Loss-of-function variants in SEMA3F and PLXNA3 encoding semaphorin-3F and its receptor plexin-A3 respectively cause idiopathic hypogonadotropic hypogonadism.

PURPOSE: Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by absent puberty and subsequent infertility due to gonadotropin-releasing hormone (GnRH) deficiency. IHH can be accompanied by normal or compromised olfaction (Kallmann syndrome). Several semaphorins are known potent modulators of GnRH, olfactory, and vomeronasal system development. In this study, we investigated the role of Semaphorin-3F signaling in the etiology of IHH. METHODS: We screened 216 IHH patients by exome sequencing. We transiently transfected HEK293T cells with plasmids encoding wild type (WT) or corresponding variants to investigate the functional consequences. We performed fluorescent IHC to assess SEMA3F and PLXNA3 expression both in the nasal region and at the nasal/forebrain junction during the early human fetal development. RESULTS: We identified ten rare missense variants in SEMA3F and PLXNA3 in 15 patients from 11 independent families. Most of these variants were predicted to be deleterious by functional assays. SEMA3F and PLXNA3 are both expressed along the olfactory nerve and intracranial projection of the vomeronasal nerve/terminal nerve. PLXNA1-A3 are expressed in the early migratory GnRH neurons. CONCLUSION: SEMA3F signaling through PLXNA1-A3 is involved in the guidance of GnRH neurons and of olfactory and vomeronasal nerve fibers in humans. Overall, our findings suggest that Semaphorin-3F signaling insufficiency contributes to the pathogenesis of IHH.

Comparison of Point-of-Care Ultrasonography and Radiography in the Diagnosis of Long-Bone Fractures.

Background and objectives: In this study, the accuracy of point-of-care ultrasonography (POCUS) was compared to radiography (XR) in the diagnosis of fractures, the determination of characteristics of the fractures, and treatment selection of fractures in patients admitted to the emergency department (ED) due to trauma and suspected long bone (LB) fractures. Materials and Methods: The patients were included in the study, who were admitted to ED due to trauma, and had physical examination findings suggesting the presence of fractures in LB (humerus, radius, ulna, femur, tibia, and fibula). The patients were evaluated by two emergency physicians (EP) in ED. The first EP examined LBs with POCUS and the second EP examined them with XR. LBs were evaluated on the anterior, posterior, medial, and lateral surfaces and from the proximal joint to the distal one (shoulder, elbow, wrist, hip, knee, and ankle joint) in both longitudinal and transverse axes with POCUS. Results: A total of 205 patients with suspected LB fractures were included in the study. LB fractures were determined in 99 patients with XR and in 105 patients with POCUS. The sensitivity, specificity, positive predictive value, negative predictive value of POCUS in determining the fractures were 99%, 93%, 93%, and 99%, respectively, compared to XR. Compared to XR, POCUS was able to determine 100% of fissure type fractures (kappa (κ) value: 0.765), 83% of linear fractures (κ: 0.848), 92% of fragmented fractures(κ: 0.756), 67% of spiral fractures (κ:0.798), 75% of avulsion type fractures (κ: 0.855), and 100% of full separation type fractures (κ: 0.855). Conclusions: This study has demonstrated that POCUS has a high sensitivity in diagnosing LB fractures. POCUS has a high sensitivity in identifying fracture characteristics. POCUS can be used as an alternative imaging method to XR in the diagnosis of LB fractures and in the determination of fracture characteristics.

Comparisons of Children with and without Type I Diabetes on Hand and Visual Motor Integration Skills and on Participation in Daily Activities.

Our aim in this study was to compare hand skills, visual-motor integration skills, and participation in daily living activities of children with and without Type 1 diabetes (T1DM). In this prospective cross-sectional study, we included 44 children with T1DM (17 males, 27 females; aged 8-12 years) and a control group of 45 healthy age-matched children without T1DM (22 males, 23 females). We compared group scores on the Jebsen-Taylor Hand Function Test (JTHFT), the Beery-Buktenica Developmental Visual Motor Integration Test (Beery VMI), and the Participation and Environment Measure - Children and Youth (PEM-CY). JTHFT and Beery VMI scores of children with T1DM were significantly lower than those of the control group (p ≤ 0.005). On the PEM-CY, children with T1DM were found to have more participation barriers in the community than controls. Relative deficits in hand skills and visual motor integration of children with T1DM should be managed with greater attention and assistance.

