Heterozygous Familial Hypobetalipoproteinemia in Children and Adolescents: Time and tide wait for no man

Heterozygous Familial Hypobetalipoproteinemia in Children and Adolescents: Time and tide wait for no man | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Heterozygous Familial Hypobetalipoproteinemia in Children and Adolescents: Time and tide wait for no man Patrizia Bruzzi, Giulia Cammarata, Annarita Di Biase, Barbara Predieri, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7443290/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Familial hypobetalipoproteinemia (FHBL) is the most frequent monogenic form of HBL with a dominant mode of inheritance. Heterozygous patients are often asymptomatic, but the genetic mutation causes a defect of exportation of VLDL from the hepatocytes that remain stuck in the liver causing steatosis. In childhood, the diagnosis of FHBL is often underestimated and guidelines are still lacking. The aim of the study is to describe the phenotypic features of a cohort of children and adolescents with a genetic confirmed FHBL attending our pediatric lipid clinic. Methods: This is a monocentric, observational study collecting anamnestic, anthropometric, biochemical and instrumental data (liver ultrasound and elastographic profile) in children and adolescents with a genetic confirmation of heterozygous FHBL. Results: 12 children and adolescents (4 females), aged 12.14 ± 1.80 years, were genetically diagnosed with heterozygous FHBL. Overweight and/or obesity were identified in 7/12 cases while failure to thrive was detected in 4/12 cases. Only one patient was fully asymptomatic. In 6/12 patients, steatosis was graded from moderate to severe, mainly when accompanied by overweight and/or obesity (p 0.05). Transient elastography was more elevated in FHBL patients if overweight and/or obese (5.65 ± 0.71 vs. 4.60 ± 0.28, p 0.06). Conclusions: Our data document an unexpectedly wide phenotype of FHBL in childhood and adolescence ranging from no symptoms to growth failure or, on the other side, to obesity. Moreover, we document a frequent precocious hepatic involvement in FHBL children, especially if obese and overweight with a potential rapid evolution in fibrosis. familial hypobetalipoproteinemia lipids lipoproteins liver steatosis children Background Familial Hypobetalipoproteinemia (FHBL) is a rare autosomal codominant genetic disease characterized by low level of plasma Total Cholesterol (TC), Low-Density-Lipoprotein (LDL), Triglycerides (TG) and Apolipoprotein B (APOB) ( 1 ). More than 140 mutations in the APOB gene have been found to cause FHBL. They lead to the production of abnormally short ApoB proteins (ApoB100 and ApoB-48) that confer lower rates of synthesis and secretion of apoB-containing lipoproteins and higher rates of catabolism of truncated apoB-containing lipoproteins. ( 2 ). The shorter the length of the truncated apoBs, the more severe the degree of complications ( 1 , 2 ). Less frequently mutations involve Proprotein Convertase Subtilisin Kexin type 9 gene (PCSK9), Microsomal Triglyceride Transfer Protein gene (MTTP), SAR1 gene homolog B (SAR1B or SARA2) and angiopoietin-like protein 3 (ANGPTL3) and 8 (ANGPTL8). The estimated prevalence of FHBL in the general population is between 1:1000 to 1:3000 ( 3 ). Nevertheless, in adults, a monogenic origin of HBL is identified in only 20–50% of patients suggesting a frequent polygenic inheritance, involving multiple common genetic variants with small to moderate effects ( 4 ). Patients carrying a heterozygous mutation are often asymptomatic and the diagnosis is frequently only incidental, suspected on hypocholesterolemia at blood tests performed for other medical reasons. Mild intestinal symptoms are described such as abdominal pain and diarrhea associated with lipid rich meals ( 5 ). Affected patients benefit from a reduced cardiovascular risk but they are not free from complications. In fact, ApoB mutation causes a decreased secretion of apoB100-containing lipoproteins and determines a defect in assembly and export of VLDL from the hepatocytes that remains stack in the liver ( 6 , 7 ) and cause early liver steatosis, steatohepatitis that can develop in fibrosis and cirrhosis ( 3 , 5 ). This observation is consistent with the hepatic adverse effects observed in patients treated with APOB antisense (mipomersen) for severe familial hypercholesterolemia ( 8 ). Moreover, FHBL patients are predisposed to fat-soluble vitamin malabsorption, and related symptoms such as ataxia, dysmetria, ophthalmological abnormalities and bone loss ( 3 ). Due to the potential and severe hepatic harm, early recognition of affected children and adolescents has a pivotal role to evaluate prognostic risk factors of liver damage and to plan a personalized follow up ( 9 – 12 ). Nevertheless, in pediatric literature, data are mainly derived from case reports, while cohort study and guidelines are lacking. In this paper, we illustrate the phenotypic features of a cohort of children and adolescents with a genetic confirmed FHBL attending our Pediatric Lipid Clinic. Methods This is a monocentric, observational study enrolling children and adolescents with a genetic diagnosis of FHBL followed up at our tertiary Pediatric Lipid Clinic in the last 2 years. The study was conducted in agreement with the Declaration of Helsinki and was approved by the local Ethical Committee (Protocol number 245/2016). Parental written informed consent and patient assent were obtained before starting the data collection. Anamnestic data Anthropometric data All recruited patients underwent a complete physical examination performed by a team of fully trained examiners according to the Anthropometric Standardization Reference Manual ( 13 ). Height (H) was measured to the nearest 0.1 cm with a calibrated well-mounted Harpenden’s stadiometer (Crymych, UK), compared with age-matched reference values and expressed as standard deviation score (H SDS) ( 14 ). Body weight was measured to the nearest 0.1 kg with a calibrated scale. BMI was calculated by dividing weight in kg by height square (m 2 ) and was standardized to SDS (BMI SDS) according to age using appropriate Italian chart ( 14 ). According to BMI SDS, patients were classified as normal weighted or overweighted and obese ( 15 ). The waist circumference (WC) was measured using an elastic tape at the iliac crest. Previous literature indicated that dichotomized WC/H ratio cut points at ≥ 0.5 or 0.55 are surrogates of increased cardiovascular risk in children ( 16 ). Pubertal staging was assessed using the Marshall and Tanner maturity scale ( 17 ). Blood pressure (BP) was measured according to a standardized protocol on the right arm using an appropriate-sized cuff. Participants sit quietly for at least 5 minutes prior to measurement and the average of three following measurements was registered. Systolic and diastolic blood pressure (SBP and DBP, respectively) were standardized using the international child BP reference ( 18 ). Biochemical and genetic data After a 12 h overnight fast, blood samples were obtained from the antecubital vein of study participants. Fasting lipids [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG) and ApoB lipoprotein (ApoB)] were measured using in vitro enzyme test kits on a Hitachi system (Cholesterol CHOD-PAD, HDL-C plus, Triglycerides GPO-PAP, and LDL-C plus; Roche Diagnostics GmbH, Mannheim, Germany). Their concentrations were standardized using the available international paediatric reference ( 19 , 20 ). Insulin was determined using an electrochemiluminescence immunoassay (IMMULITE 2000; Siemens Healthcare Diagnostics, NJ, US). Fasting glucose was measured by enzymatic absorption photometry on a Cobas 8000 analyzer (Gluco-Quant, Roche Diagnostics GmbH, Mannheim, Germany). Insulin resistance (IR) was defined by homeostatic model assessment index (HOMA index), compared to specific paediatric percentiles according to gender and pubertal stage ( 21 ), and by fasting glucose/insulin ratio (FGIR) less than 7 ( 22 ). The liver enzymes, alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (γGT) concentrations, were measured using an Immulite 2000 analyzer (Bio-DPC; Siemens Medical, Gwynedd, UK). All biochemical analyses were performed in the same laboratory. A genetic test by NGS Sequencing, Sanger Sequencing was performed to all patients, the genes investigated were ANGPTL3, ANGPTL4, ANGPTL8, APOB, APOC3, MTTP, MYLIP, PCSK9, SAR1B. Instrumental data After a 12 h overnight fast, all patients underwent liver ultrasound (US) and elastography performed by the same radiologist using a Philips EpiQ Elite Diagnostic Ultrasound System (with a 15L8 probe) and a Fibroscan Expert 630, respectively. Steatosis was instrumentally defined through a US semiquantitative assessment including liver brightness, contrast between the liver and the kidney, US appearance of the intrahepatic vessels, liver parenchyma and diaphragm. Steatosis was graded as: absent (score 0) when the echotexture of the liver was normal; mild (score 1) when there was a slight and diffuse increase of liver echogenicity with normal visualization of the diaphragm and of the portal vein wall; moderate (score 2) in case of a moderate increase of liver echogenicity with slightly impaired appearance of the portal vein wall and the diaphragm; severe (score 3) in case of marked increase of liver echogenicity with poor or no visualization of portal vein wall, diaphragm, and posterior part of the right liver lobe ( 23 ). Elastography quantified liver steatosis and fibrosis. Literature already supports that Controlled Attenuation Parameter (CAP) correlated with histopathological findings of liver steatosis: no steatosis (CAP 150–248 dB/m, amount 0–10%), mild steatosis S0 (CAP 248–260 db/m, amount 11–33%), moderate S1 (260–280 db/m, amount 34–66%) and severe S2 (higher than 280 db/m, amount higher than 67%) ( 24 ). Liver stiffness, a surrogate of fibrosis, was expressed by Transient Elastography (TE): if 9 KPa advanced fibrosis ( 25 ). Statistical analyses Continuous data are reported as mean ± standard deviation (SD), while categorical ones as percent values. Between-group comparisons were performed using Mann-Whitney U test (for numerical variables) and Pearson χ2 test (for percent values). Spearman correlation was used to identify the association between anthropometric, biochemical and instrumental variables. For each test, statistical significance was for p < 0.05. The statistical analysis was performed using the STATISTICA™ software (StatSoft Inc., Tulsa, OK, USA). Results In the last 2 years, 12 children and adolescents (4 females) aged 12.14 ± 1.80 years (range 9.71–16.05, median 12.02 years) were diagnosed with heterozygous FHBL at our tertiary Pediatric Lipid Clinic. Table 1 describes the identified genetic mutations of FHBL in our cohort, classified as pathogenic or likely pathogenic, and the potential correlated symptoms: gastrointestinal symptoms as diarrhea, fat malabsorption and steatorrhea have been complained only by one patient with a concomitant diagnosis of FHBL, celiac disease and thyroiditis. 