Familial Hypercholesterolaemia

Literature and regulatory information updated: 6 October 2026. Integration of the French PNDS (French National Diagnosis and Care Protocol) on the homozygous form: 6 November 2026.

Heterozygous (HeFH) and homozygous (HoFH) familial hypercholesterolaemia · Familial Hypercholesterolaemia · Type IIa hyperlipoproteinaemia · Familial defective apolipoprotein B-100 (FDB) · Autosomal recessive hypercholesterolaemia (ARH, LDLRAP1)

0. Initial Reference Table

1. Introduction

Familial hypercholesterolaemia (FH) is the most common monogenic metabolic disease in humans and the classic model of disease caused by a cellular receptor defect [16, 17]. It is characterised by elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C, low-density lipoprotein cholesterol) from birth, with accelerated cholesterol deposition in the arterial wall and other tissues, resulting in premature atherosclerosis, tendon xanthomas, xanthelasma and corneal arcus [16]. The importance of FH extends beyond its frequency: it provides the strongest genetic demonstration of the causal relationship between plasma cholesterol and coronary disease, and studying the homozygous form made it possible to understand the cellular regulation of cholesterol metabolism [17].

The first clinical link between hypercholesterolaemia, xanthomas and premature coronary disease was established by the Norwegian physician Carl Müller (1886–1983), whose work in 1938–1939 provided the initial evidence of a hereditary component of cholesterol-associated coronary disease [18]. In 1964, Avedis Khachadurian, studying Lebanese families with high consanguinity and an unusually large number of homozygotes, demonstrated that variation at a single locus produced three distinct phenotypes — affected homozygous, heterozygous and normal homozygous — establishing the codominant (now termed semidominant) nature of the disease [17, 19]. The relationship between the disease and the LDL fraction was established by the work of Gofman and Fredrickson, which gave rise to the designation type IIa hyperlipoproteinaemia [17].

The decisive step was taken by Michael Brown and Joseph Goldstein, who in 1974 demonstrated, in cultured fibroblasts from a homozygous patient, the absence of high-affinity LDL binding to the cell surface and the loss of regulation of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) [20, 21]. This discovery led to the characterisation of the LDL receptor, receptor-mediated endocytosis in clathrin-coated pits and the five classes of receptor defects [17]; this body of work earned Brown and Goldstein the 1985 Nobel Prize in Physiology or Medicine. Other genes were subsequently identified: familial defective apolipoprotein B-100, described by Innerarity and colleagues in 1987 [22]; autosomal recessive hypercholesterolaemia caused by LDLRAP1 variants, described by Garcia and colleagues in 2001 [23]; and PCSK9 gain-of-function variants, identified by Abifadel and colleagues in 2003 as the third cause of autosomal dominant hypercholesterolaemia [24]. The observation that PCSK9 loss-of-function variants reduce LDL-C by 15%–28% and coronary risk by 47%–88% [25] underpinned the development of PCSK9 inhibitors, one of the clearest demonstrations of the translation of human genetic findings into therapy.

Epidemiologically, HeFH prevalence was estimated for decades at 1:500, a figure revised by recent molecular and population studies to approximately 1:250 [1, 26]; a meta-analysis of 11 million people estimated 1:313 [3]. HoFH has a prevalence of 1:250,000 to 1:360,000, corresponding to approximately 30,000 people worldwide, fewer than 5% of whom have been identified [2]. Despite being treatable, FH remains underdiagnosed and undertreated: in the global EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry, comprising 42,167 adults from 56 countries, the median age at diagnosis was 44.4 years and only 2.7% of treated patients had LDL-C below 1.8 mmol/L [27]. Orphanet classifies the heterozygous form as an entity that is «non rare in Europe» (ORPHA:406) and maintains a separate entry for the homozygous form (ORPHA:391665) [4, 5].

This article addresses the heterozygous and homozygous forms together (including ARH), because they share their mechanism, genes, criteria and much of the therapeutic arsenal, but provides separate subsections whenever their clinical presentation, prognosis or treatment differ.

2. Molecular Genetics and Pathophysiology

2.1 LDL metabolism and the role of the receptor

LDL results from the hydrolysis of very-low-density lipoproteins (VLDL) by lipoprotein lipase, through intermediate-density lipoproteins (IDL); approximately half of VLDL remnants are taken up directly by the liver through the LDL receptor (LDLR), while the other half become LDL [16]. LDL carries more than 75% of plasma cholesterol, and 70%–80% of its clearance depends on hepatic LDLR, which recognises apolipoprotein B-100 (apoB-100) — each LDL particle contains a single apoB-100 molecule [16]. Following binding, the receptor–LDL complex is internalised in clathrin-coated pits; in the endosome, the fall in pH releases LDL, which proceeds to the lysosome, while the receptor is recycled to the surface [16, 17]. Cholesterol released in the lysosome exerts three regulatory effects: it suppresses HMG-CoA reductase (the rate-limiting step in endogenous synthesis), activates acyl-CoA:cholesterol acyltransferase (ACAT, which esterifies excess cholesterol) and represses the synthesis of new LDL receptors [17].

PCSK9 protein, secreted predominantly by the liver, binds LDLR and diverts it towards lysosomal degradation, preventing its recycling; its expression is regulated by intracellular cholesterol, so statins increase PCSK9 and partially counteract their own effect, explaining the synergism between statins and PCSK9 inhibitors [16]. The LDLRAP1 (ARH) adaptor protein binds, through its phosphotyrosine-binding domain, to the cytoplasmic tail of LDLR and is required for efficient endocytosis of the receptor–LDL complex in polarised cells such as hepatocytes, but not in fibroblasts — hence a functional assay in fibroblasts may be normal in ARH [1, 16].

2.2 Pathophysiological consequences

In FH, a reduction in the number or function of hepatic LDL receptors prolongs the residence time of LDL in plasma and raises LDL-C above the 95th percentile for age and sex [16]. The reduction in the hepatic cholesterol pool additionally stimulates endogenous synthesis and VLDL production, further increasing LDL [16]. Excess LDL infiltrates the arterial intima, where it undergoes oxidative modification and is taken up by macrophage scavenger receptors, which have no negative feedback, turning the macrophages into foam cells that form the core of the atherosclerotic plaque [16]. The same mechanism explains extra-arterial deposits: tendon, tuberous and cutaneous xanthomas, xanthelasma and corneal arcus [17]. In HoFH, deposition also affects the endocardium and valves, particularly the aortic root, coronary ostia and aortic valve, causing valvular and supravalvular stenosis [2, 17].

The concept of cumulative LDL-C burden (concentration × years of exposure) is central to understanding the natural history. The risk of symptomatic atherosclerotic cardiovascular disease (ASCVD) doubles when cumulative exposure exceeds approximately 175 mmol/L × year (6800 mg/dL × year); this threshold is reached after age 60 in a person without FH, before age 33 in a person with untreated HeFH and at approximately age 12 in a child with untreated HoFH [9].

2.3 LDLR

The LDLR gene, at 19p13.2, has 18 exons distributed over approximately 45 kb and encodes a 5.3 kb mRNA and an 860-amino-acid glycoprotein, synthesised as a 120 kDa precursor in the endoplasmic reticulum and converted into a mature form of apparent mass 160 kDa in the Golgi apparatus [1, 17]. More than 3000 causal variants have been described [2, 16]. Exon 4, which encodes type A repeats 3, 4 and 5 of the ligand-binding domain, is the hotspot with the greatest number of pathogenic variants per nucleotide, and exons 2 to 8 and 14 contain 60 conserved cysteine residues essential for protein folding; sequencing should include the regulatory region (200 bp upstream of the initiation codon) [1]. In a French series of 1358 probands with autosomal dominant hypercholesterolaemia, LDLR variants were 46% missense, 13.6% frameshift, 11.3% nonsense and 9.7% large rearrangements; APOB accounted for 6.6%, PCSK9 for 0.7%, and no variant was found in 19% [17]. Synonymous variants affecting splicing have been identified in patients negative for all three genes [17]; the Atlas transcribes them as «R85R and C186G», but the synonymous LDLR splicing variants recorded in ClinVar under these historical designations are NM_000527.5:c.621C>T, p.(Gly207=) (historical G186G), and c.1216C>A, p.(Arg406=) (historical R385R), classified as pathogenic/likely pathogenic and likely pathogenic, respectively [28]. Historical LDLR numbering subtracts the 21 amino acids of the signal peptide (for example, the «Lebanese» allele C660X corresponds to p.Cys681Ter and the G197del deletion in Lithuanian Jews to p.Gly219del), so the two numbering systems should not be mixed in the same report [29].

LDLR variants fall into five functional classes, described by Brown and Goldstein using fibroblast cell lines [17]:

Clinically, variants are grouped as «null» (residual receptor activity of 2% or less) and «defective» (2%–70%) [2]. Individuals carrying two null alleles have the highest LDL-C, the earliest disease and the poorest response to therapies dependent on receptor overexpression (statins, PCSK9 inhibitors) [1, 2]. Before current therapies, homozygotes without receptor function had a mean age at death of 11 years, whereas among 26 patients with defective receptors only one had died, at age 23 [17].

2.4 APOB

The APOB gene, at 2p24.1, encodes apoB-100 (hepatic) and, through RNA editing, apoB-48 (intestinal) [1]. Its intron distribution is unusual: 24 of its 29 introns lie at the 5′ end, and more than half of the protein is encoded by exon 26, which is 7572 bp long and one of the largest in the human genome [1]. FH-associated variants lie in the receptor-binding domain of apoB-100 and reduce the affinity of the LDL particle for LDLR; the most frequent is NM_000384.3:c.10580G>A, p.(Arg3527Gln), known by the historical nomenclature R3500Q, present in approximately 1:1000 Europeans and showing a founder effect in the Amish community; NM_000384.3:c.10579C>T, p.(Arg3527Trp) (historical R3500W), is more common in Asian populations [1, 16, 26]. In contrast, truncating APOB variants in other regions of the gene reduce lipoprotein secretion and cause familial hypobetalipoproteinaemia, the opposite phenotype [1].

2.5 PCSK9

The PCSK9 gene, at 1p32.3, encodes a zymogen of the subtilase family that undergoes autocatalytic processing in the endoplasmic reticulum and is secreted [26]. Gain-of-function variants increase LDLR degradation and cause FH (approximately 1%–3% of cases; in the United Kingdom, approximately 2% of patients have the NM_174936.4:c.1120G>T, p.(Asp374Tyr) variant) [2, 26]. Penetrance is approximately 90% for NM_174936.4:c.381T>A, p.(Ser127Arg) and high, with early onset, for p.(Asp374Tyr); complete gene duplication has been described in two families with severe FH [1]. The direction of the effect is decisive for interpretation: loss-of-function variants reduce LDL-C and protect against coronary disease, so a PCSK9 variant can only be considered causal if gain of function is demonstrated [1, 25].

2.6 LDLRAP1 and autosomal recessive hypercholesterolaemia

The LDLRAP1 gene, at 1p36.11, is the only known cause of classical autosomal recessive hypercholesterolaemia [1, 16]. Approximately 30 pathogenic variants have been described, mostly truncating and biallelic loss-of-function variants [1]. In ARH, the receptor is synthesised, reaches the surface and binds LDL, but the complex is not efficiently internalised in the hepatocyte; residual LDLR activity demonstrated in fibroblasts helps explain the relatively better response to statins [16]. Heterozygotes are true carriers, with LDL-C within the reference range or slightly elevated [2, 16]. In Sardinia, the founder variants NM_015627.3:c.431dup, p.(His144GlnfsTer27), and NM_015627.3:c.65G>A, p.(Trp22Ter), result in a carrier frequency of 1:143 and an affected frequency of approximately 1:40,000 [1, 16].

2.7 Genetic nomenclature of the homozygous form

The term «HoFH» is now used as an umbrella clinical designation for any biallelic combination of pathogenic variants that compromises the LDLR pathway [2]. The 2023 European Atherosclerosis Society (EAS) consensus proposes precise genetic nomenclature, replacing the terms «true homozygous», «compound heterozygous» and «double heterozygous» [2]:

When genotype and phenotype are discordant — for example, patients with two pathogenic variants who behave as heterozygotes and respond to statins, or patients with a homozygous phenotype and only one identified variant — the phenotypic diagnosis takes precedence over the genetic diagnosis [2].

The French PNDS of 2026 follows this nomenclature and adds three clarifications [11]. It reserves the term "phenotypic HoFH" for the severe form that meets the EAS clinical and biochemical criteria without genetic characterisation. It includes APOE (loss of function, chiefly NM_000041.4:c.500_502del p.(Leu167del)) among the semidominant genes that can make up a digenic biallelic form together with an LDLR variant, with incomplete penetrance; these exceptional forms are left out of the frequency table. And it describes the transmission of digenic forms: as a rule each parent transmits one variant and both have a heterozygous phenotype, but exceptionally the two variants, on different chromosomes, come from the same parent, who then has a severe phenotype, while the other parent is normolipidaemic [11]. In ARH, homozygosity is the rule, generally in the context of consanguinity, and compound heterozygosity is rare [11]. The term semidominant denotes a dose–effect relationship: biallelic carriers have more severe disease than monoallelic carriers [11].