Cranial MRI Abnormalities and Long-term Follow-up of the Lesions in 770 Girls With Central Precocious Puberty.

CONTEXT: Central precocious puberty (CPP) may arise from central nervous system (CNS) lesions in a few affected girls. Recently, the incidence of girls with CPP has increased mostly in 6-8 year olds, in whom the necessity of magnetic resonance imaging (MRI) is debated. OBJECTIVE: To investigate the frequency, long-term outcome and potential predictors of CNS lesions in a large cohort of girls with CPP. METHODS: A multicenter cohort of 770 Turkish girls with CPP who had systematic cranial MRI between 2005 and 2017. Age at puberty onset was <6 years in 116 and 6-8 years in 654. CNS lesions were followed until final decision(6.2 ± 3.1 years). Potential predictors of CNS lesions were evaluated by univariate analyses. RESULTS: A total of 104/770 (13.5%) girls had abnormal brain MRI. Of these, 2.8% were previously known CNS lesions, 3.8% had newly detected and causally related CNS lesions, 3.1 % were possibly, related and 3.8% were incidental. Only 2 (0.25%) neoplastic lesions (1 low grade glioma and 1 meningioma) were identified; neither required intervention over follow-up of 6 and 3.5 years respectively. Age at breast development <6 years (odds ratio [OR] 2.38; 95% CI 1.08-5.21) and the peak luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio >0.6 (OR 3.13; 95% CI 1.02-9.68) were significantly associated with CNS lesions. However, both patients with neoplastic lesions were >6 years old. CONCLUSION: Although age and LH/FSH ratio are significant predictors of CNS lesions, their predictive power is weak. Thus, systematic MRI seems to be the most efficient current approach to avoid missing an occult CNS lesion in girls with CPP, despite the low likelihood of finding a lesion requiring intervention.

Management of Thyrotoxicosis in Children and Adolescents: A Turkish Multi-center Experience

Objective: To determine the demographic and biochemical features of childhood and juvenile thyrotoxicosis and treatment outcome. Methods: We reviewed the records of children from 22 centers in Turkey who were diagnosed with thyrotoxicosis between 2007 to 2017. Results: A total of 503 children had been diagnosed with thyrotoxicosis at the centers during the study period. Of these, 375 (74.6%) had been diagnosed with Graves' disease (GD), 75 (14.9%) with hashitoxicosis and 53 (10.5%) with other less common causes of thyrotoxicosis. The most common presenting features in children with GD or hashitoxicosis were tachycardia and/or palpitations, weight loss and excessive sweating. The cumulative remission rate was 17.6% in 370 patients with GD who had received anti-thyroid drugs (ATDs) for initial treatment. The median (range) treatment period was 22.8 (0.3-127) months. No variables predictive of achieving remission were identified. Twenty-seven received second-line treatment because of poor disease control and/or adverse events associated with ATDs. Total thyroidectomy was performed in 17 patients with no recurrence of thyrotoxicosis and all became hypothyroid. Ten patients received radioiodine and six became hypothyroid, one remained hyperthyroid and restarted ATDs and one patient achieved remission. Two patients were lost to follow up. Conclusion: This study has demonstrated that using ATDs is the generally accepted first-line approach and there seems to be low remission rate with ATDs in pediatric GD patients in Turkey.

Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus.

BACKGROUND/AIMS: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. METHODS: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. RESULTS: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30-21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. CONCLUSION: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.

Incidence of Type 1 Diabetes in Children Aged Below 18 Years during 2013-2015 in Northwest Turkey

Objective: To assess the incidence of type 1 diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9, 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6%) were girls and 911 (51.4%) were boys. The mean age at diagnosis was 9.2±4.2 years and it was not significantly different between girls (9.0±4.1 years) and boys (9.4±4.4 years) (p=0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/100.000 respectively. The incidence of T1DM was similar over the course of three years (p=0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study.

Evaluation of therapeutics management patterns and glycemic control of pediatric type 1 diabetes mellitus patients in Turkey: A nationwide cross-sectional study.

AIMS: To evaluate the management strategies, glycemic control and complications of pediatric type 1 diabetes mellitus (T1DM) patients in Turkey. METHODS: Study included 498 patients with T1DM between the ages 1-18. Data provided from patients' hospital files were recorded on standard case report forms by applicant clinicians within the 3months of data collection period between October 2012 and July 2013. RESULTS: Mean age of patients was 11.3±3.8years. Mean duration of DM was determined as 3.7±3.1years. Majority of patients (85.5%) used basal/bolus injection (BBI), and 6.5% used continuous subcutaneous insulin infusion pump. Assessment of glycemic control based on HbA1c levels showed that 29.1% of patients had an HbA1c value <7.5% (58mmol/mol), 16.1% had a value between 7.5% (58mmol/mol) and 8% (64mmol/mol), 19.1% had a value between 8.1% (64mmol/mol) and 9%(75mmol/mol) and 35.7% a value >9%(75mmol/mol). Hypoglycemia was reported in 145 (29.1%) patients and the number of severe hypoglycemic attacks in the last 3months was 1.0±2.4. Taking into consideration the carbohydrate count and insulin correction dose and parents with high socioeconomic status was related to have better glycemic control. The most common comorbidities were Hashimoto's thyroiditis/hypothyroidism (6.2%) followed by celiac disease (3.8%), epilepsy(1.2%), and asthma(1.0%). CONCLUSIONS: BBI insulin therapy is widely used among pediatric T1DM patients in Turkey. However, despite improvements in treatment facilities and diabetic care, glycemic control is not at a satisfactory level. Therefore, new and comprehensive initiatives require for pediatric T1DM patients with poor glycemic control. Promoting use of carbohydrate count and insulin correction doses may improve the glycemic control of pediatric T1DM in Turkey.

A new insight into food addiction in childhood obesity.

Uncontrolled eating behavior in obese subjects is very similar to behavior in food addiction, suggesting a relationship. This study was designed to evaluate the relationship between childhood obesity and food addiction and to determine the frequency of food addiction among obese children and adolescents. The study included 100 overweight and obese children. Food addiction was evaluated by the Yale Food Addiction Scale (YFAS). The cutoff value for food addiction was defined as the presence of 3 or more symptoms. Participants were between 10 and 18 years of age; 63% were girls. Of the participants, 71% had food addiction. The most addictive foods were chocolate, ice cream, carbonated beverages, French fries, white bread, rice, candy, chips and pasta, in decreasing order of frequency. Experiencing a frequent feeling of hunger was associated with a 2.2-fold increase in food addiction risk, while consumption of French fries ≥1-2 times per week was associated with a 2.3-fold increase in risk (p<0.05). The high YFAS scores in obese and overweight adolescents suggest that food addiction plays an important role in childhood obesity. Evaluation of food addiction in more detail may open a new perspective on the prevention and treatment of obesity.

Features of two cases with 18q deletion syndrome.

The 18q Deletion syndrome is seen in 1 out of 10 000 live births. The main features of the syndrome are short stature, hearing loss, hypotonia, mental retardation, endocrine disorders and autoimmunity. Here, we present 2 patients with this syndrome admitted to our clinic who were found to have insulin resistance in addition to mental retardation, short stature, autoimmune thyroiditis and hearing loss. The need to perform a karyogram analysis in cases presenting with these features is emphasized.

Evaluation of vitamin D supplementation doses during pregnancy in a population at high risk for deficiency.

AIM/BACKGROUND: Vitamin D supplementation during pregnancy is a well-accepted recommendation worldwide; however, the debate about the correct dose is ongoing. We aimed to compare daily doses of 600, 1,200, and 2,000 IU in this randomized, controlled study. METHODS: The study group consisted of 91 pregnant women aged 16-42 years admitted to Kocaeli Maternity and Children Hospital between April 2011 and April 2012. The participants were randomly divided into 3 groups. 600, 1,200, and 2,000 IU/day of vitamin D was supplemented to group 1 (control group, n = 31), group 2 (n = 31), and group 3 (n = 32), respectively. Serum calcium, 25-hydroxyvitamin D (25OHD), and the calcium/creatinine ratio in spot urine samples were measured in the follow-up period. The serum calcium and 25OHD levels of the mothers' infants were measured as well. RESULTS: The frequency of vitamin D sufficiency after supplementation was 80% in group 3 and it was significantly higher than in groups 1 (42%) and 2 (39%) (p = 0.03). The frequency of vitamin D sufficiency in the infants of the participants was 91% in group 3 and it was significantly higher than in groups 1 (36%) and 2 (52%) (p = 0.006). CONCLUSIONS: At least 2,000 IU/day of vitamin D is needed to ensure adequate vitamin D status in pregnancy and early infancy.