Objective: MOTS-c is a mitochondria-derived peptide associated with reduced insulin resistance and obesity. The m.1382A>C polymorphism of the MOTS-c gene is linked to an increased risk of type 2 diabetes in men. However, no studies have explored the relationship between this polymorphism and MOTS-c levels in adolescents with polycystic ovary syndrome (PCOS). This study aimed to investigate the differences in MOTS-c levels between adolescents diagnosed with PCOS and those without PCOS, as well as the associations with metabolic parameters. The association between the MOTS-c gene polymorphism and serum MOTS-c levels in adolescents with PCOS was also evaluated. Subjects and methods: Adolescents aged 12-18 diagnosed with PCOS were recruited based on irregular menstrual cycles and clinical/biochemical hyperandrogenism, excluding other conditions. The control group consisted of adolescents with regular menstruation. Serum MOTS-c levels were measured using ELISA, and the m.1382A>C polymorphism was analyzed by sequencing. Results: The study included 121 adolescents with PCOS and 125 healthy controls. The mean serum MOTS-c levels in the PCOS group were higher than in the control group; however, this difference did not reach statistical significance (p = 0.059). There was no significant association between MOTS-c levels and anthropometric or metabolic parameters within the PCOS group (p > 0.05). All participants had the wild-type (A/A) genotype for the m.1382A>C polymorphism. Conclusion: Results indicate that the MOTS-c gene (m.1382A>C) polymorphism shows no significant association with PCOS, and serum MOTS-c levels are comparable between individuals with PCOS and healthy controls, suggesting that MOTS-c may have a minor involvement in the pathophysiology of PCOS.

BACKGROUND:The cytochrome P450 side-chain cleavage enzyme (P450scc), encoded by the CYP11A1 gene, regulates the first and rate-limiting step of steroidogenesis. c.1351C > T (p.R451W) is the most commonly identified pathogenic variant in the CYP11A1 gene, and is associated with a mild P450scc deficiency. Long-term follow-up data of affected individuals are insufficient. AIM:To investigate the long-term growth, pubertal development, and adrenal and gonadal functions of patients with homozygous CYP11A1 c.1351C > T (p.R451W) variant. METHOD:Retrospective follow-up data were obtained from the medical records of patients managed at tertiary pediatric endocrinology centers. RESULTS:Twenty-two patients (16 males) from 16 families were included. The median age at presentation was 4.8 ± 4.2 years (range: 1-14.6 years), and the mean follow-up period was 7.8 ± 5.2 years (range: 0.5-17.9 years). Primary adrenal insufficiency (PAI) was present in all cases. Three patients were diagnosed during family screening. Mineralocorticoid (MC) deficiency was detected in 20 patients (83%), and recovered in 2 cases during follow-up. One patient with no MC deficiency at presentation had developed a salt-wasting crisis during acute illness. None of the 46,XY cases showed atypical genitalia; 3 had micropenis, 1 had cryptorchidism, and 2 patients required sex steroid therapy because of subsequent hypergonadotropic hypogonadism later. CONCLUSION:Mild P450scc deficiency due to p.R451W variant in the CYP11A1 gene is associated with late onset PAI with variable MC and sex hormone deficiency. The growth is consistent with genetic potential, and pubertal onset and progression are normal in affected patients, while long-term follow-up is required with regard to the risk of gonadal failure.

