Mehrdad Zeinalian

Background: Inborn errors of metabolism cause significant infant morbidity and mortality. Birth prevalence is elevated in the Eastern Mediterranean region, influenced by consanguinity. This study presents the first findings of an expanded newborn screening program for IEMs in Isfahan Province, Central Iran. In this cross-sectional study (2023–2025), 71,004 neonates were screened via tandem mass spectrometry (MS/MS) of dried blood spots for 50 metabolic disorders. Positive cases underwent confirmatory testing. Data on demographics and consanguinity were analyzed. Results: From 71,004 newborns, 48 cases were confirmed, corresponding to a prevalence of 67.6 per 100,000 live births, including organic acid, amino acid, and fatty acid oxidation disorders. The most frequent disorders included Short-chain acyl-CoA dehydrogenase (SCAD) deficiency, benign hyperphenylalaninemia (HPA), and 2-Methylbutyryl-CoA dehydrogenase (SBCAD) and 3-Methylcrotonyl-CoA carboxylase (3MCC) deficiencies. Consanguinity was a major risk factor, present in 56.3% of cases (Relative Risk = 2.05). All mortality (10.4%) occurred in the organic acid disorder group. Birth prevalence was highest in smaller towns (e.g., Khansar: 384.6/100,000). Conclusion: The high prevalence of IEMs in Isfahan, linked to consanguinity and a distinct disorder profile, underscores the critical importance of expanded NBS. The findings advocate for integrated public health strategies, including genetic counseling and targeted screening, to reduce the disease burden in this region.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited enzymatic disorder, typically associated with hemolytic anemia. However, emerging evidence points to its involvement in a wider range of physiological processes, including the regulation of oxidative stress, immune defense, and epithelial repair which could lead to various manifestations. This is the first report of association between G6PD deficiency and perianal abscess and fistula. A 16-year-old male with a five-year history of recurrent perianal abscess and fistula presented with renewed symptoms despite prior surgical management. His mother and brother had also reportedly been diagnosed with perianal abscess and fistula. Laboratory findings showed anemia and elevated inflammatory markers, while imaging revealed an intersphincteric fistula tract. Colonoscopy exhibited focal active ileitis without granulomas. Whole-exome sequencing identified a hemizygous pathogenic/likely pathogenic mutation in the G6PD gene (c.653 C > T), suggesting a genetic contribution to the chronic inflammatory process. This case highlights a possible association between G6PD deficiency and recurrent perianal abscess and fistula. Impaired immune response and epithelial repair linked to G6PD dysfunction may contribute to chronic perianal disease. Further studies are warranted to clarify this potential relationship.

Sarcomas are rare cancers that occur in mesenchymal tissues. The acknowledgment of genetic factors in these heterogeneous neoplasms could cause progress in diagnoses and targeted therapy. Sarcomas have two main categories: soft tissue and bone sarcoma. These cancers have been associated with some hereditary cancer syndrome like Li-Fraumeni Syndrome. In this research, we present a pedigree with familial sarcoma. Our proband is a young woman with osteosarcoma involving her upper jawbone. The patient had a family history of many cases of sarcoma, brain tumors, especially osteosarcoma; also, we considered the association of cancer predisposing syndrome and high rate of sarcomas in this family. By means of whole-exome sequencing, one pathogenic variant of TP53 gene was recognized. Additional investigation like co-segregation analysis assessed the existence of this mutation in some of affected and unaffected family members and showed that probably this family is a case of familial Li-Fraumeni syndrome. This finding suggested that germline mutation of TP53 gene play an important role in initiating and spreading sarcoma in this family with Li-Fraumeni syndrome.

Background: Cancer of unknown primary (CUP) is characterized by metastatic cancer cells with no identifiable primary tumor despite extensive diagnostics. This study investigates the epidemiologic, histopathological, and prognostic factors in 352 CUP cases in Iran. Materials and Methods: This retrospective study reviewed the clinical documents of CUP patients registered in MACSA, a charity-based referral center in central Iran, Isfahan, within 2016–2021. The patients’ data were analyzed, and survival associations were assessed using Cox proportional hazards regression models. Results: Altogether 352 CUP patients were included in the study. The mean age at diagnosis was 65.9 ± 14.3 years, with 52.6% being male. Abdominal pain (32.1%) was the most common presentation. Metastatic adenocarcinoma (31.5%) was the most frequent histopathological type, with the liver (48.6%) as the most prevalent metastatic site. Single-site metastasis was seen in 55.4% of patients. Immunohistochemistry, conducted in 40.3% of patients, was inconclusive in identifying the primary site. The median overall survival was 5 months (95% confidence interval [CI]: 4.0–7.0). Multivariable Cox regression analysis showed older age increased risk of death (hazard ratio [HR]: 1.028, 95% CI: 1.019–1.037). Neuroendocrine tumors were linked to a lower risk (HR: 0.553, 95% CI: 0.313–0.978), while metastasis to the liver (HR: 1.382, 95% CI: 1.076–1.774) and pancreas (HR: 2.138, 95% CI: 1.094–4.176) increased mortality risk. Conclusion: This study provides large-scale evaluation of CUP in an Iranian population, revealing its poor prognosis and the limited diagnostic utility of IHC. The findings align with global data and highlight the urgent need for improved diagnosis and treatment to enhance patient outcomes.

