From Xanthomas to Genetic Diagnosis: A Case Report of Sitosterolemia in an Infant with a Homozygous ABCG5 c.1166G>A (p.Arg389His) Variant

Introduction

Sitosterolemia is a rare inherited lipid metabolism disorder caused by biallelic (homozygous or compound heterozygous) pathogenic mutations in either the ABCG5 or ABCG8 gene. This leads to increased intestinal absorption of plant sterols and impaired biliary sterol excretion.^1,2 ABCG5 mutations are more common in Asian patients, whereas ABCG8 mutations predominate in Caucasian populations.³ Children often initially present with xanthomas, which leads to a high rate of misdiagnosis as familial hypercholesterolemia (FH).

Case Report

An 11-month-old female infant was referred to our dermatology clinic for progressively enlarging xanthomas on both ankles over a 5-month period. The parents first noticed faint yellow papulonodular lesions on the infant’s ankles at 6 months of age, which gradually increased in size and coalesced into linear configurations. There was no history of fever, arthralgia, anemia, or bleeding tendencies. Family history was unremarkable: both parents were healthy with normal lipid profiles, denied consanguinity, and reported no family history of hyperlipidemia.

Physical examination revealed normal growth and development (weight: 9.1 kg, height: 72 cm). Firm, linear xanthomas (approximately 0.5–1.0 cm in size) were observed on both ankles (Figure 1A). Cardiopulmonary and abdominal examinations were normal, with no hepatosplenomegaly. Laboratory investigations showed: Total Cholesterol 8.22 mmol/L (↑, reference range 0–5.18 mmol/L); LDL-C 6.81 mmol/L (↑, reference range 0–3.37 mmol/L); Apolipoprotein B 1.73 g/L (↑, reference range 0.60–1.14 g/L). Complete Blood Count: Red Blood Cell count 5.52 ×10¹²/L (↑, reference range 4.0–5.5×10¹²/L); Hematocrit 0.434 (↑, reference range 0.3–0.41); Red Cell Distribution Width 15.40% (↑, reference range 0–15%). Renal Function: Bicarbonate 17.7 mmol/L (↓, reference range 22.0–29.0 mmol/L). C-reactive Protein <2.00 mg/L (reference <8.00 mg/L); Complement C3 1.09 g/L (reference 0.70–1.40 g/L); Complement C4 0.240 g/L (reference 0.100–0.40 g/L); Alanine Aminotransferase 33.3 U/L (reference 8.0–71.0 U/L); Aspartate Aminotransferase 63.1 U/L (reference 21.0–80.0 U/L); Total Protein 69.5 g/L (reference 55.0–75.0 g/L); Albumin 44.1 g/L (reference 39.0–54.0 g/L); Globulin 25.4 g/L (reference 10.0–30.0 g/L). Plant sterol concentration testing was unavailable locally; therefore, plasma plant sterol levels could not be determined.

Figure 1 (A) Linear xanthomas (approximately 0.5–1.0 cm in size) with firm consistency were observed bilaterally on the ankles (The blue arrow indicates the site of the lesion). (B) The Sanger sequencing results showed that the proband had a homozygous ABCG5 c.1166G>A (p.Arg389His) variant, which was inherited from both her father and mother (red arrows indicate mutation sites).

Genetic testing was performed on peripheral blood samples from the patient and her parents. Sequencing of coding regions for genes associated with FH and sitosterolemia was conducted on the Illumina platform. Data analysis and validation of suspected pathogenic mutations were performed by KingMed Diagnostics. The average sequencing depth for the targeted exons and their flanking 5bp regions was ≥200X, with ~99.5% of bases covered at >20X. Analysis against the gnomAD database indicated that the identified c.1166G>A (p.Arg389His) variant is a missense mutation in the ABCG5 coding region, revealing a homozygous ABCG5 mutation: c.1166G>A (p.Arg389His). Sanger sequencing confirmed that both parents were heterozygous carriers (Figure 1B), consistent with autosomal recessive inheritance, and neither parent exhibited clinical symptoms.