2.8 Modifiers and non-monogenic causes

No causal variant is identified in 20%–40% of adults with a clinical diagnosis of FH [1]. In these cases, hypercholesterolaemia is often polygenic, explainable by a polygenic risk score based on 12 common alleles that raise LDL-C, or is due to elevated lipoprotein(a) [Lp(a)] [9, 26]. In the Portuguese FH Study, among individuals with a clinical phenotype without a causal variant, 30% had Lp(a) above 50 mg/dL and 16% a high polygenic score [30]. Phenotypic expression is modulated by genetic and environmental factors: siblings with the same LDLR variant may differ markedly (one died at age three and the other was asymptomatic at 14) [17]; heterozygotes who inherited the variant from their mother have slightly higher total cholesterol, LDL-C and apoB levels in adulthood than those who inherited it from their father, suggesting maternal programming during gestation [17]; and loss-of-function variants in hypocholesterolaemia genes (truncating APOB, ANGPTL3, PCSK9, MTTP, SAR1B) may mask FH within a family [9]. Coronary disease in FH also exemplifies the genetic architecture of atherosclerosis: genes for monogenic forms (LDLR, PCSK9, APOB, LPA) also generate signals in genome-wide association studies, forming an allelic series ranging from rare variants with large effects to common variants with small effects [18].

3. Clinical Spectrum and Manifestations by System

3.1 Heterozygous familial hypercholesterolaemia (HeFH)

HeFH is asymptomatic for decades: the patient feels well while arterial damage accumulates, so diagnosis depends on lipid measurement, family history and screening [1]. Cholesterol is elevated from birth, generally to approximately twice normal values, and adult total cholesterol typically lies between 9.0 and 14.0 mmol/L (approximately 350–540 mg/dL) [26]. In classical series, mean LDL-C was 241 ± 60 mg/dL in HeFH and 625 ± 160 mg/dL in HoFH, compared with a normal value of 110 ± 25 mg/dL; triglycerides are usually normal and high-density lipoprotein cholesterol (HDL-C) tends to be slightly lower than in the population [17]. In carriers of APOB (FDB) and PCSK9 variants, LDL-C tends to be lower and the presentation less severe than in LDLR-related HeFH [1, 16].

Cardiovascular system. Without treatment, approximately 50% of men and 30% of women with HeFH have symptomatic cardiovascular disease before age 50 [16]; data from the pre-statin era indicate a 50% risk of a fatal or non-fatal coronary event by age 50 in men and 30% by age 60 in women [1, 26], so sources differ on the reference age for women (50 or 60 years). In a classical series, the probability of a coronary event was 16% by age 40 and 52% by age 60 in men, and 33% by age 60 in women; mean age at death was 55 years in men and 64 in women [17]. People with LDL-C above 190 mg/dL and a pathogenic variant have a coronary disease risk 22 times that of the general population, whereas those with the same LDL-C without a variant have a 6-fold risk [1, 31]. Approximately 1 in every 10 people with early myocardial infarction has FH [1]. The excess risk of stroke is less clear [1]. In the FHSC, coronary disease prevalence was 17.4%, stroke 2.1% and peripheral arterial disease 5.2%, approximately half as high in women [27]. Echocardiography may reveal proximal and valvular aortic stenosis, and abdominal ultrasound aortic calcification [17]. Children with HeFH already show endothelial dysfunction and increased carotid intima–media thickness (cIMT) compared with unaffected siblings, with differences detectable before age 10 [9, 16], and coronary calcification in approximately 25% of young people aged 11 to 23 with an HeFH phenotype [32].

Skin, tendons and eyes. Tendon xanthomas occur predominantly in the Achilles tendons and finger extensors and worsen with age; historically described in 30%–50% of patients, they are now less frequent because of widespread statin use, and are rare in heterozygous children [1]. Fibrous swelling often overlies the deposit, so an Achilles tendon xanthoma may feel hard on palpation [26]. Xanthelasma is frequent in heterozygotes, although it also occurs in normolipidaemic individuals [17]. Corneal arcus has diagnostic value when it appears before age 45; it is present in 10% of heterozygotes at age 30 and in 50% above that age in older series, and in 7%–30% in recent series; it does not regress with treatment [1, 17].

Musculoskeletal system. Episodes of Achilles tendon «tenosynovitis» and migratory polyarthritis with an elevated erythrocyte sedimentation rate, which may mimic rheumatic fever, have been described, particularly in the homozygous form [17, 26].

3.2 Homozygous familial hypercholesterolaemia (HoFH)

Lipid profile. Homozygotes have total cholesterol between 600 and 1200 mg/dL (15–30 mmol/L) and LDL-C usually above 500 mg/dL (13 mmol/L) [1, 17]. In the international HICC registry (HoFH International Clinical Collaborators), comprising 751 patients from 38 countries, median pretreatment LDL-C was 14.7 mmol/L and median age at diagnosis 12 years [33].

According to the French PNDS, LDL-C is usually between 4 and 12 g/L (approximately 10 to 31 mmol/L) from birth, with total cholesterol of 6–12 g/L and LDL-C close to 6 g/L (approximately 15.5 mmol/L); values below 4 g/L, particularly in children, do not exclude the diagnosis [11]. In patients diagnosed in adulthood, untreated LDL-C rarely exceeds 6 g/L, which may reflect survival bias, less severe variants or digenic forms; with very high LDL-C, triglycerides may be slightly increased and HDL-C slightly decreased, in both adults and children [11].

Age at diagnosis. Median age at diagnosis ranges from 12 to 24 years in published cohorts and is 17.5 years in the French REFERCHOL registry (unpublished data cited by the PNDS); it depends on genotype severity, with medians of 10 years in carriers of two null LDLR alleles and of up to 37 years in carriers of non-null variants in the Spanish SAFEHEART cohort [11]. In adults, the diagnosis is generally made before age 40; given the prevalence of HeFH, many patients with attenuated-phenotype HoFH are probably classified as severe HeFH, which justifies genetic testing in these forms [11]. In the French cohort of 53 patients followed at one centre between 1976 and 2015, 94% had a family history of cardiovascular events, 91% had xanthomas, all of which appeared before age 10, the first cardiovascular event occurred at a mean age of 19.0 ± 8.2 years and the latest age at diagnosis was 36 years; in the HICC, 68.7% of patients had xanthomas at diagnosis [11]. These are patients referred to specialised centres, not a population sample.

Skin. The first manifestation is usually the appearance of xanthomas before age 10: planar, tuberous or tendinous, over the Achilles tendon, hand extensors, elbows, knees, buttocks and popliteal and antecubital fossae; interdigital xanthomas, particularly in the web space between the first and second fingers, are characteristic of the biallelic form [1, 17, 26]. Subperiosteal xanthomas may occur at the tibial tuberosity and elbow and, rarely, on the tongue and oral mucosa; trauma appears to influence their location [17]. Corneal arcus regularly appears before age 10 [17].

The French PNDS describes planar xanthomas as buff-yellow lesions (rarely orange-red), formed by lipid-laden macrophages and visible from the first years of life in the folds of the elbows and wrists, the interdigital spaces, knees, ankles, feet, trunk, intergluteal cleft and buttocks; tuberous xanthomas as painless subcutaneous nodules, soft at first and later firm, ranging from a few millimetres to several centimetres, on the extensor surfaces of the elbows and knees; and tendon xanthomas (Achilles tendon, finger extensors, patellar tendons) as appearing later in children and as less specific, because they also occur in severe HeFH, albeit smaller and later [11]. In contrast to the classical description of a regular corneal arcus before age 10 [17], the PNDS considers it inconsistent in children, with prevalence increasing with age, as is xanthelasma, which is rare in early childhood [11]. In adults, the homozygous form is distinguished from the heterozygous form by the extent and early onset of tendon xanthomas and by the presence of tuberous xanthomas on the elbows and knees [11].

Heart and great vessels. Atherosclerosis preferentially affects the aortic root, coronary ostia and aortic valve; valvular and supravalvular aortic stenosis is frequent and may progress even with LDL-C reduction, because of haemodynamic stress and fibrosis [2, 9]. Angina at age five and myocardial infarction at 18 months and three years of age have been described [17]. Valvular haemodynamics may be indistinguishable from those of rheumatic or calcific aortic stenosis [17]. Most untreated patients develop severe coronary disease by the middle of the second decade and die before age 20–30 [1, 16, 26]. In the HICC, 9% of patients already had ASCVD or aortic stenosis at diagnosis, and the first major cardiovascular event occurred at a median of 24.5 years in non-high-income countries versus 37 years in high-income countries [33].

Cohorts and course of cardiovascular complications. Coronary disease in HoFH is characterised by its early onset and the ostial nature of the lesions; angina at age 4 and infarction at age 10 treated by coronary reimplantation, fatal acute coronary syndromes from age 3 and sudden death at 3–4 years have been described [11]. Before effective therapies, the first coronary event often occurred before age 10, approximately 10 years later with statins and after age 20 with apheresis; at a median age of 12 years, 10% of HICC patients already had severe coronary lesions and aortic valve involvement [11]. Coronary manifestations are not, however, universal in adults: in a Dutch cohort, 29% of patients had had a cardiovascular event (mean age 34 years) and, in a series with a mean pre-treatment LDL-C of 6.5 g/L (approximately 16.8 mmol/L), 38.3% had cardiovascular manifestations (mean age 26 years), with coronary events at a mean age of 28 years, aortic valve replacement at 26 and coronary artery bypass grafting at 29, which suggests a relationship between LDL-C and severity [11]. The Dutch cohort corresponds to the 49 patients with a molecular diagnosis identified among 104,682 people tested at the national diagnostic centre [34]. The PNDS describes the second series as Italian, but the work it cites is a pooled analysis of three international studies with 167 patients aged 1 to 75 years, whose abstract does not present these figures and whose conclusion is the diversity of ages and LDL-C levels in HoFH [35]. In a meta-analysis of 94 studies published in 2022, the pooled prevalence was 15.1% for myocardial infarction (95% CI 10.7–20.0) and 28.3% for coronary revascularisation (22.5–34.3), with a mean age at onset of 24.5 years (95% CI 19.2–29.8) and 32.2 years (26.6–37.8), respectively; the age at first myocardial infarction moved back by more than a decade between publications before and after 1990, which the authors attribute to statins and other therapies [36]. These values are means with confidence intervals, not medians with interquartile ranges, as one passage of the PNDS presents them [11, 36]. In an HICC study of sex differences (389 women and 362 men alive in 2010 or later), the prevalence of myocardial infarction was 8% in women (31/389) and 16.3% in men (59/362), with a similar mean age at first infarction (39 and 38 years) [11, 37]. In a Canadian series of 48 patients with a mean follow-up of 10 years, major adverse cardiovascular events occurred in 11.1% of women (3/27) and 19.1% of men (4/21), a difference without statistical significance (p = 0.2) that the authors interpret as the loss, in HoFH, of the usual premenopausal cardiovascular protection in women [38].

Aortic valve, aorta and other vascular territories. Aortic involvement may affect the valve leaflets, the sinuses of Valsalva and the sinotubular junction. In a systematic review covering nine decades of publications (19 studies and 108 individual cases, 424 patients), aortic stenosis (valvular or supravalvular) was identified in 57% of patients in the pre-statin era and in 35% of those described after 2000, and the ratio of supravalvular to valvular forms shifted from 47:53 to 10:90, with a move towards calcified valvular stenosis similar to that of common atherosclerosis [39]; the PNDS gives 59% and 39% for the same periods [11]. Supravalvular stenosis remains a poor prognostic factor, associated with sudden death, and often leads to early valve replacement, generally in adulthood but described from age 5 [11]. Symptomatic peripheral arterial disease is less frequent and later: in the Dutch cohort, a single patient developed it, at age 69, and in the HICC the prevalence was 6.6%, with a median age at onset below 40 years; cerebrovascular disease had a prevalence of 1.7%, with a first event at a median age below 45 years, which justifies surveillance of the supra-aortic trunks and screening for transient ischaemic attacks [11]. In children, diastolic dysfunction and early remodelling of the ascending aorta have been described [11].

Other manifestations. Recurrent arthritis or tenosynovitis of the ankles, wrists and proximal interphalangeal joints, lasting 3 to 12 days and resolving spontaneously, persistently elevated erythrocyte sedimentation rate, fibrinogen increased up to twofold and non-arteritic ischaemic optic neuropathy before age 49 have been described [17].

