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.

Neonatal Bartter syndrome with cholelithiasis and hydrocephalus: Rare association.

Neonatal Bartter syndrome (NBS) is a rare autosomal recessive renal tubular disorder. This disease is characterized by hypokalemia, hypochloremia, and metabolic alkalosis that is often associated with failure to thrive and recurrent episodes of dehydration. The combination of BS and cholelithiasis in an infant is very rare. Herein, we report a premature male infant with NBS who developed cholelithiasis and hydrocephalus on clinical follow up. We recommend that periodic routine hepatobiliary ultrasonograpic screening for cholelithiasis should be performed in patients with NBS.

Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia.

OBJECTIVE: There are a few studies regarding the prevalence of testicular adrenal rest tumours (TARTs) in boys and adolescent males with congenital adrenal hyperplasia (CAH), and there is little information regarding the treatment outcomes in patients with TARTs. The aim of this study was to determine the long-term treatment outcomes in boys and adolescent males with CAH. PATIENTS AND METHODS: Sixty boys and adolescent males with CAH, who were between 2 and 18 years of age, were included in the study. Fifty-five patients had 21-hydroxylase deficiency (21-OHD), and five patients had 11-ß hydroxylase deficiency (11ß-OHD). All patients were screened for TARTs by scrotal ultrasonography (US) performed by an experienced radiologist. RESULTS: TART prevalence was 18·3% in 2-18 years' of age; eight patients had 21-OHD, and three had 11ß-OHD. The youngest patient with TART was 4 years old, whereas eight patients with RTs were at puberty. Only two patients had tight metabolic control: eight patients had stage 2, one had stage 4, and two had stage five rest tumours. In four patients with stage 2 TARTs, tumours disappeared after high-dose steroid treatment and did not recur. Shrinkage of tumour was observed in two patients. Testis-sparing surgery was performed in one patient with stage five tumour. Gonadal functions were normal in patients with partially regressed tumours. Two patients became fathers of healthy male off-springs. CONCLUSIONS: Detection and treatment for TARTs in children with CAH at younger ages, earlier stages, may prevent infertility in adulthood. Therefore, we recommend that scrotal US screening should be performed in every 1-2 years starting from early childhood.

Peroxisome proliferator activated receptor (PPAR)-gamma concentrations in childhood obesity.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are nuclear proteins that regulate transcriptional responses to peroxisome proliferators. There has been limited research concerned with the childhood expression of these receptors. In this study, we aimed to evaluate PPAR-gamma (PPAR-γ) concentrations and their relationship to body mass index (BMI), ratio of waist and hip, blood pressure levels, insulin resistance and lipid profile in obese children and adolescents. SUBJECTS AND METHODS: Children aged 8-16 years old were included in the study; 44 obese children and 25 healthy children were taken into the study. Blood pressure and waist-hip circumference of obese patients were measured. Following a 12-hour nighttime fasting, venous blood samples were taken, including blood glucose, insulin, lipid profile, liver function tests and PPAR-γ concentrations, and all samples were analyzed at the same time. FINDINGS: PPAR-γ concentrations were 0.226 + 0.128 in obese children and 0.547 + 0.546 in the control group. PPAR-γ concentrations were lower in obese children and this difference was statistically significant (p = 0.008). PPAR-γ concentrations of control children were 2.42-fold higher than obese children. There was a negative correlation between PPAR-γ concentrations and waist circumference, and a positive correlation between birth weight and PPAR-γ concentrations in obese children. CONCLUSION: In our study we found that PPAR-γ concentrations were low in obese children. In adults, treatment modalities aimed at enhancing the activation of PPAR in obesity lead to a decrease in obesity, insulin resistance, dyslipidemia and cardiovascular disease and this gives hope that similar treatment modalities can be used for children.

Prevalence of hyperthyrotropinemia in obese children before and after weight loss.

