Though the aforementioned criteria provide a dimension to diagnosis with some degree of sensitivity but in clinical practice it is far from being specific. The problem part starts in clinics where the defining criteria are not equated with clinical presentation of the patient due to variable phenotypic presentations. Attributes to molecular pathogenesis of “FCHL” have been varying across the literature. Most evidence related to date focus on USF1 transcription factor located on Chromosome-1q21-q24. 1013 Pajukanta et al pioneered the genetic work by elucidating the region Ch.1q21-24 nearby Apolipoprotein-A2 region through linkage analysis to provide a LOD of 5.93 thus indicating strong phenotype-genotype linkage along with a possibility dominant mode of inheritance for FCHL. 10 These studies in fact led to the initial molecular work shortlisting Ch.1q23.3 as culprit region for FCHL and provided us some molecular pathological details about USF1 gene to combined hyperlipidemia. (Figure 1) However, later studies identified other genetic loci and biochemical evidence to suggest other molecular pathological defects leading to a similar phenotype. de Graaf et al have suggested that the presence of obesity and insulin resistance accompany subjects diagnose to have FCHL with probable defective adipose tissue metabolism leading to increase in free fatty acids could be the main culprit implying a defect in adipose tissue metabolism. 14 Wijsman et al have identified that Apo-B levels and size are both major determinants associated with FCHL with SNP genotyping identifying an important candidate region on Ch.4q32.3. 15 Further studies in the past have identified multiple other loci which could lead to a FCHL phenotype apart from Chromosome: 1q21 (USF1) gene, including candidate genes like Lipoprotein lipase gene and Apo lipoproteins A1/c3/a4/a5 genes. 16 Another study by Cruz-Bautista et al have shown that atherogenic particles like Apo-B containing VLDL, along with Apo-CIII and AII along with adiponectin hormone appear to be the major factors involved in defining FCHL phenotype. 17 Other related evidence is presented in Table 1 and Table 2. Converging these pieces of evidences together, it seems that multiple factors and mutations/polymorphisms at different genetic loci are involved in shaping up the clinical phenotype of “FCHL”.

The aforementioned referenced discussion over last 3 decades thus concluded “phenotype FCHL” to be emerging from various genetic alterations across various chromosomal regions with slightly different clinical presentations. The genetic and metabolic pathways linked to FCHL may involve: 1-Defective clearance of Apo-B containing lipoproteins, 2-Overproduction of Apo-B containing lipoprotein i.e., VLDL and 3-Adipose tissue dysfunction. A detailed account of various genes affected in the above pathway has earlier been given by Brouwers et al. 2Figure 2 explains an overview of pathways and key areas proposed to be affected in different organs identifying the multifaceted dimensions to FCHL pathology.

Apart from establishing link between FCH and associated genetic and loci, there is also a clear evidence of overlapping features between metabolic syndrome (insulin resistance syndrome) and clinical and laboratory symptomology of FCHL. While some data contrast due to higher mortality for FCHL, still the two entities show co-occurrence, mixed traits and matching phenotype. 33 Santilli et al have identified the risk of cardio-metabolic disorders to become additive with both metabolic syndrome or FCHL traits only once these patients lost a so-called “protective gene cluster”, thus signifying that specific gene abnormalities are more associated with certain traits than simpler concept of monogenic inheritance. 34 The most associated USF1 on chromosome-1 is also linked with both metabolism of lipids and glucose like PPAR-gamma, HNA4a and PTEN, so it’s very probable that some of the common symptomatology of FCHL related to USF1 region with metabolic syndrome could be because of this multiple transcription factor regulation and associated signaling mechanisms. 35Table 3 shows provides an insight into the biochemical alterations in FCHL in comparison to metabolic syndrome.

Provided the search on PubMed yielded some data as mentioned in Table 3, still we believe the evidence is not convincing to segregate the two phenotypically similar disorders. Only take home message here is the fact that the two disorders are overlapping with slightly higher gravity risk gravity attributed with underlying FCHL than the mere presence of metabolic syndrome symptomatology.

While Framingham’s hyperlipidemia classification of type-2b with mixed hyperlipidemia is the initial clicker to include FCHL in your diagnosis, still we do learnt from above discussion that the FCHL phenotypes differ in terms of lipid levels, lipid types, associated metabolic component, clinical presentations, underlying genetics and inconsistent data on the subject. 56 These considerations make the diagnosis of FCHL very much heterogeneous and a real life diagnostic dilemma for diagnosticians. Alongside we must appreciate the atherosclerotic cardiovascular disease associations of FCHL in terms of very high prevalence in patients having myocardial ischemia. 1 Sniderman et al have provided a general criteria for its diagnosis, but this still suffers with lack of specificity. 8 Not so recently we also had a nomogram for predicating susceptibility of FCHL as depicted in Figure 3, but unfortunately it could not gain widespread acceptability. 42

Keeping in view the heterogeneity in FCHL phenotypes, the availability of various molecular tools and providing precise and accurate diagnosis it would be accurate to suggest that FCHL is convergence phenotype due to definitive molecular defects arising from a singular gene pathway like USF1 to genetic alterations across multiple other chromosomal regions as shown in Table 1. Furthermore, varying obesity patterns especially the “Asian obesity paradox” may not even present with hyperlipidemia, or sometimes as hypercholesterolemia or hypertriglyceridemia. 43

Recent data in conventional medical science is being reshaped and supplanted with deeper insights into molecular physiology and pathological mechanisms. We are deemed to enter the arena of “molecular medicine”. We need to appreciate the fact that conventional medicine relies heavily on clinical phenotypes with biochemical evidence going alongside; however it can be said with confidence now that reliance on clinical phenotypes simply will not be able to provide personalized and nano-evidence based solutions for a specific patient. Further we move into the revolutionizing and innovative field of biotechnology, we are bound to find new tools and mechanistic set ups to better visualize the disease pathology. Below we attempt to provide a draft molecular diagnostic algorithm to approach subjects with either FCHL phenotype or a pattern like “Metabolic syndrome”. (Figure 4) This document is simply an attempt to combine new phenotype-genotype evidence to incorporate commonly appreciated molecular pathology on the subject. The limitations attached to this review must be understood: Firstly, the document is by no means intended to provide complete account of molecular defects due to evolving nature of both molecular pathology and discovery of newer dimensions of molecular pathology entering into the dimensions like miRNAs pathways, epigenetic mechanism and discovery of roles like “Alu element”. The data is bound to evolve and improve with further insight into complexities of various genetic pathways, miRNAs and related epigenetic methylation marks along with newer developments in nano-biotechnological tools. 4445 More so current text on metabolic syndrome and FCHL phenotype overlap is no more a mystery but we still need to appreciate the little differences in phenotypes with a specific genetic defect, for which the authors feel the genotype-phenotype data is limited and need more research.

Provided certain limitations and lack of most recent molecular data on the subject, this review has clinical significance because it provided a wholesome overview of FCHL in terms of its contrasting phenotype molecular pathogenesis, polygenic nature of the disease, non-molecular metabolomics of FCHL within attempt to focus on futuristic way forward to diagnose and paving ways for gene therapy. It also emphasize the pushing needs for more research in defining further insights into FCHL with regards to emerging epigenetic markers like microRNAs, methylation studies and regional molecular differences within our community.