Diagnosis

Sitosterolemia (based on typical xanthomas, hypercholesterolemia, and homozygous ABCG5 gene mutation).

Treatment and Outcome

The patient tragically died due to accidental drowning before treatment could be initiated. No autopsy was performed.

Discussion

The global incidence of sitosterolemia is estimated to be between 1/500,000 and 1/1,000,000, with approximately 200 cases reported worldwide to date.⁴ The condition was first described in 1974 by Bhattacharyya and Conner in two sisters with tendon and tuberous xanthomas and elevated plasma plant sterol levels.⁵ Berge et al first reported the association of sitosterolemia with mutations in the ABCG5/ABCG8 genes.⁶ The ABCG5 and ABCG8 genes encode the sterol transporters sterolin-1 and sterolin-2, respectively. These proteins form a heterodimeric complex responsible for effluxing plant sterols from enterocytes into the intestinal lumen and from hepatocytes into the bile ducts, maintaining low levels of plant sterol absorption.⁶ Mutations in ABCG5 or ABCG8 lead to increased intestinal absorption and reduced biliary excretion of plant sterols, resulting in their accumulation in the blood and tissues.

This case demonstrates typical features: early-onset xanthomas (6 months), hypercholesterolemia, and a homozygous ABCG5 c.1166G>A (p.Arg389His) mutation. The ABCG5 gene is located on chromosome 2p21, spans 26,368 base pairs, and contains 13 exons. The c.1166G>A mutation in this patient is located in exon 9, resulting in the substitution of arginine (Arg) with histidine (His) at position 389 of the protein. The gnomAD database reports no homozygous individuals for this specific variant. Among reported Asian cases of ABCG5-related sitosterolemia, c.1166G>A (p.Arg389His) is one of the common variants.^7–9 Sitosterolemia exhibits significant phenotypic heterogeneity, with some patients being almost entirely asymptomatic. Tendon and tuberous xanthomas are hallmark features, commonly occurring on the Achilles tendons, knees, elbows, and buttocks; infants often present with multiple xanthomas. Patients with sitosterolemia are at risk for premature atherosclerosis due to elevated plasma cholesterol and plant sterols, which can affect lipoprotein stability and promote atherosclerotic plaque formation.^3,8,10 Accumulation of excess plant sterols occurs in the skin and blood vessels.¹¹ Elevated free sterols also accumulate in platelet membranes, potentially dysregulating platelet activation pathways,¹² leading to macrothrombocytopenia and bleeding tendencies.¹³ Our patient did not exhibit hemoglobin or platelet abnormalities, presenting primarily with xanthomas and hypercholesterolemia, underscoring the importance of early diagnosis.

Literature review indicates that sitosterolemia presenting with xanthomas in children is often misdiagnosed as homozygous FH (HoFH).¹⁴ As noted by the American Heart Association in 2015, patients with HoFH typically develop xanthomas before age 10, whereas those with heterozygous FH (HeFH) usually present in adulthood.¹⁵ In HoFH due to autosomal dominant mutations (eg, in LDLR, PCSK9, APOB), parents are typically heterozygotes with elevated LDL-C levels and a family history of premature ASCVD. In contrast, for autosomal recessive hypercholesterolemia (due to LDLRAP1 mutations), parental LDL-C levels may be normal.¹⁶ Sitosterolemia is an autosomal recessive disorder involving ABCG5/ABCG8 mutations and increased plant sterol absorption. Its clinical features overlap with HoFH,¹³ as both can present with elevated LDL-C and total cholesterol levels, as well as early-onset xanthomas at multiple sites, making clinical differentiation crucial. In individuals with ABCG5/ABCG8 mutations, plasma plant sterol levels are markedly elevated (30–200 times normal),^1,17 and excess plant sterols accumulate in the skin and vasculature. Definitive diagnosis relies on genetic testing (ABCG5/ABCG8) or serum plant sterol profile analysis. Significant differences exist in the treatment and prognosis of these two conditions, stemming from their distinct pathogenic mechanisms. Cholesterol elevation in sitosterolemia is more dependent on dietary sterol intake. Consequently, LDL-C levels in sitosterolemia patients may decrease significantly with appropriate dietary modifications, unlike in FH.

