Metin Eser

Cite this article as: Adali G, Kose M, Dertsiz B, Eser M, Kirbas I, Parlak E. Familial low-phospholipid-associated cholelithiasis syndrome presenting with recurrent intrahepatic stones after cholecystectomy with a heterozygous ABCB4 variant. Turk J Gastroenterol. Published online July 20, 2026. doi: 10.5152/tjg.2026.26254.

Objective: This study aimed to investigate the genetic etiology of congenital hypothyroidism (CH) with gland-in-situ (GIS) by screening 23 candidate genes using next-generation sequencing (NGS) in a cohort of Turkish patients. Methods: A total of 44 patients diagnosed with GIS-CH were enrolled. Genetic analysis was performed using a targeted gene panel including 23 genes related to thyroid development and function. Clinical and demographic features were compared between permanent CH (PCH) and transient CH (TCH) groups. Patients with thyroid dysgenesis, central hypothyroidism, syndromic features, or insufficient follow-up were excluded. Results: Genetic variants were identified in 43.1% (19/44) of patients, with similar frequencies in PCH (46.1%) and TCH (38.8%) groups. Ultrasonography revealed hyperplasia in two patients, hypoplasia in 10, and normal-sized gland-in-situ (GIS) in 32 patients. The most frequently identified variant was in the TSHR gene (15.9%), followed by DUOX2 (11.3%), PAX8 (6.8%), TG (4.5%), and DUOXA2 (2.2%). Homozygous or compound heterozygous variants were consistently associated with PCH. In contrast, heterozygous variants showed variable clinical outcomes, ranging from transient disease to persistent hypothyroidism requiring ongoing L-thyroxine therapy. An oligogenic variant (DUOX2+TG) was identified in one patient and was associated with a milder clinical course. Thyroid hypoplasia was predominantly observed in patients with TSHR and PAX8 variants and was strongly associated with the need for continued treatment, even in heterozygous cases. Conclusions: The most common genetic causes of GIS-CH in our cohort were mono- and biallelic TSHR, DUOX2, and monoallelic PAX8 variants. Thyroid hypoplasia was observed predominantly in patients with TSHR and PAX8 variants and was consistently associated with the continued requirement for L-thyroxine therapy, even among heterozygous cases. The main limitations of this study include the relatively small sample size and lack of functional validation of identified variants.

Background: The increasing use of multigene germline testing in breast cancer has expanded the detection of pathogenic/likely pathogenic (P/LP) variants and variants of uncertain significance (VUSs) across a broad range of breast cancer susceptibility genes. However, the extent to which pathogenic certainty and penetrance level are associated with distinct clinicopathological phenotypes and management patterns remains incompletely defined. Methods: In this multicenter retrospective study, we included 405 breast cancer patients with germline alterations in breast cancer susceptibility genes. Patients were classified into three groups: high-penetrance P/LP (n = 116), moderate/low-penetrance P/LP (n = 69), and VUS (n = 220). The primary endpoint was non-luminal invasive breast cancer phenotype, defined as HER2-positive or triple-negative disease versus luminal A/B disease. Multivariable logistic regression was performed to assess the association between genetic group and non-luminal phenotype, adjusted for age at diagnosis and family history. Secondary analyses evaluated management patterns across groups and examined a prespecified non-BRCA cohort. Results: Patients with high-penetrance P/LP variants were younger at diagnosis and had higher Ki-67 values than those in the other groups. Molecular subtype distribution differed significantly across groups, with triple-negative disease most frequent in the high-penetrance P/LP group (33.9%) compared with the moderate/low-penetrance P/LP (9.8%) and VUS (12.9%) groups. In multivariable analysis, high-penetrance P/LP status was independently associated with increased odds of non-luminal phenotype compared with VUS (OR 1.79, 95% CI 1.06–3.04; p = 0.029), whereas moderate/low-penetrance P/LP status was not (OR 0.96, 95% CI 0.48–1.91; p = 0.911). Management patterns also differed significantly. Initial mastectomy was performed in 65.4% of evaluable patients in the high-penetrance P/LP group, compared with 46.4% in the moderate/low-penetrance P/LP group and 45.5% in the VUS group. Final bilateral mastectomy was observed in 62.6%, 17.5%, and 9.9%, respectively (p < 0.001). In the prespecified non-BRCA analysis, non-BRCA P/LP status was not associated with non-luminal phenotype compared with non-BRCA VUS (OR 0.83, 95% CI 0.40–1.72; p = 0.609). Conclusions: Among breast cancer patients with germline alterations in breast cancer susceptibility genes, high-penetrance P/LP variants are associated with a distinct clinicopathological profile characterized by younger age at diagnosis, higher proliferative activity, and increased likelihood of non-luminal disease. In contrast, moderate/low-penetrance P/LP variants, especially VUSs, do not show the same degree of phenotype specificity. These findings support a framework in which pathogenic certainty and penetrance level remain central to the interpretation of multigene germline testing in breast cancer.