Dear Editor, Appreciating your trust in me, the Manuscript: "Investigating the Role of Vitamin D in the Prevention and Control of Dengue Virus Vectors and Related Diseases: A Systematic Review" is evaluated as follows: The manuscript is well-struct...

Nonmedullary thyroid cancer (NMTC) comprises approximately 90% of all thyroid cancers, and about 3% to 9% of NMTC cases have a familial origin. Familial NMTC (FNMTC) in the absence of a documented familial cancer syndrome such as Cowden syndrome is characterized by the occurrence of thyroid cancer of follicular cell origin in 2 or more first-degree relatives. Whole-exome sequencing (WES) was used to identify pathogenic genetic variants in 2 Persian families with FNMTC. The purpose of this work is to assess the pathogenic status of these variants as well as the cosegregation status of the variants observed in the examined families. By analyzing WES data in the first family, SRGAP1: NM_020762: exon16: c.C1849T was identified as a pathogenic variant. This variant was confirmed by Sanger sequencing. In the second family, the variant FOXE1: NM_004473: exon1: c.531_532insCGCGA was identified but was not confirmed by Sanger sequencing. Based on the data, SRGAP1 can be a potential candidate gene for susceptibility to FNMTC in the first family. However, additional analyses like whole genome sequencing and copy number variations are required to ascertain the disease status in second family.

Background: Breast cancer (BC) is the leading cause of cancer death in women. The current study is designed to evaluate the association of lipid profiles, FBS, and body mass index (BMI) with BC recurrence and metastasis. Materials and Methods: This is a case–control study on estrogen receptor-positive BC patients in Isfahan Province, Central Iran, between 2008 and 2020. The control group was patients who had no evidence of recurrence or metastasis at least 1 year after the end of chemotherapy and hormone therapy. The case group was patients with evidence of metastasis or recurrence within 1 year after the end of chemotherapy and hormone therapy. Fasting blood sugar (FBS), total cholesterol (Chol), triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) were measured before treatment, after chemotherapy, and after hormone therapy as well as BMI in the case and control groups. Results: There were 108 patients in the case and 119 patients in the control group with a mean age of 50.72 ± 13.26 and 51.91 ± 11.79, respectively. There were no meaningful differences between the case and control groups regarding serum FBS, Chol, TG, HDL, LDL, and BMI. Conclusion: We found no association between serum FBS, lipid profile, and BMI at initial diagnosis and BC recurrence or metastasis.

Background: Only 5 to 10% of cancers are hereditary, but they are particularly important since they can be passed down from generation to generation, and family members are at elevated risk. Although screening methods are one of the essential strategies for dealing with hereditary cancers, they do not have high specificity and sensitivity. The emergence of whole-exome sequencing (WES) causes a significant increase in the diagnostic rate of cancer-causing variants in at-risk families. Materials and Methods: We performed WES on the proband's DNA sample from an Iranian family with multiple cancer-affected members to identify potential causative variants. Multiple in silico tools were used to evaluate the candidate variants' pathogenicity and their effects on the protein's structure, function, and stability. Moreover, the candidate variants were co-segregated in the family with Sanger sequencing. Results: The WES data analysis identified two pathogenic variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr). Sanger sequencing data showed each of the variants was incompletely segregated with phenotype, but both of them explained the patient's phenotype together. Also, the structural analysis demonstrated that due to the variant (c.538C>T), a salt bridge between arginine 180 and glutamic acid 149 was lost. Indeed, several protein stability tools described both variants as destabilizing. Conclusion: Herein, we interestingly identify two distinct deleterious causative variants (CHEK2: NM_007194.4: c.538C>T, p.Arg180Cys and MLH1: NM_000249.4, c.844G>A, p.Ala282Thr) in a family with several cancer-affected members. Furthermore, this study's findings established the utility of WES in the genetic diagnostics of cancer.