Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment

Investigating CFTR gene variations in patient groups with positive newborn screening test results and preliminary clinical diagnosis of cystic fibrosis in the eastern anatolia region of Turkey

Cystic fibrosis (CF, OMIM: #219700), caused by biallelic pathogenic variations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common monogenic disease. The present study aimed to investigate CFTR gene variations in patients with a positive screening test result for CF and those with a clinical suspicion of CF. Overall, 443 patients (190 females/253 males) were retrospectively included. Of these, a positive neonatal screening test result for CF was reported in 124 patients (58 females/66 males) and a preliminary clinical diagnosis of CF based on recurrent lung infection and/or delayed weight gain was reported in 327 patients (134 females/193 males). All patients were evaluated based on clinical findings, sweat test (ST) results, and CFTR gene sequence analysis results. In the group of 116 patients having a positive neonatal screening test result for CF, heterozygous variations were observed in 21 (18%) patients, compound heterozygous variations in 9 (8%) patients, and homozygous variations in 5 (4%) patients. In the group of 327 patients with a clinical suspicion of CF, heterozygous variations were observed in 52 (16%) patients, compound heterozygous variations in 26 (8%) patients, and homozygous variations in 11 (3%) patients. When the two groups were cumulatively evaluated, the most common mutant alleles were Pro1013Leu (10.4%), Tyr515* (9.6%), and Phe508del (4.8%). In the total study sample of 443 patients, 51 different variants were detected. To the best of our knowledge, this is the first comprehensive study that demonstrated CFTR gene variation distribution in the Eastern Anatolia Region of Turkey. In this study, mutation distribution was highly heterogeneous, and we believe that investigation of the entire CFTR gene is necessary and would improve the diagnostic rates for CF in the Turkish population. [Med-Science 2021; 10(2.000): 293-8

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

The aim of this study was to determine the prevalence of leptin (LEP), leptin receptors (LEPR), melanocortin-4-receptor (MC4R), proopiomelanocortin (POMC), single-minded 1 (SIM1), and SH2B1 gene variations in Turkish children and adolescents, and to conduct a detailed examination of the clinical and laboratory findings of patients with variants. In this study, we included 49 children and adolescents (29 male/20 female) who presented to the Pediatric Endocrinology clinic of Erzurum Regional Training and Research Hospital between 2017 and 2020 with obesity. Family history with regards to obesity, parental consanguinity, obesity-related comorbidities, anthropometric measurements, and laboratory tests of the patients were recorded in the clinical evaluation. LEP, LEPR, MC4R, POMC, SIM1, and SH2B1 genes, which are associated with monogenic obesity, were evaluated by the next generation sequencing analysis in all patients. The mean age of 49 patients included in the study was 8.4 ± 5.2 years (range: 0.616.8), their mean height standard deviation score (SDS) was 0.9 ± 1.6, mean body mass index (BMI) was 31.3 ± 8.1 kg/m2, and their mean BMI SDS was 3.5 ± 0.6. A total of four different variants (c.380C>T and c.870delG variants in MC4R gene; c.2992A>C and c.448delA variants in LEPR gene) were detected in four patients. The determination of a molecular etiology in patients with monogenic obesity is important in view of the treatment options to be introduced in the near future (MC4R agonist) and for the family to receive appropriate genetic counseling. In this study, we evaluated the clinical and genetic findings of the patients with monogenic obesity in detail, and contributed the findings of the novel variants to the literature. [Med-Science 2021; 10(2.000): 328-33

Expanding the clinical and immunological phenotypes of PAX1-deficient SCID and CID patients

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34+ cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment