Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

Clinical Characteristics of Children with Combined Pituitary Hormone Deficiency and the Effects of Growth Hormone Treatment.

AIM: We aimed to describe the clinical characteristics of patients with congenital combined pituitary hormone deficiency (CPHD) and evaluate the first-year growth responses of individuals with CPHD and isolated growth hormone deficiency (IGHD) in order to establish the influence of other hormone deficiencies on growth response. PATIENTS AND METHODS: This retrospective study was conducted in four tertiary care centers in Turkey. The records of patients diagnosed with CPHD (n=39) and severe IGHD (n=50) were collected. Cases with acquired lesions or chronic diseases were not included in the study. Data are presented as median (interquartile range). RESULTS: Among 39 patients (13 females; 33%) with a diagnosis of CPHD, the majority of patients (64%) presented initially with combined deficits at baseline examination, whereas isolated deficiencies (36%) were less prevalent. Among all patients with GH deficiency, TSH, ACTH, FSH/LH, and ADH deficiencies were present in 94%, 74%, 44%, and 9% of patients, respectively. Patients with CPHD were diagnosed at a younger age (4.9 (8.4) vs. 11.6 (4.1), p<0.001, respectively) and had lower peak GH concentrations (0.4 (1.8) vs. 3.7 (2.9), p<0.001, respectively) than patients with IGHD. Patients with IGHD and CPHD had similar first-year growth responses (Δheight SD score of 0.55 (0.63) vs. 0.76 (0.71), respectively, p=0.45). CONCLUSIONS: We established the nature and timing of numerous hormonal deficits emerging over time. We also identified that the existence of CPHD did not hinder growth response.

Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

Oxytocin receptor gene polymorphism and low serum oxytocin level are associated with hyperphagia and obesity in adolescents.

BACKGROUND/OBJECTIVES: In recent years, oxytocin (OXT) and polymorphisms in the oxytocin receptor (OXTR) gene have been reported to play roles in obesity pathogenesis. However, there was no study evaluating OXTR gene variants in childhood obesity. The aim of the study was to investigate the relation of OXTR gene polymorphisms and serum OXT levels with metabolic and anthropometric parameters in obese and healthy adolescents. SUBJECTS/METHODS: The study was a multi-centered case-control study, which was conducted on obese and healthy adolescents aged between 12 and 17 years. Serum OXT and leptin levels were measured, and OXTR gene variants were studied by qPCR (rs53576) and RFLP (rs2254298) methods. RESULTS: A total of 250 obese and 250 healthy adolescents were included in this study. In the obese group, serum OXT level was lower and leptin level was higher than the control group. In the obese group, frequencies of homozygous mutant (G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were higher than the control group. Homozygous mutant(G/G) and heterozygous (A/G) genotypes for rs53576 polymorphism were found to increase the risk of obesity compared to the wild type (A/A) genotype [OR = 6.05 and OR = 3.06; p < 0.001, respectively]. In patients with homozygous mutant (G/G) and heterozygous (A/G) genotype for rs53576 polymorphism, serum OXT levels were lower than the wild type (A/A) genotype. In the obese group, hyperphagia score was higher than the control group and correlated negatively with serum OXT level. CONCLUSIONS: This study revealed that low serum OXT level, which is associated with hyperphagia may be an underlying cause for obesity in adolescents. For rs53576 polymorphism of the OXTR gene, obesity risk is higher in patients with homozygous mutant(G/G) and heterozygous(A/G)genotypes.

Early and late diagnoses of 17ß-Hydroxysteroid dehydrogenase type-3 deficiency in two unrelated patients.

17ß-hydroxysteroid dehydrogenase type 3 deficiency is a rare cause of 46 XY disorders of sexual development. Mutations in the HSD17B3 gene result in reduced activity of the 17ß-HSD3 enzyme, decreasing the conversion of androstenedione to testosterone. In this report, two cases, admitted with different clinical findings in the neonatal and adolescent periods and were decided to be raised in different genders are presented. The first case who had complete female external genitalia presented on the third postnatal day with the complaint of swelling in the groin. He was decided to be raised as a male and was treated successfully with parenteral testosterone in order to increase phallus size before surgical correction of the external genitalia. The second case was an adolescent girl who presented due to pubertal virilisation and primary amenorrhoea and chose female gender. Molecular genetic analyses of the HSD17B3 gene revealed two different previously reported homozygous variants. We emphasise that patients with 17ß-hydroxysteroid dehydrogenase type 3 deficiency can present with heterogeneous clinical findings in different age groups. Early diagnosis is important to prevent future gender confusion and related problems.

Does fludrocortisone treatment cause hypomagnesemia in children with primary adrenal insufficiency?

Background/aim: Aldosterone is a mineralocorticoid that secreted from adrenal glands and a known factor to increase magnesium excretion by direct and indirect effects on renal tubular cells. Although the frequency of hypomagnesemia was found to be approximately 5% in adult studies, there is no study in the literature investigating the frequency of hypomagnesemia in children by using fludrocortisone, which has a mineralocorticoid activity. Materials and methods: A multi-center retrospective study was conducted, including children who were under fludrocortisone treatment for primary adrenal insufficiency and applied to participant pediatric endocrinology outpatient clinics. Results: Forty-three patients (58.1% male, 41.9% prepubertal) included in the study, whose median age was 9.18 (0.61-19) years, and the most common diagnosis among the patients was a salt-wasting form of congenital adrenal hyperplasia (67.4%). Mean serum magnesium level was 2.05 (±0.13) mg/dL, and hypomagnesemia was not observed in any of the patients treated with fludrocortisone. None of the patients had increased urinary excretion of magnesium. Conclusion: Unlike the studies performed in adults, we could not find any evidence of magnesium wasting effect of fludrocortisone treatment with normal or even high doses in children and adolescents.

The relationship of carotid intima-media thickness with anthropometric and metabolic parameters in patients with classic congenital adrenal hyperplasia

Background/aim: We aimed to determine the presence of subclinical atherosclerosis using carotid intima-media thickness (CIMT) and biochemical parameters in children and adolescents with congenital adrenal hyperplasia (CAH). Materials and methods: Thirty-four patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency on regular glucocorticoid treatment for ≥3 years and 31 healthy subjects were included in the study. The patients were divided into two groups according to the degree of control of the clinic, laboratory, and radiological parameters as a) "uncontrolled" [n= 22; with increased height velocity (HV) standard deviation score (SDS) (≥2 SDS), advanced bone age, serum 17-OH progesterone <2.0 and ≥10.0 ng/mL or androstenedione <0.3 and ≥ 3.0 ng/mL] or b) "controlled" [n= 12; with HV SDS < 2, bone age (BA)/ chronologic age (CA) ratio < 1.2, serum 17-OH progesterone between 2 and 10 ng/mL and androstenedione between 0.3 and 3.0 ng/mL]. Ultrasonographic examination of carotid artery was performed by the same radiologist using a B-mode ultrasound system. Results: There was no significant difference between the CAH and control groups in terms of median (IQR) CIMT values [0.47 (0.05) mm and 0.47 (0.07) mm, respectively; p > 0.05]. When subgroup comparisons were done in terms of median (IQR) CIMT values, there was no significant difference among the controlled, uncontrolled, and healthy control groups [0.45 (0.03) mm, 0.47 (0.04) mm, 0.47 (0.07) mm, respectively; p> 0.05]. In addition, CIMT levels were similar according to sex and disease control status. Conclusion: In this study, the CIMT values of CAH cases were similar to those of healthy subjects.

Comparison of the effectiveness of simple carbohydrates on hypoglycemic episodes in children and adolescents with type 1 diabetes mellitus: A randomized study in a diabetes camp.

BACKGROUND: Hypoglycemia is the most common and severe complication of insulin treatment during the management of type 1 diabetes mellitus (T1DM). Despite its importance, there is a lack of data about the efficacy and superiority of the carbohydrate sources used in hypoglycemia management in children and adolescents. OBJECTIVE: We aimed to compare the effectiveness of honey, fruit juice, and sugar cubes as simple carbohydrates used in the primary treatment of hypoglycemia in children and adolescents with T1DM, who attended a diabetes summer camp. METHODS: A prospective randomized study was performed in a 5-days-long diabetes summer camp. Three different types of simple carbohydrates; sugar cubes, honey, or fruit juice were randomly given for the treatment of hypoglycemia and the recovery results in the three groups were compared. RESULTS: About 32 patients (53.1% male, mean age 12.9 ± 1.9 years) were included and 158 mild hypoglycemic episodes were observed. Sugar cubes, honey, and fruit juice were given in 46 (29.1%), 60 (37.9%), and 52 (33%) events, respectively. We found that honey and fruit juice had similar efficiency in recovering hypoglycemia in 15 minutes with a rate of 95% and 98%, respectively. However, sugar cubes had a significantly lower impact on treatment of hypoglycemia than the others, with a recovery rate of 84.7% at 15 minutes. CONCLUSIONS: This study showed, for the first time, that honey and fruit juice were more effective in treating hypoglycemia than sugar cubes, and can be preferred in treating hypoglycemic events in children and adolescents with T1DM.

NOVEL VDR MUTATIONS IN PATIENTS WITH VITAMIN D-DEPENDENT RICKETS TYPE 2A: A MILD DISEASE PHENOTYPE CAUSED BY A NOVEL CANONICAL SPLICE-SITE MUTATION.

Objective: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare autosomal recessive disorder caused by mutations in the vitamin D receptor gene (VDR), leading to end-organ resistance to 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). The objective of this study was to investigate VDR mutations in 11 patients from 8 Turkish-Arab families. Methods: All coding exons and intron-exon boundaries of the VDR gene were amplified by polymerase chain reaction from peripheral leukocyte DNA and sequenced. The effect of splice-site mutations on mRNA splicing was evaluated by a customized VDR mini-gene assay. Results: Homozygous VDR mutations were found in all the patients, including four novel mutations: c.473G>T (p.R158L), c.1-4A>G (IVS3-2A>G), c.755+1G>T, and c.352_356delGACAG (p.D118Sfs*7). The c.1-4A>G mutation was located in the canonical splice acceptor site and 4 base pairs from the original ATG start codon. The mutation resulted in both complete (60% of transcripts) and partial exon 4 skipping (15% of transcripts). The latter was due to activation of a cryptic splice acceptor site and did not disrupt the open reading frame. Both c.755+1G>T and c.352_356delGACAG resulted in frameshifts and a premature stop codon. Clinically, all the patients required continued treatment, except for patient IV-3, who presented with alopecia, hypocalcemia, and increased 1,25(OH)2D3 at 1.5 years of age as a result of the c.1-4A>G mutation. He stopped taking medication at 6 years of age and still maintained normal height and biochemical profile. Conclusion: We have identified four novel VDR mutations. Although canonical splice-site mutations cause premRNA splicing errors that usually lead to a severe disease phenotype, mild disease can also occur due to activation of a cryptic splice site. Abbreviations: 1,25(OH)2D3 = 1,25-dihydroxyvitamin D3 (calcitriol); 25OHD3 = 25-hydroxyvitamin D3; PCR = polymerase chain reaction; PTH = parathyroid hormone; VDDR2A = vitamin D-dependent rickets type 2A; VDR = vitamin D receptor.

Can ocular changes be detected early in children and adolescents with type 1 diabetes mellitus without retinopathy by using optical biometry and optical coherence tomography?

PURPOSE: To determine early ocular changes in children and adolescents with type 1 diabetes mellitus without retinopathy (T1DM-woR) by optical biometry (OB) and optical coherence tomography (OCT). METHODS: Seventy children and adolescents with T1DM-woR (patient group) and 72 healthy children and adolescents (control group) were included. Demographic data, anthropometric measurements and anterior-posterior segment parameters of groups were compared. Correlations between ocular parameters and glycosylated hemoglobin (HbA1c) level, age at diabetes mellitus (DM) onset and DM duration were evaluated. RESULTS: Patients with T1DM-woR had significantly shallower anterior chambers (3.50 ± 0.12 vs 3.67 ± 0.11 mm, p < 0.001), thicker lenses (3.65 ± 0.15 vs 3.37 ± 0.14 mm, p < 0.001), thinner central retinal nerve fiber layer (RNFL) thicknesses (95.3 ± 6.7 vs 104.8 ± 6.2 µm, p < 0.001) and thinner central choroidal thicknesses (292.8 ± 23.6 vs 325.1 ± 24.7 µm, p < 0.001) than healthy individuals. As the lens thickness (LT) increased, anterior chamber depth (ACD) decreased in patient group (r = - 0.368, p = 0.040). Other anterior (central corneal thickness, axial length, keratometry, spherical equivalent) and posterior (superior temporal, superior nasal, nasal, inferior nasal, inferior temporal, temporal RNFL thicknesses; nasal and temporal choroidal thicknesses; central part's and inner-outer macular segments' thickness and volume measurements) segment parameters of groups were similar (p > 0.05). In patient group, as HbA1c level increased, central RNFL and choroidal thicknesses decreased (r = - 0.639, p < 0.001; r = - 0.486, p = 0.010, respectively). CONCLUSIONS: In patients with T1DM, we found that LT increased, and ACD, central RNFL and choroidal thicknesses decreased by OB and OCT before visible findings appeared in routine ophthalmological examination. Determination of early changes is warning to physician and patient in order to prevent more serious damages occurring later.