Background. Mevalonate kinase deficiency (MKD) is a rare autosomal recessive autoinflammatory disease. Chronic nonbacterial osteomyelitis (CNO) represents another autoinflammatory disorder characterized by sterile bone inflammation. Although musculoskeletal pain is common in MKD, CNO-like bone lesions have rarely been described. Tocilizumab has been used separately in MKD / hyper-IgD syndrome (HIDS) and in CNO; however, pediatric cases showing both conditions together and responding completely to IL-6 blockade have not been previously reported. Case Presentation. We present a 16-year-old boy born to consanguineous parents who experienced early-onset recurrent fever episodes with abdominal pain, maculopapular rash, oral ulcers, and conjunctival injection. He was initially misdiagnosed with FMF and IgA vasculitis and treated with colchicine with partial improvement. Persistent systemic inflammation prompted referral to our tertiary center at age 9. A periodic fever gene panel revealed a homozygous MVK p.V377I mutation, confirming MKD. Anakinra therapy was initiated. Although no attacks occurred during the first month, flares characterized by fever, abdominal pain, rash, and elevated acute-phase reactants recurred in the second and third months, reflecting a partial response. Consequently, treatment was switched to canakinumab. Toward the end of the second year of IL-1 blockade, attack frequency increased to once every three months, and at age 12 he developed diffuse musculoskeletal pain. Whole-body magnetic resonance imaging demonstrated multifocal metaphyseal bone marrow edema compatible with CNO-like lesions. Sulfasalazine was added but discontinued after drug-induced pancreatitis. Given persistent systemic inflammation and inadequate response to IL-1 inhibitors, canakinumab was replaced with weekly subcutaneous tocilizumab, resulting in rapid improvement in bone pain and systemic inflammation. Since the third month of tocilizumab therapy, he has remained clinically stable with normalized inflammatory markers and only a single mild flare over the last year. Conclusion. This case highlights the potential role of IL-6 inhibition in complicated MKD presenting with autoinflammatory bone disease refractory to standard therapies.