3.3 Familial defective apolipoprotein B-100 (FDB) and PCSK9-related FH

FDB is clinically indistinguishable from LDLR-related FH, although LDL-C is slightly lower and xanthomas fewer; clinical FH criteria underdiagnose R3500Q carriers [16, 26]. In FDB homozygotes, LDL-C is comparable to that of LDLR heterozygotes rather than homozygotes [26]. In the Amish community, p.(Arg3527Gln) heterozygotes have mean LDL-C below diagnostic thresholds but develop coronary calcification and atherosclerosis [1]. Penetrance in APOB heterozygotes may be reduced; for LDLR, only 73% of carriers have LDL-C above 130 mg/dL [1]. Biallelic APOB and PCSK9 forms are rare and more closely resemble LDLR-related HeFH than LDLR-related HoFH [1].

3.4 Autosomal recessive hypercholesterolaemia (ARH)

ARH has a phenotype resembling LDLR-related HoFH — severe hypercholesterolaemia, bulky xanthomas and premature ASCVD — but is generally milder: LDL-C lies between that of HeFH and HoFH, HDL-C is higher, the response to lipid-lowering therapy is better and event-free survival is longer [16, 26]. Paradoxically, xanthomas are frequently large and bulky [26]. In childhood, 97% develop planar, tuberous and tendon xanthomas and almost 50% have coronary disease; aortic valve and aortic root disease are possible, and ascending aortic atherosclerosis is rare and later [32]. There are generally no symptoms before age 20, and parents have a normal lipid profile [16, 32].

3.5 Summary by gene

4. Clinical Recognition and Warning Signs

As HeFH is silent until the first event, recognition relies on laboratory, family and physical signs that should be actively sought. The clinical approach begins with a three-generation pedigree, recording relatives with hypercholesterolaemia, myocardial infarction (with age), angina (with age at onset), and cause and age of death, and enquiring about a history of Achilles tendon «tenosynovitis» [26]. Physical examination should include careful palpation of the Achilles tendons and finger extensors with the fingers extended, and assessment for corneal arcus [26].

Isolated cholesterol elevation should always prompt exclusion of secondary causes — obesity, diabetes, obstructive liver disease, hypothyroidism, renal disease (nephrotic syndrome) and drugs such as corticosteroids — before attributing the phenotype to FH [1, 16]. Population risk calculation systems, such as European SCORE or the Framingham score, do not apply to FH because they underestimate the risk conferred by lifelong exposure to elevated LDL-C [1, 8]. An apparently negative family history does not exclude the diagnosis: relatives may not have been tested, the disease may not have been recognised, or affected relatives may have been taking statins for many years without events [1].

Suspected HoFH. The French PNDS recommends prompt referral to a specialised centre of any child with tendon, cutaneous or ocular cholesterol deposits and LDL-C close to 4 g/L (approximately 10 mmol/L) or higher, and requesting a lipid profile in the presence of exertional chest pain, dyspnoea, presyncope or syncope, a systolic murmur or an ischaemic event in a child or young adult; the discovery of aortic stenosis in a child or young adult requires screening for hypercholesterolaemia in the patient and in first-degree relatives [11]. When both parents have HeFH or LDL-C of 1.9 g/L (approximately 4.9 mmol/L) or higher, HoFH should be sought in the children [11]. In children, ischaemic pain may present as ill-defined abdominal pain, so it should be actively sought at each visit, with palpation of all peripheral pulses [11]. HoFH does not affect growth in height and weight or puberty; hepatosplenomegaly, jaundice, developmental delay or oedema of the lower limbs or eyelids point to an alternative diagnosis [11]. The assessment includes associated risk factors: arterial hypertension, smoking from adolescence and other addictions, diabetes, age at first events in relatives, Lp(a), and growth and body mass index charts [11]. The disease may also be discovered incidentally in young adults, in the less severe forms, or in migrants without previous access to healthcare [11].

5. Diagnosis: Criteria, Tests and Algorithms

5.1 Laboratory assessment

The lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) is the first-line investigation, ideally before any treatment; Lp(a) should be measured at the initial assessment [1, 2]. In FH, total cholesterol is usually 8 mmol/L or above in adults (6 mmol/L in children), without relevant changes in triglycerides or HDL-C; hypertriglyceridaemia does not exclude FH [8]. ApoB may be useful in distinguishing FH from other dyslipidaemias [16]. Thresholds should be interpreted in light of percentiles for age, sex and country [1].

5.2 Clinical criteria

Three formal systems are widely used in Western countries — Dutch Lipid Clinic Network (DLCN), Simon Broome and MEDPED (Make Early Diagnosis to Prevent Early Deaths) — all based on LDL-C or total cholesterol, supplemented by personal and family history, physical examination and, in the first two, genetics [1, 40]. Non-Western countries have their own criteria, such as the Japanese criteria [1].

DLCN criteria. This is the most widely used scoring system in Europe and in the FHSC registry (75.4% of diagnoses) [27]. Only the highest applicable item is scored in each group [8, 16]:

Simon Broome criteria. Developed by the British registry, these distinguish definite and possible FH [26, 40]. The lipid criterion is total cholesterol above 7.5 mmol/L (290 mg/dL) or LDL-C above 4.9 mmol/L in adults, and total cholesterol above 6.7 mmol/L (259 mg/dL) or LDL-C above 4.0 mmol/L in children under 16. FH is definite if, in addition to the lipid criterion, tendon xanthomas are present in the patient or a 1st- or 2nd-degree relative, or if a causal LDLR, APOB or PCSK9 variant is identified; it is possible if, in addition to the lipid criterion, there is a family history of myocardial infarction before age 50 in a 2nd-degree relative or before age 60 in a 1st-degree relative, or a family history of total cholesterol above 7.5 mmol/L in a 1st- or 2nd-degree relative [40]. Some experts prefer Simon Broome to DLCN criteria in paediatric probands [1].

MEDPED criteria. Used in the United States, these are based on total cholesterol cut-offs adjusted for age and degree of relatedness to a confirmed case; in the absence of known FH in the family, the values in the «general population» column apply [40]:

Despite differences in structure and cut-offs, the three systems have comparable predictive values [40]. An approach based solely on LDL-C concentration may have diagnostic accuracy similar to the DLCN score [7].

Paediatric criteria. Systems designed for adults miss a substantial proportion of children with a causal variant; the 2015 EAS criteria would miss early diagnosis in almost half of carrier children [9]. The 2026 EAS consensus proposes revised criteria for «clinical FH» in children: LDL-C above 4.5 mmol/L (175 mg/dL) in universal or opportunistic screening; above 3.5 mmol/L (135 mg/dL) if a grandparent or parent has premature ASCVD and/or a parent has elevated cholesterol; or above 3.0 mmol/L (115 mg/dL) if a parent has a genetic diagnosis and the child is not tested [9]. A child with a causal variant has «definite FH» and should be referred for treatment if LDL-C is above 3.5 mmol/L before age 10 or above 3.0 mmol/L from age 10 onwards [9]. A new paediatric score (FH-PeDS) has been developed, derived from the Slovenian universal screening cohort and validated in the Portuguese FH Study, but still requires validation in other populations [9].

HoFH criteria. The 2023 EAS consensus replaced the previous threshold (untreated LDL-C above 13 mmol/L or treated LDL-C above 8 mmol/L) with a threshold for suspicion of untreated LDL-C above 10 mmol/L (approximately 400 mg/dL), supplemented by cutaneous or tendon xanthomas before age 10 and/or LDL-C compatible with HeFH in both parents (in the digenic form, one parent may have normal LDL-C); the genetic criterion is confirmation of biallelic pathogenic or likely pathogenic variants in LDLR, APOB, PCSK9 or LDLRAP1, or two or more variants at different loci [2].

The French PNDS adopts these criteria, stresses that concentrations below 10 mmol/L, particularly in children, do not rule out the diagnosis, and specifies the genes of the digenic form (two of LDLR, APOB, PCSK9 and APOE); in the recessive form, both parents have normal LDL-C [11].

5.3 Genetic testing

Genetic testing confirms the diagnosis, distinguishes monogenic and polygenic forms, enables definitive cascade screening, predicts severity and therapeutic response in the homozygous form, and may improve treatment adherence [2, 10]. In HeFH, however, treatment should never be delayed while awaiting the genetic result [8]. The recommended approach is a next-generation sequencing (NGS) panel with deletion and duplication analysis; a restricted panel includes APOB, LDLR, LDLRAP1 and PCSK9, while an extended dyslipidaemia panel adds ABCG5, ABCG8, APOE and LIPA [1]. The eight-gene panel proposed by the expert panel includes the three main causal genes, APOE (variant NM_000041.4:c.500_502del, p.(Leu167del)) and LDLRAP1, and the phenocopy genes ABCG5, ABCG8 and LIPA [9, 10]. Interpretation should follow American College of Medical Genetics and Genomics (ACMG) criteria adapted to FH by the ClinGen expert panel; only pathogenic or likely pathogenic variants are diagnostic, and variants of uncertain significance neither confirm nor exclude the diagnosis [1, 2].

Source: GeneReviews, Table 1 [1].

Testing yield depends on pre-test probability: variants are identified in 60%–80% of adults with a clinical diagnosis, in 60%–95% of children with strong clinical suspicion [1], in 70%–80% of patients with definite FH by Simon Broome criteria and in only 25%–30% of those with «possible» FH [26]. Overall, current testing yield in referred patients is between 54% and 70% [16]. In the Portuguese FH Study, 42% of the 1005 index cases had genetic confirmation (408 heterozygotes and 9 homozygotes), and cascade screening increased the number of identified patients to 1000, including 11 homozygotes [30]. When testing is negative and LDL-C is elevated, a 12-allele polygenic score above the 80th percentile provides an explanation for hypercholesterolaemia and increases the diagnostic rate in adults, with no evidence of benefit in children yet [9]. DNA storage should be considered for probands without a molecular diagnosis [1]. When the familial variant is known, targeted testing is sufficient and can be performed on cord blood, saliva or a buccal swab [9].

In France, testing is performed in authorised laboratories, under the responsibility of biologists accredited by the Agence de la biomédecine, on whole blood collected in a hospital setting; it requires written consent from the adult patient or from both parents for a minor, and the result generally takes 4 to 9 months [11]. It is delivered at a dedicated consultation by a physician competent in genetics, with a written report explaining the nature of the test, its limitations and the interpretation; the result is subject to medical confidentiality and may only be disclosed to third parties with the patient's express agreement [11]. In HoFH, the PNDS assigns the test a role in guiding treatment, because it identifies the null LDLR genotypes that do not respond to receptor-dependent therapies [11].

5.4 Functional tests and prenatal diagnosis

LDLR function can be documented in cultured fibroblasts or lymphocytes, but these assays are now reserved for research [17]. In ARH, the fibroblast assay may be normal and therefore does not exclude the diagnosis [1]. Measuring cholesterol in cord blood allows heterozygosity to be diagnosed but is not a reliable population screening method; even at one year of age, family investigation is necessary to attribute LDL-C elevation to FH [17].

5.5 Initial assessment after diagnosis

First visit in HoFH (French PNDS). The history records consanguinity, familial hypercholesterolaemia, use of lipid-lowering drugs before age 45, premature cardiovascular events (men before age 55, women before age 60) and premature or unexplained sudden cardiac deaths, exertional symptoms, dietary habits, physical activity and risk factors; the examination looks for corneal arcus, xanthelasma and planar, tuberous and tendon xanthomas, peripheral pulses, an aortic stenosis murmur and carotid, femoral and renal bruits, and in children records the growth chart and body mass index [11]. The laboratory work-up includes a full lipid profile, Lp(a), transaminases and creatine kinase (baseline values before treatment), TSH, GGT, total and conjugated bilirubin, a urine dipstick for proteinuria and genetic testing [11]. Even in asymptomatic patients, the initial cardiovascular assessment comprises an electrocardiogram, echocardiogram, coronary CT angiography and Doppler ultrasound of the supra-aortic trunks, the aorta and the lower limbs [11].

5.6 Diagnostic algorithm

Diagnosis of genetic dyslipidaemias follows four steps: exclude secondary causes; assess the probability of a genetic cause (very high LDL-C or triglycerides, very low HDL-C, characteristic clinical signs, family history of dyslipidaemia or premature atherosclerosis); perform specialised biochemical tests and/or targeted sequencing; and initiate family studies [16]. In practice:

1. Adult with LDL-C above 190 mg/dL (or child above paediatric thresholds) → exclude secondary causes and repeat the measurement.
2. Apply the DLCN score (or Simon Broome in children) and record the three-generation pedigree [1, 8].
3. DLCN score above 5 or probable or definite FH → genetic testing (NGS panel with copy number analysis) and immediate initiation of treatment [8, 16].
4. Pathogenic variant identified → genetic cascade screening of 1st-degree relatives, followed by 2nd-degree relatives [1, 8].
5. Negative test → consider polygenic hypercholesterolaemia, elevated Lp(a) and phenocopies; maintain treatment and family screening based on LDL-C [9, 30].
6. Untreated LDL-C above 10 mmol/L or xanthomas before age 10 → suspect HoFH, refer to a specialist centre and perform «reverse» cascade screening of parents and siblings [2].

