Implication of transcription factor FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) are the predominant cause for chronic kidney disease below age 30 years. Many monogenic forms have been discovered due to comprehensive genetic testing like exome sequencing. However, disease-causing variants in known disease-associated genes only explain a proportion of cases. Here, we aim to unravel underlying molecular mechanisms of syndromic CAKUT in three unrelated multiplex families with presumed autosomal recessive inheritance. Exome sequencing in the index individuals revealed three different rare homozygous variants in FOXD2, encoding a transcription factor not previously implicated in CAKUT in humans: a frameshift in the Arabic and a missense variant each in the Turkish and the Israeli family with segregation patterns consistent with autosomal recessive inheritance. CRISPR/Cas9-derived Foxd2 knockout mice presented with a bilateral dilated kidney pelvis accompanied by atrophy of the kidney papilla and mandibular, ophthalmologic, and behavioral anomalies, recapitulating the human phenotype. In a complementary approach to study pathomechanisms of FOXD2-dysfunction-mediated developmental kidney defects, we generated CRISPR/Cas9-mediated knockout of Foxd2 in ureteric bud-induced mouse metanephric mesenchyme cells. Transcriptomic analyses revealed enrichment of numerous differentially expressed genes important for kidney/urogenital development, including Pax2 and Wnt4 as well as gene expression changes indicating a shift toward a stromal cell identity. Histology of Foxd2 knockout mouse kidneys confirmed increased fibrosis. Further, genome-wide association studies suggest that FOXD2 could play a role for maintenance of podocyte integrity during adulthood. Thus, our studies help in genetic diagnostics of monogenic CAKUT and in understanding of monogenic and multifactorial kidney diseases.

Metabolic and other morbid complications in congenital generalized lipodystrophy type 4.

Morbidity and mortality rates in patients with autosomal recessive, congenital generalized lipodystrophy type 4 (CGL4), an ultra-rare disorder, remain unclear. We report on 30 females and 16 males from 10 countries with biallelic null variants in CAVIN1 gene (mean age, 12 years; range, 2 months to 41 years). Hypertriglyceridemia was seen in 79% (34/43), hepatic steatosis in 82% (27/33) but diabetes mellitus in only 21% (8/44). Myopathy with elevated serum creatine kinase levels (346-3325 IU/L) affected all of them (38/38). 39% had scoliosis (10/26) and 57% had atlantoaxial instability (8/14). Cardiac arrhythmias were detected in 57% (20/35) and 46% had ventricular tachycardia (16/35). Congenital pyloric stenosis was diagnosed in 39% (18/46), 9 had esophageal dysmotility and 19 had intestinal dysmotility. Four patients suffered from intestinal perforations. Seven patients died at mean age of 17 years (range: 2 months to 39 years). The cause of death in four patients was cardiac arrhythmia and sudden death, while others died of prematurity, gastrointestinal perforation, and infected foot ulcers leading to sepsis. Our study highlights high prevalence of myopathy, metabolic abnormalities, cardiac, and gastrointestinal problems in patients with CGL4. CGL4 patients are at high risk of early death mainly caused by cardiac arrhythmias.

A case control study investigating the methylation levels of GHRL and GHSR genes in alcohol use disorder.

BACKGROUND: Alcohol use disorder (AUD) is a relapsing disease described as excessive use of alcohol. Evidence of the role of DNA methylation in addiction is accumulating. Ghrelin is an important peptide known as appetite hormone and its role in addictive behavior has been identified. Here we aimed to determine the methylation levels of two crucial genes (GHRL and GHSR) in ghrelin signaling and further investigate the association between methylation ratios and plasma ghrelin levels. METHODS: Individuals diagnosed with (n = 71) and without (n = 82) AUD were recruited in this study. DNA methylation levels were measured through methylation-sensitive high-resolution melting (MS-HRM). Acylated ghrelin levels were detected by ELISA. The GHRL rs696217 polymorphism was analyzed by the standard PCR-RFLP method. RESULTS: GHRL was significantly hypermethylated (P < 0.0022) in AUD between 25 and 50% methylation than in control subjects but no significant changes of GHSR methylation were observed. Moreover, GHRL showed significant positive correlation of methylation ratio between 25 and 50% with age. A significant positive correlation between GHSR methylation and ghrelin levels in the AUD group was determined (P = 0.037). The level of GHRL methylation and the ghrelin levels showed a significant association in the control subjects (P = 0.042). CONCLUSION: GHSR and GHRL methylation levels did not change significantly between control and AUD groups. However, GHRL and GHSR methylations seemed to have associations with plasma ghrelin levels in two groups. This is the first study investigating the DNA methylation of GHRL and GHSR genes in AUD.

