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CASE REPORT
Year : 2021  |  Volume : 5  |  Issue : 2  |  Page : 229-232

Pleomorphic xanthomas: A clue to rare familial hypercholesterolemia


Department of Skin and VD, PMCH, Patna, Bihar, India

Date of Submission28-Apr-2020
Date of Decision13-Jul-2020
Date of Acceptance18-Jul-2020
Date of Web Publication26-Aug-2021

Correspondence Address:
Pankaj Kumar Tiwary
Department of Skin and VD, PMCH, Patna, Bihar
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_73_20

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  Abstract 


Xanthomas are the subcutaneous lipid deposits which can be seen in normolipedemic or hyperlipidemic conditions. Xanathomas are usually of single type and presence of polymorphic xanthomas arise suspicion of dyslipidemia. We report a case of young girl presenting with pleomorphic xanthomas (Xanthelasma palpebrarum, intertriginous Xanthomas, tendon Xanthomas, and eruptive xanthomas), hypothyroidism and multiple cardiac valvular involvements with very high serum total cholesterol and low-density lipoprotein along with deranged lipid profile in both parents. Pleomorphic xanthoma arouses a suspicion and helped in making a diagnosis of rare homozygous familial hypercholesterolemia.

Keywords: Hypercholesterolemia, intertriginous xanthoma, pleomorphic xanthoma


How to cite this article:
Singh S, Tiwary PK, Singh A. Pleomorphic xanthomas: A clue to rare familial hypercholesterolemia. Clin Dermatol Rev 2021;5:229-32

How to cite this URL:
Singh S, Tiwary PK, Singh A. Pleomorphic xanthomas: A clue to rare familial hypercholesterolemia. Clin Dermatol Rev [serial online] 2021 [cited 2021 Dec 1];5:229-32. Available from: https://www.cdriadvlkn.org/text.asp?2021/5/2/229/324574




  Introduction Top


Xanthomas are the subcutaneous lipid deposits characterized by accumulation of lipid laden macrophages (foamy macrophages).[1] They can be seen in normolipedemic or hyperlipidemic conditions and can be of various clinical morphologies namely plane xanthomas, intertriginous xanthomas, xanthelasma palpebrarum, tendon xanthomas, tuberous xanthomas, and eruptive xanthomas. Nowadays, importance of xanthomas has been growing because of similar pathogenetic mechanism associated with early stages of atherosclerotic plaques and coronary vascular diseases.[2],[3]

Xanathomas of single type are generally present in any individual depending on the underlying pathology. The presence of polymorphic xanthomas arise suspicion of dyslipidemia which ranges from monogenic diseases with high penetrance through polygenic disorders to those that are paradigms of gene-environment interaction. Some are entirely or partially secondary to diabetes, hypothyroidism, renal failure, or liver disease. One such example is that of familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is characterized by a triad of elevated low-density lipoprotein (LDL) cholesterol, presence of xanthomas (especially tendon Xanthomas), and premature coronary heart disease.[4] It is an autosomal co-dominant disorder characterized by defective functioning of LDL receptor discovered in 1973 by Goldstein and Brown.[5] FH can be heterozygous (one mutant allele) and homozygous (both mutant allele). Heterozygous FH is more common with the prevalence of 1 in 500 individual worldwide, whereas homozygous FH is rare and occurs in approximately 1 in 1 million persons.[6]

Here, we report a rare case of 14-year-old girl with multiple pleomorphic xanthomas in association with cardiac abnormality and elevated serum LDL raising suspicion towards the diagnosis of homozygous familial hypercholesterolemia (HoFH).


  Case Report Top


A 14-year-old thin built girl born out of non-consanguineous marriage presented with a 11 years history of asymptomatic, slowly progressive, multiple yellowish, elevated lesions of variable forms and size around face, both upper and lower limbs especially axillae, antecubital fossa, elbow, dorsum of hand, bilateral knee, ankle, and buttocks. She was otherwise healthy and none of the family members had similar skin lesions. In past, at the age of 1 year, she used to turn blue on crying for which no evaluation was done at that time. She has normal bowel and bladder habits. On cutaneous examination, each lesion was defined on morphological pattern:

Soft velvety, yellowish orange plaques around both eyes and over left eyelid (Xanthelasma palpebrarum) [Figure 1].
Figure 1: Xanthelesma palpebrerum

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Intertriginous xanthomas and a confluence of plane eruptive xanthomas [Figure 2]a and [Figure 2]b small yellowish brown papules coalescing to form plaques over both axillae, cubital fossae, forearm, elbow, and dorsum of hands at knuckles and Tendon Xanthoma at Achilles tendon [Figure 3].
Figure 2: (a) Intertriginous xanthomas, (b) tuberous xanthoma

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Figure 3: Tendon xanthoma

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Few firm, yellow, indurated nodules of variable size (Tuberous Xanthomas) [Figure 4]a and [Figure 4]b were present on both buttocks, natal cleft and both knee. There was no xanthomatous infiltration of cornea, oral, pharyngeal, and laryngeal mucosae. On systemic examination, pansystolic murmur was heard at parasternal and aortic area. Rest systemic examination was normal.
Figure 4: (a and b) Tuberous xanthoma

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On biochemical investigation, serum lipid profile was deranged with raised total cholesterol (590 mg/dl), raised low-density lipoprotein (530.20 mg/dl) and low high-density lipoprotein (40.2 mg/dl), normal VLDL, and triglycerides (TG). Elevated serum Thyroid stimulating hormone (12.46 microIU/ml) but normal serum-free T3 and free T4. Liver function test, renal function test, and blood sugar were normal. ECG showed sinus tachycardia, ST elevation in aVR, V1, and V2 leads, with left ventricular hypertrophy. Echocardiogram revealed severe aortic stenosis, moderate aortic regurgitation, mild–to-moderate mitral regurgitation, biscuspid aortic valve, coarctation of aorta and ejection fraction was 60%. Ultrasonography of bilateral Achilles tendon showed isoechoic lesion suggestive of Xanthoma.

Histopathology of skin biopsy [Figure 5]a and [Figure 5]b showed a small nodular granulomatous infiltrate in upper dermis with accompanying sparse perivascular lymphocytic infiltrate. Granuloma consisted of pale stained histiocytes with abundant foamy cytoplasm. At places, these histiocytes were interstitial whereas at other foci they were surrounded by mild fibroplasia with unaffected epidermis suggesting xanthoma.
Figure 5: (a) Image showing cholesterol clefts and giant cells. (b) Granuloma consists of pale stained histiocytes with abundant foamy cytoplasm

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Serum lipid profile of her parents was also deranged with moderate elevation of total cholesterol and LDL while her elder brother has normal lipid levels. The patient was referred to internal medicine department and cardiology department for the management of hypothyroidism and associated cardiac abnormality.

On the basis of clinical, biochemistry and histological features, the diagnosis of HoFH was made. The patient was treated with atorvastatin (40 mg/day), ezitimibe (20 mg/day), thyroxine 50 mcg/day on which her raised lipid levels started decreasing.


  Discussion Top


From the clinical point of view, xanthomas cannot be considered as mere cosmetic lesions. They can be a marker of serious dyslipidemias, both common and rare, as well as present with an increased risk of metabolic and cardiovascular diseases.X The term xanthoma (Greek “xanthos” meaning yellow) was first coined by Smith in 1869.[7] Xanthomas can be seen as a primary disorder (primary dyslipidemia, an inherited abnormality of lipoprotein metabolism) or secondary disorder (hyperlipidemia secondary to systemic disease or medications).[3],[8],[9] Xanthomas can be classified following clinical and patho-anatomical schemes useful in clinical practice as - Normolipidemic xanthomas, Hyperlipidemia xanthomas, and Necrobiotic xanthogranulomas.[3],[9],[10]

The presence of pleomorphic xanthomas especially tendon xanthoma gives a clue to evaluate for lipoprotein disorders. On the basis of electrophoretic lipoprotein phenotype, Fredrickson et al.[11] classified primary hyperlipoproteinemia into five major types. It was not until the widespread uptake of serum cholesterol measurements methods in 1950s that the association of hypercholesterolemia with atherosclerotic cardiovascular disease and cutaneous or tendon xanthomas was gradually revealed.[12]

FH (Fredrickson Type IIa) is a genetic disease caused by mutations in LDL receptor gene located on chromosome 19.[11] This leads to impaired uptake of LDL into cells especially hepatic cells resulting in raised serum LDL cholesterol. These are of two types: Heterozygous familial hypercholesterolemia (HeFH) and HoFH. HoFH is rare and presents with the development of xanthomatosis before first decade of life. HoFH patients have multiple types of xanthomata, such as tuberous sub-periosteal, tendon xanthomas, elevated xanthomatosis plaques, and the rare but characteristic intertriginous xanthomas.[13] These patient shows 6–8 fold increase in serum LDL cholesterol.

