A novel homozygous nonsense NDNF variant in Kallmann syndrome.

Kallmann syndrome (KS) is a rare genetic disease characterized by pubertal failure and olfactory defects. Although many genes associated with KS have been reported, most are rare. Recently, heterozygous inactivating mutations in the neuron-derived neurotrophic factor gene (NDNF) were reported to cause KS. Here, we present a 14-year-old Kurdish boy with KS who has a novel homozygous nonsense c.1251C>A (p.Tyr417Ter) variant in NDNF. The variant was not observed in reference population databases and was predicted to be deleterious. Segregation analysis performed with Sanger sequencing indicated the autosomal recessive inheritance of the clinical phenotype. His heterozygous parents have experienced timely pubertal development and normal reproductive features. This study reported the first homozygous truncating NDNF variant, enabling the direct observation of the clinical consequences of predictively absent NDNF function. These results support the contention that the inactivating mutations in NDNF cause KS, and provide additional evidence for the complex inheritance of KS.

The utility of annual growth velocity standard deviation scores and measurements of biochemical parameters in long-term treatment monitoring of children with 21-hydroxylase deficiency.

PURPOSE: This study aimed to investigate the utility of annual growth velocity (GV) standard deviation scores (SDSs) and compatibility and effectiveness of biochemical parameters in long-term treatment monitoring and management of 21-hydroxylase deficiency (21-OHD) in children. METHODS: Fifty children with 21-OHD were included in this study, and the biochemical parameters obtained during 402 visits were retrospectively evaluated. The follow-up period was divided between two GV SDS groups (GV SDS < 2 and GV SDS ≥ 2) and compared with auxological, biochemical, and clinical findings. RESULTS: Elevation of 17-hydroxyprogesterone (17-OHP) values was observed at 193/402 visits, and both adrenocorticotropic hormone (ACTH) and total testosterone (tT) were observed at 53 of 193 (27.5%) visits. The calculated cut-off value for 17-OHP was > 4.3 ng/ml, with a sensitivity of 85.48% and specificity of 37.59% in the GV SDS ≥ 2 group. In the GV SDS ≥ 2 group, the corrected final height SDS (cFH SDS) was lower, and the delta height was higher than in the GV SDS < 2 group (p = 0.005 and p = 0.008, respectively). Linear regression analysis of the GV SDSs revealed that 17-OHP values and the hydrocortisone dose (mg/m2) were affected (ß = 0.037, p = 0.035, and ß = - 0.147, p = 0.001, respectively). CONCLUSIONS: Annual GV was critical in the final height (FH) of children with 21-OHD. However, we observed inconsistency between the biochemical parameters in the follow-ups, and there were difficulties in evaluating these markers. Therefore, annual GV SDSs and biochemical findings should be used together in patients with 21-OHD at follow-ups.

Short-term Side Effects of Pulse Steroid Treatment in Children.

This study is aimed to evaluate pediatric patients, who were hospitalised in the Department of Pediatrics, University of Health Sciences, Adana City Training and Research Hospital, Turkey, between January, 2019 and January, 2020, and treated with pulse steroid therapy and the early side effects of their treatment. The fasting blood glucose levels of the patients during treatment were statistically significantly higher than those prior to the treatment. The most common side effects observed in the patients were dermatological (48.5%), psychiatric (31.4%), and gastrointestinal (31.4%). Hypertension was detected in seven patients (20%) after treatment; and continued in three, who subsequently underwent antihypertensive treatment. Pulse steroid treatment was administered for a median of five days (3-11 days). It was found that 24 patients responded to treatment, 11 patients did not respond, and one patient died. There is a shortage of studies in literature on pulse steroid therapy and its side effects, especially focusing on children. Multicentre and randomised controlled studies are needed comprising different patient groups to evaluate the efficacy and complications associated with its use. Key Words: Children, Side effect, Pulse steroid treatment.

Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.

Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate nucleus of the hypothalamus constitute the GnRH (gonadotropin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in-silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2's critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

Post-exposure Rabies Prophylaxis for Children in Southern Turkey.

