Biray Ertürk

Objectives: A rare autosomal recessive disorder known as Fanconi–Bickel syndrome (FBS) is caused by variants in the SLC2A2 gene. This gene is responsible for encoding the glucose transporter 2 (GLUT2) protein. FBS is characterised by hepatomegaly, proximal renal tubular dysfunction, glucosuria, rickets and growth retardation. Here, we present a case of an SLC2A2 gene variant with an unusual clinical presentation involving extreme hepatic transaminase elevations during infectious episodes, a feature not commonly associated with FBS. Case presentation: A male infant presented at 12 days of age with severe cholestasis and hepatomegaly. During follow-up, hypophosphatemic rickets and proximal renal tubular dysfunction emerged. Genetic analysis revealed a novel homozygous frameshift variant in the SLC2A2 gene (c.482dup; p.Gly162ArgfsTer17). During the clinical course, the most severe episodes were observed during infections, accompanied by elevations in liver enzymes. Management required glucose infusion and supportive therapy. Conclusions: This article describes an SLC2A2 gene variant that had not been identified previously and shows that patients carrying this variant may be at risk of excessive liver involvement during infections. Therefore, it is emphasized that such patients should be monitored more closely and treated promptly during infections.

Cardiofaciocutaneous syndrome (CFCS) is a RASopathy involving craniofacial, cardiac, cutaneous, and neurologic features. MAP2K1 mutations, particularly in the kinase domain, are linked to CFCS type 3. Immune dysfunction has not previously been reported with the p.Tyr130His variant. To describe the case of combined immunodeficiency (CID) associated with the MAP2K1 p.Tyr130His variant. A 4‐month‐old female with CFCS presented with recurrent infections, growth failure, and ectodermal findings. Immunologic workup revealed hypogammaglobulinemia, low T cell subsets, and absent vaccine responses. Genetic analysis identified the MAP2K1 p.Tyr130His variant. She was started on intravenous immunoglobulin and prophylaxis, with clinical improvement. We describe a case of CID associated with the MAP2K1 p.Tyr130His variant adding to the growing evidence of immune dysregulation in CFCS.

Aim: To evaluate the diagnostic yield and clinical triage performance of a structured, multistep algorithm in children referred for suspected inborn errors of immunity (IEI) due to recurrent infections. Methods: This single‐centre study included 705 children (0–18 years) referred for recurrent infections. All were screened using JMF and/or MENA criteria. Of these, 132 met at least one criterion and underwent stepwise immunologic evaluation, including advanced testing when indicated. Results: Of 705 children referred with recurrent infections, 132 (18.7%) met screening criteria and underwent structured immunologic evaluation. Inborn errors of immunity were diagnosed in 50 patients (7.1%), with a 71% diagnostic confirmation rate. Pathogenic variants were detected in 74%, immunoglobulin abnormalities in 78% and all showed lymphocyte subset disturbances. The most common classifications were antibody deficiencies (32%) and syndromic combined immunodeficiencies (28%). Half received intravenous immunoglobulin, and no mortality occurred during follow‐up. Conclusion: The structured diagnostic algorithm based on JMF and MENA criteria improved IEI diagnosis and enabled effective prioritisation of children presenting with non‐infectious immune phenotypes. This model reduced unnecessary testing, supported efficient allocation of limited resources and facilitated timely diagnosis. The approach offers a practical, cost‐effective solution particularly applicable in regions with high consanguinity rates and limited access to advanced immunologic diagnostics.

Background/aim: This study aimed to investigate the relationship between the presence of BRAF, HRAS, NRAS, and KRAS gene mutations and the development of dedifferentiation (iodine-refractory disease) and extrathyroidal disease in patients with differentiated thyroid carcinoma (DTC).Materials and methods: Seventy-seven adult patients classified as intermediate and high-risk according to the ATA 2015 guidelines, who underwent total thyroidectomy followed by radioiodine I-131(RAI) therapy between June 2014 and December 2022, were included. Clinical data were collected via the hospital information system, including the number of surgeries, RAI treatments, and levels of thyroglobulin(Tg), anti-thyroglobulin, and thyroid-stimulating hormone. Histopathological subtypes of DTC were re-evaluated, and mutation analyses of BRAF, KRAS, NRAS, and HRAS genes were performed using real-time polymerase chain reaction (PCR). Statistical analyses were conducted using Medcalc software, with p-values <0.05 considered significant.Results: Of the 77 patients, most had classical papillary thyroid carcinoma, while others represented various subtypes. No mutations were found in BRAF K601E/V600_K601, KRAS G12x-G13D, or NRAS G12-G13; however, NRAS Q61x was found in one patient, HRAS Q61x in 12, and BRAFV600E/Ec in 36. A significant relationship was observed between HRAS Q61x mutation and disease response, alongside a significant association between gene mutations and iodine-refractory disease development (p=0.0004). ROC curve analysis indicated a 49.2 ng/ml threshold for Tg with 75% sensitivity and 94.1% specificity.Conclusion: Our findings suggest that the HRAS Q61x gene mutation is significantly associated with iodine-resistant disease and may serve as a prognostic biomarker in early-stage thyroid cancer and aid in disease monitoring in metastatic patients.