5.7 Limitations of genetic tests and report content

Coverage. A next-generation sequencing panel detects single-nucleotide variants and small insertions or deletions in coding regions and exon–intron junctions, but approximately 10% to 15% of causal LDLR variants are large deletions or duplications requiring copy number analysis (by MLPA or a validated algorithm applied to panel data), and the LDLR promoter region should be included [1, 17]. Deep intronic variants and synonymous variants that alter splicing may escape automated interpretation, and interpretation of PCSK9 alleles requires demonstration of gain of function [1, 2]. The proportion of variants detectable by each method (table in 5.3) is not the clinical sensitivity of the test: among adults with an FH phenotype, 20%–40% have no identifiable variant, mainly because of polygenic hypercholesterolaemia or elevated Lp(a), and this negative result does not negate the risk or the indication for treatment, which depend on LDL-C [1, 9, 30]. Parental mosaicism is rare but should be considered when the proband's variant is not found in either parent [1].

Minimum report content. The report should state the gene, the reference transcript with version — MANE Select transcripts: LDLR NM_000527.5, APOB NM_000384.3, PCSK9 NM_174936.4, LDLRAP1 NM_015627.3 and APOE NM_000041.4 [41] — the normalised HGVS designation at DNA and protein levels, zygosity (and, in the biallelic form, whether the variants are in trans, which requires parental testing), classification according to ACMG/AMP with the ClinGen expert panel specifications for LDLR, and the technical limitations of the test [29, 42]. When the literature uses historical nomenclature, both should be given: APOB R3500Q corresponds to NM_000384.3:c.10580G>A, p.(Arg3527Gln); PCSK9 D374Y to NM_174936.4:c.1120G>T, p.(Asp374Tyr); and the Sardinian LDLRAP1 variants to NM_015627.3:c.431dup, p.(His144GlnfsTer27), and NM_015627.3:c.65G>A, p.(Trp22Ter), all recorded in ClinVar as pathogenic or pathogenic/likely pathogenic [28]. The APOE p.Leu167del designation, used in the phenocopy literature, matches that of the ClinVar record on the MANE transcript (NM_000041.4:c.500_502del; repeat description c.497_502TCC[1]) [28].

Variants of uncertain significance. A variant of uncertain significance does not become pathogenic because the patient responds to a statin or a PCSK9 inhibitor, or because of partial segregation in a small family with hypercholesterolaemia, which is frequent and polygenic in the population; segregation studies and functional assays in cell lines are research that may later underpin reclassification according to ACMG/AMP rules [29, 42]. While the variant remains uncertain, cascade screening is performed using LDL-C rather than targeted testing [1].

Requirements of the French PNDS for HoFH. Only ACMG class 4 and 5 variants (with the ClinGen specifications for LDLR) enter the genetic nomenclature; methods must be accredited to the ISO 15189 standard, cover at least the coding exons and exon–intron junctions and detect large rearrangements, which the PNDS estimates at 6% to 10% of deleterious LDLR variants on the basis of French experience, a figure lower than the 10%–15% given by GeneReviews [1, 11]. It classifies as null (activity below 2%) large rearrangements of one or more exons, variants creating premature termination codons (nonsense variants and small frameshifting insertions, deletions or duplications), splicing variants and missense variants with absent activity demonstrated in vitro or ex vivo; as defective, missense variants, small in-frame insertions or deletions and variants in the 5′ regulatory region; and it notes that residual activity has been measured in fewer than 10% of the LDLR variants described [11]. The PNDS text assigns defective variants 2%–25% residual activity and its summary table 2%–70%, the latter matching the EAS figure [2, 11]. Segregation studies are essential to confirm the monogenic biallelic form (variants in trans) and support cascade screening; for a variant of uncertain significance, the PNDS calls for a segregation study and targeted testing for the variant in relatives, whatever their lipid profile, while clinical management depends on LDL-C [11]. Among the technical limitations, it lists restricted panels, mobile elements, inversions and other complex rearrangements, deep intronic variants and variants in the 5′ and 3′ untranslated regions; in the event of genotype–phenotype discordance, the EAS and the Nouvelle Société Francophone d'Athérosclérose (NSFA) recommend guiding treatment by the phenotype [11].

6. Differential Diagnosis

In a child with an HoFH phenotype, sitosterolaemia is the most important differential diagnosis because treatment differs radically (plant sterol restriction and ezetimibe instead of statins and apheresis) [2]. Differential diagnosis between HoFH and ARH is based on parental assessment: if both parents have a normal lipid profile, the recessive form should be considered [16].

The French PNDS considers the differential diagnoses of HoFH exceptional: among secondary causes, only severe cholestasis produces hypercholesterolaemia of comparable intensity, and in the presence of xanthomas without major hypercholesterolaemia, sitosterolaemia and cerebrotendinous xanthomatosis should be sought [11].

7. Treatments and Risk Management Strategies

7.1 General principles and therapeutic targets

FH is treated as a high cardiovascular risk condition from diagnosis, without using population risk calculators [1, 8]. The aim is to reduce cumulative LDL-C burden as early and as intensively as possible: each 1 mmol/L reduction in LDL-C is associated with a proportional reduction in cardiovascular and all-cause mortality, and the inverse relationship between LDL-C and risk persists even at very low values without apparent adverse effects [8, 16]. Treatment always includes lifestyle modification — abstinence from smoking, a diet low in saturated and trans fats, regular physical activity and control of weight, blood pressure and blood glucose — but LDL-C rarely reaches the target with non-pharmacological measures alone [1, 8].

LDL-C targets follow the European dyslipidaemia guidelines of the European Society of Cardiology (ESC) and EAS. In the 2019 guideline, patients with FH and established ASCVD or another major risk factor are classified as very high risk, and the remaining patients with FH as high risk [6]. The 2025 focused update retained the 2019 targets and reinforced the extreme-risk category [7, 44]:

The 2025 update also considers Lp(a) above 50 mg/dL a risk-enhancing factor, and recommends bempedoic acid in patients intolerant of statins or outside target, and evinacumab in HoFH (class IIa recommendation) [44]. In the US guidelines summarised in GeneReviews, the objective is an LDL-C reduction of at least 50% or to below 100 mg/dL (2.6 mmol/L), and to below 70 mg/dL in the presence of coronary disease or stroke; referral to a lipid specialist is recommended if the objective is not achieved after six months of maximal therapy, and low-dose aspirin (75–81 mg/day) should be considered in patients with coronary disease, previous stroke or high risk [1]. The 2013 EAS consensus proposed targets of <3.5 mmol/L in children, <2.5 mmol/L in adults and <1.8 mmol/L in adults with coronary disease or diabetes [8]; these targets have progressively been lowered.

Targets in HoFH according to the French PNDS. The 2026 PNDS proposes indicative targets, because there are no trials with clinical outcomes in this population, to be modulated according to the severity of hypercholesterolaemia, the delay in starting treatment, the atheromatous burden and associated risk factors; these targets do not apply to HeFH or to polygenic hypercholesterolaemia [11]:

The French targets are less stringent in primary prevention (approximately 2.6 versus 1.8 mmol/L in adults and 3.4 versus 3.0 mmol/L in children) and more stringent in children with atheroma (1.4 versus 1.8 mmol/L). The PNDS also accepts less ambitious targets when lipid control is early and effective in a patient without complications [11].

7.2 Lifestyle and diet

The diet should be low in saturated and trans fats and rich in soluble fibre (10–20 g/day in adults) [1]. In children, the 2026 EAS consensus recommends limiting dietary cholesterol to 200–300 mg/day, saturated and trans fats to less than 7% of energy intake and simple sugars to less than 10%, favouring polyunsaturated (5%–10%) and monounsaturated (10%–15%) fatty acids, oily fish twice weekly and 25–40 g/day of fibre; a low-fat diet is safe from 7 months of age (STRIP study) and should target the whole family [9]. Phytosterols and stanols reduce LDL-C, but there are no outcome studies, so no firm recommendation exists [9]. Energy malnutrition, essential fatty acid and vitamin E deficiencies and the development of eating disorders should be avoided [9]. Smoking and electronic cigarettes should be strongly discouraged from the first consultation [9].

Diet in HoFH (French PNDS). Nutritional measures reduce LDL-C by approximately 10% and complement treatment. The PNDS recommends a Mediterranean-type diet, varied and non-restrictive, adapted to the patient's habits to avoid rigidity and eating disorders, and proposes practical reference amounts: red meat 2–3 portions per week; processed meats up to 50 g per week; cheese up to 30–40 g/day; butter up to 10 g/day; olive oil (with rapeseed, walnut or linseed oil for dressing) 1–2 tablespoons per meal; fish twice a week, one of them oily; a daily handful of unsalted, unroasted nuts; avocado 1–2 times per week; approximately 7 eggs per week; 5 daily portions of fruit and vegetables; pulses at least twice a week; wholegrain cereals and 30 g/day of oats; salt up to 5–6 g/day; and alcohol up to 10 standard drinks per week, not exceeding 2 per day [11]. The nutritional assessment looks for unjustified exclusions (eggs, red meat, cheese, butter) and for iron, calcium and omega-3 deficiencies [11]. In children, particularly before age 3, when lipid requirements are high, the diet should be supervised by a dietitian; the aim is to improve the quality of fats rather than reduce their quantity, and dairy products should be maintained during growth [11]. On lomitapide, fat should remain below 20% of energy intake or 30 g/day, with specialised dietetic supervision [11]. Physical activity is advised after a full cardiological assessment, which allows exertion to be adjusted to existing lesions (aortic stenosis, coronary disease, heart failure) [11].

7.3 Statins

Statins (HMG-CoA reductase inhibitors) are first-line treatment and the most effective strategy for reducing cardiovascular risk in FH [16]. They reduce hepatic cholesterol synthesis and increase LDLR expression, with a mean LDL-C reduction of approximately 50% at high-intensity doses [1]. The history of the class begins with mevastatin (compactin), isolated from Penicillium, and lovastatin (mevinolin), isolated from Aspergillus [17]. Their impact in FH is well documented: in the British Simon Broome registry, the relative risk of coronary mortality between ages 20 and 59 fell from 8-fold before 1992 to 3.7-fold after statins were introduced [26]; in Japan, the age at coronary disease onset was 58.8 ± 12.5 years in statin-treated patients versus 47.6 ± 10.5 years in untreated patients [17]. In children, 20-year follow-up of 214 patients treated with pravastatin showed a cumulative incidence of cardiovascular events by age 39 of 1% versus 26% in affected parents, and cardiovascular death of 0% versus 7%, with cIMT progression similar to that in unaffected siblings [45].

Adverse effects and monitoring. The most relevant adverse effects are myopathy and, rarely, rhabdomyolysis and immune-mediated necrotising myopathy, hepatic dysfunction and increased haemoglobin A1c and fasting glucose [17, 46]. A meta-analysis of large adult trials concluded that most reported muscle symptoms are not caused by the statin [9]. In children, creatine kinase and transaminase elevations are rare and no changes in insulin sensitivity were observed after seven months of treatment [9]. Creatine kinase, transaminases and creatinine should be measured before initiation and periodically [32]; in children, repeating the lipid profile, creatine kinase and transaminases 8–12 weeks after each adjustment and then annually is recommended [9]. A meta-analysis of eight randomised trials in 897 patients under 18 showed LDL-C reductions of 23%–40% without differences in transaminases or creatine kinase [17]. In intolerance, the dose should be reduced or another statin tried before abandoning the class [9]. In adults with severe renal impairment (CrCl <30 mL/min/1.73 m²) not on dialysis, rosuvastatin should be started at 5 mg once daily, with a maximum dose of 10 mg once daily [46]. Homozygotes with two null alleles respond poorly to statins, whereas those retaining some residual receptor function respond [1, 17].

Statins in HoFH (French PNDS). Transaminases and creatine kinase are assessed before initiation [11]. The PNDS recommends starting a high-potency statin at high dose at diagnosis, orally — rosuvastatin 10–20 mg/day or atorvastatin 40–80 mg/day; in young children, moderate doses, starting from 5–10 mg of rosuvastatin — adding ezetimibe 10 mg/day after one month of good tolerance and then increasing the statin according to age, weight and tolerance, up to 80 mg of atorvastatin or 20–40 mg of rosuvastatin (maximum 20 mg in children and in Asian patients); simvastatin, fluvastatin and pravastatin are reserved for second line, as they are less effective [11]. The LDL-C reduction in HoFH is 15%–25% in a paediatric rosuvastatin series, 30%–35% when there is residual receptor activity and below 10% without it; even so, the introduction of statins doubled life expectancy, with the age at cardiovascular death rising from 17 to 32 years in a South African cohort [11]. Under the French marketing authorisation, rosuvastatin is indicated from age 6, with a maximum of 20 mg up to age 17 (40 mg only on specialist indication; 40 mg tablets are not marketed in France), and atorvastatin from age 10; in particular situations, after validation at a multidisciplinary team meeting (RCP) of the CEDRA network, statins and ezetimibe may be prescribed off-label from diagnosis, at any age [11].