4/12 cases presented failure to thrive and/or short stature: 2 of them were already on recombinant growth hormone therapy after a diagnosis of growth hormone deficiency, one patient presented a concomitant diagnosis of celiac disease and another Kabuki’s syndrome. Overweight and/or obesity were identified in 58.3% of patients (7/12). Only one patient was fully asymptomatic. No one presented acanthocytosis or neurological symptoms. All patients declared a family history positive for hypocholesterolemia. Table 1 Descriptive summary of the identified genetic mutations of heterozygous familial hypobetalipoproteinemia in our cohort and potential correlated symptoms. Symptoms Gene (exon) Nucleotide change Protein change ACMG classification Gender (M/F) Hepatic steatosis Diarrhoea Failure to thrive Fat malabsorption Steatorrhea Acanthocytosis Neurological symptoms Asymptomatic Other ApoB ( 26 ) c.5350_5363del p.Val1784Thr Pathogenic M 1 Overweight, Paroxysmal supraventricular tachycardia ApoB ( 26 ) c.8931dup p.Ser2978lle Likely pathogenic M 1 1 1 1 Celiac disease, Thyroiditis ApoB ( 11 ) c.1468C > T p.Arg490Trp Pathogenic M 1 Growth hormone deficiency MYLIP ( 6 ) c.1015G > A p.Val339Ile Likely pathogenic M Obesity ApoB ( 22 ) c.3423_3425delinsTGTGG p.Trp1141Cys Likely pathogenic M 1 ApoB ( 26 ) c.6043dup p.Ala2015Gly Likely pathogenic F 1 Obesity, Central precocious puberty ANGPTL8 ( 3 ) c.508G > A p.Val170Met Likely pathogenic F 1 Obesity ApoB ( 26 ) c.11483del p.Pro3828Gln Likely pathogenic F 1 Obesity, Acquired Hypothyroidism ApoB ( 26 ) c.5350_5363del p.Val1784Thr p.Val1757Thr Pathogenic M 1 Obesity ApoB ( 26 ) c.5890A > G p.His1923Arg Likely pathogenic M 1 1 Kabuki’s syndrome, Growth hormone deficiency, Overweight ApoB ( 26 ) c.10351A > C p.Lys3451Gln Likely pathogenic M 1 ANGPTL8 ( 1 ) p.Arg83Trp Likely pathogenic F 1 In our cohort, despite the wide phenotype, mean H SDS resulted adequate (0.12 ± 1.76 SDS) while mean BMI SDS was elevated (1.16 ± 1.67 SDS), as shown in Table 2 . When the cohort was grouped according to BMI SDS, obese and overweight FHBL presented a worst WC/H ratio (0.58 ± 0.04 vs. 0.56 ± 0.02, p 0.03) and an apparently unfavourable blood pressure profile than normal-weighted FHBL: in fact, the mean percentile of systolic and diastolic blood pressure were higher in obese patients than normal-weight, even without reaching statistical significance (SBP percentile 90.85 ± 5.52 vs. 76.75 ± 21.46°, p 0.34 and DBP percentile 73.57 ± 17.72 vs. 60.00 ± 21.60°, p 0.34)(Table 2 ). Table 2 Anthropometric features of our heterozygous FHBL cohort (average ± SDS; range). All patients Overweight/Obese (num. 7) Normal-weight (num. 5) p Age (years) 12.14 ± 1.80 (9.71–16.05) 11.32 ± 1.12 (9.71–12.45) 13.30 ± 2.03 (10.89–16.05) 0.14 Females (%) 33% (4/12) 43% (3/7) 10% (1/5) H SDS 0.12 ± 1.76 (-2.44–3.09) 0.44 ± 2.05 (-2.44–3.09) -0.42 ± 1.12 (-1,53–0.89) 0.29 BMI SDS 1.16 ± 1.67 (-1.53–3.18) 2.29 ± 0.54 (1.57–3.18) -0.81 ± 0.77 (-1.53–0.27) 0.01* WC/H 0.58 ± 0.04 (0.53–0.66) 0.58 ± 0.04 (0.53–0.66) 0.56 ± 0.02 (0.44–0.58) 0.03* SBP (mmHg) 117.45 ± 10.73 (100–137) 117.14 ± 7.66 (102–125) 118 ± 16.30 (100–137) 0.92 SBP (°p) 85.72 ± 14.39 (50–99) 90.85 ± 5.52 (80–95) 76.75 ± 21.46 (50–99) 0.34 DBP (mmHg) 66.18 ± 9.42 (55–82) 65.57 ± 10.37 (55–82) 67.25 ± 8.84 (60–80) 0.70 DBP (°p) 68.63 ± 19.37 (40–95) 73.57 ± 17.72 (50–95) 60.00 ± 21.60 (40–90) 0.34 Legend: H, Height; BMI, Body Mass Index; WC, Waist Circumference; SBP, Systolic Blood, Pressure; DBP, Diastolic Blood Pressure; *, statistical significance (p < 0.05) In all cases, lipid assessment was suggestive of FHBL (TC 80.41 ± 14.81 mg/dl; LDL-C 31.54 ± 12.88 mg/dl; TG 43.50 ± 30.39 mg/dl and ApoB 24.66 ± 12.37 mg/dl), as reported in Table 3 . The mean percentile was 1°, 2 ± 1.78° and 27.40 ± 35.82° for TC, LDL-C and TG, respectively. Biochemically, all FHBL patients did not showed alterations in liver function (mean AST 27.37 ± 7.00 U/L, ALT 29.00 ± 10.55 U/L and γGT 15.00 ± 2.82 U/L), while glycaemic profile seemed to be influenced by the high rate of obesity and overweight (mean FGIR 6.58 ± 4.28, mean HOMA index 4.95 ± 4.36). Nevertheless, obese and overweight FHBL patients did not showed a significant worst glycaemic assessment than lean FHBL peers (Table 3 ). Table 3 Biochemical features of our heterozygous FHBL cohort (average ± SDS; range). All patients Overweight/Obese Normal-weight p Total cholesterol mg/dl 80.41 ± 14.81 (54–106) 78.85 ± 10.63 (59–92) 82.60 ± 20.58 (54–106) 0.62 p° 1 1 1 N.A. LDL cholesterol mg/dl 31.54 ± 12.88 (10–53) 33.85 ± 9.52 (23–51) 27.50 ± 18.37 (10–53) 0.39 p° 2 ± 1.78 ( 1 – 6 ) 1.87 ± 1.46 ( 1 – 4 ) 2.25 ± 2.50 ( 1 – 6 ) 0.92 HDL mg/dl 43.83 ± 13.95 (23–74) 41.71 ± 10.35 (32–57) 46.80 ± 18.86 (23–74) 0.62 p° 25.66 ± 27.40 (1–90) 20.00 ± 21.73 (4–52) 33.60 ± 34.94 (1–90) 0.62 TG mg/dl 43.50 ± 30.39 (13–106) 54.28 ± 30.34 (21–106) 18.33 ± 6.11 ( 13 – 25 ) 0.03* p° 27.40 ± 35.82 (1–90) 38.71 ± 37.78 (1–90) 1.7 ± 0.87 ( 1 – 3 ) 0.15 ApoB (mg/dl) 24.66 ± 12.37 (11–49) 24.80 ± 9.78 (14–39) 24.50 ± 16.76 (11–49) 0.53 AST (U/L) 27.37 ± 7.00 (20–43) 26.80 ± 1.92 ( 24 – 29 ) 28.33 ± 12.74 (20–43) 0.55 ALT (U/L) 29.00 ± 10.55 (11–42) 32.16 ± 5.34 (24–39) 22.66 ± 16.86 (11–42) 0.51 γGT (U/L) 15.00 ± 2.82 ( 13 – 17 ) 16.09 ± 2.11 ( 13 – 17 ) 15.32 ± 1.24 ( 15 – 17 ) 0.87 Glucose (mg/dl) 88.60 ± 8.04 (71–98) 91.57 ± 5.38 (82–98) 81.66 ± 10.06 (71–91) 0.17 Insulin (µU/ml) 22.21 ± 19.50 (6.3–62.2) 23.57 ± 20.65 (6.3–62.2) 7.55 ± 4.2 (6.5–12.7) 0.25 FGIR 6.58 ± 4.28 (1.43–13.01) 6.58 ± 4.62 (1.78–13.01) 6.53 ± 1.22 (1.43–7.75) 0.35 HOMA index 4.95 ± 4.36 (1.26–13.53) 5.29 ± 4.59 (1.26–13.53) 2.45 ± 2.3 (2.45–6.9) 0.46 Legend: LDL, Low Density Lipoprotein; HDL, High Density Lipoprotein; TG, Triglycerides; FGIR, fasting glucose/insulin ratio; HOMA index, Homeostatic Model Assessment for Insulin Resistance; N.A., Not Available. Steatosis was diagnosed in 7/12 patients (58.3%): only in one case it was defined as mild, while in others it graded from moderate to severe, mainly when associated by overweight and/or obesity (p 0.05) (Table 4 ). Moreover, TE was more elevated in FHBL patients if overweight and/or obese (5.65 ± 0.71 vs. 4.60 ± 0.28, p 0.06). CAP did not significantly differ between FHBL groups, even if noticeably higher in overweight and/or obese patients (Table 4 ). Table 4 Ultrasonographic and elastographic parameters of our heterozygous FHBL cohort (average ± SDS; range). Steatosis at Liver ultrasound All patients Overweight/Obese Normal-weight p Score 0 – Absence (num) 5 1 4 0.05* Score 1 - Mild (num) 1 1 0 0.56 Score 2–3 – Moderate - Severe (num) 6 5 1 0.05* Liver elastography TE (kPa) 5.38 ± 0.78 (4.4-7) 5.65 ± 0.71 (4.90–7.00) 4.60 ± 0.28 (4.40–4.80) 0.06 CAP 240.57 ± 74.04 (100–316) 261.20 ± 48.99 (189–316) 189.00 ± 125.86 (100–278) 0.57 Legend: TE, Transient Elastography; CAP, Controlled Attenuation Parameter Analysing correlations among FHBL obese and overweight patients, TE and CAP correlated with levels of Apo B (r -0.90, p < 0.05) and TC (r -0.90, p < 0.05), respectively. Moreover, in FHBL patients with a moderate/severe steatosis, CAP correlates with diastolic blood pressure (r 0.97, p < 0.05). Discussion Literature uniformly suggests that FHBL should be suspected in childhood and adolescence when: family history is positive for hypocholesterolemia; patients present growth delay, abdominal pain, diarrhea mainly associated with lipid rich meals; early presence of liver steatosis and steatohepatitis not associated with an already known metabolic conditions ( 12 ). A suggestive fasting lipid profile comprises LDL-C levels between 10–50 mg/dL, apoB and triglycerides less than 5°centile according to gender and age ( 3 , 5 ). In pediatrics, appropriate centile should be selected ( 19 , 20 ). Our cohort demonstrated a wide phenotypic spectrum of heterozygous FHBL in pediatric age, frequently associated with misleading conditions as celiac disease, growth hormone deficiency and overweight/obesity. The typical clinical presentation of FHBL of a lean patient with steatosis is no more feasible and should not be exclusively expected, especially in childhood and adolescents. This finding support clinicians in prescribing the evaluation of a complete lipid profile as first line tests in all children with growth deviations, ranging from failure to thrive to overweight and obesity. In case of suspicion (low lipid levels and positive family history), it is reasonable, in our opinion, to perform the dosage of ApoB, liver function (ASL, ALT, GGT, coagulation, liver ultrasound and elastography), glucose metabolism, fat-soluble vitamin, and finally, the proper genetic test to confirm the diagnosis and to screen complications ( 10 ). Other causative conditions such as malnutrition, malabsorption, hyperthyroidism, cancers, drugs and liver failure should be primarily ruled out ( 5 ). Adults affected by FHBL have a higher grade of liver fibrosis at biopsy and a higher speed of progression compared to patients with nonalcoholic fatty liver disease (NAFLD) ( 7 , 26 ). Our data support that this risk is already evident in pediatric age, especially if associated with other high-risk metabolic conditions. Overweight and obesity are known to be strongly associated with an increase of the risk of metabolic syndrome already in the first decades of life. Our data demonstrated than in a high-risk population, as children and adolescents with FHBL, the presence of concomitant factors as overweight and obesity, insulin-resistance and/or hypertension, could potentially further accelerate the liver damage. In 2012, Nobili and colleagues demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that in children with FHBL, fat accumulation per sè may be not a sufficient causal factor leading to insulin resistance ( 27 ). Our data seemed apparently in contrast: in fact, in our cohort, a mean altered metabolic pattern is documented even in lean FHBL patients, as shown in Table 3 . In our opinion, it supports that, in FHBL, the hepatic involvement could be causative of or, at least, contributing to determining a concomitant unfavourable metabolic pattern. On the other side, as in a one-to-one correlation, overweight- and obesity-related metabolic injury (e.g. visceral adiposity, insulin resistance, hypertension…) can play a role as additional triggers for the development and progression of liver steatosis. Other