Central nervous system (CNS) tumors comprise around 20% of childhood malignancies. Germline variants in cancer predisposition genes (CPGs) are found in approximately 10% of pediatric patients with CNS tumors. This study aimed to characterize variants in CPGs in pediatric patients with CNS tumors and correlate these findings with clinically relevant data. Genomic DNA was isolated from the peripheral blood of 51 pediatric patients and further analyzed by the next-generation sequencing approach. Bioinformatic analysis was done using an “in-house” gene list panel, which included 144 genes related to pediatric brain tumors, and the gene list panel Neoplasm (HP:0002664). Our study found that 27% of pediatric patients with CNS tumors have a germline variant in some of the known CPGs, like ALK, APC, CHEK2, ELP1, MLH1, MSH2, NF1, NF2 and TP53. This study represents the first comprehensive evaluation of germline variants in pediatric patients with CNS tumors in the Western Balkans region. Our results indicate the necessity of genomic research to reveal the genetic basis of pediatric CNS tumors, as well as to define targets for the application and development of innovative therapeutics that form the basis of the upcoming era of personalized medicine.

Systemic sclerosis (SSc) is a complex autoimmune inflammatory disorder with multiple organ involvement. Skin changes present the hallmark of SSc and coincide with poor prognosis. Interstitial lung diseases (ILD) are the most widely reported complications in SSc patients and the primary cause of death. It has been proposed that the processes of autophagy and apoptosis could play a significant role in the pathogenesis and clinical course of different autoimmune diseases, and accordingly in SSc. In this manuscript, we review the current knowledge of autophagy and apoptosis processes in the skin and lungs of patients with SSc. Profiling of markers involved in these processes in skin cells can be useful to recognize the stage of fibrosis and can be used in the clinical stratification of patients. Furthermore, the knowledge of the molecular mechanisms underlying these processes enables the repurposing of already known drugs and the development of new biological therapeutics that aim to reverse fibrosis by promoting apoptosis and regulate autophagy in personalized treatment approach. In SSc-ILD patients, the molecular signature of the lung tissues of each patient could be a distinctive criterion in order to establish the correct lung pattern, which directly impacts the course and prognosis of the disease. In this case, resolving the role of tissue-specific markers, which could be detected in the circulation using sensitive molecular methods, would be an important step toward development of non-invasive diagnostic procedures that enable early and precise diagnosis and preventing the high mortality of this rare disease.

Objectives: Familial hypercholesterolemia (FH) is an autosomal dominant disorder of lipid metabolism characterized by high levels of low-density lipoprotein (LDL). This study aimed to identify variants in the LDLR, APOB, PCSK9 and LDLRAP1 genes and to identify the genotype–phenotype correlation in Serbian FH patients. Method: This study included a total of 101 patients suspected of having FH based on clinical criteria. Genetic analysis was performed by the next-generation sequencing (NGS) method. Results: An overall mutation detection rate of 43.6% was achieved. Thirteen distinct variants were detected in the LDLR gene (93.2%). The most frequently observed variant was c.858C>A p.(Ser286Arg), which was present in 26% of the LDLR-positive patients. Additional variants were detected in the APOB gene. No pathogenic variants were detected in the PCSK9 or LDLRAP1 genes. Comparing genetically FH-positive and FH-negative patients, statistical significance was observed in terms of age (p < 0.001), total cholesterol (TC) (p < 0.001), low-density-lipoprotein cholesterol (LDL-C) (p < 0.001) and triglyceridemia (p < 0.001). Conclusions: This study represents the first insight into the genetic basis of FH in Serbia. Taking into consideration that variants were detected in more than one gene and that the variants in the LDLR gene were distributed across nearly all exons, the FH diagnostics in Serbia ought to be based on NGS methodology.