Background Although the underlying genetic causes of intellectual disability (ID) continue to be rapidly identified, the biological pathways and processes that could be targets for a potential molecular therapy are not yet known. This study aimed to identify ID-related shared pathways and processes utilizing enrichment analyses.Methods In this multicenter study, causative genes of patients with ID were used as input for Disease Ontology (DO), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes enrichment analysis.Results Genetic test results of 720 patients from 27 centers were obtained. Patients with chromosomal deletion/duplication, non-ID genes, novel genes, and results with changes in more than one gene were excluded. A total of 558 patients with 341 different causative genes were included in the study. Pathway-based enrichment analysis of the ID-related genes via ClusterProfiler revealed 18 shared pathways, with lysine degradation and nicotine addiction being the most common. The most common of the 25 overrepresented DO terms was ID. The most frequently overrepresented GO biological process, cellular component, and molecular function terms were regulation of membrane potential, ion channel complex, and voltage-gated ion channel activity/voltage-gated channel activity, respectively.Conclusion Lysine degradation, nicotine addiction, and thyroid hormone signaling pathways are well-suited to be research areas for the discovery of new targeted therapies in ID patients.

Background Liver damage is uncommon in Shiga toxin-producing Escherichia coli–associated hemolytic uremic syndrome (STEC-HUS). Herein, we present two cases with a diagnosis of STEC-HUS that progressed to liver damage, with findings presumably related to the SERPINB11 gene c.268G > T (p.Glu90Ter) variant. Case-diagnosis/treatment Two boys aged 3 and 2 years, respectively, were referred to our clinic with a preliminary diagnosis of STEC-HUS. The patients had low hemoglobin, thrombocyte, and haptoglobin levels but high levels of lactic dehydrogenase, urea, creatinine, and schistocytes in peripheral smears. Escherichia coli O157:H7 was detected in their stool samples. The patients underwent hemodialysis, plasma exchange, and supportive treatments. Meanwhile, cholestasis developed in the patients, resulting in elevated total bilirubin levels. During the follow-up period, kidney function recovered completely; however, liver function did not improve, and one patient developed chronic liver damage. Gene mutations that may cause liver damage were investigated, and c.268G > T (p.Glu90Ter) homozygous and heterozygous variants were detected in exon 9 of the SERPINB11 gene in the patients. Conclusions Our patients presented with kidney impairment and liver malfunction. Hepatic involvement in STEC-HUS may result from ischemia, hemolysis, and endothelial damage in the hepatic vessels. Liver injury in STEC-HUS cases may be associated with the homozygous SERPINB11 gene c.268G > T (p.Glu90Ter) variant.

Familial Mediterranean fever (FMF), the most common autoinflammatory disease in children, is characterized by recurrent febrile episodes. FMF is known to progress with chronic inflammation, particularly during attack periods. This study aimed to investigate the relationship of S100A12, an inflammatory marker, with attacks and inflammatory events in FMF patients. The study included 57 patients diagnosed with FMF, 43 in an attack-free period and 14 in an attack period, and 31 healthy children as the control group. Only white blood cell (WBC) count, C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and S100A12 level were analyzed in the control group. In addition, serum amyloid A (SAA), and fibrinogen levels were measured, and a mutation analysis was performed in the patient group. The results were compared among the attack-free period, acute attack FMF and control groups. The mean age of patients and control group was 10 (2.5 - 18) and 9.5 (2.5 - 16) years, respectively. The CRP (p = 0.001), S100A12 (p = 0.003) and ESR (p= 0.001) values differed significantly between the FMF and control groups. S100A12 level (p = 0.027), WBC count (p = 0.003), CRP level (p = 0.0001), ESR (p = 0.004), and fibrinogen level (p = 0.001) differed significantly between the acute attack and attack-free period groups. SAA level (p = 0.05), ESR (p = 0.001), fibrinogen level (p = 0.001), WBC count (p = 0.001), and S100A12 level (p = 0.027) were higher in M694V homozygous FMF patients than in other FMF patients. Patients with FMF had higher S100A12 levels than the control group, while the mean S100A12 concentration was higher in acute attack period patients than in attack-free period patients. S100A12 level might be an important indicator in the monitoring of chronic inflammation in patients with FMF.

This study aimed to determine the differences in clinicopathological features of Turkish patients with high-risk breast cancer based on the mutation status of two breast cancer susceptibility genes (BRCA1/2) . This study enrolled patients with invasive breast cancer who have been evaluated for BRCA1/2 mutations due to the presence of high-risk factors admitted to two tertiary referral centers in Turkey. Clinical and histopathological features were analyzed in BRCA1 mutation carriers, BRCA2 mutation carriers, and non-carriers. A total of 302 patients with a mean age of 44.2±9.9 (22–82) years were included. BRCA1/2 mutation was found in 75 (24%) patients, of whom 41 (13.6%) were BRCA1 mutation carriers and 37 (12.3%) were BRCA2 mutation carriers. Moreover, 104 (34.4%) and 4 (1.3%) patients had family history of breast and ovarian carcinoma, respectively. The rates of triple negativity (56.1%), histologic grade 3 (65.9%), and lymphovascular invasion (78%) were significantly higher in BRCA1 mutation carriers than in non-carriers and BRCA2 mutation carriers. Furthermore, 87% of triple-negative BRCA1 mutation carriers had histologic grade 3 tumors compared with 38.9% in non-triple-negative BRCA1 mutation carriers, and the difference was significant. Findings of this study showed that BRCA1-related breast cancers represent a distinct group with unique pathological features, which are usually associated with a poor prognosis.