Familial Homozygous Hypercholesterolemia:Report of Two Patients and Review of the

Literature

Gomathy Sethuraman, M.D.,* Selvendran Sugandhan, M.D.,* Gautam Sharma, M.D.,�Kudligi Chandramohan, M.D.,* Nimai Chand Chandra, M.D.,� Sushruta Shefali Dash, M.D.,*

Aggarwal Komal, M.D.,* and Vinod K Sharma, M.D.,*

Departments of *Dermatology and Venereology, � Cardiology and � Biochemistry, All India Institute of MedicalSciences, New Delhi, India

Abstract: Familial homozygous hypercholesterolemia is a rare autosomaldominant, metabolic disorder caused by mutation in the gene, whichencodes the synthesis of low-density lipoprotein receptors and is charac-terized by increased serum low-density lipoprotein cholesterol. Multipletypes of xanthomas occur, such as tendinous, tuberous, xanthelasma, andsub-periosteal. Intertriginous xanthomas are rare but if present are pathog-nomonic of this disorder. We report two children with familial homozygoushypercholesterolemia who had multiple xanthomas including the intertrigi-nous variety.

Familial homozygous hypercholesterolemia (FH) is arare type of hypercholesterolemia affecting one per mil-lion in the general population (1).We report two childrenwith this disorder who presented to us with the typicalclinical features and review the literature.

CASE REPORTS

Patient 1

An 11-year-old boy presented with asymptomatic yel-lowish skin lesions on his hands, elbows, knees, feet, andgluteal region since the age of 6 years. Lesions startedover the knees and subsequently involved the other sites.He did not have any other cutaneous and or systemiccomplaints. He was born to healthy nonconsanguineousparents following an uneventful pregnancy. No history

of similar or any other complaints among the other sib-lings was reported and no history of coronary arterydisease was found in the family.

Physical examination found a striking involvement ofthe web spaces in the form of yellowish plaques withcorrugated surface (intertriginous xanthomas) (Fig. 1).In addition the boy had multiple yellow to reddish, firmnodules over the extensor surface of the elbows, knees,knuckles, and buttocks (tuberoeruptive xanthomas),firm subcutaneous nodules in the extensor tendons of thehands, Achilles tendon (tendinous xanthomas) (Fig. 1),and xanthelasma palpebrarum. Systemic examinationwas within normal limits.

The routine investigations, including hemogram, liverand renal function tests had normal results. The lipidprofile was abnormal in the boy and his father. Both hadelevated total cholesterol and low-density lipoprotein

Address correspondence to G. Sethuraman, M.D., MNAMS,Associate Professor, Department of Dermatology and Venereolo-gy, All India Institute of Medical Sciences, New Delhi 110029,India, or e-mail: kgsethu@yahoo.com.

230 � 2007 The Authors. Journal compilation � 2007 Blackwell Publishing, Inc.

Pediatric Dermatology Vol. 24 No. 3 230–234, 2007

(LDL) levels and normal high-density lipoprotein(HDL), very low density lipoprotein (VLDL) and tri-glyceride levels (Table 1). Chest X-ray, electrocardio-gram (ECG), and treadmill test (TMT) had normalresults. Echocardiography revealed mild aortic regurgi-tation. Cine angiography showed right coronary arterycalcification. Skin biopsy specimen findings were sug-gestive of xanthoma.

Patient 2

An 8-year-old girl had asymptomatic yellowish papulesand plaques over her knees, thighs, ankles, elbows, uppereyelids, and hands since the age of 4 years. She did nothave any other cutaneous or systemic complaints. Herelder brother had died of acute chest pain at the age of14 years and had skin lesions suggestive of xanthoma.She was born to healthy nonconsanguineous parentsfollowing an uneventful pregnancy. Her mother, aged30 years, had xanthelasma palpebrarum.

On examination the patient had multiple types ofxanthomas: tuberous, tendinous, and xanthelasmapalpebrarum. She also had striking interiginous xan-thomas involving the web spaces of the hands(Fig. 2A,B), popliteal, and cubital fossae. Systemicexamination did not reveal any abnormalities. The

routine investigations were normal. Her lipid profile wasabnormal, as was her mother’s. They had elevated totalcholesterol and LDL levels and normal HDL, VLDLand triglyceride levels (Table 1). Her chest X-ray, ECG,echocardiography, and TMT were all normal. The skinbiopsy specimen findings were suggestive of xanthoma.

Both patients were started on diet therapy along withhypolipedemic drugs–atorvastatin and ezetemibe–andare on follow-up.