OBJECTIVE: To evaluate the prophylaxis practices used on children with animal exposures in a major southern city of Turkey, close to the Syrian border. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Emergency and Outpatient departments, Adana City Training and Research Hospital, Turkey between September 2017 and September 2018. METHODOLOGY: The demographic data of the patients, who presented due to animal contact; the interval between animal contact and hospital presentation; species of exposed animals, type, and apparent condition of the animals; risk categories based on national assessment scale; the number of rabies vaccines and anti-rabies immunoglobulin (RIG) administrations; administration of tetanus prophylaxis; adherence of patients to the follow-up schedule; vaccine refusals; and development of rabies disease (if any), were recorded. RESULTS: Of the 2,068 presentations after animal exposure, 906 (43.8%) were children, mostly boys (62%), and the mean age was 97.15 ± 57.68 months. Risky contact was most frequently caused by cats (52.8%) and dogs (45.6%). Exposure to stray animals was the most common (58.5%). For serial prophylaxis vaccinations, 761 (83.99%) families were in full compliance and 145 (16%) families had discontinued vaccinations. The discontinuation rate of the immigrant population was significantly higher (p = 0.001). CONCLUSION: Risky contacts were mostly due to stray animals. Efforts to minimise the stray animal population should be increased. The rate of discontinuation of rabies prophylaxis follow-ups was 16%. Significantly higher prophylaxis discontinuation among the immigrant population was noted. Key Words: Rabies, Vaccines, Prophylaxis, Turkey.

The Relationship between Bronchiolitis Severity and Vitamin D Status.

BACKGROUND/AIM: Acute bronchiolitis is mostly caused by viral agents in children under 2 years of age. The disease mostly has a mild clinical course however severe cases are not uncommon. Vitamin D is known to exert immune-regulatory functions. We aimed to examine the association between the clinical severity of acute bronchiolitis and serum vitamin D levels in infants. MATERIALS AND METHODS: A total of 182 children with acute bronchiolitis were prospectively enrolled. The disease severity was assessed using the Modified Tal Scoring System and their vitamin D levels were evaluated. RESULTS: Vitamin D deficiency or insufficiency was as high as 47.8% in infants with bronchiolitis. Infants with low vitamin D levels comprised a significantly larger proportion of patients with severe bronchiolitis (p = 0.002). Infants admitted to intensive care unit had significantly higher degrees of vitamin D deficiency or insufficiency (p < 0.001). CONCLUSION: Vitamin D deficiency is closely linked with severe bronchiolitis and the need for intensive care unit admission in infants. We believe that assessment of vitamin D levels in infants prior to bronchiolitis season and appropriate supplementation may have a protective effect against severe bronchiolitis.

Changes in the presentation of newly diagnosed type 1 diabetes in children during the COVID-19 pandemic in a tertiary center in Southern Turkey.

OBJECTIVES: The COVID-19 pandemic is a global health problem with high morbidity and mortality. This study aimed to investigate patients who were diagnosed with type 1 diabetes during the pandemic and evaluate the effect of the pandemic on the clinical findings of these patients by comparing them with findings from a year prior. METHODS: Patients diagnosed with type 1 diabetes mellitus between 2019 and 2021 were separated into two groups: Patients diagnosed prepandemic and those diagnosed during the pandemic. RESULTS: The number of newly diagnosed diabetes cases increased from 46 in the prepandemic period to 74 in the pandemic period. The number of cases diagnosed with diabetic ketoacidosis (DKA) in the clinic increased from 58.7 to 91.9%. We found that moderate and severe DKA rates from 18.5 and 14.8% to 23.5 and 22.1%, respectively. Besides, the average HbA1c was higher, while the average bicarbonate was lower in cases diagnosed during the pandemic period compared to the prepandemic period (p=0.048 and p<0.001, respectively). We found that celiac autoantibody positivity antibodies to glutamic acid decarboxylase (anti GAD) positivity, and islet cell antibodies (ICA), ICA and anti GAD positivity coexistence were higher (p=0.045, p=0.008, and p=0.007, respectively) among the patients diagnosed during the pandemic. CONCLUSIONS: We observed an increase in the number of patients newly diagnosed with type 1 diabetes mellitus, an increase in autoantibody positivity, and higher rates and severity of DKA during the COVID-19 pandemic period compared to the prepandemic period.

Evaluation of Pediatric Measles Cases Hospitalized in 2019.