DNAJC21-related thrombocytopenia in a young adult female.

Bone marrow failure type 3 (BMFS3) (MIM:617052) is a subtype of inherited bone marrow failure syndromes (IBMFS) caused by homozygous pathogenic variants in DNAJC21. It was first defined in 2016, and to date, 19 patients have been reported. Here we report the first adult patient; a 20-year-old female with a novel frameshift variant in DNAJC21 presents with thrombocytopenia, dysmorphic findings, and ovarian agenesis. Our patient expands the clinical spectrum to the milder end and suggests that DNAJC21-related disorders can have relatively mild presentations. Investigation of DNAJC21 variants in both childhood and adult patients with persistent, non-progressive thrombocytopenia will allow to broaden the gene-related phenotypic and genotypic spectrum and elucidate the pathophysiology. Therefore, we encourage revisiting undiagnosed patients to offer whole exome sequencing (WES) in adulthood.

Alterations in vaginal microbiota among pregnant women with COVID-19.

The maintenance of vaginal microbiota is an important factor to achieve optimum pregnancy outcomes. The study aims to describe the alterations in the composition of vaginal microbiota in pregnant women with coronavirus disease 2019 (COVID-19). This was a prospective case-control study. Vaginal swabs were collected from uninfected pregnant women (n = 28) and pregnant women with COVID-19 (n = 19) during the active phase of infection and within a month after recovering from infection. The vaginal microbiota on the swabs was examined by 16S rRNA gene sequencing. Shannon index indicates that alpha diversity is significantly higher in women with COVID-19 (p = 0.012). There was a significant decrease in Firmicutes (p = 0.014) with an increase in Bacteroidota (p = 0.018) phyla and a decrease in Lactobacillus (p = 0.007) genus in women with COVID-19 than those of uninfected pregnant women. The relative abundance of L. crispatus, L. iners, L. gasseri, and L. jensenii were lower in the COVID-19 group than in uninfected pregnant women. In subgroup analysis, the amount of Ureaplasma spp. was higher in women with moderate/severe than those of asymptomatic/mild disease (p = 0.036). The study revealed that vaginal dysbiosis with low abundance of Lactobacillus species occurred in pregnant women infected with severe acute respiratory syndrome coronavirus-2. These findings may lead to new studies to elucidate the risk of pregnancy adverse outcomes related to COVID-19.

A novel homozygous missense variant in TBC1D31 in a consanguineous family with congenital anomalies of the kidney and urinary tract (CAKUT).

Congenital anomalies of the kidney and urinary tract (CAKUT) is the leading cause of chronic kidney disease in the first three decades of life. Until now, more than 180 monogenic causes of isolated or syndromic CAKUT have been described. In addition, copy number variants (CNV) have also been implicated, however, all of these causative factors only explain a small fraction of patients with CAKUT, suggesting that additional yet-to-be-discovered novel genes are present. Herein, we report three siblings (two of them are monozygotic twin) of a consanguineous family with CAKUT. Whole-exome sequencing identified a homozygous variant in TBC1D31. Three dimensional protein modeling as well as molecular dynamics simulations predicted it as pathogenic. We therefore showed for the first time an association between a homozygous TBC1D31 variant with CAKUT in humans, expanding its genetic spectrum.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Treatment efficacy of ribociclib or palbociclib plus letrozole in hormone receptor-positive/HER2-negative metastatic breast cancer.

Background: Ribociclib, palbociclib and abemaciclib are currently approved CDK4/6 inhibitors along with aromatase inhibitors as the first-line standard-of-care for patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Methods: The authors report retrospective real-life data for 600 patients with estrogen receptor- and/or progesterone receptor-positive and HER2-negative metastatic breast cancer who were treated with ribociclib and palbociclib in combination with letrozole. Results & conclusion: The results demonstrated that the combination of palbociclib or ribociclib with letrozole has similar progression-free survival and overall survival benefit in real life for the patient group with similar clinical features. Specifically, endocrine sensitivity may be a factor to be considered in the treatment preference.

Ghrelin and impulsivity relationship in alcohol-dependent patients and healthy individuals.

AIMS: Abundant research indicates that ghrelin hormone levels are associated with alcohol use and addiction. One of the mediators of this association may be impulsivity, which is one of the common traits observed in alcohol addiction and some eating disorders. This study evaluated participants with alcohol dependency and healthy volunteers to determine whether trait impulsivity and ghrelin levels are associated. METHODS: This study analyzed trait impulsivity scores and fasting serum ghrelin levels of 44 males with alcohol dependency and 48 healthy male participants. The Barratt Impulsiveness Scale and the UPPS Impulsive Behaviour Scale (UPPS) were used to measure trait impulsivity levels. Penn Alcohol Craving Scale and Yale Brown Obsessive Compulsive Drinking Scale for heavy drinking were used to assess craving at the baseline and after the detoxification period. RESULTS: Alcohol-dependent patients' fasting ghrelin levels were significantly higher than that of healthy participants. Ghrelin plasma levels were positively correlated with UPPS total impulsivity scores and sensation-seeking among healthy individuals. In alcohol-dependent participants, there was a positive correlation between UPPS urgency scores obtained at the baseline and fasting ghrelin levels before and after the detoxification period. CONCLUSIONS: Ghrelin-impulsivity relationship could be observed in certain dimensions of impulsivity in both alcohol-dependent and healthy individuals and even independent of the effect of alcohol. Although the associated impulsivity dimensions differ in different groups, the results are parallel to other studies in terms of demonstrating the relationship between ghrelin and impulsivity.

SOCIAL COGNITION AND OXIDATIVE STRESS IN SCHIZOPHRENIA PATIENTS AND FIRST-DEGREE RELATIVES OF PATIENTS.

BACKGROUND: Misattribution of motivational salience to non-salient (neutral) stimuli could be viewed as a hallmark of psychosis in schizophrenia. Studies have recently revealed increased subjective experience of emotional arousal (EA) to neutral social stimuli in paranoid schizophrenia psychosis, suggesting a misattribution of emotional salience to them. We examined this phenomenon directly by quantifying the level of EA subjectively attributed to low-arousal, neutral-valenced faces. SUBJECTS AND METHODS: Patients with remitted schizophrenia (PG) (n=26), first-degree relatives of schizophrenic patients (RG) (n=25), and healthy controls (HCG) (n=36) were compared in terms of oxidative stress parameters -serum Superoxide Dismutase, Catalase, Glutathione Peroxidase (GPx), Nitrite, Nitrate, Malondialdehyde, and Total Glutathione levels-, social cognition measured by the Reading the Mind in the Eyes Test and working memory measured by the N-back Task. Groups were compared, assuming that HCG had a genetically lower risk of schizophrenia compared to PG and RG. RESULTS: HCG performed significantly better than PG and RG, who were genetically at high risk, in terms of social cognition (respectively p=0.000, p=0.014), working memory (respectively p=0.001, p=0.003), and had statistically lower Glutathione Peroxidase (GPX) level than the PG and RG (both p:0.000). After controlling for the effect of the general intellectual abilities measured by the Raven Standard Progressive Matrices Test and working memory the differences between groups on the Eyes Test disappeared (p=0.057). However, this value tended to be significant. CONCLUSION: It was concluded that social cognition and working memory and GPx level may be used as endophenotypes and social cognition, working memory, and general intellectual skills are different but strongly related constructs. Endophenotypes guide treatment targets even after the disease has developed. The results of our study showed that in addition to psychopharmacological treatments, interventions to reduce oxidative stress and approaches to improve cognitive skills will have a positive impact on the disease's progression.

Immunogenicity after two doses of inactivated virus vaccine in healthcare workers with and without previous COVID-19 infection: Prospective observational study.

Vaccines have been seen as the most important solution for ending the coronavirus disease 2019 (COVID-19) pandemic. The aim of this study is to evaluate the antibody levels after inactivated virus vaccination. We included 148 healthcare workers (74 with prior COVID-19 infection and 74 with not). They received two doses of inactivated virus vaccine (CoronaVac). Serum samples were prospectively collected three times (Days 0, 28, 56). We measured SARS-CoV-2 IgGsp antibodies quantitatively and neutralizing antibodies. After the first dose, antibody responses did not develop in 64.8% of the participants without prior COVID-19 infection. All participants had developed antibody responses after the second dose. We observed that IgGsp antibody titers elicited by a single vaccine dose in participants with prior COVID-19 infection were higher than after two doses of vaccine in participants without prior infection (geometric mean titer: 898 and 607 AU/ml). IgGsp antibodies, participants with prior COVID-19 infection had higher antibody levels as geometric mean titers at all time points (p < 0.001). We also found a positive correlation between IgGsp antibody titers and neutralizing capacity (rs = 0.697, p < 0.001). Although people without prior COVID-19 infection should complete their vaccination protocol, the adequacy of a single dose of vaccine is still in question for individuals with prior COVID-19. New methods are needed to measure the duration of protection of vaccines and their effectiveness against variants as the world is vaccinated. We believe quantitative IgGsp values may reflect the neutralization capacity of some vaccines.

Mutational spectrum of congenital long QT syndrome in Turkey; identification of 12 novel mutations across KCNQ1, KCNH2, SCN5A, KCNJ2, CACNA1C, and CALM1.

INTRODUCTION: Long QT syndrome (LQTS) is of great importance as it is the most common cause of sudden cardiac death in childhood. The diagnosis is made by the prolongation of the QTc interval on the electrocardiography. However, clinical heterogeneity and nondiagnostic QTc intervals may cause a delay in the diagnosis. In such cases, genetic tests such as next-generation sequencing (NGS) panel analysis enable a definitive diagnosis. We present the first study that aimed to expand the LQTS's mutational spectrum by NGS panel analysis from Turkey. METHODS: Fifty-seven unrelated patients with clinically diagnosed LQTS were investigated using an NGS panel that includes six LQTS-related genes. Clinical aspects, outcome, and molecular analysis results were reviewed. RESULTS: Pathogenic (53%)/likely pathogenic (23%)/variant of unknown significance (4%) variants were detected in any of the genes examined in 79% of the patients. Among all detected variants, KCNQ1(71%) was the most common gene, followed by SCN5A (11%), KCNH2 (10%), CALM1 (5%), and CACNA1C (3%). Twelve novel variants were detected. Among the variants in KCNQ1, the c.1097G>A variant was present in 42% of patients. This variant also composed 31% of the variants detected in all of the genes. CONCLUSION: Our study expands the spectrum of the variations associated with LQTS with twelve novel variants in five genes. And also it draws attention to the frequency of the KCNQ1 c.1097G>A variant and forms the basis for new studies to determine the possible founder effect in the Turkish population. Furthermore, identifying new variants and clinical findings has importance in elaborating the roles of related genes in pathophysiology and determining the variable expression and incomplete penetration rates in this syndrome.

Effect of BTN162b2 and CoronaVac boosters on humoral and cellular immunity of individuals previously fully vaccinated with CoronaVac against SARS-CoV-2: A longitudinal study.

BACKGROUND: It is essential to know about immune response levels after booster doses of the two different types of vaccines, mRNA, and the inactivated, currently used against COVID-19. For this purpose, we aimed to determine the effects of BNT162b2 (BNT) and CoronaVac (CV) boosters on the humoral and cellular immunity of individuals who had two doses of CV vaccination. METHODS: The study was conducted in three centers (Koc University Hospital, Istanbul University Cerrahpasa Hospital, and Istanbul University, Istanbul Medical School Hospital) in Istanbul, Turkey. Individuals who had been previously immunized with two doses of CV and no history of COVID-19 were included. The baseline blood samples were collected 3-5 months after the second dose of CV. Follow-up blood samples were taken 1 and 3 months after administration of third doses of CV, or one dose of BNT boosters. Neutralizing antibody titers were measured by plaque reduction assay. The CD4+ T cell, CD8+ T cell, effector CD4+CD38+CD69+ T cell, and effector CD8+CD38+CD69+ T cell ratios were determined by flow cytometry. The intracellular IFN-γ and IL-2 responses were measured by ELISpot assay. RESULTS: We found a 3.38-fold increase in neutralizing antibody geometric mean titers (NA GMT, 78.69) 1 month after BNT booster and maintained at the third month (NA GMT, 80). Nevertheless, in the CV booster group, significantly lower NA GMT than BNT after 1 month and 3 months were observed (21.44 and 28.44, respectively) (p < .001). In the ELISpot assay, IL-2 levels after BNT were higher than baseline and CV booster (p < .001) while IFN-γ levels were significantly higher than baseline (p < .001). The CD8+CD38+CD69+ and CD4+CD38+CD69+ T cells were stimulated predominantly in the third month of the BNT boosters. CONCLUSION: The neutralizing antibody levels after 3 months of the BNT booster were higher than the antibody levels after CV in fully vaccinated individuals. On the contrary, ratio of the effector T cells increased along with greater IFN-γ activation after BNT booster. By considering the waning immunity, we suggest a new booster dose with BNT for the countries that already had two doses of primary CV regimens.

