Early Detection of Familial Hypercholesterolemia in Children (DECOPIN)

  • End date
    Jan 13, 2030
  • participants needed
  • sponsor
    Institut Investigacio Sanitaria Pere Virgili
Updated on 4 March 2022
early diagnosis
genetic disorder


Heterozigous FH is an underdiagnosed disease in the paediatric population. Its early detection, would allow us to initiate lifestyle therapeutical changes and early pharmacological therapy if necessary. This is a key fact to reduce atherosclerosis progression and cardiovascular risk in adulthood. Moreover, it will allow, detecting the first and second degree affected relatives.


The most prevalent cause of hypercholesterolemia in childhood is Heterozygous Familial Hypercholesterolemia (HeFH).

It is a monogenic disorder that is transmitted of autosomal dominant way and affects 50% of offspring. It is characterized by the increase of low-density lipoproteins (LDL-C), which can be detected from birth. It is mostly caused by mutations in the gene that encodes the LDL receptor (LDLr) located in the short arm of chromosome 19. Nowadays, more than 1500 different mutations have been described worldwide. Less common are the ApoB3500 Family Defect, caused by the mutation of the Apolipoprotein B gene (APOB) that is located on chromosome 2, and the mutation of the gene encoding PCSK9 (proprotein convertase subtilisin-kexin type 9) located on the chromosome 1p32.2. These three entities are clinically expressed in the same way and only the genetic study will allow us to differentiate them.

HeFH has a prevalence of 1 for every 250 individuals in the European population, therefore it is the most frequent genetic disease, which is a major public health problem as it is associated with high cardiovascular risk (CVR). In spite of the current knowledge and the diagnostic techniques, it continues being an unknown disease and therefore is underdiagnosed and under-treated. In countries with active screening projects of HeFH detection, only 20% are diagnosed. In Catalonia, in order to get free access to lipid lowering therapy, a register was started in 2004. In November 2012, a total of 2,981 patients were registered in Catalonia, representing 19.53% of expected HeFH patients in Catalonia. Only 108 children were included, in the age group 0 to 14 years, In clinical practice, DLCN criteria (clinical criteria of Dutch Lipids Units) is used as a diagnostic tool, but these clinical criteria cannot be applied to the children. The criteria are based on family history, personal history, physical examination and LDL-C levels. A definite clinical diagnosis of HeFH is considered when the score obtained is equal to or greater than 8 points, its probable when the score obtained is between 6-7 points and possible when it is between 3-5 points (table 1). In these clinical criteria, the presence of tendinous xanthomas and the corneal arch are very important. These two stigmas are not present in HeFH children, and the investigators will only find xanthomas in Homozygous Familial Hypercholesterolemia (HoFH). This form of the disease is very serious and the prevalence is low, 1 per 300,000-400,000 habitants.

It suspect HeFH when the investigators observe LDL levels >135 mg/dL in children with a family history of premature cardiovascular disease (men < 55 y/o and women < 65 y/o) in first-degree relatives, or a parent with LDL levels> 240 mg/dL (according to data published in adult HeFH population in the Spanish population).

At present, there are clear evidences that high LDL-C levels in children induce the formation and development of atheromatous lesion. This lesion can be initiated during the first years of life by cholesterol deposit, causing an increase in the carotid intimate-medium thickness (cIMT), progressing silently until adulthood.

It has been observed in children over 5 years of age that high cholesterol levels cause alterations in endothelial function of the arterial wall, measured by flow-mediated dilation (FMD). Wigman and colleagues observed that cIMT of HeFH children between 8 - 18 years H was higher than the control children population, estimating cIMT growth in around 0.0047 mm/year; in front of 0.0003 mm/year in the control group. Dalmau and colleagues evaluated the cIMT of 88 HeFH children between 2 and 19 years and described a faster cIMT increase with age particularly after 12 years old, regardless of gender and other analytical parameters related to CVR.

Statin intervention studies, have described that reductions between 30 and 40% in LDL-C levels lead to an improvement in endothelial function measured by FMD and cIMT. It has also observed that arterial stiffness was increased in children with CVR compared to children without CVR.

There is evidence suggesting that HeFH children have a pro-inflammatory and pro-oxidant state that could accelerate the atherosclerosis process and increase CVR. Recent studies from our group have shown that E-selectin, sVCAM or oxLDL/LDL are associated with lower post-ischemia reactivity in small arteries in patients with high CVR.

Statin intervention studies in HeFH children have proven that these drugs are safe and effective. LDL-C reduction is associated to a reduction in cIMT. An early lipid lowering therapy decrease the lifelong CVR.

The first clinical guidelines addressing familial hypercholesterolemia (FH) in children were published in 1992 by National Cholesterol Education Program (NCEP). Since then, many Scientific Societies have given recommendations about detection, diagnosis and treatment. All guides reinforce the importance of an early detection. The most conflicting point between the different panels of experts is the type of screening. The National Heart Lung and Blood Institute (NHLBI) recommends universal screening between 9 and 11 years, in the context of the comprehensive management of CVR factors in childhood, and selective screening between 2 and 8 years. Other guidelines recommend selective screening based on family history and the presence of CVR factors.

A recent study has shown that screening based on lipid profile may be insufficient to detect HeFH population. A genetic study of 215 members of 24 families with RLDL mutations showed that 7% of the members wear the mutation despite a normal lipid profile.

The Netherlands is one of the countries with a more active health policies to detect the HeFH population. For many years, they have established a National Program based in cascade screening of all first-degree relatives of diagnosed FH patients. They propose a general screening of the children population between 1 and 9 years. This type of screening has a greater sensitivity and specificity. Universal screening together with selective screening would be the most efficient method to detect FH patients, but this goal can only be achieved by activating specific healthcare strategies in the usual clinical practice.

One group of investigators assessed the degree of control and follow-up of 207 HeFH children (0-18 y/o) from January 2007 to May 2008. Only 62% had received a lifestyle change advice,16% took functional foods every day with stanols or sterols and only 26% were taking statin therapy. Their conclusions were that a screening program is necessary but this programme should be accompanied by a proper follow-up with a multidisciplinary health group (nurses, pediatricians, dietitians and specialists involved in the management of severe hypercholesterolemia).

Previously, different studies had observed that 50% of men and 20% of woman with FH don't received adequate treatment increasing the risk of coronary episodes before 50 years old. Nowadays, it has been shown that the intensive treatment of FH patients reduce cardiovascular mortality, reaching the same proportion as the general population.

According the official data from the "Generalitat of Catalonia" the province of Tarragona has a population of 71,186 children between the ages of 0 and 14. The aim of this project is detecting FH children early to improve their CVR in adulthood.

Condition Familial Hypercholesterolemia, Familial Hypercholesterolemia - Heterozygous, Familial Hypercholesterolemia - Homozygous
Treatment lifestyle assessment
Clinical Study IdentifierNCT04370899
SponsorInstitut Investigacio Sanitaria Pere Virgili
Last Modified on4 March 2022


Yes No Not Sure

Inclusion Criteria

Children between 2 and 18 years of age
LDL-C level above 135 mg/dL
Previously, the pediatrician will have discarded secondary causes (hypercholesterolaemia such as hypothyroidism, nephrotic syndrome, diabetes, renal insufficiency)
After confirmation that one of the parents has a genetic mutation
(Lipoxip/Liponext) or clinical diagnosis (DLCN 8), the child will be studied
The progenitor with hypercholesterolemia will be considered as an index case
in this way we will demonstrate the vertical transmission of the genetic

Exclusion Criteria

The child population under 2 and over the age of 18 and children
Children with high cholesterol but by secondary causes
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