HeFH is comparatively commoner disease with 2–3 fold elevation in serum LDL cholesterol (200–400 mg/dl), normal triglycerides, development of mainly tendon xanthomas during third to fourth decade of life and premature atherosclerosis.

FH thus accounts for a significant proportion of premature CVD and of premature sudden cardiac death. HoFH patients suffer from the clinical effects of coronary heart disease as early as in their teens. They can also develop a supravalvular aortic stenosis. Untreated receptor negative (LDL receptor activity <2%) rarely survive beyond 2nd decade. Fifty percent of untreated males of HoFH suffer a myocardial infarction and 24% usually die by the age of 50. Heterozygous females have a slightly delayed onset of CVD compared with males but 58% will have had a myocardial infarction and 15% have died by the age of 60 if not treated.[14] Screening of 1st degree relatives and extended family members plays a crucial role.

After detailed literature review, history, clinical examination and investigations, the diagnosis of rare HoFH (Fredrickson Type IIa) was done in our patient. The diagnosis of homozygous FH was based on:

  1. Serum total cholesterol and LDL cholesterol (>500 mg/dl) with normal triglyceride level
  2. Appearance of xanthomas in first decade of life
  3. Documentation of mildly elevated total cholesterol and LDL cholesterol in both parents
  4. The presence of signs of atherosclerosis and aortic stenosis
  5. The presence of pleomorphic Xanthomas and especially rare pathognomonic intertriginous Xanthomas, which has been described as a marker of this homozygous type.[14]


Early diagnosis, dietary modifications, and drug therapy with statins and bile acid sequestrants are the mainstay of therapy in these patients. Genetic counseling is also very important as their positive offsprings are at high risk of developing myocardial infarction at an early age.

This case is unique by the fact that pleomorphic xanthoma are uncommon and if encountered then prompts for complete clinical and biochemical investigations and this study also highlights the need of high suspicion for rare familial hyperlipoproteinemia in patients of pleomorphic xanthomas because with their prompt diagnosis and treatment, we can prolong the lives of patient by preventing serious cardiac events at early age and also can do early genetic counseling.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Parker F. Xanthomas and hyperlipidemias. J Am Acad Dermatol 1985;13:1-30.  Back to cited text no. 1
    
2.
Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014;114:1852-66.  Back to cited text no. 2
    
3.
Zak A, Zeman M, Slaby A, Vecka M. Xanthomas: Clinical and pathophysiological relations. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2014;158:181-8.  Back to cited text no. 3
    
4.
Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. 28th ed. New York: McGraw-Hill; 2001. p. 2863-913.  Back to cited text no. 4
    
5.
Goldstein JL, Brown MS. Familial hypercholesterolaemia: Identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci USA 1973;70:2804-8.  Back to cited text no. 5
    
6.
Rader DJ, Hobbs HH. Disorders of lipoprotein metabolism. In: Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, et al., editors. Harrison's Principles of Internal Medicine. 17th ed. New York: The McGraw-Hill Companies Inc.; 2008. p. 2416-28.  Back to cited text no. 6
    
7.
Lahiri BC, Lahiri K. Homozygous hypercholesterolemia with cutaneous and tendinous xanthomas in a child. Indian J Dermatol 2000;45:205-7.  Back to cited text no. 7
  [Full text]  
8.
Cruz PD Jr., East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol 1988;19:95-111.  Back to cited text no. 8
    
9.
Vargas-Flores E, Estrada-Alpizar L, Arenas-Osuna J. Tuberous xanthomatosis as a presentation of familial hypercholesterolemia. JSM Clin Case Rep 2016;4:1114.  Back to cited text no. 9
    
10.
Fredrickson DS, Levy RI, Lees RS. Fat transport in lipoproteins – An integrated approach to mechanisms and disorders. N Engl J Med 1967;276:34-44.  Back to cited text no. 10
    
11.
Mabuchi H, Tatami R, Haba T, Ueda K, Ueda R, Kametani T, et al. Homozygous familial hypercholesterolemia in Japan. Am J Med 1978;65:290-7.  Back to cited text no. 11
    
12.
Goldstein JL, Brown MS. A century of cholesterol and coronaries: From plaques to genes to statins. Cell 2015;161:161-72.  Back to cited text no. 12
    
13.
Slack J. Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet. 1969;2(7635):1380-2. doi: 10.1016/s0140-6736(69)90930-1. PMID: 4188273.  Back to cited text no. 13
    
14.
Sethuraman G, Thappa DM, Karthikeyan K. Intertriginous xanthomas – A marker of homozygous familial hypercholesterolemia. Indian Pediatr 2000;37:338.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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