7.4 Ezetimibe

Ezetimibe (Ezetrol®/Zetia®) inhibits the NPC1L1 protein (Niemann-Pick C1-like 1) and reduces intestinal cholesterol absorption; it was the first non-statin drug to demonstrate improvement in clinical outcomes when combined with a statin [16]. It reduces LDL-C by approximately 15% as add-on therapy, or 20% in some series; the statin–ezetimibe combination reduces LDL-C by 60%–70% [1, 8, 17]. The dose is 10 mg orally once daily, with or without food [50]. It is approved by the FDA, in combination with a statin, from age 10 in HeFH and HoFH, and by the EMA from age 6; as monotherapy, it reduced LDL-C by 27% in children aged 6 to 10 [9, 50]. The most common adverse effects are upper respiratory tract infection, diarrhoea, arthralgia, sinusitis, pain in the extremities and fatigue [50]. It is also the treatment of choice for sitosterolaemia [2].

In HoFH, ezetimibe retains efficacy, with an LDL-C reduction of approximately 15%–20%; the French marketing authorisation covers children from age 6, and the PNDS advises caution in pregnancy and monitoring of transaminases when combined with a statin [11].

7.5 Bile acid sequestrants

Bile acid sequestrants (colestyramine, colestipol, colesevelam) interrupt the enterohepatic circulation of bile acids, increase hepatic cholesterol conversion and LDLR expression, and reduce LDL-C by 15%–20%; a 10-year prospective study showed a 20% reduction in infarctions [1, 17]. In a paediatric series, 8 g of colestyramine reduced LDL-C by 16.9%, with frequent adverse effects and one case of intestinal obstruction [17]. Colesevelam (Cholestagel®/Welchol®) is better tolerated; the recommended dose in adults and in boys and postmenarchal girls aged 10 to 17 is 3.75 g/day, with the oral suspension preferred in children [16, 51]. Adverse effects include hypertriglyceridaemia and pancreatitis, gastrointestinal obstruction, vitamin K and fat-soluble vitamin deficiencies, and reduced absorption of other drugs, which should be taken more than 4 hours beforehand [16, 51]. With newer therapies available, the 2026 paediatric consensus reserves these agents for situations where the newer therapies are unavailable or not tolerated [9].

7.6 Bempedoic acid

Bempedoic acid inhibits adenosine triphosphate-citrate lyase (ACL), upstream of HMG-CoA reductase, and reduces LDL-C by approximately 20% as monotherapy and 48% in combination with ezetimibe [16]. In the CLEAR Outcomes trial, involving 13,970 statin-intolerant patients, it reduced major cardiovascular events (11.7% versus 13.3%; hazard ratio 0.87) [52]. The dose is 180 mg orally once daily, with lipid reassessment at 8–12 weeks; a fixed combination with ezetimibe is available (180 mg/10 mg; Nustendi®/Nexlizet®) [53, 54]. In the European Union, Nilemdo® has been approved since April 2020 in adults with primary hypercholesterolaemia, including HeFH; when simvastatin is coadministered, it should be limited to 20 mg/day (40 mg in selected cases) [54]. Adverse effects include hyperuricaemia and gout, tendon rupture, muscle spasms, anaemia, liver enzyme elevation, renal dysfunction and cholelithiasis [53]. There are no data in children; a phase 2 trial in children aged 6 to 17 with HeFH has been completed (NCT05694260) [9].

7.7 PCSK9 inhibitors

By preventing lysosomal LDLR degradation, PCSK9 inhibitors increase the hepatic receptor pool and act synergistically with statins [16]. Meta-analyses involving more than 10,000 patients showed a mean LDL-C reduction of 50%, a 6% HDL-C increase and a 26% Lp(a) reduction, with a 17% reduction in cardiovascular events [16]. In 2026, the VESALIUS-CV trial extended the benefit of evolocumab to prevention of first events in patients with atherosclerosis or diabetes without previous infarction or stroke (hazard ratio 0.75 for the three-component composite) [55]; the current European Repatha® SmPC (latest European Commission decision on 21/08/2026) indicates cardiovascular risk reduction in adults with established atherosclerotic disease or at high risk, and the US label refers to reduction of major cardiovascular events in adults at increased risk [15, 56, 57]. In HoFH, response depends on residual LDLR activity: in TESLA Part B, monthly evolocumab 420 mg reduced LDL-C by 30.9% versus placebo [58], but patients with two null LDLR alleles have virtually no response [1]. Individual prediction by genotype is, however, imperfect: in the LIBerate-HoFH crossover trial (66 patients with genetically confirmed HoFH, 30% of paediatric age, mean baseline LDL-C 10.6 mmol/L), LDL-C reduction at week 24 was only 4.9% with lerodalcibep and 10.3% with evolocumab, with substantial interpatient variability; non-inferiority of lerodalcibep was not demonstrated, and neither genotype nor suppression of free PCSK9 predicted response [59]. In HeFH, a pooled non-randomised analysis of 703 patients treated with lerodalcibep for 72 weeks showed a mean LDL-C reduction of approximately 50%, independent of residual activity of the LDLR variant [60]. Treatment should be continued if additional LDL-C reduction exceeds 15% after one to two administrations [2, 9].

Evolocumab (Repatha®) — a human monoclonal antibody, 140 mg/mL solution in a pen, autoinjector or pre-filled syringe, administered subcutaneously into the abdomen, thigh or upper arm [56]. In HeFH in adults and children aged 10 or older: 140 mg every 2 weeks or 420 mg once monthly. In HoFH in adults and children aged 10 or older: start with 420 mg monthly, which may be increased to 420 mg every 2 weeks if there is no clinically relevant response at 12 weeks; patients undergoing apheresis may start with 420 mg every 2 weeks, administered after the session [56, 57]. In the European Union, the indication covers HeFH in adults and children aged 10 or older and HoFH in adults and children aged 10 or older [57]. In HAUSER-RCT (157 patients aged 10 to 17), monthly evolocumab 420 mg reduced LDL-C by 44.5% versus 6.2% with placebo [61]. Adverse effects: nasopharyngitis, upper respiratory tract infection, influenza, back pain and injection-site reactions; contraindicated in previous serious hypersensitivity, including angioedema [56].

Alirocumab (Praluent®) — a human monoclonal antibody, in 75 mg/mL and 150 mg/mL pre-filled pens [62]. In adults with HeFH: start with 75 mg every 2 weeks or 300 mg every 4 weeks, with adjustment to 150 mg every 2 weeks (maximum dose) possible; in adults with HeFH undergoing apheresis and adults with HoFH (FDA indication): 150 mg every 2 weeks, without the need to coordinate with apheresis [62, 63]. In children with HeFH from age 8: weight below 50 kg, 150 mg every 4 weeks (or 75 mg every 2 weeks if response is insufficient); weight 50 kg or above, 300 mg every 4 weeks (or 150 mg every 2 weeks) [62, 63]. In the paediatric phase 3 trial (153 patients aged 8 to 17), LDL-C reduction versus placebo was 43.3% with the fortnightly regimen and 33.8% with the monthly regimen [64]. In the European Union, the HoFH indication does not appear in the summary of product characteristics [63]. Adverse effects: injection-site reactions, influenza and myalgia; contraindicated after serious hypersensitivity [62].

Inclisiran (Leqvio®) — a small interfering RNA (siRNA) whose antisense strand binds the RNA-induced silencing complex and degrades PCSK9 mRNA in the hepatocyte [16]. The dose is 284 mg of inclisiran (equivalent to 300 mg of inclisiran sodium) as a subcutaneous injection, repeated at 3 months and then every 6 months, administered by a healthcare professional [65, 66]. If a dose is missed by less than 3 months, it is administered and the schedule maintained; if the delay exceeds 3 months, the regimen is restarted [65]. The FDA approves it in adults with hypercholesterolaemia, in adults and children aged 12 or older with HeFH, and in children aged 12 or older with HoFH [65]; in the European Union, it is approved in adults and children aged 12 or older with HeFH [66]. In ORION-9 (482 adults with HeFH), it reduced LDL-C by 47.9 percentage points versus placebo at day 510 [67]; in ORION-16 (141 adolescents with HeFH), the difference was −28.5% at day 330, maintained at 2 years [68]; in ORION-13 (13 adolescents with HoFH, excluding LDLR null/null genotypes), the placebo-adjusted reduction was 33.3% [69]. Adverse effects: injection-site reactions, arthralgia and bronchitis; contraindicated after serious hypersensitivity [65].

Position of the French PNDS in HoFH. The anti-PCSK9 antibody is the third line, after the statin and ezetimibe; in carriers of two null LDLR alleles the reduction is below 15% and treatment is not indicated, and the next step should be taken directly, whereas with residual activity the reduction is around 30% [11]. In France, only evolocumab is reimbursed in HoFH, from age 10, at a dose of 420 mg monthly (three 140 mg pens subcutaneously); in the most severe forms already on apheresis, it may be doubled to three injections every 2 weeks, a regimen rarely used [11]. Response is reassessed at 8–12 weeks and treatment is stopped if the additional reduction is below 15%; after validation at the CEDRA multidisciplinary team meeting (RCP), evolocumab and alirocumab may be used off-label at any age [11]. The 15% criterion matches that of the EAS, but the PNDS sets reassessment at 8–12 weeks, whereas the evolocumab labels provide for dose escalation if there is no response at 12 weeks; the PNDS does not mention inclisiran in HoFH [2, 11, 56, 57].

7.8 LDL receptor-independent therapies (HoFH)

Evinacumab (Evkeeza®) — a monoclonal antibody against angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase and endothelial lipase; it reduces LDL-C independently of receptor presence by promoting VLDL processing and clearance upstream of LDL formation [2, 16]. In ELIPSE HoFH (65 patients), it reduced LDL-C by 47.1% versus a 1.9% increase with placebo, with similar efficacy in null/null (−43.4%) and non-null (−49.1%) genotypes [70]. In children aged 5 to 11, the reduction was 45% at 48 weeks, and in adolescents 48% [71]. The dose is 15 mg/kg by intravenous infusion over 60 minutes every 4 weeks (no maximum dose defined in the source), through a 0.2–5 μm filter, without the need for adjustment in renal or hepatic impairment or in children, or coordination with apheresis [72, 73]. It is approved by the FDA from 1 year of age and by the EMA from 6 months, always as an adjunct to other therapies [72, 73]. Adverse effects: nasopharyngitis, influenza-like illness, dizziness, rhinorrhoea, nausea and fatigue; risk of serious hypersensitivity reactions, including anaphylaxis, and embryofoetal toxicity (contraception is recommended during treatment and for 5 months after the last dose) [72].

The French PNDS uses the same dose of 15 mg/kg monthly in children and adults, in a day-hospital setting, but proposes giving the first infusion over 2 hours and subsequent ones over 1 hour, with 30 minutes of observation after each infusion, and, in patients on apheresis, administration at the end of the session; the labels specify a 60-minute infusion without the need for coordination with apheresis [11, 72, 73]. In France, evinacumab is available through early access from 6 months of age, and its introduction should be discussed at the national multidisciplinary team meeting (RCP) of the CEDRA network [11]. According to the PNDS, the additional LDL-C reduction reaches 55% even without functional LDLR, the most frequent adverse effects in the trials were nasopharyngitis (16% versus 24% with placebo) and influenza-like illness (11% versus 0%), and pregnancy is a contraindication [11].

Lomitapide (Lojuxta®/Juxtapid®) — an oral inhibitor of microsomal triglyceride transfer protein (MTP), which reduces the hepatic assembly and secretion of apoB-containing lipoproteins [16]. In the phase 3 trial in 29 adults, it reduced LDL-C by 50% at 26 weeks (median dose 40 mg/day) [74]; in the paediatric APH-19 trial (43 patients aged 5 to 17), the reduction was 53.5% at 24 weeks [75]. The LOWER registry (at least 300 patients followed for 10 years) confirmed the benefit–risk profile at 3 years [16]. Before initiation, transaminases, alkaline phosphatase and total bilirubin are measured, a negative pregnancy test obtained and a diet with less than 20% of energy from fat instituted [76]. The dose is taken once daily, fasting, at least 2 hours after the evening meal, with progressive titration [76, 77]:

Daily supplements of vitamin E (400 IU from age 9; 200 IU from age 2 to 8) and essential fatty acids (linoleic acid 200 mg, alpha-linolenic acid 210 mg, eicosapentaenoic acid 110 mg and docosahexaenoic acid 80 mg) are mandatory [76]. Lomitapide carries a boxed warning for hepatotoxicity: 34% of adults and 14% of children had transaminases ≥3 times the upper limit of normal, and hepatic fat increases (absolute median of 6% in adults); in the United States it is available only through a restricted risk management programme (REMS) [76]. It is contraindicated in pregnancy, moderate or severe hepatic impairment and with moderate or strong CYP3A4 inhibitors [76]. The most frequent adverse effects are diarrhoea, nausea, dyspepsia, vomiting and abdominal pain [76]. The FDA approves it from age 2 and the EMA from age 5 in HoFH, and genetic confirmation should be obtained whenever possible [76, 77].