Purpose: Colorectal cancer (CRC) is a highly aggressive malignancy of the digestive system. Somatic variants in the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene have a significant influence on CRC progression and serve as key predictors of resistance to anti-epidermal growth factor receptor (EGFR) therapy. This study aimed to determine the prevalence of KRAS variants, with a particular focus on G12D variants, which represent potential for targeted therapy. Methods: A cohort of 73 CRC patients was evaluated between January 2021 and August 2024. Next-generation sequencing (NGS) was performed using the Archer^® VariantPlex^® Solid Tumor Focus v2 (Integrated DNA Technologies, Inc., Boulder, CO, USA) assay on the Illumina NextSeq platform. The gene panel included 20 genes frequently mutated in solid tumors, assessing point variants, insertions/deletions, and microsatellite instability. Results: The cohort of the study comprised 38 female (52%) and 35 males (48%) patients aged 31–83 years (mean, 58.77 ± 12.72). No significant difference in mean age was observed between males and females (60.31 ± 12.32 vs. 57.34 ± 13.08; p > 0.05). KRAS variants were detected in 30 patients (41%). Among these, the variant frequencies for G12D, G12V, and G13D were 7%, 11%, and 11%, respectively. Additionally, one patient (1.4%) harbored an ERBB2 amplification. All KRAS variants were associated with resistance to anti-EGFR therapy. Notably, KRAS G12D variants have potential responsiveness to targeted therapy, while human epidermal growth factor receptor 2 (ERBB2) amplifications are responsive to anti-HER2 treatments and resistant to anti-EGFR therapies. Conclusions: These findings highlight the clinical significance of KRAS variant profiling for prognosis and personalized treatment planning in CRC. Moreover, assessing KRAS variants individually is crucial to better understanding treatment response and exploring the potential targeted therapy in CRC management.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by difficulties in social interactions, communication impairments, repetitive behaviors, and restricted interests. A genetic basis for ASD is now well-established. With the availability of high-throughput microarray and sequencing platforms, major advances have been made in our understanding of genetic risk factors. This study assessed the patient records of 62 children diagnosed with ASD or at risk for ASD. Cytogenetics, molecular karyotyping, and whole-exome sequencing (WES) were conducted for these cases. Three likely pathogenic variants were detected in the genes KMT2C, FOXP2, and MAN1B1, each at a rate of 1.6% of total cases. Additionally, variants of uncertain significance (VUS) were found in 13 genes previously associated with ASD. The frequencies of these VUS in total cases were as follows: DLG3-1.6%, MECP2-1.6%, SETD5-1.6%, GRIN1-1.6%, ASXL3-3%, KMT2D - 5%, AP1G1-3%, SPTBN1-3%, TRIP12-1.6%, HCN1-3%, ZNF292-1.6%, and ACSL4-1.6%. We found gene variants in 35% of cases, a rate consistent with previous reports, emphasizing the importance of comprehensive genetic analysis in diagnosing ASD with unclear etiology. This study offers valuable insights into the genetic landscape of ASD within a small cohort and highlights the need for ongoing monitoring and genetic counseling in conditions that present with ASD-like symptoms.

High-grade serous ovarian cancer (HGSOC) is an aggressive form of epithelial carcinoma associated with poor prognosis. Although relatively uncommon, mutations in the BRCA1/2 genes are linked to HGSOC. Poly(ADP-ribose) polymerase inhibitors (PARPi) have been approved for treating patients with BRCA1/2 mutations, significantly improving outcomes for this subgroup. To assess the prevalence of BRCA1/2 mutations in high-grade serous ovarian cancer (HGSOC) patients who tested negative for germline BRCA1/2 mutations and to evaluate the potential implications of tumor-based genetic testing for expanding PARPi therapy eligibility. 75 patients who underwent Somatic BRCA1/BRCA2 Next Generation Sequencing (NGS) and positive for somatic but negative for germline BRCA1/2 mutations were selected and included in the study. Tumor tissue samples, either formalin-fixed paraffin-embedded or fresh, were analyzed using NGS to detect somatic mutations in BRCA1/2 genes. The study also examined variants of uncertain significance (VUS) within these genes. Pathogenic somatic mutations in the BRCA1/2 genes were identified in 8 patients (11%), while a VUS was detected in 1 patient (1%). Variant mutations c.135-8A>G, c.1084G>T (p.Glu362Ter), c.5095C>T (p.Arg1699Trp), and c.3756_3759del (p.Ser1253fs) were found in the BRCA1 gene, while c.5073dup (p.Trp1692fs), c.426-1G>A, c.3751_3752insA (p.Thr1251AsnfsTer14), and c.771_775del (p.Asn257fs) were found in the BRCA2 gene. Our study highlights the importance of expanding the availability of PARPi therapy to patients with somatic BRCA1/2 mutations and providing targeted therapy to guide patients with high-grade ovarian serous cancer. As treatments evolve, integrating comprehensive genetic testing into clinical practice is vital to improving care.