BACKGROUND: Obesity is a worldwide epidemic. In recent years, increasing attention has been focused on thyroid function in obesity. OBJECTIVES: To establish the prevalence of elevated thyroid-stimulating hormone (TSH) levels in obese children and adolescents, and identify the relationship between TSH levels and other metabolic and hormonal variables before and after weight reduction. MATERIALS AND METHODS: We evaluated 150 obese subjects (aged 3-17 years) for anthropometric, biochemical, metabolic and hormonal variables. Measurements were taken at baseline and, in a subgroup of children with hyperthyrotropinemia, after a 6-month intervention program based on exercise, behavior therapy, and nutrition education. RESULTS: At baseline, 23 participants (15.3 %) had hyperthyrotropinemia, and 21 of these patients completed the weight reduction intervention. Among these 21 patients, 14 had substantial weight loss and a significant decrease in TSH and free T3 levels. CONCLUSION: We conclude that TSH and T3 levels are significantly increased in childhood obesity; in most cases, however, these increases cannot be elucidated by thyroid autoimmunity or iodine deficiency. If thyroid disorders are excluded beforehand, an elevated TSH with normal thyroid hormone levels in obese children seems rather a consequence than a cause of obesity since weight loss leads to a normalization of elevated TSH levels. In this context, thyroid hormone alterations in obesity suggest an adaptation process.

Assessment of the 21-hydroxylase deficiency and the adrenal functions in young females with Turner syndrome.

There are few reports of an association between Turner syndrome (TS) and 21-hydroxylase deficiency. However, this association is more frequent in some populations. The aim of this study was to evaluate the incidence of 21-hydroxylase deficiency in patients with TS in our population. 21-hydroxylase deficiency was evaluated in 44 TS cases with 45X (n=20) and 24 mosaic cases. A standard dose adrenocorticotropic (ACTH) stimulation test (Synacthen, Novartis, Basel, Switzerland) was performed, and 17 hydroxyprogesterone (17OHP), dehydroepiandrosterone sulfate (DHEAS) and cortisol responses were evaluated. Patients with increased 17OHP responses in the stimulation test also underwent 21-hydroxylase gene analysis. The mean age was 14.6 +/- 4 (2.6-22.4); 37 patients were on growth hormone (GH) treatment. Nine patients were at prepubertal stage, whereas 35 were pubertal (24 on gonadal steroids and 11 spontaneously). Six patients were obese. Only one of our patients had a level of 7.5 ng/mL of 17OHP, and there was no mutation found in congenital adrenal hyperplasia (CAH) genetic analysis. In other cases, peak 17OHP levels were < or = 6 ng/mL. The mean peak 17OHP was 2.62 +/- 1.48 (1.19-7.5) ng/mL, the cortisol level was 37.6 +/- 8.43 (23.9-56.2) microg/dL and the DHEAS was 135.2+/- 87.3 (15-413) microg/dL. The increased mean basal and peak cortisol levels (20.5 +/- 10.2 and 37.6 +/- 8.4 microg/dL) were remarkable findings. Whereas basal cortisol was above 20 microg/dL in 38.7% of patients, exaggerated results up to 56.2 microg/dL were obtained in peak cortisol levels. The basal and peak 17OHP cortisol levels were not correlated with the presence of puberty, chromosome structure, gonadal steroid use, obesity or growth hormone use. This trial suggested that 21-hydroxylase deficiency was not common among patients with TS in our population. Adrenal function should be assessed, at least in the presence of clitoral enlargement in patients with TS, particularly if their karyotype does not contain a Y chromosome.

A pediatric Conn syndrome case.

Conn syndrome, which is rarely encountered in children, is characterized by increased aldosterone, low renin level, and arterial hypertension. Severe complications, such as impaired vascular smooth muscle function secondary to increased aldosterone, endothelial dysfunction, deterioration of left ventricular functions, acute effects on the cardiovascular system, and proteinuria, may be observed. We present a case of primary aldosteronism in a patient who has been followed up for approximately 2 years. A 15-year-old girl complained of headache lasting for approximately 1.5 years, which was diagnosed as severe hypertension. All of her systemic examinations were normal other than the hypertension. Primary aldosteronism was diagnosed on the basis of hypokalemia and alkalosis accompanied by plasma renin activity of 3.9 ng/mL/h and an aldosterone level of 1007 pg/mL (normal: 40-480). Left adrenalectomy was performed because a 10x12x12 mm adenoma was detected on abdominal magnetic resonance imaging. Although aldosterone levels returned to normal values after the surgery, antihypertensive treatment was continued because of the persistent hypertension. As the 24-h ambulatory blood pressure values of the patient were normal at 10 months after the operation, the treatment was stopped, and she was followed up for 15 months without any treatment. Since then, she has been normotensive.

Mild and severe congenital primary hypothyroidism in two patients by thyrotropin receptor (TSHR) gene mutation.

Congenital hypothyroidism (CH) is the most commonly encountered endocrinological birth defect, with an incidence of approximately 1 in 3000-4000 live births. It could be sporadic or familial as well as goitrous or non-goitrous. Inactivating mutations of TSHR , which is one of the genes responsible for non-goitrogenic congenital hypothyroidism, are mostly inherited autosomal recessively and result in a wide clinical spectrum owing to the extent of receptor function loss. Here, we report detailed clinical features of two CH cases with TSHR mutations. The first case was diagnosed before the initiation of the national screening program and had a severe clinical phenotype associated with a homozygous inactivating TSHR mutation (P556R), whereas the second case was diagnosed after the introduction of the national screening program and showed a mild clinical presentation and carried another homozygous missense mutation (P162A) in the TSHR gene. We compared the clinical features of our cases with those of previously reported patients with TSHR mutations to enhance the genotype/phenotype correlations between these mutations and corresponding clinical phenotypes.

Thiamine-responsive megaloblastic anemia syndrome with atrial standstill: a case report.

Thiamine-responsive megaloblastic anemia (TRMA) syndrome is an uncommon autosomal recessive disorder. The disease is caused by mutations in the gene, SLC19A2, encoding a high-affinity thiamine transporter, which disturbs the active thiamine uptake into cells. Major features include megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Cardiac malformations with conduction defects and/or dysrhythmias, have also been described in some patients. To our knowledge, only 13 TRMA patients with cardiac defects have been reported. Here, we describe the first case of TRMA syndrome with atrial standstill, probably caused by a 2 base-pair deletion in exon 4 (1147delGT) of the gene SLC19A2.

Conus medullaris syndrome and acute colonic pseudoobstruction in a child with acute lymphoblastic leukemia.

A 5(3/12)-year-old boy with Philadelphia chromosome (+) pre-B acute lymphoblastic leukemia (ALL) without extramedullary involvement did not achieve remission after induction therapy. His family stopped therapy, but he was readmitted eight months later due to pyoderma, pneumonia and active leukemia with leukocytosis. During cytoreductive and antibiotic therapy, he developed progressive abdominal distension, pain, globe vesicale, tachypnea, and respiratory alkalosis. Bowel sounds could not be auscultated. Dilation, mainly in the large intestine, was detected radiologically. His neurological examination revealed absence of superficial reflexes and hypoesthesia along with normal motor strength and deep tendon reflexes in the lower extremities, consistent with conus medullaris syndrome, which was thought to give rise to acute colonic pseudo-obstruction.

Pediatricians' COVID-19 experiences and views on the willingness to receive COVID-19 vaccines: a cross-sectional survey in Turkey.