factors (from genetics to the environment) could be involved. To clarify the pathogenic mechanism between liver fat accumulation and steatosis and the associated metabolic pattern in FHBL patients, it would be interesting to assess differences between the liver histological pattern of FHBL children and of other peers with metabolic dysfunction-associated fatty liver disease (MAFLD). Moreover, it seems necessary to evaluate the relationship between the type of ApoB (or other involved genes) mutations and the risk of developing liver damage, but, because of the exiguity of our cohort, it is currently beyond our aims. An appropriate screening program to increase the awareness of FHBL among all the healthcare operators (from pediatrics to dieticians) should be promoted. In fact, patients with FHBL, despite their low lipid pattern, should adhere to a low-fatty diet to limit steatosis and fat malabsorption and a healthy lifestyle should be guarantee. No other treatments are available yet if liver is precociously involved ( 7 ). Patients with detected low level of fat-soluble vitamins can benefit from supplementation with an adequate dose related to the plasma level. The supplementation of vitamin E is discussed to limit liver damage. Some authors propose Vitamin E 400 UI/twice a day in case of steatosis or increased liver stiffness because it has been associated with a liver histology improvement ( 5 , 25 ). After the diagnosis, how to follow up children and adolescents with FHBL is currently not uniformly defined. In our opinion an annual follow up seems prudent. It should include a complete anthropometric evaluation, blood tests, nutritional recap and liver ultrasound with elastography. Its frequency should be guided by the severity of the liver involvement at the diagnosis or by the presence of indirect biochemical signs of progression of liver damage. How to monitor liver involvement in childhood is internationally debated. In fact, liver biopsy is the gold standard to estimate steatosis and fibrosis. Nevertheless, its use is limited in pediatric age because it is invasive and associated with possible severe complications. Moreover, there is no evidence about its timing of execution and there is no specific pediatrics score yet ( 28 ). In clinical practice, liver ultrasound has a main role, but seems to underestimate mild and moderate grades of steatosis and there is a lack of validated pediatrics cutoff to standardize the exam. Therefore, surrogate markers and non-invasive tools, as elastography, are needed to screen liver involvement. In future, we expected that they will gradually obtain a crucial role especially in pediatric setting. The literature already proposes to quantify CAP as a parameter of steatosis and to evaluate hepatic stiffness with TE, as we already periodically perform. Moreover, in adults, other no invasive biochemical prognostic factor and score to follow-up the possible progression of liver damage are already widespread, as Fib4 score ( 29 ). Further studies in pediatric setting are needed to validate them in childhood and adolescence. Nevertheless, as demonstrated in our cohort, these surrogates could be useful in clinical practice, especially in childhood. The present study has numerous limitations: first of all, it is monocentric, and the number of involved patients and the length of follow-up are now limited. Moreover, the topic stresses several already known open issues underlining the need of wide and randomized studies to: establish pediatric ultrasound and elastographic cut-off for both liver steatosis and fibrosis; validate pediatrics no-invasive risk scores for liver damage based on biochemical and imaging evaluations ( 7 ); agree to the timing of the clinical, biochemical and imaging follow up of FHBL children and adolescents; identify therapeutic options to prevent/treat liver steatosis and steatohepatitis in these patients and to consider the appropriateness of supplementation of vitamin E to limit hepatic harm also in pediatric age ( 5 , 6 , 9 , 30 ). Conclusions Our data document an unexpectedly wide phenotype of FHBL in childhood and adolescence ranging from no symptoms to growth failure or, on the other side, to obesity. Moreover, we document a frequent precocious hepatic involvement in FHBL children, especially if obese and overweight with a potential rapid evolution in fibrosis. In conclusion, even if these preliminary data require the confirmation from sizable cohort, they support the need of a precocious diagnosis of FHBL in childhood that could let to early plan a personalized follow up in the affected patients in order to monitor their growth and potential complications and, above all, to prevent liver damage. Abbreviations ALT, ALanine Transaminase ANGPTL3, Angiopoietin-like Protein 3 ANGPTL8, Angiopoietin-like Protein 8 APOB, Apolipoprotein B AST, ASpartate aminoTransferase BMI, Body Mass Index CAP, Controlled Attenuation Parameter DBP, Diastolic Blood Pressure FGIR, Fasting Glucose/Insulin Ratio FHBL, Familial Hypobetalipoproteinemia H, Height HOMA, Homeostatic Model Assessment Index LDL, Low-Density-Lipoprotein MAFLD, Metabolic dysfunction-Associated Fatty Liver Disease MTTP, Microsomal Triglyceride Transfer Protein gene NAFLD, Non Alcoholic Fatty Liver Disease PCSK9, Proprotein Convertase Subtilisin Kexin type 9 gene SAR1B or SARA2, SAR1 gene homolog B SDS, Standard Deviation Score SBP, Systolic Blood Pressure TE, Transient Elastography TC, Total Cholesterol TG, Triglycerides US, UltraSound VLDL, Very Low-Density Lipoprotein WC, Waist Circumference γGT, Gamma-glutamyl Transferase Declarations Ethics approval and consent to participate: see Maintext Consent for publication: see Maintext Availability of data and materials: All data generated or analysed during this study are included in this published article Competing interests: The authors declare that they have no competing interests Funding: No funding Authors' contributions: Patrizia Bruzzi: Conceptualization, data curation, investigation, methodology, software, writing – original draft. Giulia Cammarata: Data curation, formal analysis. Rita Di Biase: Supervision, writing – review & editing. Barbara Predieri: Supervision. Laura Lucaccioni: Supervision, validation, visualization. Antonio Colecchia: Methodology, supervision. Lorenzo Iughetti: Conceptualization, writing – review & editing. Acknowledgements: Not applicable References Bredefeld C, Hussain MM, Averna M, Black DD, Brin MF, Burnett JR, et al. Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol. 2022. doi: 10.1016/j.jacl.2022.08.009. Wakabayashi T, et al. Current Diagnosis and Management of Familial HypobetalipoproteinemiA. J Atheroscler Thromb. 2024. http://doi.org/10.5551/jat.RV22018 Buryska S, Ahn JC, Allen AM, Simha V, Simonetto DA. Familial Hypobetalipoproteinemia: An Underrecognized Cause of Lean NASH. Hepatology. 2021. doi: 10.1002/hep.31988. Epub 2021 Jul 8. PMID: 34091928 Rimbert A, et al. Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia Arterioscler Thromb Vasc Biol. 2021. doi: 10.1161/ATVBAHA.120.315491. Molk N, Bitenc M, Urlep D, Zerjav Tansek M, Bertok S, Trebusak Podkrajsek K, et al. Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review. Front Med (Lausanne). 2023. doi: 10.3389/fmed.2023.1106441 Sissaoui S, Cochet M, Poinsot P, Bordat C, Collardeau-Frachon S, Lachaux A, et al. Lipids Responsible for Intestinal or Hepatic Disorder: When to Suspect a Familial Intestinal Hypocholesterolemia? J Pediatr Gastroenterol Nutr. 2021. doi: 10.1097/MPG.0000000000003145 Mouzaki M, Shah A, Arce-Clachar AC, Hardy J, Bramlage K, Xanthakos SA. Extremely low levels of low-density lipoprotein potentially suggestive of familial hypobetalipoproteinemia: A separate phenotype of NAFLD? J Clin Lipidol. 2019. doi: 10.1016/j.jacl.2019.02.002 Fogacci F, Ferri N, Toth PP, Ruscica M, Corsini A, Cicero AFG. Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials. Drugs. 2019. doi: 10.1007/s40265-019-01114-z Hegarty R, Kyrana E, Fitzpatrick E, Dhawan A. Fatty liver disease in children (MAFLD/PeFLD Type 2): unique classification considerations and challenges. Ther Adv Endocrinol Metab. 2023. doi: 10.1177/20420188231160388 Vos MB, Abrams SH, Barlow SE, Caprio S, Daniels SR, Kohli R, et al. NASPGHAN Clinical Practice Guideline for the Diagnosis and Treatment of Nonalcoholic Fatty Liver Disease in Children: Recommendations from the Expert Committee on NAFLD (ECON) and the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN). J Pediatr Gastroenterol Nutr. 2017. doi: 10.1097/MPG.0000000000001482 Xanthakos SA. Nonalcoholic Steatohepatitis in Children. Clin Liver Dis. 2022. doi: 10.1016/j.cld.2022.05.001. Brecelj J, Orel R. Non-Alcoholic Fatty Liver Disease in Children. Medicina (Kaunas). 2021. doi: 10.3390/medicina57070719 Lohman TG, Roche AF, Martorell R, eds. Anthropometric Standardization Reference Manual. Human Kinetics Books, Champaign IL, 1988 Cacciari E, Milani S, Balsamo A, Spada E, Bona G, Cavallo L, et al. Italian cross-sectional growth charts for height, weight and BMI (2 to 20 yr). J Endocrinol Invest. 2006. doi: 10.1007/BF03344156 de Onis M, A.W. Onyango, E. Borghi, A. Siyan, C. Nishida, J. Siekmann. Development of WHO growth reference for school-aged children and adolescents Bull World Health Organ, 85 (9) (2007), pp. 660-667 Ukegbu TE, Wylie‑Rosett J, Groisman‑Perelstein AE, Diamantis PM, Rieder J et al. Waist-to-height ratio associated cardiometabolic risk phenotype in children with overweight/obesity. BMC Public Health. 2023. https://doi.org/10.1186/s12889-023-16418-9 Marshall WA, Tanner JM. Variations in Pattern of Pubertal Changes in Girls. Arch Dis Child. 1969. doi: 10.1136/adc.44.235.291 Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al; SUBCOMMITTEE ON SCREENING AND MANAGEMENT OF HIGH BLOOD PRESSURE IN CHILDREN. Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Pediatrics. 2017. doi: 10.1542/peds.2017-1904 De Henauw S, et al. Blood lipids among young children in Europe: results from the European IDEFICS study. International Journal of Obesity 2014; 38: S67-75 Balder JW, Lansberg PJ, Hof MH, Wiegman A, Hutten BA, Kuivenhoven JA. Pediatric lipid reference values in the general population: The Dutch lifelines cohort study. J Clin Lipidol. 2018. doi: 10.1016/j.jacl.2018.05.011 d'Annunzio G, Vanelli M, Pistorio A, Minuto N, Bergamino L, Iafusco D, et al. Diabetes Study Group of the Italian Society for Pediatric Endocrinology and Diabetes. Insulin resistance and secretion indexes in healthy Italian children and adolescents: a multicentre study. Acta Biomed. 2009 80(1) Silfen ME, Manibo AM, Mcmahon DJ, Levine LS, Murphy AR, Oberfield SE. Comparison of Simple Measures of Insulin Sensitivity in Young Girls with Premature Adrenarche: The Fasting Glucose to Insulin Ratio May Be a Simple and Useful Measure. J Clin Endocrinol Metab. 