Effects of childhood obesity on myocardial performance, autonomic and conduction properties of the heart.

BACKGROUND: Childhood obesity tends to persist into adulthood and associated with increase in developing ischemic and non-ischemic cardiovascular diseases. We aimed to evaluate the effect of obesity on cardiac functions, atrial electromechanical coupling, and heart rate response, which are considered to be predictors of atrial fibrillation and sudden cardiac arrest. METHODS: Study population included 52 obese children and 52 healthy controls. We performed 12-lead electrocardiography, echocardiographic examination, and treadmill exercise testing. Mitral, septal, and tricuspid segments were analysed by tissue Doppler imaging. RESULTS: Myocardial performance index (p = 0.011, p < 0.001, and p = 0.001, respectively) was higher and E'/A' ratio (p = 0.011, p < 0.001, and p < 0.001, respectively) was lower in obese group than controls. Atrial electromechanical coupling was longer in the obese group at all three segments (p < 0.001, p = 0.009, and p = 0.04, respectively). They had significantly longer interatrial (p < 0.001) and intra-atrial (p = 0.003) electromechanical conduction delay. While chronotropic index was similar between two groups, heart rate reserve was lower in obese children than controls (p = 0.043). The 1st- and 2nd-minute heart rate recovery indices of the obese group were lower compared to controls (p < 0.001 and p = 0.03, respectively). Body mass index was positively correlated with intra- and inter-atrial conduction times, whereas it was negatively correlated with heart rate recovery indices. CONCLUSION: We showed a deterioration in the diastolic function, atrial conduction, and heart rate response properties in children with obesity. Given the prognostic importance of these parameters, obese patients are might be at risk for atrial fibrillation and severe dysrhythmias from a young age.

Genomic analysis to screen potential genes and mutations in children with non-syndromic early onset severe obesity: a multicentre study in Turkey.

BACKGROUND: Obesity is a complex genetic-based pediatric disorder which triggers life-threatening conditions. Therefore, the understanding the molecular mechanisms of obesity has been a significant approach in medicine. Computational methods allow rapid and comprehensive pathway analysis, which is important for generation of diagnosis and treatment of obesity. METHODS AND RESULTS: Aims of our study are to comprehensively investigate genetic characteristics of obesity in children with non-syndromic, early-onset (< 7 years), and severe obesity (BMI-SDS > 3) through computational approaches. First, the mutational analyses of 41 of obesity-related genes in 126 children with non-syndromic early-onset severe obesity and 76 healthy non-obese controls were performed using the next generation sequencing (NGS) technique, and the NGS data analyzed by using bioinformatics methods. Then, the relationship between pathogenic variants and anthropometric/biochemical parameters was further evaluated. Obtained results demonstrated that the 15 genes (ADIPOQ, ADRB2, ADRB3, IRS1, LEPR, NPY, POMC, PPARG, PPARGC1A, PPARGC1B, PTPN1, SLC22A1, SLC2A4, SREBF1 and UCP1) which directly related to obesity found linked together via biological pathways and/or functions. Among these genes, IRS1, PPARGC1A, and SLC2A4 stand out as the most central ones. Furthermore, 12 of non-synonymous pathogenic variants, including six novels, were detected on ADIPOQ (G90S and D242G), ADRB2 (V87M), PPARGC1A (E680G, A477T, and R656H), UCP1 (Q44R), and IRS1 (R302Q, R301H, R301C, H250P, and H250N) genes. CONCLUSION: We propose that 12 of non-synonymous pathogenic variations detected on ADIPOQ, ADRB2, PPARGC1A, UCP1, and IRS1 genes might have a cumulative effect on the development and progression of obesity.

Meeting Report: The Equality Project on Endocrine Complications in Thalassemia: Selected Highlights from the First Turkish Congress, Antalya, 10th-11th December 2018.