Developing an effective and safe vaccine against Covid-19 will facilitate return to normal. Due to hesitation toward the vaccine, it is crucial to explore the acceptability of the COVID-19 vaccine to the public and healthcare workers. In this cross-sectional survey, we invited 2251 pediatricians and 506 (22%) of them responded survey and 424 (84%) gave either nasopharyngeal swap or antibody assay for COVID-19 and 71 (14%) of them got diagnosis of COVID-19. If the effective and safe COVID-19 vaccine was launched on market, 420 (83%) of pediatrician accepted to get vaccine shot, 422 (83%) of them recommended vaccination to their family members, 380 (75%) of them accepted to vaccine their children and 445 (85%) of them offered vaccination to their pediatric patients. Among the participated pediatricians 304 (60%) of them thought COVID-19 vaccine should be mandatory. We found that there are high COVID-19 vaccine willingness rates for pediatricians for themselves, their own children, family members and their pediatric patients. We also found that being a pediatric subspecialist, believing in achieving an effective vaccine, willingness to participate in the phase 1-2 clinical vaccine trial, willingness to get an influenza shot this season, believing a vaccine and vaccine passport should be mandatory were significant factors in accepting the vaccine. It is important to share all information about COVID-19 vaccines, especially effectiveness and safety, with the public in a clear communication and transparency. The opposite will contribute to vaccine hesitancy and anti-vaccine movement.

Delayed diagnosis of acute leukemia in a patient with bone pain and fracture.

In childhood acute lymphoblastic leukemia (ALL), non-hematological manifestations involving the musculoskeletal system can also be encountered. These manifestations may cause a delay in the diagnosis of leukemia. The presented case in this report is a six-year-old boy who developed bone pain and long bone fracture and was diagnosed as ALL after a considerable delay. This case is presented to draw attention to the fact that leukemia must be considered in pediatric patients who present with bone manifestations.

Density of the crystalline lens in obese and nonobese children.

PURPOSE: To compare crystalline lens density in obese and nonobese children. METHODS: A total of 40 obese (25 females) and 46 age-sex matched controls (26 females) were included in this prospective study. Children with ocular diseases (except for mild refractive errors), ocular trauma, or surgery and any systemic disorders, including diabetes, were excluded. Lens densitometry (LD), central corneal thickness (CCT), anterior chamber depth (ACD) and corneal volume (CV) were measured by Pentacam HR. RESULTS: Mean participant age was 12.0 ± 1.9 (range, 7.2-18 years) in the obese group and 11.7 ± 2.0 (range, 7.5-16.1 years) in the control group. The BMI was 29.9 ± 4.5 in the obese group and 18.7 ± 2.5 in the control group (P ≤ 0.05). The vertical, horizontal, and areal lens density measurements were higher in obese group than in controls (P ≤ 0.05). There was a positive correlation between BMI and vertical, horizontal, and areal lens density measurements. The difference in CCT, ACD, and CV was not statistically significant between groups (P ≥ 0.05). CONCLUSIONS: There is increased lens density in the obese children compared with controls. Pentacam HR may provide objective data about lens density in children.

Impaired Hemorheological Parameters and Increased Carotid Intima-Media Thickness in Children with Subclinical Hypothyroidism.

BACKGROUND: Subclinical hypothyroidism (SH) is defined as elevated serum thyroid-stimulating hormone (TSH) concentration associated with normal serum-free thyroxine levels. Effects of hypothyroidism on hemorheology had widely attracted the attention of researchers during the last decade. OBJECTIVE: The purpose of this study is to determine alterations in hemorheological parameters and carotid intima-media thickness (CIMT) in children with SH. METHODS: Fifty-three SH children and 31 healthy controls were enrolled. Erythrocyte deformability and aggregation were determined by an ektacytometer and plasma viscosity (PV) by a cone-plate rotational viscometer. CIMT was evaluated sonographically. RESULTS: Erythrocyte deformability of the SH group measured at 0.53 and 1.69-30 Pa was lower than that of the control group. The erythrocyte aggregation index, aggregation half time and PV were not different between the groups. However, the aggregation amplitude and mean corpuscular hemoglobin concentration were significantly higher in SH compared to the control group. There was a negative correlation between TSH and deformability values measured at 5.33-30.0 Pa. CIMT in patients with SH was significantly higher than in the control group (p = 0.001; SH = 0.48 ± 0.04 mm, control group = 0.43 ± 0.03 mm). CONCLUSION: Impaired hemorheology and increased CIMT are well-known risk factors for developing cardiovascular pathologies. The results of the current study suggest the treatment of children with SH in order to avoid early circulatory problems.

Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing.