Diagnosis is often delayed in the majority of patients with sitosterolemia. A case series reported an average diagnostic delay of 28.8 years from symptom onset to diagnosis,¹⁸ partly because many dermatologists and non-specialists are unfamiliar with its manifestations. At the patient’s initial visit, presenting only with xanthomas, the diagnosis was challenging, as the clinicians had not previously encountered such a case. Subsequent literature review during follow-up revealed that both FH and sitosterolemia can present with xanthomas, and early diagnosis and intervention are crucial in young children. Due to the unavailability of plant sterol testing locally, the diagnosis was ultimately confirmed through lipid profiling and genetic testing. Unfortunately, the child died before treatment could be implemented. Reasons for underdiagnosis and misdiagnosis of sitosterolemia include: 1) Low clinical suspicion for rare diseases among physicians, particularly dermatologists and non-specialists. 2) Limitations in testing: routine lipid panels cannot distinguish plant sterols from cholesterol. Quantifying plasma plant sterols typically requires specialized techniques like gas-liquid chromatography (GLC), gas chromatography/mass spectrometry (GC/MS), or high-performance liquid chromatography (HPLC),¹⁹ which are not widely available in clinical laboratories, especially in underdeveloped regions. Genetic testing for sitosterolemia is also not routinely accessible in many areas. 3) Overlapping clinical features with FH, particularly regarding xanthomas. For patients with refractory FH showing insufficient LDL-C response to statins, re-evaluation for sitosterolemia, including genetic testing, should be considered to avoid missed diagnosis.

Treatment for sitosterolemia includes dietary and pharmacological management. Plant sterols (eg, sitosterol, campesterol, stigmasterol) are sterol molecules naturally present in plant-based oils, fruits, vegetables, nuts, and grains.²⁰ Dietary restriction of plant sterols forms the foundation of therapy,²¹ although this can be challenging, especially for infants. Patients with sitosterolemia often respond poorly to statins alone, because HMG-CoA reductase activity is already maximally inhibited. However, statins are effective in reducing LDL cholesterol, at least in some sitosterolemic patients.⁸ While medications including ezetimibe and bile acid sequestrants like cholestyramine are established standard treatments, consensus on managing sitosterolemia, particularly in children under 2 years, is lacking. Ezetimibe, a sterol absorption inhibitor targeting the NPC1L1 transporter, has become a first-line therapy for patients with sitosterolemia.²²

Genetic counseling is essential. Sitosterolemia is autosomal recessive. In this case, both parents are carriers, conferring a 25% risk for affected offspring in each pregnancy. The parents were advised to seek reproductive genetic counseling for future pregnancies. Other relatives of the parents are also at risk of being carriers. Once the causative mutation is identified in an affected family member, carrier testing for at-risk relatives and prenatal testing for high-risk pregnancies become possible options.²³

Conclusion

Sitosterolemia is a rare multisystem disorder. Despite its rarity, its treatable nature and the significant harms of misdiagnosis warrant high clinical vigilance. This case report describes a patient presenting solely with cutaneous xanthomas, ultimately diagnosed with sitosterolemia due to a homozygous ABCG5 c.1166G>A (p.Arg389His) mutation. This case emphasizes that sitosterolemia should be suspected in infants presenting with cutaneous xanthomas and elevated cholesterol levels, or in patients with early-onset xanthomas and hypercholesterolemia who respond poorly to statin therapy. Genetic testing (ABCG5/ABCG8) and serum plant sterol analysis are the diagnostic gold standards. Early diagnosis and treatment can significantly reverse the disease course.