Major difficulties reported by endocrinologists /pediatricians/ hematologists in the care of thalassemic patients with endocrine complications were: lack of facilities, correct interpretation of tests, unfamiliarity with medical treatment and the cost of diagnostics and therapeutics. Therefore, there is a felt need to educate and train more endocrinologists/pediatricians/hematologists in this field in order to optimise growth and prevent endocrine complications. To achieve this goal, in 2015, a project called Equality was submitted by three countries (Turkey, Spain and Italy) and approved by the European Union (EU) with the aim to train doctors and nurses, taking care of youth and young adults TM patients, in the prevention, diagnosis, and management of endocrine disorders. The selected highlights of the First Turkish Congress held in Antalya (10th-11th December 2018) are reported. Overall the conference provided a wide coverage of conventional treatment of thalassemias and endocrine complications in patients with ß-thalassemia major. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended.

A successful unrelated peripheral blood stem cell transplantation with reduced intensity-conditioning regimen in a patient with late-onset purine nucleoside phosphorylase deficiency.

PNP deficiency is a rare combined immunodeficiency with autosomal recessive mode of inheritance. The immunodeficiency is progressive with normal immune functions at birth, but then, T-cell deficiency with variable B-cell functions usually presents by the age of two yr. The only curative treatment for PNP deficiency is hematopoietic stem cell transplantation. Here, we present a 13-yr-old girl with late-onset PNP deficiency. Despite many complications of infections, she was successfully transplanted with a reduced intensity-conditioning regimen from an HLA-identical unrelated donor.

AVP-NPII gene mutations and clinical characteristics of the patients with autosomal dominant familial central diabetes insipidus.

BACKGROUND: Familial central diabetes insipidus (DI), usually an autosomal dominant disorder, is caused by mutations in arginine vasopressin-neurophysin II (AVP-NPII) gene that leads to aberrant preprohormone processing and gradual destruction of AVP-secreting cells. OBJECTIVE: To determine clinical and molecular characteristics of patients with familial central DI from two different Turkish families. MATERIALS AND METHODS: The diagnosis of central DI was established by 24-h urine collection, water deprivation test, and desmopressin challenge. To confirm the diagnosis of familial central DI, the entire coding region of AVP-NPII gene was amplified and sequenced. A total of eight affected patients and three unaffected healthy relatives from two families were studied. RESULTS: Genetic analysis revealed a previously reported heterozygous mutation (p.C98X) in family A, and a heterozygous novel mutation (p.G45C) in family B, both detected in exon 2 of AVP-NPII gene. When we compared the clinical characteristics of the two families, it was noticed that as the age of onset of symptoms in family A ranges between 4 and 7 years, it was <1 year in family B. Additionally, pituitary bright spot was present in the affected siblings, but absent in their affected parents. CONCLUSION: Familial central DI is a progressive disease, and age of onset of symptoms can differ depending on the mutation. Bright spot on pituitary MRI might be present at onset, but become invisible over time. Genetic testing and appropriate counseling should be given in familial cases of central DI to ensure adequate treatment, and to avoid chronic water deprivation that might result in growth retardation in childhood.

Familial dysalbuminemic hyperthyroxinemia (FDH) due to Arg242 His variant in ALB gene in Turkish children.

OBJECTIVES: To investigate albumin (ALB) gene variations in patients suspected from familial dysalbuminemic hyperthyroxinemia (FDH). METHODS: Eight Turkish patients were included into the study. Clinical and laboratory characteristics of the subjects and their parents were evaluated and genetic analysis were performed. RESULTS: In genetic analysis, a previously reported heterozygous, c.725G>A variant was detected in exon seven of the ALB gene. CONCLUSIONS: FDH is an asymptomatic condition however there is still a risk of misdiagnosis and unnecessary treatment. Therefore, if FDH is considered, initial ALB hotspot sequencing as a rapid and simple method is recommended instead of complex and expensive laboratory and imaging techniques.