Disclosure: G. Çatlı: None. O. Besci: None. T.Ü. Hale: None. M. Ayanoğlu: None. S.A. Hiz: None. E. Böber: None. A. Abacı: None. U. Yiş: None. Background: There have been conflicting reports on nerve conduction studies (NCS) in adults with subclinical hypothyroidism (SH). However, no study has evaluated nerve conduction and its relationship to thyroid autoimmunity in children with SH. This prospective study evaluates NCS via electroneuromyography (ENMG) in pediatric patients with SH and investigates long-term thyroid function evolution and its association with neuromuscular alterations. Methods: A total of 24 children aged 5-18 years diagnosed with SH underwent baseline ENMG to assess motor and sensory nerve conduction parameters. Following this assessment, the children were monitored for five years to determine disease progression. ENMG results were compared between groups, and associations with thyroid autoimmunity were examined. Results: Motor axonal impairments were detected in 33.3% of patients with SH. The most frequently affected nerve was the peroneal (20.8%), followed by the tibial (8.3%) and ulnar (8.3%) nerves. No sensory involvement was observed. Abnormalities included increased latency in the ulnar (4.2%), tibial (8.3%), and peroneal (8.3%) nerves and decreased amplitude in the ulnar (4.2%) and peroneal (16.7%) nerves. During follow-up, 37.5% of patients developed persistent SH, requiring levothyroxine treatment, while 62.5% experienced spontaneous normalization of thyroid function. Among patients with persistent SH, 77.8% had axonal impairments compared to only 6.7% in the euthyroid group (p=0.001). A significant association was found between axonal involvement and persistent SH, with a relative risk of 7. Patients with persistent SH had significantly prolonged tibial motor nerve conduction latency (4.9 ms [IQR 2.0] vs. 3.8 ms [IQR 1.1], p=0.02). Higher TPOAb levels were observed in patients with axonal involvement compared to those without (p=0.03), and TGAb levels positively correlated with median and tibial nerve latencies (rs=0.607, p=0.002; rs=0.44, p=0.03). Conclusion: This study is the first to assess neuromuscular function in children with SH. A significant association was found between axonal impairment and the development of persistent SH, suggesting that axonal involvement may serve as a marker for identifying patients at higher risk of disease progression. The increased susceptibility of motor nerves in SH may be linked to their myelin structure, metabolic demands, autoimmune processes, and regeneration capacity. In contrast, the preservation of sensory nerves could be attributed to their lower energy requirements and superior regenerative potential. These findings highlight the importance of neuromuscular assessment in predicting thyroid function evolution in pediatric SH. Presentation: Sunday, July 13, 2025

OBJECTIVE:To explore the association between the use of pacifiers during infancy and the occurrence of binge eating disorder (BED) and obesity in adolescence. STUDY DESIGN:A case-control study. Place and Duration of the Study: Department of Paediatric Endocrinology, Izmir Tepecik Training and Research Hospital, Izmir, Turkiye, from January 2022 to January 2023. METHODOLOGY:One hundred thirty-seven obese adolescents, aged 12-18 years, with a body mass index (BMI) above the 95th percentile, and 123 healthy subjects, with a BMI between the 3rd-95th percentiles, who had a similar age and gender distribution, were included. A survey, including questions about feeding during the infantile period and oral habits (chewing gum, nail-biting, smoking, and substance use) in adolescence, was applied to the mothers of all participants. The presence of BED was evaluated according to DSM-5 diagnostic criteria. RESULTS:No significant difference was found between the obese and control groups regarding age, gender, and the use and duration of the pacifier. In the obese group, total breast milk intake period, night feeding after one year, nail-biting behaviour, and smoking rate were higher than in the control group (p <0.015, p <0.001, p <0.027, and p <0.015, respectively). BED was detected in 53.3% of the cases in the obese group (p <0.001). There was no statistically significant difference between obese patients, with and without BED, in terms of the use and duration of pacifier (p = 0.136). CONCLUSION:This study suggested that pacifier use in the infantile period (0-12 months) was not associated with oral habits, binge eating disorder, and obesity in adolescence. However, continuing night feeding (00-07 A.M, breast milk or formula) after one year of age may be related to obesity. KEY WORDS:Childhood obesity, Pacifier, Binge eating disorder, Adolescents.

Objectives We aimed to investigate the relation of oxytocin receptor (OXTR) gene variants (rs53576 and rs2254298) and serum oxytocin (OXT) levels with psychiatric symptoms in healthy adolescents and adolescents with obesity.Methods A total of 250 adolescents with obesity and 250 healthy adolescents were included in this study. Attachment properties, anxiety, and depression were evaluated with self-reports while diagnoses were ascertained with KIDDIE-SADS-PL Turkish version. Serum OXT level was studied with the ELISA method, and OXTR gene variants were studied by quantitative polymerase chain reaction (rs53576) and restriction fragment length polymorphism (RFLP) (rs2254298) methods.Results Serum OXT level was significantly lower in adolescents with obesity than in healthy controls. Self-reported symptoms of anxiety and depression were significantly elevated, especially in female adolescents with obesity, whereas parent/peer attachment was significantly lower. The rs53576 G/G genotype was found to be significantly more prevalent among obese youth. About 29.2 % of obese youth were diagnosed with psychopathology, especially anxiety and depression. OXT levels and receptor polymorphisms were not related to self-reported symptoms, attachment, and presence of psychopathology.Conclusions Further studies should evaluate the roles of other constructs (e.g., early adversity, parenting, social supports, coping, temperament, etc.) and discern the roles of parent-child synchrony in elucidating relationships between OXT, pediatric obesity, and psychopathology.

Induction of puberty in boys with constitutional delay of growth and puberty (CDGP) through a short course of low-dose testosterone therapy indicates the critical interaction between testosterone and the androgen receptor (AR) during the activation and maturation of the hypothalamic-pituitary-gonadal axis at puberty onset. Previous studies have shown an inverse relationship between the CAG repeat length and the transactivation function or expression level of the AR gene. We aimed to investigate whether the AR CAG repeat polymorphism has any implications on pubertal delay. Thirty-three male patients with CDGP were enrolled in the study group, while 53 age-matched healthy individuals who had entered puberty on time were included in the control group. The CAG repeat length was determined through direct DNA sequencing analysis. The median chronological age of boys with CDGP was 14.2 (14.1–14.6) years, compared to 14.2 (13.65–14.8) years for healthy subjects (p = 0.5). In the CDGP group, 22 (66.7

Introduction:Wolfram Syndrome (WS) is a rare autosomal recessively inherited disorder characterized by juvenile-onset diabetes mellitus (DM), diabetes insipidus, optic atrophy (OA), hearing loss and neurodegeneration. This report describes three cases with WS. Case report:The first case was diagnosed with DM and OA at the age of 6 and 11 years, respectively. Second patient was the sibling of the first patient, also had DM and was investigated for WS after his brothers' diagnosis. The third patient was diagnosed with DM at the age of 5 years and developed bilateral sensorineural hearing loss and OA at the ages of 7 and 12 years, respectively. Preliminary diagnoses of all patients were confirmed by Sanger sequencing of the WFS1 gene. Two previously reported and a novel mutation were detected. While our first patient was diagnosed with attention deficit hyperactivity disorder previously described in WS patients, obsessive compulsive disorder observed in case 2, was not previously reported in WS to the best of our knowledge. Puberty delay was detected in our first patient and was diagnosed as constitutional delay of puberty and growth. Conclusion:Early diagnosis of WS can lead to early detection of associated pathologies and to decrease complications, morbidity and mortality.

Background High blood iodine levels have been reported after voiding cystourethrography (VCUG). This excess iodine can cause thyroid hormone disorders, particularly in children with reduced renal clearance. Objective We aimed to evaluate the thyroid functions of pediatric patients with chronic kidney disease (CKD) exposed to iodinated contrast media (ICM) during VCUG. Materials and methods We retrospectively studied children with CKD who had VCUG between March 2015-March 2019, whose thyroid function tests were within normal limits in last three months before VCUG, and who had thyroid function tests after the exposure. 44 patients were included in the study. 32 CKD patients were in the ICM exposure group, and 12 CKD patients were in the control group. Results Seventeen (56%) of 32 cases included in the VCUG group were male. The mean age of patients in this group was 9.4 ± 4.75 years. The median duration time from VCUG to thyroid functions testing was 13 months. There was no statistically significant difference between the thyroid function test results before and after VCUG in terms of fT3 and TSH levels. fT4 levels were significantly reduced after VCUG (p:0.03). Only one patient was diagnosed with subclinical hypothyroidism, and no patient was diagnosed with overt hypothyroidism. Conclusion This study demonstrated that overt hypothyroidism did not develop in children with CKD at least six months after ICM exposure during VCUG. A significant decrease in fT4 levels was detected after ICM exposure, indicating that these cases should be followed up in terms of thyroid dysfunctions.

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.

Objectives Current guidelines for genetic testing in childhood-onset diabetes focusses on Maturity Onset Diabetes of the Young (MODY) or rare genetic syndromes and children with diabetes and unclear or isolated additional clinical features are often not tested.1 We aim to determine whether routine genetic testing should be recommended for children with diabetes and additional syndromic features and assess if novel biomarker, type 1 diabetes genetic risk score, can help to select children for genetic testing. Methods We conducted a study of 1093 children with diabetes across seven paediatric diabetes clinics. The diabetes related clinical features, islet autoantibody status and additional non-autoimmune extra-pancreatic features were recorded. We generated 30 variants type 1 diabetes genetic risk score (T1D-GRS).2 3 All children with syndromic diabetes had targeted next-generation sequencing to analyse all known dominant and recessive genes causing monogenic diabetes.4 Results Among the 1093 participants, 68 (6.2%) children had diabetes with additional non-autoimmune extra-pancreatic features. In this syndromic cohort, 22% (15/68) found to have monogenic diabetes. The most common causes were WSF (n=3, 20%) and SLC19A2 (n=3, 20%). Of the 30/68 children with high T1D-GRS (>50th centile of T1D population), only 1 (1/30, 3%) was found to have monogenic diabetes compared to 14 (14/38, 37%) of the children with low T1D-GRS (<50th centile) (p=0.0009). Of those with monogenic diabetes, only 2 participants (2/15, 13.3%) would have been tested using current guidance as their clinical features were in keeping with recognised clinical syndromes (https://omim.org). Furthermore, clinician diagnosis of T1D or non-T1D proved to be an ineffective discriminator as 9/46 (19.6%) children with suspected T1D were found to have monogenic diabetes. This was similar in children with clinician suspicion of non-T1D (6/22, 27.3%, p=0.53). Conclusion One in five children with diabetes and additional non-autoimmune features have monogenic diabetes. Many of these children do not display features in keeping with typical clinical syndromes and clinician predictions often fail to identify these cases. T1D-GRS is a useful, novel biomarker in these children. Our study recommends routine genetic testing for all children presenting diabetes alongside additional syndromic features. This approach can enable personalised and precise management strategies, ultimately leading to improved patient outcomes. References Hattersley et al. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents 2018. Patel et al. Type 1 Diabetes Genetic Risk Score: A Novel Tool to Discriminate Monogenic and Type 1 Diabetes 2016. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls, The Wellcome Trust Case Control Consortium 2007. Patel et al. Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics 2022.

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 (Delta height 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.

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.

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, func-tional, 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.

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.

Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by the absence of pubertal development and subsequent impaired fertility often due to gonadotropin-releasing hormone (GnRH) deficits. Exome sequencing of two independent cohorts of IHH patients identified 12 rare missense variants in POU6F2 in 15 patients. POU6F2 encodes two distinct isoforms. In the adult mouse, expression of both isoform1 and isoform2 was detected in the brain, pituitary, and gonads. However, only isoform1 was detected in mouse primary GnRH cells and three immortalized GnRH cell lines, two mouse and one human. To date, the function of isoform2 has been verified as a transcription factor, while the function of isoform1 has been unknown. In the present report, bioinformatics and cell assays on a human-derived GnRH cell line reveal a novel function for isoform1, demonstrating it can act as a transcriptional regulator, decreasing GNRH1 expression. In addition, the impact of the two most prevalent POU6F2 variants, identified in five IHH patients, that were located at/or close to the DNA-binding domain was examined. Notably, one of these mutations prevented the repression of GnRH transcripts by isoform1. Normally, GnRH transcription increases as GnRH cells mature as they near migrate into the brain. Augmentation earlier during development can disrupt normal GnRH cell migration, consistent with some POU6F2 variants contributing to the IHH pathogenesis.