CASE DESCRIPTION
A 22-month-old female toddler was referred for yellow skin nodules. These lesions, which emerged gradually over the past 6 months involved the flexor creases but were also present on the ankles, elbows, shoulders and back (Figure 1). Notably, there was no joint involvement or ocular findings.
(A) Yellow nodules over the Achilles tendon, shown with a ruler for scale (B). Similar yellow discoloration seen in the popliteal fossa.
The child was born at term in southern India following an uneventful pregnancy and delivery by caesarean section. The child migrated to Canada at 15 months of age, shortly after which her skin lesions first appeared. The child demonstrated normal growth and development, and there were no previous hospitalizations or surgeries.
Apart from the noted skin lesions, the physical examination was otherwise unremarkable: a well-nourished appearing girl weighing 10.9 kg (45th percentile) and a height of 81 cm (12th percentile) with pink and well-perfused extremities; no signs of respiratory distress; a chest clear to auscultation; and no hepatosplenomegaly. The general precordial exam was unremarkable, and her blood pressure measured at 103/72 mmHg. The child’s parents hail from a similar region in southern India but are non-consanguineous. Both parents display an elevated total cholesterol and low-density lipoprotein cholesterol (LDL-C) level, and a low–high-density lipoprotein cholesterol (HDL-C) level but are otherwise healthy. Neither parent exhibited ocular nor cutaneous findings.
DISCUSSION
Based on morphology, the cutaneous findings in this patient likely resemble xanthomas; however, a biopsy is definitive to differentiate it from other conditions such as rheumatoid nodules, gouty tophi or erythema elevatum diutinum.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder usually caused by pathogenic mutations to the LDL receptor gene (LDLR), leading to impaired clearance of LDL cholesterol from the bloodstream. Heterozygous familial hypercholesterolemia (HeFH), whose prevalence is estimated at 1:300 in Canada (1), frequently escapes detection in early childhood due to an unremarkable physical exam. In contrast, homozygous familial hypercholesterolemia (HoFH) often features cutaneous deposits of localized lipids, termed xanthomas.
Though not exclusive to HoFH, xanthomas provide a diagnostic clue when associated with markedly elevated cholesterol levels. Other conditions that may present with xanthomas include sitosterolemia, cholesteryl ester storage disease, heterozygous lipoprotein lipase (LPL) deficiency, hypothyroidism and hepatic disorders. A comprehensive evaluation of the causes of secondary hypercholesterolemia may be useful. Other physical manifestations of HoFH not observed in this case include corneal arcus, xanthelasma and tendon xanthomas which could elicit pain.
In this case, both parents demonstrated a screening lipid profile compatible with HeFH (LDL-c between 7 mmol/L and 8 mmol/L). Conversely, the child presented with xanthomas, and further investigation revealed an LDL-c greater than 10 mmol/L, suggesting a diagnosis of HoFH (2).
Both forms of FH carry a high risk of premature cardiovascular events (1). In HeFH, these events may occur before age 55 in men and 65 in women. In HoFH, atherosclerotic cardiovascular disease (ASCVD) events such as heart attack and stroke will occur before the first two decades of life without proper intervention. Given the significant risk of near-future morbidity and mortality, urgent recognition, confirmation and treatment of HoFH are required early in life (1).
The initiation and continuation of lifestyle modifications are required to prevent future cardiovascular events (1). Moreover, a surveillance plan incorporating regular lipid monitoring and cardiovascular assessments will also facilitate early pathology detection and timely interventions. In HoFH specifically, annual echocardiographic evaluation is recommended along with serial CT angiography and exercise testing (2).
The consideration of cholesterol-lowering medications, particularly statins, is a common management strategy in HeFH. In pediatrics, the safety and efficacy of statin initiation must be carefully evaluated and monitored in each case, and therefore a referral to a pediatric lipid specialist is recommended (1). For HoFH, where cholesterol levels are already excessively high, statins and other LDLR activity-dependent medications in combination with appropriate lifestyle modifications are likely inadequate. In such situations, aggressive interventions such as ongoing lipoprotein apheresis are often necessary, though emergent medical therapies also exist (2).
In summary, FH is a genetic disorder with preventable long-term consequences. Whereas HeFH is common and often silent in childhood, the presentation of a child with xanthomas requires urgent evaluation for the possibility of HoFH. HoFH carries a significant risk of morbidity and mortality by a patient’s teenage years, and therefore requires pediatricians to promptly work up and facilitate management.
FUNDING
There are no financial relationships relevant to this article to disclose from all authors.
POTENTIAL CONFLICT OF INTEREST
All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
INFORMED CONSENT
Family consent has been obtained in writing for this case
