Familial chylomicronemia syndrome in children: a diagnosis challenge

Genetic rare diseases are often challenging to diagnose and treat (1). First, because their rarity and diversity of symptoms limits knowledge of them among clinicians. Second, because their diagnosis workflow usually requires laboratory tests that are not always accessible in clinical settings. Third, many of them have no specific therapy. Such is the case of familial chylomicronemia syndrome (FCS), a very rare genetic dyslipidaemia (1-2 cases/million people) presenting with persistent chylomicronemia refractory to conventional treatment. Eruptive xanthomas, lipemia retinalis and/or hepatosplenomegaly have been described in patients with FCS and, as the most severe manifestation, recurrent episodes of abdominal pain and acute pancreatitis that are potentially fatal (2).

FCS is caused by the presence of biallelic pathogenic variants in the five genes encoding the enzyme and proteins directly involved in the lipolytic cascade of triglycerides. Most cases appear in the LPL gene, but also APOC2, APOA5, GPIHBP1 and LMF1 harbour FCS causative variants. LPL is the main enzyme that catalyses the hydrolysis of circulating triglycerides; ApoC-II and ApoA-V are its activators, Gpihbp1 its interstitial shuttle and support on the endothelium, and Lmf1 a lipase chaperone responsible for its correct folding, as Shi and Wang depict in the article which is object of this editorial (3). The direct consequence of these genetic alterations is the lack of LPL activity that causes a sharp elevation of chylomicrons known in the literature as type I hyperlipidaemia (4).

As a genetic disease, FCS often manifests in infancy (5). However, many patients are diagnosed in adulthood and the start of symptoms in childhood is assessed retrospectively (Table 1). As mentioned, the diversity of symptoms and the difficulty of performing genetic and biochemical tests can explain, at least partially, the delay in achieving an FCS diagnosis. In addition, symptoms overlap with those of other chylomicronemia syndromes such as multifactorial chylomicronemia (MCS), lipodystrophy, glycogen storage disease and the presence of autoantibodies against LPL or Gpihbp1 (2,11-13). Furthermore, most cases of chylomicronemia and even pancreatitis in children and adolescents are due to secondary causes (14).

The article by Shi and Wang presents a paediatric patient who was referred to her Thrombosis and Hemostasis centre due to an abnormal coagulation profile, although she was asymptomatic. The girl was finally diagnosed as having FCS due to LPL gene variants in compound heterozygosity. The main importance of this article is based on four key points. Firstly, the indicator which lead these authors to the final diagnosis was simply the observation of milky serum. Secondly, they performed in vitro functional studies to prove variants pathogenicity. Thirdly, the authors extend the genetic study to the patient’s family providing it with segregation data. Finally, their work contributes to make FCS known among clinicians not necessarily specialised in lipidology.

As mentioned, most FCS cases are due to pathogenic variants in LPL. A revision of paediatric patients from different publications (with patients’ ages ranging from a few days after birth to 16 years old) suggests that FCS symptoms in children are more elusive than those in adults (Table 1). Seventeen cases out of 50 were asymptomatic at presentation and clinicians just observed febrile episodes, vomiting and/or diarrhoea, and lactescent serum after examination. Physical manifestations of chylomicronemia (hepatosplenomegaly, eruptive xanthomas and/or lipemia retinalis) were observed in 26 cases either at presentation or after examination. Among cases summarised in Table 1, only one child failed to thrive and acute pancreatitis or abdominal pain was reported in 14 of these children (28%). In the adult FCS series, pancreatitis prevalence is higher (>85%) (15,16). Apart from a possible selection bias in these studies and patients’ individual susceptibility to pancreatitis, the shorter time of exposition to chylomicronemia can explain the lower prevalence in children. In fact, some of the patients shown in Table 1 had pancreatitis episodes later, in adulthood.

Shi and Wang found an extremely prolonged activated partial thromboplastin, prothrombin and thrombin times in their patient. It has been extensively described that a lipemic serum can interfere with biochemical measurements (17). However, fewer studies report the alteration of haemostasis parameters (18). The girl studied has splenomegaly but, fortunately, she has not had pancreatitis episodes and she thrives well. These “mild” and diverse symptoms exhibited by some FCS paediatric patients highlight the importance of authors’ observations of an altered coagulation profile as another non-specific observation to take into account in FCS paediatric patients.