DISCUSSION

The termhyperlipidemiaorhyperlipoproteinemia is usedwhen an elevation of serum lipid levels is found, whereasdyslipoprotenemia refers to abnormalities in serumlipoproteins whether or not serum lipid levels areelevated. The lipoproteins enter tissues such as skin,subcutaneous tissue, and tendons and the lipid accumu-lation results in xanthomas.Xanthomas can also developsecondary to systemic diseases such as hypothyroidism,biliary cirrhosis, diabetes mellitus, nephrotic syndrome,monoclonal gammopathy, and drug therapy withbeta-blockers and diuretics (1,2). On the basis of theelectrophoretic lipoprotein phenotype, primary hyper-lipoproteinemias are classified into five major types(types I–V) (3).

Familial hypercholesterolemia, a form of primaryhyperlipoproteinemia, is an autosomal dominant disor-der characterized by an increase in serum LDL choles-terol concentrations. Two variants have been described:heterozygous and homozygous. The former has a pre-valence of one per 500 and the latter type, one per onemillion in the general population (1).

In heterozygous form, the affected individuals have atwo- to threefold elevation in LDL cholesterol from thetime of birth but the xanthomatous lesions developduring the third to sixth decades. The clinical hallmark isthe presence of tendon xanthomas, usually involving theextensor tendons of the hands and Achilles tendons.They can also be seen on the extensors of the forearmsand arms. Tendon xanthomas are firm subcutaneousnodules, which may be hard, due to fibrosis. They areusually skin colored and do not appear yellow because

Figure 1. Intertriginous, tendinous and tuberous xanthomas(patient 1).

TABLE 1. The Lipid Profile of the Children and Affected Parents

Pt. 1 Father of pt. 1 Pt. 2 Mother of pt. 2 Normal values mg/dL

Total cholesterol 663 306 801 378 <200LDL 595 237 737 308 <130HDL 45 44 49 53 >35VLDL 23 25 15 17 10–30Triglyceride 100 111 50 58 50–150

Sethuraman et al: Familial Homozygous Hypercholesterolemia 231

the cholesterol ester is deposited deepwithin the tendons.Sometimes, Achilles tenosynovitis or generalized ten-dinitis may occur. Xanthelasma palpebrarum can occurin a few patients (4).

In the homozygous form, a six- to eightfold increasein plasma LDL cholesterol is found, which can be seenas early as the 20th week of intrauterine life. Clinically, itis characterized by severe xanthomatosis developing inthe first few years of life. Multiple types of xanthomascan occur. Tendinous xanthomas (especially in theAchilles tendons and extensor tendons of the hands) arethe most common type, seen in 40 to 50% of patients,followed by xanthelasma in 23% and tuberous xan-thomas in about 10 to 15%. Rarely, subperiosteal xan-thomas (below the knee and over the olecranon) canoccur (4). Very rarely, intertriginous xanthomas thatmanifest as flat or slightly raised yellow dermal plaqueswith corrugated surfaces are seen in the finger webs,axillae, buttocks, antecubital, and popliteal fossae.These intertriginous xanthomas are pathognomonic of

FH (5–7). Coronary atherosclerosis usually developsbefore the teenage years (1). Arcus presenilis is seen inapproximately 50% of patients (4).

Familial homozygous hypercholesterolemia is a typeIIhyperlipoproteinemia. It is sub-classifiedonthebasisofdefects found in LDL-receptor protein in type IIa and atendency for elevated VLDL in addition in type IIb. TheLDL receptor is one of the major plasma membraneproteins, which transfer cholesterol particles from bloodplasma into cells by endocytosis. The liver is the majorsource of LDL receptors. The LDL-receptor gene islocated on the short arm of chromosome 19 and anyabnormality in the LDL-receptor gene expression affectsreceptor protein functioning (8,9). Among the severalmechanisms that affect LDL-receptor protein function,mutation, hereditary gene abnormality, and abnormaldevelopment of organ-specific receptors play importantroles.So far,more than700differentmutationshavebeenreported, ranging from single-nucleotide substitutions tolarge deletions. Six different classes of LDL-receptordefects having various mutations have been described.Class 1 defects are due to promoter mutations, whichaffect the mRNA synthesis, with no detectable LDLreceptor. In class 2 defects, an impairment of glycosyla-tion of LDL receptors (2A complete impairment, 2Blimited impairment) is found. Class 3 is a confirmationaldefect in LDL receptor which affects its binding with theligand. Class 4 mutational defects affect the cytoplasmictail of the receptors interferingwith endocytosis. InClass5 receptor protein degradation prevents the receptorsfrom reaching the cell surface and recycling. Class 6mutations are due to failure in directing the LDL recep-tors to the basolateral surface of polarized cells (10).

Recently, down regulation of LDL-receptor functionby suppression of gene transcription by inhibition ofbinding of sterol response element binding protein(SREBP) with sterol response element (SRE) on thepromoter of LDL-receptor gene has been detected(11,12). The mechanism for SREBP-mediated LDL-receptor expression is engineered under normal circum-stances by molecular activation and deactivation ofSREBP-transcription factor. Such SREBP activation isregulated by a net intracellular cholesterol pool. Over-saturation of cells with cholesterol inhibits SRE-SREBPbinding, whereas depletion of intracellular cholesterolfacilitates active binding of SREBP with SRE. Varioushormones and growth factors also play some role in suchregulation (11,12).

In the homozygous form, the defective alleles for theLDL receptors are inherited from each parent. Eachallele is characterized by the absence of receptor pro-duction (a null allele) with activity of less than 3%.Sometimes homozygous patients can inherit alleles with

A

B

Figure 2. (A) Intertriginous xanthomas (patient 2). (B) Tu-beroeruptive xanthomas (patient 2).

232 Pediatric Dermatology Vol. 24 No. 3 May ⁄ June 2007

different mutations from each parent with the LDL-receptor activity of less than 20% or the gene can have adifferent type of mutation in which the binding of cho-lesterol with LDLmay be normal but the internalizationof the bound LDL into the cell may be defective (1,13)(i.e., nonfunctional of LDL receptor). The heterozygousform is due to the inheritance of a single allele for LDLreceptor (1).

Apart from LDL-receptor mutations, familialdefective apolipoprotein B-100 (FDB), autosomal reces-sive hypercholesterolemia (ARH), and phytosterolemiacan result in phenotypes similar to that of FH (10).Familial defective apolipoprotein B is an autosomaldominant disorder results from substitution of glutaminefor arginine at residue 3500 of apolipoprotein B-100(10,14). The defective apoB100 binds poorly to theLDLreceptors resulting in elevated levels of serumLDL.Mostpatients with FDB are heterozygous and their findingsresemble those of heterozygous FH (benign phenotypes)except that they typically have somewhat lowerLDL-cholesterol levels. The rare homozygous patientshave severe hypercholesterolemia but not to the degreeseen in homozygous FH (1). The LDL receptors arefunctional in these patients and permit normal entry ofcholesterol into the liver from remnants of chylomicronsand VLDL. Compensatory upregulation of LDLreceptors occurs, especially in homozygotes, which tendsto improve the biochemical abnormality (10). ARH iscaused by mutations in the phosphotyrosine bindingdomain of a putative adaptor protein, which preventsnormal internalization of the LDL receptors in the liver.The clinical phenotype is similar to that of homozygousFH but is more variable and less severe. The parents ofthe affected patients have normal lipid levels andconsanguinity may be present (10,15). Phytosterolemiaresults from excessive absorption of plant sterols fromenterocytes and reduced biliary excretion. These patientsdevelop xanthomas as in FH but the LDL cholesterollevel remains unaltered (10).

Low-density lipoprotein receptor and apolipoproteinB-100 defects can be detected by PCR methods. Cellculture is more reliable and in fibroblast cultures theLDL-receptor mutations will result in low binding,whereas ARH protein mutations will not (10).

In our patients, the lipid profile was suggestive of typeIIa hyperlipoproteinemia, with markedly elevated LDLcholesterol levels with normal VLDL and triglyceridelevels and a diagnosis of homozygous FH was made onthe basis of the typical clinical features with childhoodonset: the pathognomonic intertriginous xanthomas;tendinous, tuberous xanthomas, and xanthelasma palp-ebrarum; affected parent and exclusion of secondarycauses.

Dietary modification and drug therapy with statinsform the initial treatment strategy. Statins (HMG-CoAreductase inhibitors) act by reducing the liver cholesterolstores, which upregulate LDL-receptor expression andproduce a subsequent fall in the plasma LDL levels.Several statins havebeenused in the treatment ofFHandrosuvastatin, which is a newer statin, has been found tolower LDL cholesterol significantly more thanatorvastatin (9). Inmany patients, however, statins aloneare inadequate and combination therapy with othercholesterol lowering agents, such as nicotinamide, chol-estyramine, and fibrates may be necessary (16). Ezetim-ibe is a novel druguseful in familial hypercholesterolemia(17). It acts by selectively inhibiting the absorption ofdietary and biliary cholesterol within the brush-borderenzyme system of the small intestine without decreasingthe absorption of bile acids, fatty acids, fat-soluble vita-mins, or triglycerides. It can be used as monotherapy orin combination with statins (17).