Before starting lomitapide, the French PNDS requires a hepatic assessment with laboratory tests (including the FIB-4 index), ultrasound or magnetic resonance imaging to quantify steatosis and liver elastography for fibrosis, and advises against starting it if there is moderate steatosis or liver disease [11]. It proposes starting at 5 mg/day with increases of 5–10 mg per month, up to 60 mg/day in adults and 20 mg/day in children, with daily supplementation of vitamin E (500 mg, one tablet) and long-chain omega-3 fatty acids (1000 mg three times daily); monitoring includes monthly transaminases in the first 6 months and after each adjustment, annual elastography and liver imaging, control of alcohol consumption and attention to CYP3A4-mediated interactions (atorvastatin, anticoagulants) [11]. From age 5, and exceptionally after validation at the CEDRA multidisciplinary team meeting (RCP), it accepts doses of 2 to 20 mg/day with slow titration, which it treats as off-label use [11]. These recommendations differ from the labels: in the SmPC and the FDA label, escalation follows fixed steps (in adults, 10 mg at 2 weeks and then minimum intervals of 4 weeks), the maximum from 11 to 17 years is 40 mg and the recommended vitamin E is 400 IU; moreover, the current European SmPC authorises lomitapide from age 5, whereas the PNDS table indicates authorisation only from age 18 [11, 76, 77].

7.9 Lipoprotein apheresis

Lipoprotein apheresis (or, if unavailable, plasmapheresis) is a cornerstone of HoFH treatment, particularly where newer therapies are unavailable [2]. It is performed weekly or fortnightly; it acutely reduces LDL-C by approximately 55%–80%, with a chronic reduction of approximately 30%, and reduces Lp(a) by more than 50% [1, 2]. It should ideally start by age 3 and never after age 8, depending on venous access [2]. Apheresis initiated in childhood is associated with a reduction in long-term ASCVD and mortality risk [78]. It leads to regression of xanthomas and flow-limiting coronary lesions [17]. Drawbacks include cost, limited access, impact on quality of life and, over time, reductions in ferritin, transferrin and vitamin B12, with mild anaemia in some patients [2, 17]. In HeFH, apheresis is reserved for patients with coronary disease and very high LDL-C despite treatment or statin intolerance [8].

Apheresis according to the French PNDS. With drugs that act without LDLR, the PNDS now treats apheresis as a resource for when drug treatment is insufficient, although it often remains indispensable, sometimes immediately, in LDLR null/null genotypes with very high LDL-C; the indication is decided case by case by a multidisciplinary team [11]. Each 2–3-hour session reduces LDL-C by 60%–75% depending on the technique, but the value returns to baseline within 3–4 days, with a mean reduction of approximately 30%, which requires sessions every 7 to 10 days, or twice weekly in the most severe cases [11]. Techniques are divided into plasma-based — non-selective plasma exchange with 4%–5% albumin, which depletes coagulation factors; double-filtration cascade, semi-selective; dextran sulphate adsorption with regenerable columns (Liposorber LA15), the longest and most complex; and anti-apoB immunoadsorption (TheraSorb), highly selective, with a small extracorporeal volume, widely used in paediatrics and the most expensive — and whole-blood techniques — DALI (polyacrylate) and Liposorber D (dextran sulphate) — with extracorporeal volumes between approximately 130 and 705 mL; all require anticoagulation of the circuit, and whole-blood adsorption techniques activate bradykinin and are incompatible with angiotensin-converting enzyme (ACE) inhibitors [11]. Peripheral venous access is preferred; an arteriovenous fistula (high flow and low infection risk, but surgery and slow maturation in young children) and a central venous catheter (painless and usable in young children, but with a risk of infection, thrombosis and displacement) are alternatives; with a fistula, heavy loads, sleeping on the arm and violent sports should be avoided [11]. Adverse effects occur in fewer than 4% in the Société française d'hémaphérèse registry: hypotension, chest pain, paraesthesiae due to hypocalcaemia or hypomagnesaemia, bleeding, multifactorial anaemia (iron deficiency, mechanical haemolysis, losses) and, at the end of the session, fatigue and swelling of the face and extremities, which are reversible; replacing ACE inhibitors with angiotensin receptor blockers before starting, or using double filtration, is recommended [11]. In children, long-term vascular access is preferred; selective techniques (LA15, double filtration) achieve acute reductions above 70%, with treated plasma volumes of 40–60 mL/kg (plasma-based techniques) or 1.3–1.5 times the blood volume (whole blood); plasma-based techniques have been used successfully from age 2, the LA15 system has an extracorporeal volume equivalent to approximately 130 mL of blood and does not require blood priming above 13 kg, and starting with flow rates of 15–30 mL/min and priming with heparinised saline or, if there is hypotension, 4%–5% albumin is recommended [11]. Because LDL-C recovers mostly in the first 48 hours, session frequency matters more than prolonging each session to gain 3%–5% of removal [11]. This position differs from that of the 2023 EAS consensus, which recommends starting apheresis ideally by age 3 and at the latest by age 8 [2].

7.10 Liver transplantation and investigational therapies

Liver transplantation corrects the defect by providing a liver with normal receptors; the first was performed in 1984 in a 6-year-old child with HoFH [79]. It is a last-resort option in selected patients, particularly children with two null alleles, progressive coronary disease and LDL-C above 1.8 mmol/L, or LDL-C above 13 mmol/L despite maximal treatment; combined heart–liver transplantation may be indicated in rapidly progressive disease [2]. LDL-C normalisation occurs within weeks and persists for up to 28 years, but the effect on aortic stenosis is uncertain [2]. Investigational therapies include gene therapy using adeno-associated virus (AAV8) vectors carrying human LDLR, CRISPR gene editing of PCSK9 and ANGPTL3, siRNAs targeting ANGPTL3, the oral PCSK9 inhibitor enlicitide and lerodalcibep, the latter two in paediatric trials [2, 9, 16]. Mipomersen, an antisense oligonucleotide targeting apoB approved by the FDA in 2013 for HoFH, is no longer marketed [16].

The French PNDS considers liver transplantation a last-resort option, now rare and exceptional in France, to be discussed at a national multidisciplinary team meeting (RCP) in null/null forms with coronary and valvular progression without access to apheresis or LDLR-independent therapies; lipid efficacy has been demonstrated, but not benefit on coronary or valvular disease — aortic stenosis may progress after paediatric transplantation, although regression of coronary lesions has been described — and lifelong immunosuppression poses an adherence problem; it may be combined with cardiac surgery or, in advanced ischaemic cardiomyopathy with end-stage heart failure, with heart transplantation [11]. Among research priorities, the PNDS lists the relationship between cumulative cholesterol burden and complications, the effect of Lp(a), the risk of digenic versus monogenic forms, genetic modifier factors (SAFIR project), neonatal cholesterol screening, continuation of lipid-lowering drugs in pregnancy, sex differences, quality of life and gene editing [11].

Developments in the last 12 months (explicit hierarchy of evidence). (a) Authorisations in the United States. Lerodalcibep (Lerochol®), an anti-PCSK9 fusion protein (adnectin linked to albumin) administered subcutaneously at 300 mg once monthly, was approved by the FDA on 12/12/2025 for adults with hypercholesterolaemia, including HeFH; in LIBerate-HeFH (478 adults), the difference versus placebo was −58.6% at week 24 [80, 81]. Enlicitide (Lipfendra®), an oral macrocyclic peptide PCSK9 inhibitor, was approved on 15/07/2026 for adults with hypercholesterolaemia, including HeFH, at 20 mg once daily, fasting, in the morning, with water, plain coffee or tea, waiting at least 30 minutes before eating; in CORALreef HeFH (303 adults on statins), the difference versus placebo was −59.4% at week 24 (95% CI −65.6% to −53.2%) and −61.5% at week 52 [82, 83]. Neither has yet demonstrated a reduction in cardiovascular events: CORALreef Outcomes (NCT06008756; 14,550 participants) is ongoing, as are the paediatric trials of enlicitide (NCT07058077) and lerodalcibep in children aged 6 to 17 (NCT07102511) [82, 84]. (b) Opinions in the European Union. On 23/07/2026, the CHMP issued a favourable opinion for lerodalcibep (Lyrokaul®) and obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, as monotherapy (Ubeslo®) and in fixed combination with ezetimibe (Evlarco®); a favourable opinion is not an authorisation, and the EMA data file consulted on 06/10/2026 did not yet record the European Commission decision [15]. In BROOKLYN (354 patients with HeFH and LDL-C ≥70 mg/dL on maximally tolerated therapy), obicetrapib 10 mg/day reduced LDL-C by 36.3% versus placebo at day 84 and Lp(a) by 45.9% [85]; no FDA authorisation was identified in Drugs@FDA, and the PREVAIL outcomes trial (NCT05202509) remains ongoing [14, 84]. (c) Early- or intermediate-phase human studies, without authorisation. In GATEWAY, an open-label phase 2 trial in 18 patients with HoFH, the anti-ANGPTL3 siRNA zodasiran (200 or 300 mg subcutaneously every three months) reduced LDL-C by 35.7% and 39.9% at month 6, and a phase 3 trial in adolescents and adults with HoFH (YOSEMITE, NCT07037771) is active [84, 86]. PCSK9-targeted base editing with VERVE-102 (single intravenous dose, 35 adults with HeFH or premature coronary disease) reduced LDL-C by up to 62% at the highest dose, with an effect maintained for at least 1 year in 15 participants [87], and ANGPTL3 editing by CRISPR-Cas9 with CTX310 (15 participants) reduced ANGPTL3 by up to approximately 80%, with one sudden death at 179 days at the lowest dose [88]; these are phase 1 studies, without long-term safety or outcome data.

7.11 Therapeutic algorithms

Adult HeFH. High-intensity statin from the outset; if LDL-C does not reach target, add ezetimibe; if it remains outside target, add a PCSK9 inhibitor (antibody or inclisiran) and/or bempedoic acid; in statin intolerance, ezetimibe, bempedoic acid and PCSK9 inhibitors alone or in combination [1, 6, 44].

Childhood HeFH. Lifestyle measures from diagnosis; pharmacological treatment should ideally start from age 6 and never after age 10, equally in girls and boys (women accumulate an average of 2.3 years without treatment because of pregnancy and breastfeeding); a high-potency statin (rosuvastatin or atorvastatin) as first line; add ezetimibe if LDL-C is close to target (below 4.0 mmol/L) or a PCSK9 inhibitor if far from target (4.0 mmol/L or above on two measurements); avoid three drugs whenever possible [9]. From age 16, adolescents with major risk factors should approach adult targets [9].

HoFH. Initiate a high-intensity statin with ezetimibe at diagnosis; add a PCSK9 inhibitor within the following 8 weeks if there are not two null alleles, and continue it if the additional reduction exceeds 15%; consider apheresis if LDL-C is above 8 mmol/L (300 mg/dL) and receptor-independent therapies (evinacumab, lomitapide) if LDL-C remains above 3 mmol/L; liver transplantation if these options are unavailable [2]. The phenotype (LDL-C), rather than the genotype, guides decisions [2]. In the HICC, more than half of the few patients receiving five therapies achieved their LDL-C target [2].

ARH. Patients respond to diet and statins; combinations with ezetimibe and lomitapide have been described, and combining a statin (with or without ezetimibe) with lomitapide produced the greatest reductions; most described patients undergo apheresis, alone or with drugs [16].

7.12 Pregnancy and contraception

In pregnancy, total cholesterol and LDL-C increase by 25%–50%, with a much greater absolute rise in FH, particularly HoFH [2, 40]. Traditionally, all lipid-lowering agents were considered contraindicated in pregnancy [17], and GeneReviews recommends stopping statins before conception and not using them during breastfeeding [1]. Following review of the evidence, the FDA changed statin labelling in pregnancy: the current rosuvastatin label recommends discontinuing the drug when pregnancy is recognised or, alternatively, considering each patient's therapeutic needs [2, 46]. Bile acid sequestrants are not associated with malformations, but colestyramine may deplete fat-soluble vitamins, including vitamin K [1]. The safety of PCSK9 inhibitors, ezetimibe, lomitapide and bempedoic acid in pregnancy is not established; lomitapide is contraindicated and evinacumab carries a risk of foetal toxicity [1, 72, 76]. In women with HoFH, preconception cardiovascular assessment is recommended (valvular and aortic root gradients, ideally coronary CT angiography), together with weekly or fortnightly apheresis during gestation and, if this is unavailable, continuation or reintroduction of a statin with other lipid-lowering agents from the second trimester; reintroduction should be delayed during breastfeeding [2]. Women with HeFH with good previous control should not be discouraged from becoming pregnant [40].