2001. doi: 10.1210/jcem.86.6.7537 Ferraioli G, Soares Monteiro LB. Ultrasound-based techniques for the diagnosis of liver steatosis. World J Gastroenterol. 2019. doi: 10.3748/wjg.v25.i40.6053 Karlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de Lédinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017. doi: 10.1016/j.jhep.2016.12.022 Alkhouri N, Sedki E, Alisi A, Lopez R, Pinzani M, Feldstein AE, Nobili V. Combined paediatric NAFLD fibrosis index and transient elastography to predict clinically significant fibrosis in children with fatty liver disease. Liver Int. 2013. doi: 10.1111/liv.12024 Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia: liver disease and cardiovascular disease. Curr Opin Lipidol. 2020. doi: 10.1097/MOL.0000000000000663. Della Corte C, Fintini D, Giordano U, Cappa M, Brufani C, Majo F, Mennini C, Nobili V. Fatty liver and insulin resistance in children with hypobetalipoproteinemia: the importance of aetiology. Clin Endocrinol (Oxf). 2013. doi: 10.1111/j.1365-2265.2012.04498.x Cao YT, Xiang LL, Qi F, Zhang YJ, Chen Y, Zhou XQ. Accuracy of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) for assessing steatosis and fibrosis in non-alcoholic fatty liver disease: A systematic review and meta-analysis. EClinicalMedicine. 2022. doi: 10.1016/j.eclinm.2022.101547 Kjaergaard M, Lindvig KP, Holtz Thorhauge K, et al. Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease. J Hepatol. 2023. doi: 10.1016/j.jhep.2023.04.002 Attia SL, Softic S, Mouzaki M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin Transl Sci.2021. doi:10.1111/cts.12839 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7443290","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":506311742,"identity":"4a517d45-5297-43be-9c3c-5de38ed03890","order_by":0,"name":"Patrizia Bruzzi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+ElEQVRIiWNgGAWjYBACAySS4QCQIQeT4SGshQ2ixRiuBZceAziLDUIlNhCyxlz6jPHHHwUMefzzex8e/FFgl97f3mPAdKOCQcYehxbLvhwDAwkDhmKJY+wGByQMknNnnDljwJxzBo/DzvAYJBgYAN1zjI3hgIEBc27DjRwg2YZfy4EEoJb5IC0JBvXp8kRoMWw4ANSyAaTlgMHhBANCWix72IoZGwwkig2PpTEcbDA4brjxzLGCwzlnJHh4DuAIMR7mzR9//LHJkzt8jBnIqJaXO9688XFOhY09ewMOayBAIgGFCzRfAq96EEggqGIUjIJRMApGLgAADfhRPCOFYT0AAAAASUVORK5CYII=","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":true,"prefix":"","firstName":"Patrizia","middleName":"","lastName":"Bruzzi","suffix":""},{"id":506311743,"identity":"aa1b2232-8661-46a1-9ede-3b311d63d75b","order_by":1,"name":"Giulia Cammarata","email":"","orcid":"","institution":"University of Modena and Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Giulia","middleName":"","lastName":"Cammarata","suffix":""},{"id":506311744,"identity":"8441c29a-340a-4e64-9a1d-6f64b59c068c","order_by":2,"name":"Annarita Di Biase","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Annarita","middleName":"Di","lastName":"Biase","suffix":""},{"id":506311745,"identity":"418af63b-6675-48fa-aca4-68726600b1aa","order_by":3,"name":"Barbara Predieri","email":"","orcid":"","institution":"University of Modena and Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Predieri","suffix":""},{"id":506311746,"identity":"adda7f27-6027-4256-980e-a9e6259dc8c3","order_by":4,"name":"Laura Lucaccioni","email":"","orcid":"","institution":"University of Modena and Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Lucaccioni","suffix":""},{"id":506311754,"identity":"dbd53aa1-3307-4c9c-9040-5875af5d2da0","order_by":5,"name":"Antonio Colecchia","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Antonio","middleName":"","lastName":"Colecchia","suffix":""},{"id":506311757,"identity":"2914020e-b1d7-421a-b971-412cb52e7825","order_by":6,"name":"Lorenzo Iughetti","email":"","orcid":"","institution":"University of Modena and Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Lorenzo","middleName":"","lastName":"Iughetti","suffix":""}],"badges":[],"createdAt":"2025-08-23 21:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7443290/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7443290/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94176584,"identity":"c541c5c4-1785-41dc-bdba-8bc6dd5c0290","added_by":"auto","created_at":"2025-10-23 08:32:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":832320,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7443290/v1/43cecbae-efca-4433-bf14-211f61c79784.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eHeterozygous Familial Hypobetalipoproteinemia in Children and Adolescents: Time and tide wait for no man\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eFamilial Hypobetalipoproteinemia (FHBL) is a rare autosomal codominant genetic disease characterized by low level of plasma Total Cholesterol (TC), Low-Density-Lipoprotein (LDL), Triglycerides (TG) and Apolipoprotein B (APOB) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMore than 140 mutations in the APOB gene have been found to cause FHBL. They lead to the production of abnormally short ApoB proteins (ApoB100 and ApoB-48) that confer lower rates of synthesis and secretion of apoB-containing lipoproteins and higher rates of catabolism of truncated apoB-containing lipoproteins. (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). The shorter the length of the truncated apoBs, the more severe the degree of complications (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Less frequently mutations involve Proprotein Convertase Subtilisin Kexin type 9 gene (PCSK9), Microsomal Triglyceride Transfer Protein gene (MTTP), SAR1 gene homolog B (SAR1B or SARA2) and angiopoietin-like protein 3 (ANGPTL3) and 8 (ANGPTL8). The estimated prevalence of FHBL in the general population is between 1:1000 to 1:3000 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Nevertheless, in adults, a monogenic origin of HBL is identified in only 20\u0026ndash;50% of patients suggesting a frequent polygenic inheritance, involving multiple common genetic variants with small to moderate effects (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePatients carrying a heterozygous mutation are often asymptomatic and the diagnosis is frequently only incidental, suspected on hypocholesterolemia at blood tests performed for other medical reasons. Mild intestinal symptoms are described such as abdominal pain and diarrhea associated with lipid rich meals (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). Affected patients benefit from a reduced cardiovascular risk but they are not free from complications. In fact, ApoB mutation causes a decreased secretion of apoB100-containing lipoproteins and determines a defect in assembly and export of VLDL from the hepatocytes that remains stack in the liver (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) and cause early liver steatosis, steatohepatitis that can develop in fibrosis and cirrhosis (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). This observation is consistent with the hepatic adverse effects observed in patients treated with APOB antisense (mipomersen) for severe familial hypercholesterolemia (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Moreover, FHBL patients are predisposed to fat-soluble vitamin malabsorption, and related symptoms such as ataxia, dysmetria, ophthalmological abnormalities and bone loss (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDue to the potential and severe hepatic harm, early recognition of affected children and adolescents has a pivotal role to evaluate prognostic risk factors of liver damage and to plan a personalized follow up (\u003cspan additionalcitationids=\"CR10 CR11\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Nevertheless, in pediatric literature, data are mainly derived from case reports, while cohort study and guidelines are lacking.\u003c/p\u003e\u003cp\u003eIn this paper, we illustrate the phenotypic features of a cohort of children and adolescents with a genetic confirmed FHBL attending our Pediatric Lipid Clinic.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e This is a monocentric, observational study enrolling children and adolescents with a genetic diagnosis of FHBL followed up at our tertiary Pediatric Lipid Clinic in the last 2 years.\u003c/p\u003e\u003cp\u003e The study was conducted in agreement with the Declaration of Helsinki and was approved by the local Ethical Committee (Protocol number 245/2016). Parental written informed consent and patient assent were obtained before starting the data collection.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eAnamnestic data\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eAnthropometric data\u003c/h2\u003e\u003cp\u003eAll recruited patients underwent a complete physical examination performed by a team of fully trained examiners according to the Anthropometric Standardization Reference Manual (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). Height (H) was measured to the nearest 0.1 cm with a calibrated well-mounted Harpenden\u0026rsquo;s stadiometer (Crymych, UK), compared with age-matched reference values and expressed as standard deviation score (H SDS) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Body weight was measured to the nearest 0.1 kg with a calibrated scale. BMI was calculated by dividing weight in kg by height square (m\u003csup\u003e2\u003c/sup\u003e) and was standardized to SDS (BMI SDS) according to age using appropriate Italian chart (\u003cb\u003e14\u003c/b\u003e). According to BMI SDS, patients were classified as normal weighted or overweighted and obese (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The waist circumference (WC) was measured using an elastic tape at the iliac crest. Previous literature indicated that dichotomized WC/H ratio cut points at \u0026ge;\u0026thinsp;0.5 or 0.55 are surrogates of increased cardiovascular risk in children (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Pubertal staging was assessed using the Marshall and Tanner maturity scale (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Blood pressure (BP) was measured according to a standardized protocol on the right arm using an appropriate-sized cuff. Participants sit quietly for at least 5 minutes prior to measurement and the average of three following measurements was registered. Systolic and diastolic blood pressure (SBP and DBP, respectively) were standardized using the international child BP reference (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eBiochemical and genetic data\u003c/h3\u003e\n\u003cp\u003eAfter a 12 h overnight fast, blood samples were obtained from the antecubital vein of study participants.