Serum Ghrelin and Glucagon-like Peptide 1 Levels in Children with Prader-Willi and Bardet-Biedl Syndromes

Objective: Prader-Willi syndrome (PWS) and Bardet-Biedl syndrome (BBS) are causes of pediatric syndromic obesity. We aimed to investigate a possible role for ghrelin and glucagon-like peptide-1 (GLP-1) in the pathophysiology of PWS and BBS. Methods: The study included 12 children with PWS, 12 children with BBS, 13 pediatric obese controls (OC) and 12 pediatric lean controls (LC). Fasting serum ghrelin and GLP-1 levels were measured by ELISA. Results: In the PWS group, no significant difference was detected for median ghrelin levels when compared with OC and LC, which were 0.96 (0.69-1.15), 0.92 (0.72-1.20) and 1.13 (0.84-1.29) ng/mL, respectively. Similarly, there was no difference in PWS median GLP-1 levels when compared with OC and LC; 1.86 (1.5-2.94), 2.24 (1.62-2.78) and 2.06 (1.8-3.41) ng/mL, respectively. In the BBS group, there was no difference in median ghrelin levels when compared with OC and LC; 1.05 (0.87-1.51), 0.92 (0.72-1.20) and 1.13 (0.84-1.29) ng/mL, respectively. Neither was there a significant difference in median GLP-1 levels; 2.46 (1.91-4.17), 2.24 (1.62-2.78) and 2.06 (1.8-3.41) ng/mL for BBS, OC and LC, respectively. Conclusion: There were no differences in median fasting ghrelin or GLP-1 levels when comparing patients with PWS and BBS with obese or lean peers. However, similar studies with larger series are needed.

17α Hydroxylase/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort.

PURPOSE: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management. METHODS: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated. RESULTS: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment. CONCLUSION: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region.

A novel DAX-1 mutation presented with precocious puberty and hypogonadotropic hypogonadism in different members of a large pedigree.

Patients with DAX-1 gene mutations on chromosome Xp21 usually present with adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Yet, neither correlation between the type of mutation and the age of onset of the disease nor mechanism of the mutation on puberty is fully understood. Here, we report a novel non-sense p.Gln208X mutation in the amino terminal domain of the DAX-1 gene observed in a large family with three boys presenting with adrenal manifestations at different ages. Furthermore, two boys developed spontaneous puberty that failed to progress at similar ages, whereas the other boy developed precocious puberty at 10 month of age. The unique structure of the DAX-1 gene may explain this phenotypic variability. However, more studies are needed to understand the role of the DAX-1 gene on development of the adrenal gland and hypothalamus-pituitary-gonadal axis.

A Boy with 46,XX Karyotype (SRY double-positive) having a Leydig Cell Tumor.

Leydig cell tumors are the most common type of testicular sex cord stromal tumors. Presence of Y chromosome is associated with tumor risk in sex development disorder (DSD), however tumor development without Y chromosome are extremely rare. A 16-year-old boy diagnosed with Leydig cell tumor due to a mass in the right testis was referred after the right orchiectomy. In physical examination, left testis was 10 ml, and a labium residue in penoscrotal region with bilateral gynecomastia was present. Karyotype was 46,XX, and SRY was double-positive in FISH analysis. Ifosfamide, carboplatin and etoposide chemotherapy was initiated due to Leydig cell tumor. Here, we report the first pediatric case having 46,XX, SRY double-positive testicular DSD with Leydig cell tumor.

P300 auditory event-related potentials in children with obesity: is childhood obesity related to impairment in cognitive functions?

OBJECTIVE: To investigate alterations in P300 auditory event-related potentials in children with obesity to detect changes in cognitive functions. METHOD: A total of 50 children with obesity and 23 age- and sex-matched healthy control subjects were included in the study. Laboratory tests were performed to detect dislipidemia and insulin resistance (IR). The latencies and amplitudes of P300 waves were measured in healthy and obese subjects with or without IR. The oddball paradigm was used in recordings of P300 auditory event-related potentials. RESULTS: A significant difference was observed between groups regarding latency and amplitude of P300 component obtained from central (Cz) electrode. The grand means of P300 latency were longer, and amplitude decreased significantly in obese group compared to that of healthy controls. When the obese group was divided into two different subgroups, those with IR and without IR, the grand means of P300 latency were longer and the amplitude decreased significantly in subjects with IR compared to those without IR. CONCLUSION: Both decreased amplitude and prolonged latency of P300 are associated with IR in children with obesity, which shows the impairment of neural activity associated with sensory and cognitive information processing in these children. Further studies are necessary to strengthen the current findings and to determine the exact mechanism of cognitive impairment in obese children.

A Case of Congenital Central Hypothyroidism Caused by a Novel Variant (Gln1255Ter) in IGSF1 Gene

Loss-of-function mutations in the immunoglobulin superfamily, member 1 (IGSF1) gene cause X-linked central hypothyroidism, and therefore its mutation affects mainly males. Central hypothyroidism in males is the hallmark of the disorder, however some patients additionally present with hypoprolactinemia, transient and partial growth hormone deficiency, early/normal timing of testicular enlargement but delayed testosterone rise in puberty, and adult macro-orchidism. Here, we report a boy with congenital central hypothyroidism caused by a novel variant in the IGSF1 gene. In our patient, early testicular enlargement but delayed testosterone rise with central hypothyroidism and hypoprolactinemia were the most important clues for diagnosis. In genetic analysis, we identified a novel, hemizygous nonsense c.3763 C>T (G1n1255Ter) variant in IGSF1 gene. To our knowledge, this is the first reported case of IGSF1 deficiency from Turkey.

Final diagnosis in children with subclinical hypothyroidism and mutation analysis of the thyroid peroxidase gene (TPO).

AIM: To determine the final diagnosis of patients with subclinical hypothyroidism (SCH), and to perform mutation screening of the thyroid peroxidase gene (TPO). METHODS: Infants with SCH without an identified etiology were included in the study. Patients with thyroid dysgenesis were excluded. Children > or = 2 years of age, and still on L-thyroxine (LT4) treatment underwent a diagnostic algorithm. After LT4 was discontinued for 4 weeks, thyroid function tests (TFT) were obtained. A perchlorate discharge test (PDT) was performed in patients with normal thyroid ultrasound but abnormal TFT. Sequence analysis of TPO was studied in all children who underwent a PDT. RESULTS: Forty-eight patients (23 males and 25 females) completed the trial. Among these children, 19 (39.5%) had transient SCH, and 29 (60.5%) had permanent SCH. Among patients with permanent SCH, 19 had thyroid hypoplasia, six had partial iodide organification defect with positive PDT, and four had other dyshormonogenesis with negative PDT. Mean LT4 dose before the medication ceased was 1.2 +/- 0.5 microg/kg/day in transient cases, and 1.7 +/- 0.4 in those with permanent SCH (p < 0.05). No TPO mutation was detected. However, in five patients, seven different previously known TPO polymorphisms were detected: c.102C > G, L4L; > A, A576A; c.2088C > T, D666D; c.2263A > C, T725P; c.2630 T >C, V847A. CONCLUSIONS: LT4 treatment should be stopped after the age of 2 years in infants with SCH without a definite pathology of the thyroid gland to exclude cases with transient hypothyroidism. Additionally, we should consider particularly thyroid gland hypoplasia, and also partial defects in iodide organification in infants with SCH.

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Objective: Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with non-syndromic early onset severe obesity. Methods: Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique. Results: Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one). Conclusion: We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.

Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy.

OBJECTIVE: To evaluate the clinical response to sulphonylurea treatment in a child with a homozygous T168A GCK (glucokinase) mutation, causing permanent neonatal diabetes mellitus (PNDM). STUDY DESIGN: Oral glibenclamide was given for 3 months. Pancreatic beta cell function was assessed by a glucagon stimulation test. Mutant and wild-type (WT) GCK were characterized. RESULTS: Sulphonylurea treatment resulted in a 12-fold increase in basal and stimulated C-peptide levels. HbA1c levels were reduced from 9.4% to 8.1% on a reduced insulin dose (0.85 to 0.60 U/kg/day). Mutant T168A-GST-GCK showed reduced kinetic activity (0.02 fold) compared to WT. CONCLUSIONS: Sulphonylureas can close the adenosine triphosphate (ATP)-sensitive potassium channel and elicit insulin secretion, but the ATP generated from metabolism is insufficient to fully restore insulin secretory capacity. Nonetheless, sulphonylurea treatment should be tried in patients with GCK-PNDM, particularly those with mutations resulting in less severe kinetic defects, in whom improved glycemic control may be obtained with lower doses of insulin.

Bone metabolism markers and bone mineral density in children with neurofibromatosis type-1.