Characteristics and outcomes of carbapenemase harbouring carbapenem-resistant Klebsiella spp. bloodstream infections: a multicentre prospective cohort study in an OXA-48 endemic setting.

A prospective, multicentre observational cohort study of carbapenem-resistant Klebsiella spp. (CRK) bloodstream infections was conducted in Turkey from June 2018 to June 2019. One hundred eighty-seven patients were recruited. Single OXA-48-like carbapenemases predominated (75%), followed by OXA-48-like/NDM coproducers (16%). OXA-232 constituted 31% of all OXA-48-like carbapenemases and was mainly carried on ST2096. Thirty-day mortality was 44% overall and 51% for ST2096. In the multivariate cox regression analysis, SOFA score and immunosuppression were significant predictors of 30-day mortality and ST2096 had a non-significant effect. All OXA-48-like producers remained susceptible to ceftazidime-avibactam.

Kynurenine pathway in Coronavirus disease (COVID-19): Potential role in prognosis.

BACKGROUND: It is known that inflammatory responses play an important role in the pathophysiology of COVID-19. AIMS: In this study, we aimed to examine the role of kynurenine (KYN) metabolism on the severity of COVID-19 disease AQ5. MATERIALS & METHODS: Seventy COVID-19 patients of varying severity and 30 controls were included in the study. In addition to the classical laboratory parameters, KYN, tryptophan (TRP), kynurenic acid (KYNA), 3 hydroxykynurenine (3OHKYN), quinolinic acid (QA), and picolinic acid (PA) were measured with mass spectrometry. RESULTS: TRP, KYN, KYN:TRP ratio, KYNA, 3OHKYN, PA, and QA results were found to be significantly different in COVID-19 patients (p < 0.001 for all). The KYN:TRP ratio and PA of severe COVID-19 patients was statistically higher than that of mild-moderate COVID-19 patients (p < 0.001 for all). When results were examined, statistically significant correlations with KYN:TRP ratio, IL-6, ferritin, and procalcitonin were only found in COVID-19 patients. ROC analysis indicated that highest AUC values were obtained by KYN:TRP ratio and PA (0.751 vs 0.742). In determining the severity of COVID-19 disease, the odd ratios (and confidence intervals) of KYN:TRP ratio and PA levels that were adjusted according to age, gender, and comorbidity were determined to be 1.44 (1.1-1.87, p = 0.008) and 1.06 (1.02-1.11, p = 0.006), respectively. DISCUSSION & CONCLUSION: According to the results of this study, KYN metabolites play a role in the pathophysiology of COVID-19, especially KYN:TRP ratio and PA could be markers for identification of severe COVID-19 cases.

Does Metformin Treatment in Pediatric Population Cause Vitamin B12 Deficiency?

BACKGROUND/AIM: There have been no studies to date examining the effect of metformin treatment on vitamin B12 status in children and adolescents. In this prospective study, the effects of metformin on blood vitamin B12, serum methylmalonic acid (MMA), homocysteine and holo-transcobalamin-II (holo-TC-II) levels were assessed in pediatric age group. MATERIALS AND METHODS: This prospective study was conducted at the Pediatric Endocrinology and Adolescent Department between January 2017 and March 2019. Metabolic syndrome and polycystic ovary syndrome diagnosed patients with insulin resistance and/or impaired glucose tolerance, patients with type 2 diabetes mellitus (DM) treated with metformin were enrolled in study. Blood vitamin B12, MMA, homocysteine, holo-TC-II levels and hemogram values were evaluated. RESULTS: Twenty-four patients were enrolled in study. Among these, 15 (62.5%) were female. The mean age of patients was 13.7±2.3 (10-19) years. Sixteen patients were diagnosed with metabolic syndrome and 8 patients were type 2 DM. At 6-month follow-up of all patients, there was no statistically significant difference in terms of vitamin B12, homocysteine, MMA and holo-TC-II levels. A 0.6% decline in vitamin B12 levels were revealed. At 12-month follow-up of 11 patients (45.8%) (6 Type 2 DM, 5 metabolic syndrome), no statistically significant difference was determined in vitamin B12, homocysteine, MMA and holo-TC-II levels. There were 6% decline in vitamin B12 levels and 10.9% increase in homocysteine levels, 5.4% decrease was detected in holo-TC-II level. CONCLUSION: Although no significant changes in the serum vitamin B12, homocysteine, MMA or holo-TC-II levels with metformin therapy were detected, long-term prospective studies with high-dose metformin treatment in pediatric population are needed to confirm our results.