The development of next-generation sequencing (NGS) techniques over the last decade has facilitated genetic testing greatly. The correct assessment of pathogenicity to variations identified is crucial in order to achieve a correct diagnosis. However, with the massive amount of information generated, variant interpretation becomes a challenge. Computational analyses help in taking into consideration the potential pathogenicity of variants with unknown clinical significance. Nevertheless, taking them as the only source of evidence to assign pathogenicity can lead to wrong interpretations. For instance, LPL premature stop codons are predicted in silico to be pathogenic. However, based on biochemical and/or functional studies, pathogenicity should not be accredited automatically (19). The LPL variants described by Shi and Wang can be classified as pathogenic based on four pieces of evidence, in accordance with the recommendations of the American College of Medical Genetics and Genomics (ACMG): allele frequency, computational predictions, family segregation data and, very importantly, the functional in vitro validation performed by the authors (20). Similarly, most of the LPL variants described in the references summarised in Table 1 have confirmed pathogenicity because LPL activity deficiency was proved and in vitro functional studies were performed. These initial studies carried out in the nineties provide us with valuable knowledge to interpret variants identified in the current “NGS times”.

Shi and Wang found that the patient’s family had hypertriglyceridaemia (HTG) and performed whole exome sequencing (WES) with samples from the entire family. Compared to a targeted strategy that would focus on the five canonical genes for FCS, WES allows detection of genetic defaults responsible for other chylomicronemia syndromes mentioned before. Interestingly, no other TG-rising variants than the LPL pathogenic changes described were found in the patient’s parents and grandparents. In previous studies, it has been shown that heterozygous carriers of LPL pathogenic variants can be normolipemic (16). As the authors point out in their paper, the impact of harbouring heterozygous loss-of-function variants depends on secondary factors. We might also speculate that many variants with unknown clinical significance—among those revealed with WES—could be having an influence in the patient’s family. In fact, most cases with severe HTG are genetically undefined (21). This situation links up with the need to improve predictions of functionality (pathogenicity) as this effect remains hidden for the great majority of the variants identified. Additionally, epigenetic factors can also have an influence on the manifestation of HTG but they cannot be revealed with sequencing approaches (22). Finally, HTG is a condition that increases the risk of cardiovascular disease (CVD). The incidental discovery of HTG in the patient’s family will contribute to a convenient follow-up of these people that might reduce their CVD risk.

Among the studies summarised in this editorial, only five appear in paediatric journals. The diffusion among paediatricians of the nature, diversity of symptoms and diagnosis strategies of FCS in children is essential to achieve an early diagnosis. The most important goal is to reduce the risk of episodes of acute pancreatitis and its consequences. Volanesorsen, a novel antisense oligonucleotide targeting Apo C-III mRNA, has proven to be effective in treating adult FCS patients (23). On the other hand, treatment based on fat-restricted diet and medium-chain triglycerides (MCT) supplements must be used to reduce the risk of pancreatitis in paediatric patients (24,25).

To conclude, the article mentioned in this editorial contributes to our knowledge of FCS and shows that an interdisciplinary approach—clinical, genetic and biochemical—seems the best way to face the FCS diagnosis challenge to ensure children’s wellbeing, which is the most important task that, in fact, we all bear in mind.

Acknowledgments

The authors would like to thank all the investigators contributing to the study of FCS cases in the Lipids and Atherosclerosis Laboratory (CIMES, University of Malaga), and in the Lipid Unit of the University Hospital Virgen de la Victoria: José Rioja, PhD, Miguel Ángel Sánchez-Chaparro, MD, PhD, Mª José Benítez-Toledo, MD, PhD, Inmaculada Coca-Prieto, MD, PhD and Javier Espíldora-Hernández, MD, PhD. The authors also thank the “Servicio de Traducción e Interpretación de la Fundación General de la Universidad de Málaga” for their assistance in the English editing of this manuscript.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Pediatrics. The article did not undergo external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-22-515/coif). MJA reports that she received personal payments once for consulting services from Akcea in 2020 and for a presentation in 2021 from the European Atherosclerosis Society. PV reports that he received honoraria as a speaker from Sanofi, Amgen, Amarin, Akcea, Daiichi-Sankyo, Servier, as advisor from Sanofi, Amgen, Amarin, Akcea, Daiichi-Sankyo, a grant from Sanofi and support to travel from Daiichi-Sankyo, Servier, Sanofi, Amgen, Sobi, PTC. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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