Impaired systolic and diastolic left ventricular function in children and adolescents with congenital adrenal hyperplasia receiving corticosteroid therapy.

AimThe present study aimed to evaluate systolic and diastolic myocardial function in children and adolescents with congenital adrenal hyperplasia. METHODS: The study included 44 children with the diagnosis of classic congenital adrenal hyperplasia and 39 healthy children whose age, pubertal status, and gender were similar to those of the patient group. Anthropometric parameters and 17-hydroxyprogesterone levels were measured, and bone age was calculated. The average daily hydrocortisone dose was calculated over the last 1-year file records. Hyperandrogenic state was defined according to bone age SD score (⩾2) and 17-hydroxyprogesterone levels (>10 ng/ml). Echocardiographic examinations were assessed by conventional two-dimensional Doppler echocardiography and tissue Doppler imaging. RESULTS: Patients had higher morphological parameters, such as left ventricular end-systolic diameter, interventricular septal thickness at end diastole, left ventricular posterior wall thickness at end diastole, left ventricular mass and index, than the control group (p<0.05). On pulsed-wave and tissue Doppler echocardiography, significant subclinical alterations were observed in systolic (isovolumic contraction time), diastolic (isovolumic relaxation time), and global left ventricular functional (myocardial performance index) parameters in the congenital adrenal hyperplasia group compared to the control group (p<0.05). In partial correlation analyses, after controlling the effect of hyperandrogenism, the mean hydrocortisone dosage was positively correlated with isovolumic relaxation time in congenital adrenal hyperplasia group (p<0.05). CONCLUSION: This study demonstrated that the patients with congenital adrenal hyperplasia are at risk for left ventricular hypertrophy, systolic and diastolic myocardial subclinical alterations. Overtreatment may be responsible for the increased risk of myocardial dysfunction in patients with congenital adrenal hyperplasia.

Brain injury markers: S100 calcium-binding protein B, neuron-specific enolase and glial fibrillary acidic protein in children with diabetic ketoacidosis.

BACKGROUND: To investigate serum levels of brain injury markers in diabetic ketoacidosis (DKA) and the relation of these markers with clinical and radiological findings of brain injury and laboratory results. METHODS: Twenty-nine patients with DKA, 30 with type 1 diabetes mellitus (T1DM), and 35 healthy children were included. Clinical and laboratory findings, and the Glasgow Coma Scale (GCS) were recorded. In the DKA group, neuron-specific enolase (NSE), S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) levels were measured at baseline and 6 and 12 hours after treatment. Magnetic resonance imaging was performed in the DKA group to demonstrate any brain injury. RESULTS: No clinical or radiological findings of brain injury were found in any of the patients with DKA. In the DKA group, S100B was significantly higher than the healthy control and T1DM groups, while GFAP and NSE levels were not different from controls and T1DM patients. No significant differences were found in GFAP, NSE and S100B levels according to severity of DKA, diabetes duration and GCS. CONCLUSION: NSE and GFAP levels do not increase in DKA patients without overt brain injury. Elevated levels of S100B, which is also synthesized from non-neuronal tissues, might arise from peripheral sources. A lack of concurrent increase in serum levels of these brain injury markers might result from the yet intact blood brain barrier or a true absence of neuronal damage. In order to reveal subclinical brain injury related to DKA, there is a need for studies concurrently assessing neurocognitive functions.

Internet addiction, sleep and health-related life quality among obese individuals: a comparison study of the growing problems in adolescent health.

BACKGROUND: The rapid rise in the global prevalence of obesity suggests that environmental factors may be responsible. The increased use of technology is associated with increased rates of obesity due to declines in physical activity and significant sedentary life style. Internet addiction is also a growing health issue associated with diminished physical activity and poor sleep quality as well as various health problems. The purpose of this study was to determine associations between Internet addiction and adolescent obesity-related problems. DESIGN AND METHODS: In this case-control study, 71 adolescents with obesity were recruited from the outpatient clinic at Tepecik Teaching Hospital and Katip Celebi University Hospital, Department of Pediatric Endocrinology in Izmir, Turkey. The control group consisted of 64 non-obese adolescents that were matched with patients in the study group by age and gender. All subjects completed socio-demographic forms, an Internet addiction scale, the Pediatric Quality of Life Inventory, the Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. RESULTS: Adolescents with obesity were significantly more likely to have Internet addiction (p = 0.002), lower quality of life (p < 0.001), and higher daytime sleepiness (p = 0.008). Moreover, binary regression analysis showed that Internet addiction and less physical activity were associated with increased odds of obesity. CONCLUSION: The results indicated a significant association between Internet addiction and obesity. Health practitioners should take possible Internet addiction, online activities, and physical activities into consideration in follow-up of obese adolescents. In addition to pharmacologic therapies and dietary interventions, providing behavioral therapy targeting healthy Internet use may be promising to reduce the effects of obesity in adolescence.

Is Patch Testing with Food Additives Useful in Children with Atopic Eczema?

BACKGROUND: Atopy patch testing is a useful way to determine delayed-type hypersensitivity reactions to foods and aeroallergens. Although food additives have been accused of worsening atopic eczema symptoms, according to recent studies the role of food additives in atopic eczema remains unclear. The purpose of our study was to investigate food additive hypersensitivity in a group of children with atopic eczema by using standardized atopy patch testing and to determine the role of food additive hypersensitivity in atopic eczema. METHODS: Thirty-four children with atopic eczema and 33 healthy children were enrolled in the study. Children who consumed foods containing additives and did not use either antihistamines or local or systemic corticosteroids for at least 7 days prior to admission were enrolled in the study. All children were subjected to atopy patch testing and after 48 and 72 hours their skin reactions were evaluated by using the guidelines. RESULTS: Positive atopy patch test results were significantly higher in the atopic eczema group. Forty-one percent of the atopic eczema group (n = 14) and 15.2% (n = 5) of the control group had positive atopy patch test results with food additives (p = 0.036) (estimated relative risk 1.68, case odds 0.7, control odds 0.17). Carmine hypersensitivity and the consumption of foods containing carmine, such as gumdrops, salami, and sausage, were significantly higher in the children with atopic eczema. CONCLUSION: This is the first study investigating hypersensitivity to food additives in children with atopic eczema. Our results indicate that carmine may play a role in atopic eczema.

Isolated hyperthyrotropinemia in childhood obesity and its relation with metabolic parameters.

PURPOSE: The aim of the presented study was to evaluate the prevalence of isolated hyperthyrotropinemia (IH) in obese children and the relation between anthropometric and metabolic parameters. METHODS: Hospital records of the children, who presented to the Pediatric Endocrinology outpatient clinic of our institution with obesity, and age and gender-matched healthy children, who had undergone thyroid function test for any reason were retrospectively reviewed. RESULTS: The prevalence of IH was significantly higher in the obese group than in the controls (9.2 and 3.8 %, respectively). Body mass index-standard deviation score (BMI-SDS), thyroid-stimulating hormone (TSH), lipid parameters were significantly different in the obese group than in the control group. A positive correlation between TSH and BMI-SDS and negative correlation between TSH and free T4 (fT4) levels were found in obese subjects. Stepwise multiple linear regression analysis confirmed that BMI-SDS, fT4 and triglyceride levels were the strongest independent variables correlated with TSH level in obese subjects (r (2) = 0.046, p = 0.001). CONCLUSIONS: IH prevalence is higher in obese children as compared to healthy children and the increase in TSH level correlates negatively with serum fT4 and positively with BMI-SDS and triglyceride levels in obese children.

Genetic Findings in Short Turkish Children Born to Consanguineous Parents.

INTRODUCTION: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. METHODS: This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c). RESULTS: In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively. CONCLUSION: Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.

The relation of serum nesfatin-1 level with metabolic and clinical parameters in obese and healthy children.

BACKGROUND: Nesfatin-1, a recently discovered anorexigenic neuropeptide, is expressed in several tissues including pancreatic islet cells and central nervous system. This peptide seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis. OBJECTIVE: We aimed to investigate the relation of serum nesfatin-1 level with metabolic and anthropometric parameters in obese children. METHODS: The study included obese children with a body mass index (BMI) above the 95th percentile and healthy children with a BMI below the 85th percentile. The healthy and obese subjects had similar age and gender distribution. Fasting serum glucose, insulin, lipid profile, and nesfatin-1 levels were measured to evaluate metabolic parameters. RESULTS: Obese group (n = 37) had significantly higher BMI, BMI-SDS (standard deviation score of BMI), triglyceride, insulin, and insulin resistance index by the homeostasis model assessment, systolic and diastolic blood pressure values compared with the control group (n = 31) (p < 0.05). Serum nesfatin-1 level of the obese subjects was significantly lower than that of the control subjects (p = 0.001). No statistically significant difference was found when nesfatin-1 levels were compared among obese patients regarding the presence of insulin resistance (p = 0.202). In the obese group, nesfatin-1 level was negatively correlated with BMI-SDS, but not with insulin resistance index (p = 0.02 and p = 0.361, respectively). CONCLUSIONS: This is the first study to evaluate nesfatin-1 levels in relation with anthropometric and metabolic parameters in obese patients who had significantly lower nesfatin-1 levels. Our results underline that nesfatin-1 may play an important role in regulation of food intake in obese individuals.

Clinical and diagnostic characteristics of hyperprolactinemia in childhood and adolescence.

Pituitary adenoma is the most common cause of hyperprolactinemia, which is a rare endocrine disorder encountered in pediatric patient care. Epidemiological and clinical information about hyperprolactinemia in childhood and adolescence is limited. Clinical signs of hyperprolactinemia are very heterogeneous. In girls, disturbances in menstrual function and galactorrhea may be seen, whereas in boys, headache, visual disturbances, delayed pubertal development and hypogonadism are often present. Owing to the ease of ordering a serum prolactin measurement, an evidence-based, cost-effective approach to the management of this endocrine disorder is required. Before a diagnosis of hyperprolactinemia is made, drug use, renal insufficiency, hypothyroidism, and parasellar tumors should be excluded. The main objectives of treatment are normalization of prolactin level, adenoma shrinkage, and recovery from clinical signs related to hyperprolactinemia. In patients with microadenoma, invasive or non-invasive macroadenoma, and even in patients with visual field defects, dopamine agonists are the first-line treatment. Surgical treatment is indicated in patients who are unresponsive or intolerant to medical treatment or who have persistent neurological signs. Radiotherapy should be considered as a supportive treatment for patients in whom surgery fails or medical response is not achieved.

Resting Electroencephalography Differences Between Eyes-Closed and Eyes-Open Conditions in Children with Subclinical Hypothyroidism.

OBJECTIVE: Electroencephalography changes that occur during the transition from eyes-closed to the eyes-open state in resting condition are related to the early phase of sensory processing and are defined as activation. The present study aimed to reveal the potential deteriorations that may occur in the initial period of sensory processing in resting electroencephalography between children with subclinical hypothyroidism and a control group. MATERIALS AND METHODS: Electroencephalographies of 15 children with subclinical hypothyroidism and 15 healthy children aged 10 to 17 years were recorded for 2 minutes for EC and 2 minutes for eyes-open conditions in resting state. Absolute electroencephalography band powers (µV2 ) within the delta, theta, alpha, and beta frequency bands were calculated in Fz, Cz, Pz, and Oz electrodes, respectively, for eyes-closed and eyes-open conditions. RESULTS: The results show that, although there was no noteworthy difference between the powers of the electroencephalography frequency bands of children with subclinical hypothyroidism and healthy children during the eyes-open condition, the alpha powers of the control group were significantly higher in all electrodes during the eyes-closed condition. Furthermore, the powers of all frequency bands were observed to decrease in the eyes-open condition in the control group. However, the same net decrease was not observed in the frequency powers of children with subclinical hypothyroidism. CONCLUSION: According to the results of this study, children with subclinical hypothyroidism may experience information processing impairments starting in the early stages of sensory processing.

Atypical STAT5B deficiency, severe short stature and mild immunodeficiency associated with a novel homozygous STAT5B Variant.

STAT5B deficiency, a rare autosomal recessive disorder characterized by severe growth hormone insensitivity (GHI) and immunodeficiency, can manifest as fatal pulmonary complications. We describe atypical STAT5B deficiency associated with a novel homozygous frame-shift STAT5B variant [c.1453delG, p.(Asp485Thrfs*29)] identified in a young 17.6 yr old female subject who had severe postnatal growth impairment, biochemistries typical of GHI, an immune profile notable for hypergammaglobulinaemia and elevated B lymphocytes, and lack of pulmonary disease. Marked elevation of serum prolactin and pathologically diagnosed eczema were evident. In reconstitution studies, the STAT5B p.(Asp485Thrfs*29) was expressed although expression was reduced compared to wild-type STAT5B and a previously identified STAT5B p.(Gln368Profs*9) variant. Both truncated STAT5B peptides could not be activated by GH, nor mobilize to the nucleus. We conclude that an intact, functional, STAT5B is essential for normal GH-mediated growth, while expressed loss-of-function STAT5B variants may alleviate severe immune and pulmonary issues normally associated with STAT5B deficiency.