Contraception and pregnancy in HoFH (French PNDS). Contraception is adapted to cardiovascular risk: a new-generation progestogen-only method may be considered in women without cardiovascular disease, combined oestrogen–progestogen contraception is contraindicated when there is established cardiovascular disease and a non-hormonal method should be favoured, in particular the copper intrauterine device; the patient should report any plan for pregnancy so that drug withdrawal can be planned [11]. Before any pregnancy, a systematic cardiovascular assessment (echocardiogram and coronary imaging) is performed, and tight aortic stenosis may contraindicate pregnancy because of the risk to life; a genetics clinic appointment is offered to the couple and a lipid profile to the partner, and, if both have FH, preimplantation genetic diagnosis should be discussed [11]. During pregnancy, particularly in the first trimester, lipid-lowering drugs should be stopped, except statins, whose continuation is weighed case by case at a multidisciplinary team meeting (RCP), and apheresis should be started, maintained or resumed [11]. The PNDS itself is internally inconsistent, since its drug table classifies pregnancy as an absolute contraindication to rosuvastatin and a relative one to atorvastatin; the 2023 EAS consensus favours apheresis during pregnancy and only reintroduces the statin from the second trimester if apheresis is not available, and the FDA label allows continuation to be considered [2, 11, 46].

7.13 Surveillance

Treatment of cardiovascular complications in HoFH. Severe coronary disease is treated by angioplasty with stent implantation or by coronary artery bypass grafting, and severe aortic valve stenosis by valve replacement, even in young adults and, in children, particularly in adolescence, by paediatric cardiology and cardiac surgery teams working with adult teams during transition; after coronary intervention, antiplatelet agents (aspirin, clopidogrel) and beta-blockers are introduced according to adult protocols [11].

7.14 Models of care

Patients with FH should be followed in a lipid clinic [26], and patients with HoFH in specialist multidisciplinary centres integrating paediatrics, cardiology, lipidology and genetics [2]. HICC experience shows that unequal access to therapies determines prognosis: treated LDL-C was 3.93 mmol/L in high-income countries versus 9.3 mmol/L in the others, and the first cardiovascular event occurred a decade earlier in non-high-income countries [33]. There is no European Reference Network (ERN) dedicated to genetic dyslipidaemias; MetabERN, the network for inherited metabolic diseases, includes a subnetwork for peroxisomal and lipid-related disorders, but FH is not explicitly listed in its published scope, so patients with HoFH are usually managed by national lipid centres [12]. The FH Europe Foundation brings together European patient associations for FH, HoFH, elevated Lp(a) and familial chylomicronaemia syndrome, and is a resource for information and advocacy for access to diagnosis and treatment [13].

Organisation in France. HoFH is followed within the CEDRA network (Centre d'expertise des dyslipidémies rares) of the FIRENDO health network (rare endocrine diseases), with a coordinating reference centre in Marseille (AP-HM, Hôpital de la Conception) and competence centres in Dijon, Lille, Lyon, Nantes, Paris (Pitié-Salpêtrière and Trousseau, the latter exclusively paediatric), La Réunion and Toulouse, together with Strasbourg, which provides apheresis; eight hospital laboratories (Bordeaux, Boulogne-Billancourt, Lille, Lyon, Marseille, Nantes, Nîmes and Paris Pitié-Salpêtrière) provide molecular diagnosis [11]. The network holds a monthly national multidisciplinary team meeting (RCP), recommended before introducing evinacumab or lomitapide, in the event of partial treatment resistance and before transplantation [11]. The reference centre must provide adult and paediatric lipidology, specialised and interventional radiology, cardiology, apheresis and cardiovascular surgery; follow-up is then shared with the attending physician, and the team includes paediatricians, lipidologists, cardiologists and paediatric cardiologists, imaging specialists, biologists, geneticists and genetic counsellors, nurses, dietitians, psychologists and social workers [11]. HoFH is covered at 100% as a long-term condition (ALD 17, inherited metabolic diseases requiring prolonged specialised treatment); in 2025 there was no dedicated therapeutic education programme, one being in preparation [11]. At the first visit, the patient and the attending physician are given follow-up sheets that check follow-up at a specialised centre, genetic testing and communication of the result, family screening, the annual visit, the initial and annual cardiological assessment, information on new treatments and on pregnancy, and genetic counselling [11]. The patient association ANHET.f (Association nationale des hypercholestérolémies familiales et lipoprotéine(a)) and Alliance maladies rares are the patient resources indicated [11].

7.15 Pivotal trials and limitations of comparisons between drugs

Limitations of comparisons. The values in the table do not allow the drugs to be ranked: populations differ in genotype (proportion of null alleles), baseline LDL-C, background therapy and age; endpoints are measured at different times (day 84, week 24, day 510), using least-squares means or percentage-point differences and different rules for missing data. A 50% relative reduction has very different absolute consequences with baseline LDL-C of 3 mmol/L or 10 mmol/L, and in HoFH the group mean conceals individual responses ranging from no effect to reductions above 50% [59]. FH trials use LDL-C as a surrogate endpoint; outcome data come from trials in populations not selected for FH or from observational cohorts, such as the 20-year follow-up of paediatric pravastatin [45, 52]. Open-label single-arm trials (lomitapide) have no control group, and LIBerate-HoFH, which did not demonstrate non-inferiority, should be read alongside the positive trials.

7.16 Comparative regulatory status: United States and European Union

Regulatory information distinguishes four levels of evidence: peer-reviewed publication (for example, CORALreef HeFH, BROOKLYN), sponsor announcement or preliminary results, CHMP opinion (a scientific recommendation, which is not an authorisation), and an FDA or European Commission authorisation decision. Authorisation does not guarantee marketing, reimbursement or access in each country; access in Portugal (INFARMED) and Brazil (ANVISA/CONITEC) was not verified for recent medicines.

Evidence extrapolation and off-label use. These are distinct concepts. Extrapolation concerns the evidence: the cardiovascular outcome benefits of PCSK9 inhibitors, bempedoic acid or inclisiran are inferred for FH from trials in populations not selected for FH or from LDL-C reduction, and efficacy in HoFH of drugs studied predominantly in HeFH cannot be presumed. Off-label use depends on the label wording, age and jurisdiction: alirocumab and inclisiran in HoFH are on-label uses in the USA (in adults and from age 12, respectively), but off-label in the EU; evolocumab below age 10, inclisiran below age 12 and lomitapide at ages 2 to 4 in the EU are off-label uses, even though specialist centres may consider them justified in severe HoFH [62, 63, 65, 66, 76, 77]. In pregnancy, the absence of data in the labels of recent drugs does not equate to authorisation: the US enlicitide and lerodalcibep labels recommend stopping treatment when pregnancy is recognised or considering the patient's therapeutic needs [80, 82].

Access and off-label prescribing in France. In HoFH, evolocumab is the only anti-PCSK9 antibody reimbursed (from age 10), evinacumab is available through early access from 6 months of age, and the PNDS accepts, after validation at the CEDRA multidisciplinary team meeting (RCP), off-label statins, ezetimibe and anti-PCSK9 antibodies at any age and lomitapide from age 5 [11]. Off-label paediatric prescribing must be indicated on the prescription and justified in the medical record; non-reimbursed products may be covered by health insurance on an exceptional and temporary basis, after an opinion from the HAS and consultation of the medicines agency (ANSM), if there is no suitable alternative, through an application submitted to the national health insurance fund (CNAM) by the centre's physician [11].

8. Reproductive Options and Family Counselling

8.1 Semidominant forms (LDLR, APOB, PCSK9)

Almost all patients with HeFH have an affected parent; the proportion of de novo variants is unknown but appears very low [1]. Each child of a heterozygote has a 50% probability of inheriting the variant and the disease [1]. If both parents are heterozygotes, each child has a 25% probability of HoFH, 50% of HeFH and 25% of inheriting neither variant; all children of a patient with HoFH have FH, and the parents of a patient with HoFH are obligate heterozygotes [1]. If the proband's variant is not detected in either parent, the recurrence risk for siblings is estimated at approximately 1% (possible germline mosaicism) [1]. 2nd-degree relatives on the affected side have a 50% risk of being carriers [1]. Because FH is frequent and some populations show a founder effect, a patient's reproductive partner should have a lipid profile, followed by counselling and genetic testing if the profile or family history is suggestive, ideally before conception [1]. Preconception counselling is particularly important when both partners have a known pathogenic variant [9].

8.2 Recessive form (LDLRAP1)

The parents of a patient with ARH are presumed heterozygotes, which should be confirmed by molecular testing; in apparent homozygosity with the variant detected in only one parent, a deletion undetected by sequencing or uniparental isodisomy should be considered [1]. Siblings have a 25% risk of being affected, 50% of being carriers (asymptomatic) and 25% of inheriting neither variant; all children of an affected patient are obligate carriers [1]. Carrier testing in relatives requires prior identification of both variants [1].

8.3 Cascade screening

Cascade screening is the most cost-effective approach for identifying new patients; the Centers for Disease Control and Prevention (CDC) classify FH as a level 1 (Tier 1) condition for family screening [1, 8]. It should be systematic, centrally coordinated and combine lipid profiling and genetic testing, beginning with 1st-degree relatives (parents, siblings, children) and extending to the 2nd degree [8]. When the familial variant is known, all 1st-degree relatives should be tested; when it is not, screening is performed using LDL-C [1]. In children with a family history of FH, a lipid profile should be obtained by age 2; LDL-C above 130 mg/dL is suspicious and above 160 mg/dL is relatively specific [1]. As treatment may begin between ages 6 and 10, it is inappropriate to delay children's genetic testing until adolescence [9, 26]. In HoFH, identification of an affected child requires «reverse» screening of parents, siblings and other relatives [2]. In the Netherlands, the national cascade screening programme proved cost-effective, returning more than 8 euros for every euro invested; similar programmes exist in Wales, Spain, Norway and the Czech Republic [9, 16].

The French PNDS indicates cascade screening when there are premature cardiovascular events in the family (before age 55 in men and 60 in women), when a parent has the homozygous form or when both have HeFH, and recommends a lipid profile and genetic testing for the partner of any adult with HeFH or HoFH who wishes to have children, possibly with a genetic counsellor, in order to extend screening to the family [11].

8.4 Universal paediatric screening

The 2026 EAS consensus encourages all countries to establish a population-based paediatric FH screening programme, adapted to the healthcare system, with diagnosis preferably between ages 1 and 10 — the period when cholesterol best discriminates children with and without FH [8, 9]. Slovenia was the first country with universal screening: total cholesterol is measured in all children at age 5–6, followed by genetic testing in children at risk and parental cascade screening; in the child–parent screening pilot programme, the variant was confirmed in a parent in 99.1% of families when both parents were tested [9, 89]. Universal screening was also implemented in Bavaria (VRONI study) [9]. In the United Kingdom, child–parent screening during vaccination at age 1–2, in 10,095 children, identified a causal variant prevalence of 1:273 and enabled affected parents to be identified [90]. The cost-effectiveness of universal screening varies between healthcare systems (favourable in the United Kingdom and Argentina, unfavourable in one US study) [9]. The Prague Declaration (2022) and the European Safe Hearts plan call for integration of paediatric screening into national strategies [9]. Neonatal screening, by lipid measurement in cord blood or dried blood spots or by genotyping, remains investigational, although the HoFH consensus recommends neonatal lipid screening when both parents have HeFH or hypercholesterolaemia and in regions with a marked founder effect [2, 9].

In France there is no systematic screening; the experimental national programme PERIGENOMED, for molecular newborn screening for rare diseases at 48 hours of life, includes the HoFH genes in its panel, and the PNDS advocates systematic measurement of LDL-C in all children, as early as possible [11].

8.5 Prenatal and preimplantation diagnosis

Once the familial variants are known, prenatal diagnosis and preimplantation genetic diagnosis are possible [1]. Historically, prenatal HoFH diagnosis was performed by assaying receptor activity in cultured amniocytes and by foetal blood sampling, and the «Lebanese» variant was detected in chorionic villi [17]. Prenatal diagnosis may be considered for the homozygous form but is generally not indicated for the heterozygous form, which is treatable [26]. The ideal time to discuss genetic risk and these options is before pregnancy [1].

The French PNDS recommends discussing preimplantation genetic diagnosis when both members of the couple have HeFH, and points out that all children of a patient with HoFH inherit a causal variant [11].