\u003c/p\u003e\u003cp\u003eFasting lipids [total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG) and ApoB lipoprotein (ApoB)] were measured using in vitro enzyme test kits on a Hitachi system (Cholesterol CHOD-PAD, HDL-C plus, Triglycerides GPO-PAP, and LDL-C plus; Roche Diagnostics GmbH, Mannheim, Germany). Their concentrations were standardized using the available international paediatric reference (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eInsulin was determined using an electrochemiluminescence immunoassay (IMMULITE 2000; Siemens Healthcare Diagnostics, NJ, US). Fasting glucose was measured by enzymatic absorption photometry on a Cobas 8000 analyzer (Gluco-Quant, Roche Diagnostics GmbH, Mannheim, Germany). Insulin resistance (IR) was defined by homeostatic model assessment index (HOMA index), compared to specific paediatric percentiles according to gender and pubertal stage (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), and by fasting glucose/insulin ratio (FGIR) less than 7 (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe liver enzymes, alanine transaminase (ALT), aspartate aminotransferase (AST) and gamma-glutamyl transferase (γGT) concentrations, were measured using an Immulite 2000 analyzer (Bio-DPC; Siemens Medical, Gwynedd, UK).\u003c/p\u003e\u003cp\u003eAll biochemical analyses were performed in the same laboratory.\u003c/p\u003e\u003cp\u003eA genetic test by NGS Sequencing, Sanger Sequencing was performed to all patients, the genes investigated were ANGPTL3, ANGPTL4, ANGPTL8, APOB, APOC3, MTTP, MYLIP, PCSK9, SAR1B.\u003c/p\u003e\n\u003ch3\u003eInstrumental data\u003c/h3\u003e\n\u003cp\u003eAfter a 12 h overnight fast, all patients underwent liver ultrasound (US) and elastography performed by the same radiologist using a Philips EpiQ Elite Diagnostic Ultrasound System (with a 15L8 probe) and a Fibroscan Expert 630, respectively.\u003c/p\u003e\u003cp\u003eSteatosis was instrumentally defined through a US semiquantitative assessment including liver brightness, contrast between the liver and the kidney, US appearance of the intrahepatic vessels, liver parenchyma and diaphragm. Steatosis was graded as: absent (score 0) when the echotexture of the liver was normal; mild (score 1) when there was a slight and diffuse increase of liver echogenicity with normal visualization of the diaphragm and of the portal vein wall; moderate (score 2) in case of a moderate increase of liver echogenicity with slightly impaired appearance of the portal vein wall and the diaphragm; severe (score 3) in case of marked increase of liver echogenicity with poor or no visualization of portal vein wall, diaphragm, and posterior part of the right liver lobe (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eElastography quantified liver steatosis and fibrosis. Literature already supports that Controlled Attenuation Parameter (CAP) correlated with histopathological findings of liver steatosis: no steatosis (CAP 150\u0026ndash;248 dB/m, amount 0\u0026ndash;10%), mild steatosis S0 (CAP 248\u0026ndash;260 db/m, amount 11\u0026ndash;33%), moderate S1 (260\u0026ndash;280 db/m, amount 34\u0026ndash;66%) and severe S2 (higher than 280 db/m, amount higher than 67%) (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Liver stiffness, a surrogate of fibrosis, was expressed by Transient Elastography (TE): if\u0026thinsp;\u0026lt;\u0026thinsp;5 kPa, it indicated absence of fibrosis, if 5\u0026ndash;7 Kpa any fibrosis, if 7\u0026ndash;9 significant fibrosis, if\u0026thinsp;\u0026gt;\u0026thinsp;9 KPa advanced fibrosis (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eContinuous data are reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), while categorical ones as percent values. Between-group comparisons were performed using Mann-Whitney U test (for numerical variables) and Pearson χ2 test (for percent values). Spearman correlation was used to identify the association between anthropometric, biochemical and instrumental variables. For each test, statistical significance was for p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. The statistical analysis was performed using the STATISTICA\u0026trade; software (StatSoft Inc., Tulsa, OK, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn the last 2 years, 12 children and adolescents (4 females) aged 12.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80 years (range 9.71\u0026ndash;16.05, median 12.02 years) were diagnosed with heterozygous FHBL at our tertiary Pediatric Lipid Clinic.\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e describes the identified genetic mutations of FHBL in our cohort, classified as pathogenic or likely pathogenic, and the potential correlated symptoms: gastrointestinal symptoms as diarrhea, fat malabsorption and steatorrhea have been complained only by one patient with a concomitant diagnosis of FHBL, celiac disease and thyroiditis. 4/12 cases presented failure to thrive and/or short stature: 2 of them were already on recombinant growth hormone therapy after a diagnosis of growth hormone deficiency, one patient presented a concomitant diagnosis of celiac disease and another Kabuki\u0026rsquo;s syndrome. Overweight and/or obesity were identified in 58.3% of patients (7/12). Only one patient was fully asymptomatic. No one presented acanthocytosis or neurological symptoms. All patients declared a family history positive for hypocholesterolemia.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDescriptive summary of the identified genetic mutations of heterozygous familial hypobetalipoproteinemia in our cohort and potential correlated symptoms.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"14\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c5\" namest=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"9\" nameend=\"c14\" namest=\"c6\"\u003e\u003cp\u003eSymptoms\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGene (exon)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNucleotide change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProtein change\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eACMG classification\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGender (M/F)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHepatic steatosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eDiarrhoea\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFailure to thrive\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFat malabsorption\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSteatorrhea\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eAcanthocytosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eNeurological symptoms\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c13\"\u003e\u003cp\u003eAsymptomatic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c14\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.5350_5363del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Val1784Thr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eOverweight,\u003c/p\u003e\u003cp\u003eParoxysmal supraventricular tachycardia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.8931dup\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Ser2978lle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eCeliac disease, Thyroiditis\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.1468C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg490Trp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eGrowth hormone deficiency\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMYLIP (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.1015G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Val339Ile\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eObesity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.3423_3425delinsTGTGG\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Trp1141Cys\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.6043dup\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Ala2015Gly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eObesity, Central precocious puberty\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eANGPTL8 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.508G\u0026thinsp;\u0026gt;\u0026thinsp;A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Val170Met\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eObesity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.11483del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Pro3828Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eObesity, Acquired Hypothyroidism\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.5350_5363del\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Val1784Thr\u003c/p\u003e\u003cp\u003ep.Val1757Thr\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eObesity\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.5890A\u0026thinsp;\u0026gt;\u0026thinsp;G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.His1923Arg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u003cp\u003eKabuki\u0026rsquo;s syndrome,\u003c/p\u003e\u003cp\u003eGrowth hormone deficiency,\u003c/p\u003e\u003cp\u003eOverweight\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec.10351A\u0026thinsp;\u0026gt;\u0026thinsp;C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Lys3451Gln\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c13\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eANGPTL8 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ep.Arg83Trp\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLikely pathogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c13\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c14\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn our cohort, despite the wide phenotype, mean H SDS resulted adequate (0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76 SDS) while mean BMI SDS was elevated (1.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67 SDS), as shown in Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. When the cohort was grouped according to BMI SDS, obese and overweight FHBL presented a worst WC/H ratio (0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 vs. 0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02, p 0.03) and an apparently unfavourable blood pressure profile than normal-weighted FHBL: in fact, the mean percentile of systolic and diastolic blood pressure were higher in obese patients than normal-weight, even without reaching statistical significance (SBP percentile 90.85\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52 vs. 76.75\u0026thinsp;\u0026plusmn;\u0026thinsp;21.46\u0026deg;, p 0.34 and DBP percentile 73.57\u0026thinsp;\u0026plusmn;\u0026thinsp;17.72 vs. 60.00\u0026thinsp;\u0026plusmn;\u0026thinsp;21.60\u0026deg;, p 0.34)(Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnthropometric features of our heterozygous FHBL cohort (average\u0026thinsp;\u0026plusmn;\u0026thinsp;SDS; range).