Some experimental studies suggested that there may be a bone formation defect rather than a disorder in bone resorption in patients NF1. The aim of this study was to determine bone mineral density (BMD) with dual-energy X-ray absorptiometry (DEXA) and investigate specific bone formation and bone resorption and bone turnover markers in children with NF1. Thirty-two children and adolescents (16 boys, 16 girls; 16 prepubertal, 16 pubertal) with NF1 were recruited. Their age ranged from 3 to 17 years. They were compared with matched healthy children. Dual-energy X-ray absorptiometry were applied to 26 patients and 27 controls. Nine of 32 subjects with NF1 had a skeletal abnormality. BMD of the lumbar spine, and femoral neck in NF1 patients significantly decreased compared to that of healthy subjects. They were also significantly decreased in pubertal patients when compared to pubertal controls and in prepubertal patients when compared to prepubertal controls. Patients with skeletal abnormalities were found to have significantly lower level of osteocalcin when compared to patients without skeletal abnormality. Other biochemical markers did not exhibit any difference between the groups. In conclusion, our findings suggest that bone formation markers rather than DEXA could be good predictors of skeletal abnormalities among NF1 patients. However, in our study the number of the NF1 patients with skeletal abnormality and the number of bone formation markers studied were all limited. It is appropriate to perform larger studies with other bone formation markers beside osteocalcin.

A family with a novel TSH receptor activating germline mutation (p.Ala485Val).

Autosomal dominant nonautoimmune hyperthyroidism (ADNAH) is caused by gain of function mutations in the TSH receptor (TSHr) gene and characterized by toxic thyroid hyperplasia with a variable age of onset in the absence of thyroid antibodies and clinical symptoms of autoimmune thyroid disease in at least two generations. We report here a Turkish family with a novel TSHr gene mutation with distinct features all consistent with ADNAH. Thyroid function tests of the proband were as follows: free T3: 13.1 pg/ml (N: 1.8-4.6); free T4: 5.1 ng/dl (N: 0.9-1.7); TSH: 0.01 microIU/ml (N: 0.2-4.2); and TSH receptor antibody: 2 IU/ml (N: 0-10). A heterozygous missense mutation in exon 10 of the TSHr gene (c.1454C>T) resulting in the substitution of valine for alanine at codon 485 (p.Ala485Val) was found in the father and his son and daughter. This mutation had arisen de novo in the father. Functional studies of the novel TSHr germline mutation demonstrated a higher constitutive activation of adenyl cyclase than wild type without any effect on phospholipase C activity. In conclusion, our data indicate that gain of function germline mutations in the TSHr gene should be investigated in families with members suffering from thyrotoxicosis and progressive growth of goiter, but without clinical and biochemical evidence of autoimmune thyroid disease. In addition, patients harboring the same mutation of the TSHr gene may show wide phenotypic variability with respect to the age at onset, and severity of hyperthyroidism and thyroid growth.

A Large PROP1 Gene Deletion in a Turkish Pedigree.

Pituitary-specific paired-like homeodomain transcription factor, PROP1, is associated with multiple pituitary hormone deficiency. Alteration of the gene encoding the PROP1 may affect somatotropes, thyrotropes, and lactotropes, as well as gonadotropes and corticotropes. We performed genetic analysis of PROP1 gene in a Turkish pedigree with three siblings who presented with short stature. Parents were first degree cousins. Index case, a boy, had somatotrope, gonadotrope, thyrotrope, and corticotrope deficiency. However, two elder sisters had somatotroph, gonadotroph, and thyrotroph deficiency and no corticotroph deficiency. On pituitary magnetic resonance, partial empty sella was detected with normal bright spot in all siblings. In genetic analysis, we found a gross deletion involving PROP1 coding region. In conclusion, we report three Turkish siblings with a gross deletion in PROP1 gene. Interestingly, although little boy with combined pituitary hormone deficiency has adrenocorticotropic hormone (ACTH) deficiency, his elder sisters with the same gross PROP1 deletion have no ACTH deficiency. This finding is in line with the fact that patients with PROP1 mutations may have different phenotype/genotype correlation.