Background: To compare the clinical features and disease severity of classic polyarteritis nodosa (PAN) with its monogenic form, deficiency of adenosine deaminase 2 (DADA2), in pediatric patients, in order to distinguish overlapping vasculitic phenotypes. Methods: This cross-sectional study included 36 pediatric patients with PAN-like vasculitis, comprising 22 with classic PAN (14 systemic, 8 cutaneous) and 14 with DADA2, followed up at our tertiary referral pediatric rheumatology department between August 2016 and February 2025. Demographic features, clinical manifestations, treatment choices, and outcomes were compared between the groups. Results: DADA2 patients had significantly earlier symptom onset (median 4 vs. 11 years, p = 0.002) and higher rates of parental consanguinity ( p < 0.001) compared with systemic PAN (sPAN) patients. The most common clinical features in sPAN were constitutional symptoms (100%), followed by cutaneous (78.6%), musculoskeletal (57.1%), and renal involvement (57.1%). Growth retardation (14.3% vs. 57.1%, p = 0.018) and livedo racemosa (7.1% vs. 50%, p = 0.012) were more common in DADA2, whereas fatigue (92.9% vs. 35.7%, p = 0.002), renal involvement (57.1% vs. 0%, p < 0.011), diastolic hypertension (78.6% vs. 7.1%, p < 0.001), and purpura (35.7% vs. 0%, p = 0.014) predominated in PAN. Neurological manifestations were observed in 4 PAN patients (2 peripheral, 2 central) and 1 DADA2 patient with ischemic stroke. Biologic therapy was required in 4 PAN patients, whereas 11 of 14 DADA2 patients were treated with anti–tumor necrosis factor agents. Conclusion: Anti-TNF therapy remains the mainstay of treatment in DADA2 and is effective in preventing disease progression. In contrast, classic sPAN may require escalation to biologic agents in refractory cases or when neurologic or end-organ involvement is present.

Wiedemann-Steiner syndrome (WSS) is a rare autosomal dominant neurogenetic disorder caused by monallelic variants in KMT2A gene, characterized by neuromotor developmental delay, intellectual disability, microcephaly, seizures, behavioral disorders, dysmorphic facial features, hirsutism, and systemic anomalies. The KMT2A gene encodes a histone lysine methyltransferase crucial for the regulation of gene expression during early developmental stages. In this study, the clinical and molecular findings of 15 Turkish patients with WSS confirmed by whole exome sequencing are reported. Variant segregation was confirmed in all families. The ages of the patients were between 1.5 and 16 years. The majority of patients had neuromotor developmental delay, speech delay, and intellectual disability. The most frequently recognised dysmorphic facial features were thick eyebrows, long eyelashes, synophrys, hypertelorism, and broad nose. Other frequently observed clinical findings included short stature, congenital hypotonia, behavioral problems, genitourinary anomalies, and abnormal gait. Novel findings included focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma. Fifteen different KMT2A variants were detected, including 8 novel (p.Gln3594*, p.Glu1407Argfs*4, p.Ser610Ilefs*9, p.Ser2188Leufs*25, p.Glu970Glnfs*37, p.Ser759Valfs*22, p.Lys1346Serfs*24, and c.11146 + 1_11146 + 6delinsA) variants. Additionally, one patient exhibited a dual molecular diagnosis with a de novo variant in CSNK2A1, associated with Okur-Chung neurodevelopmental syndrome. Conclusion: This study expands the clinical and molecular spectrum of WSS, highlighting novel variants and unique manifestations. It emphasizes the importance of molecular testing in accurate diagnosis and management. By characterizing phenotypic diversity and dual diagnosis, this work contributes valuable insights for advancing clinical care and guiding future research. What is Known: • Wiedemann-Steiner syndrome (WSS) is a rare neurodevelopmental disorder caused by heterozygous KMT2A variants, characterized by developmental delay, intellectual disability, and distinctive facial features. • WSS exhibits marked clinical variability among affected individuals. What is New: • This study presents the largest Turkish WSS cohort to date, expands the phenotypic spectrum with novel findings such as focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma. • This study presents the largest Turkish WSS cohort to date and expands the phenotypic spectrum with novel findings such as focal segmental glomerulosclerosis, cholelithiasis, and sacrococcygeal teratoma, while also identifying eight novel WSS-associated variants, including p.Gln3594*, p.Glu1407Argfs*4, p.Ser610Ilefs*9, p.Ser2188Leufs*25, p.Glu970Glnfs*37, p.Ser759Valfs*22, p.Lys1346Serfs*24, and c.11146+1_11146+6delinsA.