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOverweight/Obese (num. 7)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal-weight (num. 5)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12.14\u0026thinsp;\u0026plusmn;\u0026thinsp;1.80 (9.71\u0026ndash;16.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.32\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12 (9.71\u0026ndash;12.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13.30\u0026thinsp;\u0026plusmn;\u0026thinsp;2.03 (10.89\u0026ndash;16.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemales (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33% (4/12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43% (3/7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10% (1/5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eH SDS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.76 (-2.44\u0026ndash;3.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;2.05 (-2.44\u0026ndash;3.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12 (-1,53\u0026ndash;0.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI SDS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.16\u0026thinsp;\u0026plusmn;\u0026thinsp;1.67 (-1.53\u0026ndash;3.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.29\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54 (1.57\u0026ndash;3.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.81\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77 (-1.53\u0026ndash;0.27)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.01*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWC/H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 (0.53\u0026ndash;0.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 (0.53\u0026ndash;0.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.56\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 (0.44\u0026ndash;0.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.03*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e117.45\u0026thinsp;\u0026plusmn;\u0026thinsp;10.73 (100\u0026ndash;137)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e117.14\u0026thinsp;\u0026plusmn;\u0026thinsp;7.66 (102\u0026ndash;125)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e118\u0026thinsp;\u0026plusmn;\u0026thinsp;16.30 (100\u0026ndash;137)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSBP (\u0026deg;p)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e85.72\u0026thinsp;\u0026plusmn;\u0026thinsp;14.39 (50\u0026ndash;99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e90.85\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52 (80\u0026ndash;95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e76.75\u0026thinsp;\u0026plusmn;\u0026thinsp;21.46 (50\u0026ndash;99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP (mmHg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.18\u0026thinsp;\u0026plusmn;\u0026thinsp;9.42 (55\u0026ndash;82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.57\u0026thinsp;\u0026plusmn;\u0026thinsp;10.37 (55\u0026ndash;82)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67.25\u0026thinsp;\u0026plusmn;\u0026thinsp;8.84 (60\u0026ndash;80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDBP (\u0026deg;p)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.63\u0026thinsp;\u0026plusmn;\u0026thinsp;19.37 (40\u0026ndash;95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e73.57\u0026thinsp;\u0026plusmn;\u0026thinsp;17.72 (50\u0026ndash;95)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60.00\u0026thinsp;\u0026plusmn;\u0026thinsp;21.60 (40\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eLegend: H, Height; BMI, Body Mass Index; WC, Waist Circumference; SBP, Systolic Blood, Pressure; DBP, Diastolic Blood Pressure; *, statistical significance (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05)\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn all cases, lipid assessment was suggestive of FHBL (TC 80.41\u0026thinsp;\u0026plusmn;\u0026thinsp;14.81 mg/dl; LDL-C 31.54\u0026thinsp;\u0026plusmn;\u0026thinsp;12.88 mg/dl; TG 43.50\u0026thinsp;\u0026plusmn;\u0026thinsp;30.39 mg/dl and ApoB 24.66\u0026thinsp;\u0026plusmn;\u0026thinsp;12.37 mg/dl), as reported in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The mean percentile was 1\u0026deg;, 2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78\u0026deg; and 27.40\u0026thinsp;\u0026plusmn;\u0026thinsp;35.82\u0026deg; for TC, LDL-C and TG, respectively. Biochemically, all FHBL patients did not showed alterations in liver function (mean AST 27.37\u0026thinsp;\u0026plusmn;\u0026thinsp;7.00 U/L, ALT 29.00\u0026thinsp;\u0026plusmn;\u0026thinsp;10.55 U/L and γGT 15.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.82 U/L), while glycaemic profile seemed to be influenced by the high rate of obesity and overweight (mean FGIR 6.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.28, mean HOMA index 4.95\u0026thinsp;\u0026plusmn;\u0026thinsp;4.36). Nevertheless, obese and overweight FHBL patients did not showed a significant worst glycaemic assessment than lean FHBL peers (Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBiochemical features of our heterozygous FHBL cohort (average\u0026thinsp;\u0026plusmn;\u0026thinsp;SDS; range).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOverweight/Obese\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal-weight\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eTotal cholesterol\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emg/dl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e80.41\u0026thinsp;\u0026plusmn;\u0026thinsp;14.81 (54\u0026ndash;106)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e78.85\u0026thinsp;\u0026plusmn;\u0026thinsp;10.63 (59\u0026ndash;92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e82.60\u0026thinsp;\u0026plusmn;\u0026thinsp;20.58 (54\u0026ndash;106)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep\u0026deg;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eN.A.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eLDL cholesterol\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emg/dl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.54\u0026thinsp;\u0026plusmn;\u0026thinsp;12.88 (10\u0026ndash;53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.85\u0026thinsp;\u0026plusmn;\u0026thinsp;9.52 (23\u0026ndash;51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e27.50\u0026thinsp;\u0026plusmn;\u0026thinsp;18.37 (10\u0026ndash;53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep\u0026deg;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.78 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.87\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46 (\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.25\u0026thinsp;\u0026plusmn;\u0026thinsp;2.50 (\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eHDL\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emg/dl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.83\u0026thinsp;\u0026plusmn;\u0026thinsp;13.95 (23\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41.71\u0026thinsp;\u0026plusmn;\u0026thinsp;10.35 (32\u0026ndash;57)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e46.80\u0026thinsp;\u0026plusmn;\u0026thinsp;18.86 (23\u0026ndash;74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep\u0026deg;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.66\u0026thinsp;\u0026plusmn;\u0026thinsp;27.40 (1\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.00\u0026thinsp;\u0026plusmn;\u0026thinsp;21.73 (4\u0026ndash;52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e33.60\u0026thinsp;\u0026plusmn;\u0026thinsp;34.94 (1\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eTG\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emg/dl\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e43.50\u0026thinsp;\u0026plusmn;\u0026thinsp;30.39 (13\u0026ndash;106)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54.28\u0026thinsp;\u0026plusmn;\u0026thinsp;30.34 (21\u0026ndash;106)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18.33\u0026thinsp;\u0026plusmn;\u0026thinsp;6.11 (\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.03*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ep\u0026deg;\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.40\u0026thinsp;\u0026plusmn;\u0026thinsp;35.82 (1\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38.71\u0026thinsp;\u0026plusmn;\u0026thinsp;37.78 (1\u0026ndash;90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.7\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eApoB (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e24.66\u0026thinsp;\u0026plusmn;\u0026thinsp;12.37 (11\u0026ndash;49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24.80\u0026thinsp;\u0026plusmn;\u0026thinsp;9.78 (14\u0026ndash;39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e24.50\u0026thinsp;\u0026plusmn;\u0026thinsp;16.76 (11\u0026ndash;49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.53\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAST (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e27.37\u0026thinsp;\u0026plusmn;\u0026thinsp;7.00 (20\u0026ndash;43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.92 (\u003cspan additionalcitationids=\"CR25 CR26 CR27 CR28\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e28.33\u0026thinsp;\u0026plusmn;\u0026thinsp;12.74 (20\u0026ndash;43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.55\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eALT (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.00\u0026thinsp;\u0026plusmn;\u0026thinsp;10.55 (11\u0026ndash;42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.16\u0026thinsp;\u0026plusmn;\u0026thinsp;5.34 (24\u0026ndash;39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.66\u0026thinsp;\u0026plusmn;\u0026thinsp;16.86 (11\u0026ndash;42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eγGT (U/L)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.82 (\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.09\u0026thinsp;\u0026plusmn;\u0026thinsp;2.11 (\u003cspan additionalcitationids=\"CR14 CR15 CR16\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e15.32\u0026thinsp;\u0026plusmn;\u0026thinsp;1.24 (\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.87\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGlucose (mg/dl)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e88.60\u0026thinsp;\u0026plusmn;\u0026thinsp;8.04 (71\u0026ndash;98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.57\u0026thinsp;\u0026plusmn;\u0026thinsp;5.38 (82\u0026ndash;98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e81.66\u0026thinsp;\u0026plusmn;\u0026thinsp;10.06 (71\u0026ndash;91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsulin (\u0026micro;U/ml)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.21\u0026thinsp;\u0026plusmn;\u0026thinsp;19.50 (6.3\u0026ndash;62.