Zhu–Tokita–Takenouchi–Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Haploinsufficiency in SON may affect multiple genes, including those involved in the development and metabolism of multiple organs. Considering the broad spectrum of SON functions, it is to be expected that pathogenic variants in this gene can cause a wide spectrum of clinical symptoms. We present an additional ZTTK syndrome case due to a de novo heterozygous variant in the SON gene (c.5751_5754delAGTT). The clinical manifestations of our patient were similar to those present in previously reported cases; however, the diagnosis of ZTTK syndrome was delayed for a long time and was carried out during the diagnostic work-up of significant chronic liver disease (CLD). CLD has not yet been reported in any series; therefore, our report provides new information on this rare condition and suggests the expansion of the ZTTK syndrome phenotype, including possible liver involvement. Correspondingly, we recommend screening patients with SON variants specifically for liver involvement from the first years of life. Once the CLD has been diagnosed, an appropriate follow-up is mandatory, especially considering the role of SON as an emerging player in cancer development. Further studies are needed to investigate the role of SON haploinsufficiency as a downregulator of essential genes, thus potentially impairing the normal development and/or functions of multiple organs.

The increasing prevalence of metabolic dysfunction-associated fatty liver disease (MASLD) in children requires robust, non-invasive biomarkers to enable accurate disease staging and risk stratification. Elevated serum levels of homocysteine (Hcy) have emerged as potential risk factors for cardiometabolic disease in adults, including MASLD. In this observational retrospective study, we investigated the role of serum Hcy levels as a potential biomarker for disease severity and liver fibrosis in a pediatric cohort of 182 children with MASLD. In 89 patients, liver biopsy allowed the classification into metabolic dysfunction-associated steatohepatitis (MASH). Associations between Hcy, metabolic parameters, fibrosis scores, and histological features were examined, and the diagnostic performance of Hcy for liver fibrosis was evaluated using ROC analysis. Multivariate analyses identified elevated Hcy levels as independently associated with HOMA-IR (β = 0.55; p = 0.049), TG/HDL ratio (β = 3.23; p = 0.002), and liver fibrosis (β = 2.59; p = 0.04). Hcy showed a predictive accuracy of 81% for fibrosis. However, the combined diagnostic models of Hcy with non-invasive fibrotic scores (i.e., APRI and FIB-4) or TG/HDL ratio showed only a modest accuracy (AUC = 0.62–0.69). In conclusion, our data suggest that Hcy is associated with fibrosis and cardiometabolic risk. However, these results should be interpreted as exploratory and do not establish homocysteine as a diagnostic biomarker.

Background: Pediatric liver disease is frequently associated with abnormal conventional coagulation tests; however, prothrombin time expressed as international normalized ratio (PT-INR) incompletely reflect global hemostatic balance. Thrombin generation assay (TGA) provide an integrated assessment of coagulation and may offer complementary information in children with acute liver failure (ALF) and chronic liver disease (CLD). Methods: We enrolled 61 pediatric patients with liver disease (50 CLD, 8 ALF, 3 extrahepatic portal vein obstruction EHPVO) and 51 healthy controls. Platelet-poor plasma was prepared according to international recommendations. Thrombin generation was measured using ST Genesia (STG) with normalization to reference plasma. Group comparisons were performed using non-parametric tests; correlations between PT-INR and thrombin generation parameters were assessed, and principal component analysis (PCA) was used to explore the variance structure of thrombin generation indices and conventional coagulation variables. Results: PT-INR was significantly higher in patients than controls, particularly in ALF. Bleeding events were uncommon. Compared with controls, patients showed reduced levels of fibrinogen and multiple procoagulant/anticoagulant factors (including antithrombin and protein C), with increased factor VIII. Among thrombin generation parameters, the endogenous thrombin potential (ETP) ratio differed significantly across groups (p = 0.001), while correlations between PT-INR and thrombin generation parameters were weak or absent, no significant associations were observed even at higher Pediatric/Model for End-Stage Liver Disease scores. PCA separated thrombin generation indices from PT-INR and conventional coagulation factors, suggesting complementary information. Conclusions: In pediatric liver disease, PT-INR does not reliably reflect global coagulation capacity. Thrombin generation testing provides additional, integrative information on hemostasis and may improve laboratory assessment beyond conventional tests.

The increasing prevalence of metabolic dysfunction-associated fatty liver disease (MASLD) in children requires robust, non-invasive biomarkers to enable accurate disease staging and risk stratification. Elevated serum levels of homocysteine (Hcy) have emerged as potential risk factors of cardiometabolic disease including MASLD in adults. In this observational retrospective study, we investigated the role of serum Hcy levels as a potential biomarker for disease severity and liver fibrosis in a pediatric cohort of 182 children with MASLD. Liver biopsies in 89 patients, allowed the classification into metabolic dysfunction-associated steatohepatitis (MASH). Associations between Hcy, metabolic parameters, fibrosis scores, and histological features were examined, and the Hcy diagnostic performance for liver fibrosis evaluated through ROC analysis. Multivariate analyses identified elevated Hcy levels as independently associated with HOMA-IR (β=0.55; p=0.049), TG/HDL ratio (β=3.23; p=0.002) and liver fibrosis (β=2.59; p=0.04). HCy showed excellent predictive accuracy for fibrosis (AUC= 0.0809) superior to that of other fibrosis scores. Finally, combined diagnostic models of Hcy with APRI, FIB-4, or TG/HDL ratio showed only modest accuracy, (AUC=0.62-0.69). Our data demonstrated that serum Hcy is a strong independent predictor of fibrosis in pediatric MASLD patients, supporting its role as a non-invasive biomarker to identify patients at risk of severe liver complications.