8.6 Psychosocial aspects

Genetic testing should be preceded by counselling, with shared decision-making and informed consent from parents or guardians [9]. Disadvantages include possible confusion caused by variants of uncertain significance, insurance issues, stigmatisation and psychological distress, including parental guilt over transmission [9]. Identification and treatment of an affected parent also benefit the child, who is more likely to grow up with both parents free of ASCVD [9].

In HoFH, the French PNDS describes the impact on schooling and work of absences for apheresis and appointments, the isolation and stigmatisation associated with xanthomas, the arteriovenous fistula or central catheter, and the limitation of physical activity by coronary disease; it recommends psychological support from the time the diagnosis is disclosed, an individualised school support plan (diet, permitted level of physical activity, precautions with the vascular access and adaptation of the timetable to absences), the involvement of a social worker for financial support and for parents' employment rights, and, when necessary, recognition of disability by the Maison départementale des personnes handicapées (MDPH), which allows schooling, higher education or the workplace to be adapted [11]. For transition, it proposes a structured plan started early, for example at age 15 [11].

9. Special Considerations: Population Diversity and Epidemiology

HeFH prevalence in the general population is approximately 1:250–1:300; the meta-analysis by Beheshti and colleagues (11 million people) estimated 1:313, and in the Copenhagen General Population Study the prevalence of probable or definite FH by DLCN criteria was approximately 1:200 [3, 8]. Prevalence is unknown in approximately 90% of countries, including most of Africa, Asia and South America [1]. An estimated 500,000 children in Europe have FH, fewer than 10% of whom have been identified [9].

The French PNDS gives prevalences for HoFH between 1:1,000,000 and 1:300,000, and of approximately 1:300,000 for the biallelic semidominant form, higher with a founder effect or consanguinity; the recessive form accounts for less than 1% of severe forms [11]. These estimates, close to those of the EAS (1:250,000–1:360,000), are not derived from French population data [2, 11].

In these populations, HoFH may be at least 10 times more frequent than in the general population, also because of consanguinity [2, 16]. FDB has an estimated prevalence of 1:1000 in Europeans and North Americans of European ancestry, potentially reaching 1:200 in some European regions because of a founder effect [16]. Genetic distribution also varies: R3500W (NM_000384.3:c.10579C>T, p.(Arg3527Trp)) is more common in Asia, and a Taiwanese series described LDLR variants and large rearrangements detected by MLPA [1, 17].

Brazil. In ELSA-Brasil (14,460 adults), the prevalence of probable or definite FH was 1:263, higher in women (1:244) than men (1:333) and higher in people classified as brown (1:204) and black (1:156) than white (1:417) [91]. HipercolBrasil, the largest Brazilian cascade screening programme, identified more than 2000 carriers of causal variants and demonstrated the feasibility of screening in small towns [92].

Portugal. The Portuguese FH Study, coordinated by the Instituto Nacional de Saúde Doutor Ricardo Jorge, genetically confirmed 42% of 1005 index cases and, through cascade screening, identified 1000 patients, 11 of whom were homozygotes [30]. Portugal uses selective screening combined with cascade screening [9].

Sex and equity. Women with FH have a lower prevalence of coronary disease but receive less intensive treatment [27], and accumulate a greater LDL-C burden at a young age because of periods without treatment associated with pregnancy [9]. In HoFH, inequalities in access to therapies bring the first cardiovascular event forward by approximately a decade in non-high-income countries [33]. The sources consulted did not identify representative prevalence data for most African and Middle Eastern countries (except founder populations) or Latin America beyond Brazil and Argentina, which does not demonstrate that no published studies exist; hospital series and index-case registries describe referred patients and do not estimate population prevalence.

10. Illustrative Clinical Case

10.1 HoFH caused by a homozygous LDLR deletion (published case)

A girl from northern India was diagnosed with HoFH at age 2, after the appearance of cutaneous and Achilles tendon xanthomas [93]. Genetic testing revealed a pathogenic homozygous LDLR deletion. Despite lifestyle measures, a low-fat diet and maximal doses of atorvastatin and ezetimibe, mean LDL-C over the following decade remained at 320.3 mg/dL; the family declined apheresis and there was no response to evolocumab — an expected finding in a genotype without residual receptor activity. The patient developed progressive calcific aortic stenosis and concentric left ventricular hypertrophy, requiring aortic valve replacement at age 16. Introduction of evinacumab reduced LDL-C by 76.16%, to 82 mg/dL, a value maintained over the following four months [93].

Learning points. The case illustrates the typical presentation of HoFH (xanthomas before age 10), the lack of response to receptor-dependent therapies in null genotypes, preferential aortic valve involvement and the efficacy of LDLR-independent therapies [2, 70]. It also illustrates the impact of late diagnosis and limited access to apheresis and recent drugs, documented in the HICC [33]. «Reverse» cascade screening of the parents, who are obligate heterozygotes, and siblings is mandatory [2].

10.2 Acute coronary syndrome in a 7-year-old child (published case)

A 7-year-old girl with HoFH presented with acute coronary syndrome; coronary angiography showed critical ostial and mid-third left main coronary artery stenosis, treated by intravascular ultrasound-guided angioplasty with drug-eluting stent implantation; she also had mild supravalvular aortic stenosis [94]. Born to parents in a third-degree consanguineous marriage, she had infraorbital and palpebral xanthomas and xanthomas on the extensor surfaces of the elbows and knees (figure 1 of the article), a two-week history of exertional chest pain, diffuse ST depression with elevation in aVR, elevated troponin I, total cholesterol of 883 mg/dL and LDL-C of 836 mg/dL; her parents and 12-year-old sister had lipid profiles compatible with HeFH, without clinical atherosclerosis, and a paternal uncle had undergone coronary angioplasty at age 35 [94]. Echocardiography showed a supravalvular aortic ridge with a gradient of 38/17 mm Hg (figure 3), and coronary angiography critical ostial and mid-third left main lesions (figure 4); following heart team discussion, bypass surgery was rejected because of arterial size and the anticipated progression of supravalvular disease [94]. She was discharged on the third day on aspirin, clopidogrel, atorvastatin 20 mg/day, ezetimibe 10 mg/day, a beta-blocker and evolocumab 140 mg every 2 weeks; atorvastatin was reduced to 10 mg/day because of transaminase elevation and, with the target unmet, evolocumab was replaced by inclisiran, with LDL-C of 414 mg/dL two months later (approximately 50% reduction) [94]. The genetic study reported only a «homozygous variant in LDLR intron 3», without published HGVS nomenclature or classification, so the variant cannot be normalised or confirmed as causal from the report. Figures are available in the original open-access article (https://pmc.ncbi.nlm.nih.gov/articles/PMC12802874/). Use of evolocumab at age 7 and inclisiran before age 12 is off-label in both jurisdictions, and residual LDL-C of 414 mg/dL remains far above targets, a setting in which the EAS consensus considers apheresis, evinacumab or lomitapide, which the authors mention only as future options [2, 94]. The case reinforces the recommendation for systematic cardiovascular imaging assessment at HoFH diagnosis, with coronary CT angiography at least once after age 3 [2].

10.3 Teaching vignette: cascade screening starting with a child (case constructed for educational purposes)

Composite vignette, not corresponding to a real patient. An asymptomatic 5-year-old child has total cholesterol of 290 mg/dL on universal preschool screening; repeat measurement confirms LDL-C of 215 mg/dL (5.6 mmol/L), without secondary causes. The father, aged 38 and a smoker, has never had blood tests; the paternal grandfather had a myocardial infarction at age 49. The NGS panel identifies a heterozygous pathogenic LDLR variant. The father has LDL-C of 265 mg/dL and the same variant (DLCN score: 5 points for LDL-C of 6.9 mmol/L, 2 for family history — a child with LDL-C above the 95th percentile — and 8 for genetics, total 15 — definite FH); as he has FH with an additional major risk factor (smoking), he is classified as very high risk, with an LDL-C target below 1.4 mmol/L and a reduction of at least 50% [6, 8]. He starts high-intensity rosuvastatin and ezetimibe and is encouraged to stop smoking. The child starts a family diet and, at age 6, a low-dose statin, with an LDL-C target of 3.5 mmol/L or less until age 10 and 3.0 mmol/L or less thereafter [9]. Screening proceeds to the paternal uncles, aunts and cousins.

11. Prognosis and Long-Term Follow-up

The prognosis of HeFH has been transformed by treatment. In the pre-statin era, half of men had a coronary event by age 50 and 30% of women by age 60 [1, 26]. In the Simon Broome registry, the relative risk of coronary mortality between ages 20 and 59 fell from 8-fold to 3.7-fold after statins were introduced [26]. Event-free survival depends more on the LDL-C actually achieved than on the variant type [16]. Early diagnosis and treatment can reduce cardiovascular risk to levels equivalent to those of the general population [18], and treatment initiated in childhood reduced the incidence of events by age 39 from 26% (parents) to 1% (treated children) [45]. Even so, in the FHSC only 2.7% of treated patients achieve LDL-C below 1.8 mmol/L, and drug combinations, particularly with PCSK9 inhibitors, are associated with a greater probability of reaching target [27].

In untreated HoFH, most patients die before age 20–30 [16, 26]. In the HICC, the first major cardiovascular event occurred at a median age of 31, and before age 18 in 4% of patients [2]; in high-income countries, where 66% of patients received three or more therapies, median age at the first event was 37 years [33]. Apheresis initiated in childhood is associated with a lower long-term risk of ASCVD and death [78]. Valvular and supravalvular aortic disease may progress even with lipid control and requires annual echocardiographic follow-up [2]. Quality of life is reduced overall, particularly in patients undergoing apheresis; in a Dutch study in which 90% of patients were treated only with drugs, quality of life was only slightly below the national average [2]. In ARH, event-free survival is longer than in LDLR-related HoFH [16].

HoFH surveillance. The table summarises the French PNDS protocol, compared with the 2023 EAS consensus:

In children, examinations involving radiation are repeated only when the benefit justifies it, and echocardiography allows them to be spaced out; some teams use magnetic resonance imaging, which requires general anaesthesia in young children and is little used in France. The calcium score alone does not quantify atherosclerosis in children and young adults, whose plaques may not be calcified, and in adults cardiac magnetic resonance imaging has no role in the search for coronary lesions outside research [11]. The annual frequency of cardiovascular assessment matches that of the EAS, which recommends annual echocardiography and coronary CT angiography at least once after age 3 [2].

Long-term follow-up should include regular lipid monitoring, adherence assessment, control of additional risk factors, educating the child about the disease and a structured transition to adult care, a period when treatment discontinuation is frequent [2, 9].

12. Summary and Final Considerations

Familial hypercholesterolaemia is the most common monogenic metabolic disease, with a prevalence of approximately 1:250–1:300 in the heterozygous form and 1:250,000–1:360,000 in the homozygous form. It results from loss-of-function LDLR variants, loss-of-binding APOB variants or gain-of-function PCSK9 variants, with semidominant transmission, or, rarely, from biallelic LDLRAP1 variants, with recessive transmission. The shared mechanism is reduced hepatic LDL clearance, exposing arteries to high LDL-C concentrations from birth; cumulative burden determines age at ASCVD onset.

Diagnosis is based on LDL-C, family history and physical examination, organised within the DLCN, Simon Broome and MEDPED criteria, and is confirmed by genetic testing, which identifies a variant in 60%–80% of adults with a clinical diagnosis. In children, adult criteria have low sensitivity and the 2026 EAS consensus proposes specific thresholds. Cascade screening with genetic testing is the most cost-effective way to identify patients, and universal paediatric screening, already implemented in Slovenia, enables diagnosis in the first decade and identification of affected parents.

Treatment targets LDL-C: in adult HeFH, below 1.8 or 1.4 mmol/L according to risk, with high-intensity statins, ezetimibe, bempedoic acid and PCSK9 inhibitors; in children, pharmacological treatment ideally from age 6, with targets of 3.5 and 3.0 mmol/L. In HoFH, combining a statin, ezetimibe, PCSK9 inhibitors (when residual receptor activity is present), receptor-independent therapies (evinacumab and lomitapide), apheresis and, as a last resort, liver transplantation now makes previously unattainable targets achievable. Current challenges are underdiagnosis, late treatment initiation, unequal access to therapies and maintaining lifelong adherence. Between 2025 and 2026, the FDA approved two new PCSK9 inhibitors for adults with HeFH (monthly lerodalcibep and oral enlicitide) and the CHMP issued favourable opinions for lerodalcibep and obicetrapib, all with evidence based on LDL-C reduction and without outcome trial results at the date of this update.

The 2026 French PNDS on HoFH proposes its own indicative targets (approximately 1.0 g/L in adults and 1.3 g/L in children in primary prevention; down to 0.55 g/L in the presence of atherosclerosis), places apheresis as a resource after receptor-independent drugs, defines annual cardiovascular surveillance and organises care within the CEDRA network, with a national multidisciplinary team meeting (RCP) for exceptional therapies [11].

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