The pharmacotherapy, along with dietary modifica-tion is generally helpful in patients with the heterozygousform, but it may not be adequate for those with thehomozygous form, in whom LDL-apheresis and livertransplantation are recommended (9).

Low-density lipoprotein apheresis is an extracorpor-eal plasma-perfusion method that involves selectiveremoval of LDL particles. The procedure takes three ormore hours and is performed at 1- to 2-week intervals(18). It results in the regression of coronary lesions andhas been found to increase life expectancy. However, itsuse is limited by its limited availability, higher cost, anddifficulties with vascular access (19). Liver transplanta-tion alone or in combination with pharmacotherapy iseffective in normalizing the plasma cholesterol levels. Asmost of the LDL receptors in the body are present in theliver, transplantation provides these receptors and pro-duces an immediate, marked, and sustained reduction inthe cholesterol levels. But liver transplantation involvesconsiderable risk and requires life-long immuno-suppressive therapy (9). Themost recent advance is liver-directed ex vivo gene therapy, which could be thetreatment of choice in the future (8).

REFERENCES

1. Goldsmith LA. Xanthomas and lipoprotein disorders. In:Freedberg IM, Eisen AZ, Wolff K, eds. Fitzpatricksdermatology in general medicine. New York: McGrawHill, 2003: 1466–1474.

2. Pandhi D, Grover C, Reddy BSN. Type IIa hyperlipopro-teinemia manifesting with different types of cutaneousxanthomas. Indian Pediatr 2001;38:550–553.

3. Durrington PN. Lipid and lipoprotein disorders. In:Weatherall DJ, Ledingham JGG, Warell Da, eds. Oxford

Sethuraman et al: Familial Homozygous Hypercholesterolemia 233

textbook of medicine. Oxford: Oxford Medical Publica-tions, 1996:1406.

4. Parker F. Xanthomas and hyperlipidemias. J Am AcadDermatol 1985;13:1–30.

5. Sethuraman G, Thappa DM, Karthikeyan K. Intertrigi-nous xanthomas-A marker of homozygous familial hypercholesterolemia. Indian Pediatr 2000;37:338.

6. Cutaneous infiltrates-non-lymphoid. In: Weedon D, ed.Skin pathology, 2nd ed. London: Churchill Livingstone,2002: 1077.

7. Elias P, Goldsmith LA. Intertriginous xanthomata in type2 hyperbetalipoproteinemia. Arch Dermatol 1973;107:761–762.

8. Raper SE, Grossman M, Rader DJ et al. Safety andfeasibility of liver-directed ex vivo gene therapy forhomozygous familial hypercholesterolemia. Ann Surg1996;223:116–126.

9. Hopkins PN. Familial hypercholesterolemia-improvingtreatment and meeting guidelines. Int J Cardiol 2003;89:13–23.

10. Marias AD. Familial hypercholesterolemia. Clin BiochemRev 2004;25:49–68.

11. Brown MS, Goldstein JL. A proteolytic pathway thatcontrols the cholesterol content of membranes, cellsand blood. Proc Natl Acad Sci USA 1999;96:11041–11048.

12. Hua X, Nohturfft A, Goldstein JL, Brown MS. Sterolresistance inCHOcells traced to pointmutation in SREBPcleavage activating protein. Cell 1996;87:415–426.

13. Lopez-Santamaria M, Migliazza L, Gamez M et al. Livertransplantation in patients with homozygotic familialhypercholesterolemia previously treated by end-to-sideportocaval shunt and ileal bypass. J Pediatr Surg2000;35:630–633.

14. Schuster H, Rauh G, Kormann B et al. Familial defectiveapolipoprotein B-100. Comparison with familial hyper-cholesterolemia in 18 cases detected in Munich. Arterio-sclerosis 1990;10:577–581.

15. Rodenburg J, Wiegman A, Vissers MN et al. A boy withautosomal recessive hypercholesterolaemia. Neth J Med2004;62:89–93.

16. Rachna S, Gulati S, Seth S et al. Familial hypercholeste-rolemia. Ind J Pediatr 2004;71:97–99.

17. Morris S, Tiller R. Ezetimibe for hypercholesterolemia.Am Fam Physician 2003;68:1595–1596.

18. Gordon BR, Saal SD. Advances in LDL-apheresis for thetreatment of severe hypercholesterolemia. Curr OpinLipidol 1994;5:69–73.

19. MoyleM, Tate B. Homozygous familial hypercholesterol-aemia presenting with cutaneous xanthomas: response toliver transplantation. Australas J Dermatol 2004;45:226–228.

234 Pediatric Dermatology Vol. 24 No. 3 May ⁄ June 2007