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.57\u0026thinsp;\u0026plusmn;\u0026thinsp;20.65 (6.3\u0026ndash;62.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.55\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2 (6.5\u0026ndash;12.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFGIR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.28 (1.43\u0026ndash;13.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.58\u0026thinsp;\u0026plusmn;\u0026thinsp;4.62 (1.78\u0026ndash;13.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.22 (1.43\u0026ndash;7.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.35\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHOMA index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.95\u0026thinsp;\u0026plusmn;\u0026thinsp;4.36 (1.26\u0026ndash;13.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.29\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59 (1.26\u0026ndash;13.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.45\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 (2.45\u0026ndash;6.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eLegend: LDL, Low Density Lipoprotein; HDL, High Density Lipoprotein; TG, Triglycerides; FGIR, fasting glucose/insulin ratio; HOMA index, Homeostatic Model Assessment for Insulin Resistance; N.A., Not Available.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eSteatosis was diagnosed in 7/12 patients (58.3%): only in one case it was defined as mild, while in others it graded from moderate to severe, mainly when associated by overweight and/or obesity (p 0.05) (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Moreover, TE was more elevated in FHBL patients if overweight and/or obese (5.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71 vs. 4.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28, p 0.06). CAP did not significantly differ between FHBL groups, even if noticeably higher in overweight and/or obese patients (Table \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eUltrasonographic and elastographic parameters of our heterozygous FHBL cohort (average\u0026thinsp;\u0026plusmn;\u0026thinsp;SDS; range).\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSteatosis at Liver ultrasound\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll patients\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOverweight/Obese\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eNormal-weight\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ep\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScore 0 \u0026ndash; Absence (num)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.05*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScore 1 - Mild (num)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eScore 2\u0026ndash;3 \u0026ndash; Moderate - Severe (num)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.05*\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver elastography\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTE (kPa)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.38\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78 (4.4-7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71 (4.90\u0026ndash;7.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.60\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28 (4.40\u0026ndash;4.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.06\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCAP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e240.57\u0026thinsp;\u0026plusmn;\u0026thinsp;74.04 (100\u0026ndash;316)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e261.20\u0026thinsp;\u0026plusmn;\u0026thinsp;48.99 (189\u0026ndash;316)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e189.00\u0026thinsp;\u0026plusmn;\u0026thinsp;125.86 (100\u0026ndash;278)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.57\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eLegend: TE, Transient Elastography; CAP, Controlled Attenuation Parameter\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAnalysing correlations among FHBL obese and overweight patients, TE and CAP correlated with levels of Apo B (r -0.90, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and TC (r -0.90, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), respectively. Moreover, in FHBL patients with a moderate/severe steatosis, CAP correlates with diastolic blood pressure (r 0.97, p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eLiterature uniformly suggests that FHBL should be suspected in childhood and adolescence when: family history is positive for hypocholesterolemia; patients present growth delay, abdominal pain, diarrhea mainly associated with lipid rich meals; early presence of liver steatosis and steatohepatitis not associated with an already known metabolic conditions (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). A suggestive fasting lipid profile comprises LDL-C levels between 10\u0026ndash;50 mg/dL, apoB and triglycerides less than 5\u0026deg;centile according to gender and age (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). In pediatrics, appropriate centile should be selected (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). Our cohort demonstrated a wide phenotypic spectrum of heterozygous FHBL in pediatric age, frequently associated with misleading conditions as celiac disease, growth hormone deficiency and overweight/obesity. The typical clinical presentation of FHBL of a lean patient with steatosis is no more feasible and should not be exclusively expected, especially in childhood and adolescents. This finding support clinicians in prescribing the evaluation of a complete lipid profile as first line tests in all children with growth deviations, ranging from failure to thrive to overweight and obesity. In case of suspicion (low lipid levels and positive family history), it is reasonable, in our opinion, to perform the dosage of ApoB, liver function (ASL, ALT, GGT, coagulation, liver ultrasound and elastography), glucose metabolism, fat-soluble vitamin, and finally, the proper genetic test to confirm the diagnosis and to screen complications (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Other causative conditions such as malnutrition, malabsorption, hyperthyroidism, cancers, drugs and liver failure should be primarily ruled out (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAdults affected by FHBL have a higher grade of liver fibrosis at biopsy and a higher speed of progression compared to patients with nonalcoholic fatty liver disease (NAFLD) (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Our data support that this risk is already evident in pediatric age, especially if associated with other high-risk metabolic conditions. Overweight and obesity are known to be strongly associated with an increase of the risk of metabolic syndrome already in the first decades of life. Our data demonstrated than in a high-risk population, as children and adolescents with FHBL, the presence of concomitant factors as overweight and obesity, insulin-resistance and/or hypertension, could potentially further accelerate the liver damage. In 2012, Nobili and colleagues demonstrated that in children with FHBL, hepatic steatosis is dissociated from insulin resistance. This finding suggests that in children with FHBL, fat accumulation \u003cem\u003eper s\u0026egrave;\u003c/em\u003e may be not a sufficient causal factor leading to insulin resistance (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Our data seemed apparently in contrast: in fact, in our cohort, a mean altered metabolic pattern is documented even in lean FHBL patients, as shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. In our opinion, it supports that, in FHBL, the hepatic involvement could be causative of or, at least, contributing to determining a concomitant unfavourable metabolic pattern. On the other side, as in a one-to-one correlation, overweight- and obesity-related metabolic injury (e.g. visceral adiposity, insulin resistance, hypertension\u0026hellip;) can play a role as additional triggers for the development and progression of liver steatosis. Other factors (from genetics to the environment) could be involved. To clarify the pathogenic mechanism between liver fat accumulation and steatosis and the associated metabolic pattern in FHBL patients, it would be interesting to assess differences between the liver histological pattern of FHBL children and of other peers with metabolic dysfunction-associated fatty liver disease (MAFLD). Moreover, it seems necessary to evaluate the relationship between the type of ApoB (or other involved genes) mutations and the risk of developing liver damage, but, because of the exiguity of our cohort, it is currently beyond our aims.\u003c/p\u003e\u003cp\u003eAn appropriate screening program to increase the awareness of FHBL among all the healthcare operators (from pediatrics to dieticians) should be promoted. In fact, patients with FHBL, despite their low lipid pattern, should adhere to a low-fatty diet to limit steatosis and fat malabsorption and a healthy lifestyle should be guarantee. No other treatments are available yet if liver is precociously involved (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Patients with detected low level of fat-soluble vitamins can benefit from supplementation with an adequate dose related to the plasma level. The supplementation of vitamin E is discussed to limit liver damage. Some authors propose Vitamin E 400 UI/twice a day in case of steatosis or increased liver stiffness because it has been associated with a liver histology improvement (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eAfter the diagnosis, how to follow up children and adolescents with FHBL is currently not uniformly defined. In our opinion an annual follow up seems prudent. It should include a complete anthropometric evaluation, blood tests, nutritional recap and liver ultrasound with elastography. Its frequency should be guided by the severity of the liver involvement at the diagnosis or by the presence of indirect biochemical signs of progression of liver damage. How to monitor liver involvement in childhood is internationally debated. In fact, liver biopsy is the gold standard to estimate steatosis and fibrosis. Nevertheless, its use is limited in pediatric age because it is invasive and associated with possible severe complications. Moreover, there is no evidence about its timing of execution and there is no specific pediatrics score yet (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In clinical practice, liver ultrasound has a main role, but seems to underestimate mild and moderate grades of steatosis and there is a lack of validated pediatrics cutoff to standardize the exam. Therefore, surrogate markers and non-invasive tools, as elastography, are needed to screen liver involvement. In future, we expected that they will gradually obtain a crucial role especially in pediatric setting. The literature already proposes to quantify CAP as a parameter of steatosis and to evaluate hepatic stiffness with TE, as we already periodically perform. Moreover, in adults, other no invasive biochemical prognostic factor and score to follow-up the possible progression of liver damage are already widespread, as Fib4 score (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Further studies in pediatric setting are needed to validate them in childhood and adolescence. Nevertheless, as demonstrated in our cohort, these surrogates could be useful in clinical practice, especially in childhood.