Estimation of the Development of Depression and PTSD in Children Exposed to Sexual Abuse and Development of Decision Support Systems by Using Artificial Intelligence.

The most common diagnoses after childhood sexual abuse are Post-Traumatic Stress Disorder and depression. The aim of this study is to design a decision support system to help psychiatry physicians in the treatment of childhood sexual abuse. Computer aided decision support system (CADSS) based on ANN, which predicts the development of PTSD and Major Depressive Disorder, using different parameters of the act of abuse and patients was designed. The data of 149 girls and 21 boys who were victims of sexual abuse were included in the study. In the designed CADDS, the gender of the victim, the type of sexual abuse, the age of exposure, the duration until reporting, the time of abuse, the proximity of the abuser to the victim, number of sexual abuse, whether the child is exposed to threats and violence during the abuse, the person who reported the event, and the intelligence level of the victim are used as input parameters. The average accuracy values for all three designed systems were calculated as 99.2%. It has been shown that the system designed by using these data can be used safely in the psychiatric assessment process, in order to differentiate psychiatric diagnoses in the early post-abuse period.

The same mutation in a family with adenosine deaminase 2 deficiency.

The deficiency of adenosine deaminase 2 (DADA2) has recently been defined as a monogenetic autosomal recessive autoinflammatory disease. DADA2 is mainly characterized by high fever, livedo racemose, early-onset stroke, mild immunodeficiency and clinically polyarteritis nodosa (PAN)-like symptoms. Mutations in CECR1 (cat eye syndrome chromosome region, candidate 1) are responsible for DADA2. Livedoid racemose, lacunar infarct due to involvement in small vessel of the central nervous system, peripheral neuropathy, digital ulcers and loss of fingers are predominantly seen in the disease which could progress to end-stage organ failure and death in some patients. A wide spectrum of severity in phenotype as well as in the age of onset has been reported in the literature. This phenotypic variability is also found in our clinical practice even in patients with the same mutation. Here, we present a family diagnosed with DADA2, with the previously reported p.Gly47Arg mutation in CECR1.

H syndrome with a novel homozygous SLC29A3 mutation in two sisters.

H syndrome (OMIM 602782) is a recently defined autosomal recessive genodermatosis. Cutaneous findings of H syndrome include hyperpigmentation, hypertrichosis, and induration, while hearing loss, heart anomalies, hepatomegaly, hypogonadism, hyperglycemia (diabetes mellitus), low height (short stature), hallux valgus (flexion contractures), and hematological abnormalities are the extracutaneous abnormalities. We report a novel homozygous missense mutation, c.416T > C p.(Leu139Pro), in the SLC29A3 (NM_001174098.1) gene in two sisters with H syndrome presenting with different phenotypes.

The changing resistance patterns of bacterial uropathogens in children.

BACKGROUND: Increased antimicrobial resistance is a problem in managing urinary tract infections (UTI). With this study we assessed the resistance patterns of urinary isolates in children with UTI between January 2017 and January 2018. METHODS: A retrospective cohort study was conducted. Among 5,443 isolates, a total of 776 UTI episodes in 698 patients were included. Patients' gender, age, voiding dysfunction, UTI history, prophylaxis status, and presence of vesicoureteral reflux were noted. Patients were divided into three age groups: group 1 for ages ≤12 months; group 2 for ages 13-60 months; and group 3 for ages >60 months. The susceptibilities of etiologic agents to different antimicrobials were explored. RESULTS: Median age was 54 months (range 1 month-21 years); male to female ratio was 1:5. The most common causative agent was Escherichia coli (83% of the cases), followed by Klebsiella pneumoniae (7.5%). Resistance to ampicillin (62.6%) and co-trimoxazole (39.8%) were remarkable in all isolates. Overall extended-spectrum beta-lactamase (ESBL) positivity was 23.5%. The highest resistance rates, higher ESBL positivity (28.6%), and K. pneumoniae frequency (13.5%) were observed in group 1. Ceftriaxone resistance was significantly low (0.5%) in the ESBL (-) group, which constituted the majority of the isolates. Higher resistance rates were observed among the patients on prophylaxis compared to those off prophylaxis (P < 0.001). CONCLUSION: Ceftriaxone can still be used for empirical treatment; however, initial urine culture results are crucial due to high ESBL positivity. Special consideration must be taken for patients under 1 year of age. Periodical surveillance studies are needed to explore the changing resistance patterns of uropathogens and modify treatment plans.