Diagnosis of Homozygous Familial Hypercholesterolaemia
Diagnosis of HoFH can be made on the basis of genetic or clinical criteria (Box 1). While genetic testing may provide a definitive diagnosis of HoFH, it is recognized that in some patients genetic confirmation remains elusive, despite exhaustive investigation; indeed, the existence of additional FH genes cannot be excluded. Historically, HoFH has been most commonly diagnosed on the basis of an untreated LDL-C plasma concentration >13 mmol/L (>500 mg/dL), or a treated LDL-C concentration of ≥8 mmol/L (≥300 mg/dL), and the presence of cutaneous or tendon xanthomas before the age of 10 years, or the presence of untreated elevated LDL-C levels consistent with HeFH in both parents.
Plasma Low-density Lipoprotein Cholesterol Levels
Within a family, the plasma LDL-C level is the critical discriminator, being about four times and about two times higher in family members with HoFH or HeFH, respectively, compared with unaffected members. At the population level, however, the range of LDL-C levels may overlap significantly between HeFH and HoFH (Figure 4), and untreated LDL-C levels <13 mmol/L (<500 mg/dL) can be found in genetically confirmed HoFH. This is especially relevant for children, who tend to have lower LDL-C levels than adults. More than 50% of HoFH children identified in the Netherlands have LDL-C levels between 5.6 and 9.8 mmol/L (A Wiegman personal communication). Such phenotypic heterogeneity can be at least partly explained by the previously described genotypic heterogeneity. Thus, the LDL-C cut-offs given here should not be the sole guide for diagnosis. Indeed, the treated LDL-C cut-off of >8 mmol/L (>300 mg/dL) is now considered obsolete, given the multiplicity of lipid-lowering treatments that these patients typically receive. This point is clearly illustrated in a recent trial, in which HoFH patients with a confirmed genetic diagnosis had baseline LDL-C levels as low as 3.9 mmol/L (~150 mg/dL) while on multiple LDL-C lowering agents, as well as in a recent report.
Xanthomas and Arcus Corneae
Although not exclusively associated with HoFH, the presence of cutaneous or tuberous xanthomas in children is highly suggestive of diagnosis (Figure 5). Evidence of arcus corneae reinforces the clinical diagnosis. As seen for LDL-C levels, variability in the age at appearance and extension of xanthomas can be partly explained by the underlying mutations, with earlier appearance of xanthomas associated with receptor-negative vs. receptor-defective status. Cholesterol deposits in the tendons and joints may lead to tendinitis and joint pain, which impairs the quality of life of patients, and these may require surgical removal. In rare cases, patients may present with giant ectopic cholesterol xanthomas in the brain, mediastinum, and muscles of the buttock. As referral following the appearance of xanthomas in young children is frequently the key driver of HoFH diagnosis, prompt recognition is crucial to early diagnosis. The presence of markedly elevated LDL-C levels and the absence of neurological, cognitive, and ophthalmic symptoms in patients with HoFH distinguish them from patients with cerebrotendinous xanthomatosis.
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Figure 5.
Cutaneous and tuberous xanthomas in homozygous familial hypercholesterolaemia. Interdigital xanthomas (see B, yellow arrows) in children are highly suggestive of homozygous familial hypercholesterolaemia diagnosis. Photograph (A) kindly provided by Prof. Eric Bruckert. Photograph (B) kindly supplied by Prof. Frederick Raal.
Family History
A careful family history is essential for comprehensive assessment of possible FH in general, and HoFH in particular. In the case of autosomal dominant mutations (in LDLR, PCSK9, and APOB genes), both parents are obligate heterozygotes and therefore display elevated LDL-C levels (frequently >95th percentile by country-specific age and gender criteria) and a strong positive family history of premature ACVD (<55 years in men and <60 years in women among first-degree relatives). In the case of autosomal recessive hypercholesterolaemia (due to LDLRAP1 mutations), parents may exhibit LDL-C levels in the normal range, and determination of an extended family pedigree may reveal an autosomal recessive pattern of inheritance. Systematic cascade or opportunistic screening offers prospective parents with HeFH the possibility of making informed decisions prenatally, and identifying HoFH patients at birth, thereby allowing for early initiation of treatment. Identification of HoFH can also guide 'reverse' cascade screening for parents and relatives to identify patients with FH.
Differentiation From Sitosterolaemia
Although in most cases the diagnosis of HoFH is relatively straightforward, another disorder of lipid metabolism, sitosterolaemia (alternatively termed 'phytosterolaemia'), may have a very similar clinical presentation, with the presence of tendinous and/or tuberous xanthomas in childhood associated with a dramatic increase in plasma cholesterol and atherosclerotic complications. It is, however, of relevance that atherosclerotic disease is not always present in genetically defined sitosterolaemic subjects, as shown in a recent report. Similar to autosomal recessive hypercholesterolaemia, sitosterolaemia has an autosomal recessive pattern of inheritance and consequently parents may present with normal cholesterol levels. Two major features differentiate sitosterolaemia from HoFH: (i) markedly (>30-fold) increased plasma concentrations of plant sterols, and (ii) elevated cholesterol levels, which respond well to diet and bile acid sequestrants or ezetimibe and may not persist after the first two decades of life. Diagnosis is confirmed by genetic analysis, with mutations in two ATP binding cassette transporter genes, ABCG5 and/or ABCG8, shown to be causative for sitosterolaemia.
In summary, this Consensus Panel recommends that diagnosis is made by careful assessment of the clinical characteristics and family history, as well as genetic testing when the clinical diagnosis of HoFH is uncertain or to facilitate 'reverse' cascade screening. 'Reverse' cascade screening is in any case strongly recommended.