\u003c/p\u003e\u003cp\u003eThe present study has numerous limitations: first of all, it is monocentric, and the number of involved patients and the length of follow-up are now limited. Moreover, the topic stresses several already known open issues underlining the need of wide and randomized studies to: establish pediatric ultrasound and elastographic cut-off for both liver steatosis and fibrosis; validate pediatrics no-invasive risk scores for liver damage based on biochemical and imaging evaluations (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e); agree to the timing of the clinical, biochemical and imaging follow up of FHBL children and adolescents; identify therapeutic options to prevent/treat liver steatosis and steatohepatitis in these patients and to consider the appropriateness of supplementation of vitamin E to limit hepatic harm also in pediatric age (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur data document an unexpectedly wide phenotype of FHBL in childhood and adolescence ranging from no symptoms to growth failure or, on the other side, to obesity. Moreover, we document a frequent precocious hepatic involvement in FHBL children, especially if obese and overweight with a potential rapid evolution in fibrosis.\u003c/p\u003e\u003cp\u003eIn conclusion, even if these preliminary data require the confirmation from sizable cohort, they support the need of a precocious diagnosis of FHBL in childhood that could let to early plan a personalized follow up in the affected patients in order to monitor their growth and potential complications and, above all, to prevent liver damage.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALT, ALanine Transaminase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eANGPTL3, Angiopoietin-like Protein 3\u003c/p\u003e\n\u003cp\u003eANGPTL8, Angiopoietin-like Protein 8\u003c/p\u003e\n\u003cp\u003eAPOB, Apolipoprotein B\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAST, ASpartate aminoTransferase\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI, Body Mass Index\u003c/p\u003e\n\u003cp\u003eCAP, Controlled Attenuation Parameter\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDBP, Diastolic Blood Pressure\u003c/p\u003e\n\u003cp\u003eFGIR, Fasting Glucose/Insulin Ratio\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFHBL, Familial Hypobetalipoproteinemia\u003c/p\u003e\n\u003cp\u003eH, Height\u003c/p\u003e\n\u003cp\u003eHOMA, Homeostatic Model Assessment Index\u003c/p\u003e\n\u003cp\u003eLDL, Low-Density-Lipoprotein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMAFLD, Metabolic dysfunction-Associated Fatty Liver Disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMTTP, Microsomal Triglyceride Transfer Protein gene\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNAFLD, Non Alcoholic Fatty Liver Disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCSK9, Proprotein Convertase Subtilisin Kexin type 9 gene\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSAR1B or SARA2, SAR1 gene homolog B\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSDS, Standard Deviation Score\u003c/p\u003e\n\u003cp\u003eSBP, Systolic Blood Pressure\u003c/p\u003e\n\u003cp\u003eTE, Transient Elastography\u003c/p\u003e\n\u003cp\u003eTC, Total Cholesterol\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTG, Triglycerides\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUS, UltraSound\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVLDL, Very Low-Density Lipoprotein\u003c/p\u003e\n\u003cp\u003eWC, Waist Circumference\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eγGT, Gamma-glutamyl Transferase\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthics approval and consent to participate:\u003c/em\u003e\u003c/strong\u003e see Maintext\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication:\u003c/em\u003e\u003c/strong\u003e see Maintext\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials:\u003c/em\u003e\u003c/strong\u003e\u0026nbsp; All data generated or analysed during this study are included in this published article\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests:\u003c/em\u003e\u003c/strong\u003e The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding:\u003c/em\u003e\u003c/strong\u003e No funding\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors' contributions:\u003c/em\u003e\u003c/strong\u003e \u003cem\u003ePatrizia Bruzzi: Conceptualization, data curation, investigation, methodology, software, writing – original draft.\u0026nbsp;\u003c/em\u003e\u003cem\u003eGiulia Cammarata: Data curation, formal analysis. Rita Di Biase: Supervision, writing – review \u0026amp; editing. Barbara Predieri: Supervision. Laura Lucaccioni: Supervision, validation, visualization. Antonio Colecchia: Methodology, supervision. Lorenzo Iughetti: Conceptualization, writing – review \u0026amp; editing.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAcknowledgements:\u003c/em\u003e\u003c/strong\u003e Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBredefeld C, Hussain MM, Averna M, Black DD, Brin MF, Burnett JR, et al. Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol. 2022. doi: 10.1016/j.jacl.2022.08.009. \u003c/li\u003e\n\u003cli\u003eWakabayashi T, et al. Current Diagnosis and Management of Familial HypobetalipoproteinemiA. J Atheroscler Thromb. 2024. http://doi.org/10.5551/jat.RV22018\u003c/li\u003e\n\u003cli\u003eBuryska S, Ahn JC, Allen AM, Simha V, Simonetto DA. 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Acta Biomed. 2009 80(1)\u003c/li\u003e\n\u003cli\u003eSilfen ME, Manibo AM, Mcmahon DJ, Levine LS, Murphy AR, Oberfield SE. Comparison of Simple Measures of Insulin Sensitivity in Young Girls with Premature Adrenarche: The Fasting Glucose to Insulin Ratio May Be a Simple and Useful Measure. J Clin Endocrinol Metab. 2001. doi: 10.1210/jcem.86.6.7537\u003c/li\u003e\n\u003cli\u003eFerraioli G, Soares Monteiro LB. Ultrasound-based techniques for the diagnosis of liver steatosis. World J Gastroenterol. 2019. doi: 10.3748/wjg.v25.i40.6053\u003c/li\u003e\n\u003cli\u003eKarlas T, Petroff D, Sasso M, Fan JG, Mi YQ, de L\u0026eacute;dinghen V, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis. J Hepatol. 2017. doi: 10.1016/j.jhep.2016.12.022\u003c/li\u003e\n\u003cli\u003eAlkhouri N, Sedki E, Alisi A, Lopez R, Pinzani M, Feldstein AE, Nobili V. 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EClinicalMedicine. 2022. doi: 10.1016/j.eclinm.2022.101547\u003c/li\u003e\n\u003cli\u003eKjaergaard M, Lindvig KP, Holtz Thorhauge K, et al. Using the ELF test, FIB-4 and NAFLD fibrosis score to screen the population for liver disease. J Hepatol. 2023. doi: 10.1016/j.jhep.2023.04.002\u003c/li\u003e\n\u003cli\u003eAttia SL, Softic S, Mouzaki M. Evolving Role for Pharmacotherapy in NAFLD/NASH. Clin Transl Sci.2021. doi:10.1111/cts.12839\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"familial hypobetalipoproteinemia, lipids, lipoproteins, liver steatosis, children","lastPublishedDoi":"10.21203/rs.3.rs-7443290/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7443290/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eFamilial hypobetalipoproteinemia (FHBL) is the most frequent monogenic form of HBL with a dominant mode of inheritance. Heterozygous patients are often asymptomatic, but the genetic mutation causes a defect of exportation of VLDL from the hepatocytes that remain stuck in the liver causing steatosis. In childhood, the diagnosis of FHBL is often underestimated and guidelines are still lacking. The aim of the study is to describe the phenotypic features of a cohort of children and adolescents with a genetic confirmed FHBL attending our pediatric lipid clinic.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis is a monocentric, observational study collecting anamnestic, anthropometric, biochemical and instrumental data (liver ultrasound and elastographic profile) in children and adolescents with a genetic confirmation of heterozygous FHBL.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e12 children and adolescents (4 females), aged 12.14 ± 1.80 years, were genetically diagnosed with heterozygous FHBL. Overweight and/or obesity were identified in 7/12 cases while failure to thrive was detected in 4/12 cases. Only one patient was fully asymptomatic. In 6/12 patients, steatosis was graded from moderate to severe, mainly when accompanied by overweight and/or obesity (p 0.05). Transient elastography was more elevated in FHBL patients if overweight and/or obese (5.65 ± 0.71 vs. 4.60 ± 0.28, p 0.06).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur data document an unexpectedly wide phenotype of FHBL in childhood and adolescence ranging from no symptoms to growth failure or, on the other side, to obesity. Moreover, we document a frequent precocious hepatic involvement in FHBL children, especially if obese and overweight with a potential rapid evolution in fibrosis.\u003c/p\u003e","manuscriptTitle":"Heterozygous Familial Hypobetalipoproteinemia in Children and Adolescents: Time and tide wait for no man","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-02 10:54:07","doi":"10.21203/rs.3.rs-7443290/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16d350f3-9fff-4bc8-a848-f223ebf78eb9","owner":[],"postedDate":"September 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-23T08:24:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-02 10:54:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7443290","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7443290","identity":"rs-7443290","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}