BACKGROUND: Maturity-onset diabetes of the youth (MODY), is a genetically and clinically heterogeneous group of diseasesand is often misdiagnosed as type 1 or type 2 diabetes. The aim of this study is to investigate both novel and proven mutations of 11 MODY genes in Turkish children by using targeted next generation sequencing. METHODS: A panel of 11 MODY genes were screened in 43 children with MODY diagnosed by clinical criterias. Studies of index cases was done with MISEQ-ILLUMINA, and family screenings and confirmation studies of mutations was done by Sanger sequencing. RESULTS: We identified 28 (65%) point mutations among 43 patients. Eighteen patients have GCK mutations, four have HNF1A, one has HNF4A, one has HNF1B, two have NEUROD1, one has PDX1 gene variations and one patient has both HNF1A and HNF4A heterozygote mutations. CONCLUSIONS: This is the first study including molecular studies of 11 MODY genes in Turkish children. GCK is the most frequent type of MODY in our study population. Very high frequency of novel mutations (42%) in our study population, supports that in heterogenous disorders like MODY sequence analysis provides rapid, cost effective and accurate genetic diagnosis.

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. PATIENTS: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Urinary C-Peptide/Creatinine Ratio Can Distinguish Maturity-Onset Diabetes of the Young from Type 1 Diabetes in Children and Adolescents: A Single-Center Experience.

BACKGROUND: The urinary C-peptide/creatinine ratio (UCPCR) and fasting C-peptide level can assess beta-cell function in clinical practice. In the present study, the use of the UCPCR and fasting C-peptide levels was investigated in the differential diagnosis between maturity-onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM). METHODS: Twenty-seven patients with genetically confirmed MODY by next-generation sequence analysis and 42 children with T1DM were included. C-peptide levels were measured after an overnight fast before breakfast, and urine samples were collected 2 h after a standard lunch in the hospital. RESULTS: The UCPCR in the T1DM group was 0.17 ± 0.5 nmol/mmol, and in the MODY group it was 1.27 ± 1.03 nmol/mmol (p = 0.001). The receiver operating characteristic (ROC) curves showed excellent discrimination (area under the curve 0.93). A UCPCR ≥0.22 nmol/mmol yielded a 96.3% sensitivity and an 85.7% specificity. The fasting C-peptide level in the T1DM group was lower than that in the MODY group (p = 0.001). The fasting C-peptide cutoff determined by ROC curve analysis was 0.62 ng/ml, with a sensitivity of 93% and a specificity of 90% for discriminating between MODY and T1DM. CONCLUSIONS: We showed that the UCPCR and fasting C-peptide levels in children and adolescents can distinguish patients with MODY from patients with T1DM with high specificity and sensitivity. A value of UCPCR ≥0.22 nmol/mmol may indicate further genetic testing for MODY.

Evaluating the Efficacy of Treatment with a GnRH Analogue in Patients with Central Precocious Puberty.

Objective. GnRH analogues (GnRHa) are used in the treatment of central precocious puberty (CPP). The purpose of this study was to evaluate the efficacy of treatment with a GnRHa (leuprolide acetate) in patients with CPP. Subjects and Methods. A total of 62 female child patients who had been diagnosed with CPP, rapidly progressive precocious puberty (RP-PP), or advanced puberty (AP) and started on GnRHa treatment (leuprolide acetate, Lucrin depot, 3.75 mg once every 28 days) were included in the study. The efficacy of treatment was evaluated with anthropometric data obtained, progression of pubertal symptoms observed, as well as GnRHa tests, and, when necessary, intravenous GnRH tests carried out in physical examinations that were performed once every 3 months. Results. In the current study, treatment of early/advanced puberty at a dose of 3.75 mg once every 28 days resulted in the suppression of the HHG axis in 85.5% of the patients. Conclusion. The findings of this study revealed that a high starting dose of leuprolide acetate may not be necessary in every patient for the treatment of CPP. Starting at a dose of 3.75 mg once every 28 days and increasing it with regard to findings in follow-ups would be a better approach.