterolemia results when both the alleles have the defective mutation. It is characterized by cutaneous and tendinous xanthomas, premature corneal arcing, and is associated with an increased risk of coronary arterial disease. It is also seriously underdiagnosed, resulting in delayed treatment. We present a cross-sectional study of 5 patients with familial homozygous hypercholesterolemia who presented to the department of cardiology at Sri Jayadeva Institute of Cardiology, Bangalore, India. All of them underwent coronary angiography as part of the investigation of their angina. All 5 patients were in 2nd or 3rd decade of life, 4 being male, and 4 presenting with effort angina, the other having unstable angina. All had multiple tendinous xanthomas. The majority had significant high grade coronary arterial stenosis. Coronary arterial bypass grafting was necessary in 3, with the others undergoing percutaneous insertion of coronary arterial stents. Familial homozygous hypercholesterolemia is a potentially dangerous risk factor that can result in premature coronary arterial disease in children and young adults. This can result in severe morbidity and premature death in young individuals. We also emphasise the need to screen first-degree relatives and extended family members, this playing an important role in early detection and treatment. Despite recent advances in treatment using lipid lowering agents, the disease remains a significant challenge.

A new mouse mutant for the LDL receptor identified using ENU mutagenesis

In an effort to discover new mouse models of cardiovascular disease using N-ethyl-N-nitrosourea (ENU) mutagenesis followed by high-throughput phenotyping, we have identified a new mouse mutation, C699Y, in the LDL receptor (Ldlr), named wicked high cholesterol (WHC). When WHC was compared with the widely used Ldlr knockout (KO) mouse, notable phenotypic differences between strains were observed, such as accelerated atherosclerotic lesion formation and reduced hepatosteatosis in the ENU mutant after a short exposure to an atherogenic diet. This loss-of-function mouse model carries a single base mutation in the Ldlr gene on an otherwise pure C57BL/6J (B6) genetic background, making it a useful new tool for understanding the pathophysiology of atherosclerosis and for evaluating additional genetic modifiers regulating hyperlipidemia and atherogenesis. Further investigation of genomic differences between the ENU mutant and KO strains may reveal previously unappreciated sequence functionality.

178: Potential mechanism of probucol-mediated cutaneous xanthoma reduction: In vitro studies

178: Potential mechanism of probucol-mediated cutaneous xanthoma reduction: In vitro studies

Xanthoma Disseminatum in a Child With Cranial Bone Involvement

Xanthoma disseminatum is a normolipemic xanthomatosis classified in the group of non-Langerhans cell histiocytic disorders. Classic clinical findings are cutaneous and mucosal xanthomas and diabetes insipidus. Ocular, liver, bone marrow, respiratory, skeletal, and central nervous system involvement may accompany the classic findings of the disease. Skeletal involvement is a rare manifestation of the disease in children. We report on a 5-year-old boy with cranial bone involvement, proptosis and xanthomatous cutaneous lesions, treated successfully with systemic corticosteroids.

Plant Sterols Cause Macrothrombocytopenia in a Mouse Model of Sitosterolemia

Mutations in either ABCG5 or ABCG8 cause sitosterolemia, an inborn error of metabolism characterized by high plasma plant sterol concentrations. Recently, macrothrombocytopenia was described in a number of sitosterolemia patients, linking hematological dysfunction to disturbed sterol metabolism. Here, we demonstrate that macrothrombocytopenia is an intrinsic feature of murine sitosterolemia. Abcg5-deficient (Abcg5(-/-)) mice showed a 68% reduction in platelet count, and platelets were enlarged compared with wild-type controls. Macrothrombocytopenia was not due to decreased numbers of megakaryocytes or their progenitors, but defective megakaryocyte development with deterioration of the demarcation membrane system was evident. Lethally irradiated wild-type mice transplanted with bone marrow from Abcg5(-/-) mice displayed normal platelets, whereas Abcg5(-/-) mice transplanted with wild-type bone marrow still showed macrothrombocytopenia. Treatment with the sterol absorption inhibitor ezetimibe rapidly reversed macrothrombocytopenia in Abcg5(-/-) mice concomitant with a strong decrease in plasma plant sterols. Thus, accumulation of plant sterols is responsible for development of macrothrombocytopenia in sitosterolemia, and blocking intestinal plant sterol absorption provides an effective means of treatment.

Mixed Hypercholesterolemia and Hypertriglyceridemic Xanthomatosis: Four classic types of Xanthomas in one patient at the same time

Xanthomas are localized infiltrates oftipid-containing cells found within the dermis. Cutaneous xanthomas are mostly cosmetic disorders but xanthomas can indicate the presence of an underlying generalized disturbance in lipid metabolism possibly associated with coronary artery disease. Because hyperlipidemia may present as xanthomatosis, a dermatologist might be the first to diagnose these associated lipid abnormalities, We report a 36-year-old male who presented with four classic types of xanthomas (Xanthelasma, Tuberous, Eruptive and Plane xanthomas) at the same time. Laboratory tests confirmed hypercholesterolemia and hypertriglyceridemia of dysbetalipoprotein Type III of the Fredrickson classification. The occurrence of four clinical types of xanthomas simultaneously in the same patient is rarely reported in the literature. The clinical, histopathology, laboratory investigation and management of hyperlipidemia and cutaneous lesions is fully discussed together with a review of the literature.