Background: Familial hypercholesterolemia (FH) is characterised by elevated low-density lipoprotein cholesterol (LDL-C) levels and an increased risk of premature cardiovascular disease. The present study aimed to investigate the genetic background, associated biochemical profiles, clinical manifestations, and therapeutic response in patients with clinically suspected FH in Serbia. Methods: A total of 101 patients with clinically suspected FH were recruited from the Clinic for Endocrinology, Diabetes and Metabolic Diseases in Serbia between 2015 and 2023. Clinical diagnosis was established using the Dutch Lipid Clinic Network (DLCN) criteria. Genetic profiles of all patients were previously determined using next-generation sequencing. Fasting serum lipids, apolipoprotein A-I [ApoA-I], apolipoprotein B [ApoB], and lipoprotein(a) (Lp(a)) were measured enzymatically. Levels of serum lipids were compared between genetically FH-positive (carriers of variants in LDLR, APOB, PCSK9 and LDLRAP1 genes) and FH-negative patients. Therapeutic response was assessed by achieving the LDL-C target level. Statistical analyses were conducted in SPSS (version 30.0). Results: Genetically confirmed FH patients exhibited significantly higher levels of ApoB (p=0.001) compared with variant-negative individuals, while ApoA-I (p=0.413) and Lp(a) (p=0.421) levels did not differ significantly between groups. Patients with pathogenic FH-associated variants were less likely to reach target LDL-C levels after therapy than those without identified variants. Conclusions: This study demonstrates biochemical diversity in familial hypercholesterolemia associated with genetic background in the Serbian population. Pathogenic FH mutations were associated with higher ApoB levels, underscoring the importance of combining genetic testing with lipid profiling for precise diagnosis and management.

Background/Objectives: Hypoparathyroidism (HPT) is a disorder caused by the insufficient production of parathyroid hormone (PTH). Its main features include decreased serum calcium, increased serum phosphorus, and abnormal bone modeling. In children, HPT is most commonly due to genetic disorders. Among rare genetic syndromes that can include HPT in their clinical spectrum is Kenny–Caffey syndrome (KCS) type 2. Conventional therapy for HPT primarily consists of oral calcium and active vitamin D metabolites. The major limitation of conventional therapy is hypercalciuria with an increased risk of nephrocalcinosis. However, a subset of patients fails to achieve the desired therapeutic response to conventional treatment; the reasons for this remain incompletely understood in some cases. The failure to achieve therapeutic targets and persistent hypercalciuria are the main indications for considering therapy with recombinant human parathyroid hormone (rhPTH). Methods: In addition to the review of the literature on rhPTH use in pediatric hypoparathyroidism, the first application of rhPTH in the treatment of genetically caused HPT in a child with Kenny–Caffey syndrome type 2 (KCS2) was described. Results: In this paper, we present a two-month-old infant who received rhPTH for 14 months. A heterozygous de novo p.Ser541Pro variant in the FAM111A gene was identified through whole-genome sequencing, indicating a diagnosis of KCS2. A biological mechanism linking FAM111A protein function with a more profound disruption of parathyroid development or function was proposed, suggesting that rhPTH therapy may be particularly beneficial in KCS2 cases. Conclusions: This is the first reported use of rhPTH in a child in Serbia and the first reported use in KCS type 2. By reviewing the literature, we analyzed the conditions in which rhPTH has been used, dosing approaches and durations, requirements for concomitant conventional therapy during rhPTH treatment, and the effects of rhPTH on calciuria. We provide an overview of rhPTH use in children. Additionally, based on the pathogenic genetic variant responsible for KCS2 in our patient, we propose possible etiologic explanations. This work aims to encourage a consideration of rhPTH use in children following its official approval.

Glycogen storage disease Ib (GSD Ib) is an ultra-rare metabolic disease caused by variants in the SLC37A4 gene affecting activity of the glucose-6-phosphate transporter (G6PT). G6PT mediates transport of glucose-6 phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, thereby playing a key role in glucose homeostasis. To date, no approved therapies directly restore G6PT function, highlighting a major unmet need. Pharmacological chaperone (PC) therapies, including those targeting membrane transporters, are a known and clinically employed therapeutic strategy. The efficacy of PC therapy is highly dependent on the underlying pathogenic variant. While certain missense variants may respond favorably, particularly those associated with protein misfolding and residual function, null variants are generally considered unsuitable targets due to the absence of a protein that could be rescued. To the best of our knowledge, no previous review has systematically examined the global landscape of SLC37A4 variants. The aim of this review was to collect the spectrum and frequency of SLC37A4 variants reported worldwide and connect them with all available structural and functional data. In 425 GSD Ib patients, we found that approximately 10% of all variants are strong PC candidates and 14–30% are reasonable but lower-confidence candidates (other missense non-deactivating variants), while the rest are poor PC candidates (substrate-pocket variants) and null variants (nonsense, frameshift and splicing). Although functional studies are required to definitely validate PC-responsive missense variants in the SLC37A4 gene, our review suggests, for the first time, the existence of a minimal threshold at which a PC approach may become clinically relevant for GSD Ib patients.