OBJECTIVE: Outbreaks of measles were seen throughout the world in 2018-2019, including Turkey. Measles outbreak in Turkey may be attributed to cases imported from European countries and increased rate of unvaccinated children due to the massive influx of refugees from neighboring countries. MATERIALS AND METHODS: The demographic details and clinical and laboratory findings of the patients hospitalized with diagnosis of measles in the Pediatric Clinic of Adana City Hospital in 2019 were evaluated retrospectively. RESULTS: Among the 38 children enrolled, 18 were female (47.4%), the median age was 12 months (3-199 months), 20 were Turkish citizens (52.6%), and 18 (47.4%) were refugees. Twenty-seven children had vaccination data available, with 25 unvaccinated for measles. None of the families declared vaccine hesitancy. Of the unvaccinated subgroup (n = 25), 19 (76%) were younger than 12 months. The mean duration of hospitalization was 5.13 ± 2.67 days, no mortalities occurred. Measles was encountered in the social circle of 10 cases, although only 2 families applied for prophylaxis. CONCLUSIONS: Among the children with measles, 10 of the cases were reported to be within the household of previously diagnosed measles cases, but only 2 of them were given prophylaxis. Awareness regarding use of post-exposure prophylaxis against measles should be increased. Efforts to keep the measles vaccination coverage rate above optimal levels should be encouraged in regions with concentration of irregular refugees.

Diagnostic contribution of postmortem needle biopsies in neonates.

OBJECTIVE: We examined the contribution of neonatal postmortem needle biopsy in circumstances of autopsy denial where magnetic resonance imaging cannot be performed. MATERIAL AND METHOD: 247 postmortem needle biopsy specimens of 76 neonatal cases who died in the neonatal intensive care ward of a tertiary hospital between 2005 and 2010 and where the family did not give permission for an autopsy were retrospectively evaluated. RESULTS: 90 needle biopsy attempts (36.4%) were unsuccessful among the 247 biopsies. Liver needle biopsies were found to yield the most valuable diagnostic contribution. A total of 53 liver biopsies provided clinical information that contributed to the diagnosis. CONCLUSION: The postmortem needle biopsy should be applied in all cases in which standard biopsy cannot be performed. Success rates and level of information gained by extrahepatic needle organ biopsies in neonates were found to be quite low whereas needle biopsies of the liver yielded valuable results. We believe it is more appropriate to perform percutaneous postmortem biopsies solely on the liver in neonates.

Atypical presentations of celiac disease.

Celiac disease (CD) has a wide variety of clinical presentations; together with the "classical form", in which the intestinal symptomatology is prevalent, there are "atypical forms" with predominating extra-intestinal clinical features, and the "silent form", with no clinical symptom. The "atypical forms" of the disease are characterized by few or no gastrointestinal symptoms, and predominating extra-intestinal features such as neurologic, dermatologic, hematologic, endocrinologic, reproductive, renal, psychiatric, skeletal, and liver involvement(s). Silent presentation of CD may be identified through screening of high-risk groups. Today, it is well known that CD might account for several chronic health issues, so it is essential for healthcare professionals to have a high level of suspicion for the atypical presentations of CD.

Presence of a D8/17 B lymphocyte marker and HLA-DR subgroups in patients with rheumatic heart disease.

OBJECTIVE: The aim of our study was to investigate the association of HLA antigens and a non-HLA protein D8/17 with rheumatic heart disease and its pattern of cardiac involvement. METHODS: This cross- sectional observational study included 35 children and 12 adult patients who have rheumatic heart disease and 35 healthy children and 12 healthy adult controls. After physical examination, all patients and control group members were evaluated with 2D and color-coded echocardiography. B- lymphocyte D8/17 expression was tested by a flow cytometry assay. HLA genotyping was performed using polymerase chain reaction sequence-specific primers. In statistical analysis, Chi-square, unpaired t and Mann-Whitney U tests were used for comparison groups. RESULTS: The percentage of the D8/17-expressing B lymphocytes of the patient group was significantly higher than of the control group (77.3±15.6% vs. 67.7±20.0%, p=0.013). When compared with the control group, the HLA DRB5 (38.6% vs. 13.6%, p=0.007) and HLA DRB1*15 (31.8% vs. 9.0%, p=0.008) expression levels of the patient group were significantly higher and the DRB4 expression of the patient group was significantly lower (29.5% vs. 50.0%, p=0.049). CONCLUSION: Our findings support the association between HLA Class 2 subgroups and rheumatic heart disease, and an association between D8/17 expression and rheumatic heart disease. Further studies including higher number of patients and control group members should be performed for the confirmation of our results.