Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.

Medical nutrition therapy is a cornerstone in type 1 diabetes management and is based on the principles of healthy eating. The recommendations presented are valid for all children and their families. A number of frequently asked questions will be addressed in this article. Although carbohydrates are the main nutrient that affects postprandial blood glucose in individuals with type 1 diabetes, intake of carbohydrates (type and amount), protein and fat content of the meal, and glycemic index affect the postprandial glycemic response. In recent years, the relative increase in studies about Ramadan fasting for individuals with type 1 diabetes has indicated that health professionals should be informed about this issue. The difficulties in nutritional management of preschool children should be solved with a professional approach. The increasing frequency of celiac disease in people with type 1 diabetes and an increasing interest in a gluten-free diet for non-celiac reasons (popular diet trends for weight loss or healthy eating) further complicate diabetes management. This review provides evidence-based approaches to frequently encountered problems on medical nutrition therapy in children and adolescents with type 1 diabetes.

INTRODUCTION: Type 1 diabetes (T1D), one of the most common childhood diseases worldwide, can cause hearing loss through systemic effects. Diabetes-induced hearing loss is considered a progressive sensorineural hearing loss with a gradual onset, typically occurring at high frequencies (HFs). Extended HF (EHF) hearing sensitivity in children with T1D who did not complain of hearing loss was investigated as an early marker for hearing loss at the standard/conventional frequency range of hearing.
METHODS: Forty-two children (21 with T1D and 21 healthy controls) were evaluated in a case-control design. Conventional and EHF (14,000, 16,000, and 18,000 Hz) audiometry were performed. The diabetes group underwent routine blood biochemistry and glycated hemoglobin A1c measurements. The data were analyzed by the Student’s t-test, Mann-Whitney U test, chi-square test, and logistic regression analysis.
RESULTS: The mean hearing thresholds were significantly higher (p<0.05) in the diabetes group than in controls at 500, 2,000, 4,000, and 8,000 Hz [all <15 decibel hearing level (dB HL)]. The number of ears with thresholds >15 dB HL at 14,000-18,000 Hz but ≤15 dB HL at 500-4,000 Hz was significantly higher in the diabetes group than in the control group (p=0.049).
DISCUSSION AND CONCLUSION: Children with diabetes showed normal hearing thresholds within the conventional audiometric frequency range but they had higher hearing thresholds during EHF audiometry when compared with controls. Audiometry in these children should be performed using frequencies above 8,000 Hz combined with the conventional frequency range. EHF audiometry may be an effective method for identifying subclinical hearing loss in children with diabetes. Thus, diabetic children with an EHF mean hearing threshold above 15 dB HL should be monitored more closely in terms of blood glucose regulation to prevent diabetes-related hearing loss at the conventional frequency range.

INTRODUCTION: This aim of this study was to investigate the effect of additional insulin dosing for high fat/high energy density mixed meal over 12 hours.
METHODS: In this single-center, non-blinded, randomized, cross-over study, a high fat/high energy density test meal was used to study the impact on glycemic response of either carbohydrate counting (CC) on the first day and the Pańkowska algorithm (PA) on the second test day. The two methods were compared in 20 adolescents with type 1 diabetes (T1D), aged 9-18 years, using insulin pump therapy and continuous glucose monitoring on postprandial early (0-120 min), late (120-720 min), and total (0-720 min) glycemic response.
RESULTS: There was no difference between groups in the duration of normoglycemia in the early period. Postprandially, 50% of patients developed hypoglycemia using the PA at a median of 6.3 (5.6-7.9) hours and the PA was subsequently modified for the remaining ten patients. Area under the curve (AUC) for the early period decreased non-significantly in the CC group, indicating less normoglycemia. No significant difference was found in the AUC of the PA (no hypoglycemia n=4) and modified PA groups (no hypoglycemia n=6) over the whole period (0-12 hours). AUC for level 2 hyperglycemia was statistically greater in the PA-no hypoglycemia patients compared to modified PA-no hypoglycemia patients.
DISCUSSION AND CONCLUSION: There were inter-individual differences in glycemic response to high fat/high energy density meals. An individualized approach to insulin dosing by evaluating food diary and postprandial glucose monitoring appears to be optimal for children and adolescents with T1D.

INTRODUCTION: This study was planned to determine the effects of carob use on puberty because of the observation of early puberty or pubertal variants due to the long-term use of carob in our clinic.
METHODS: Forty-eight Wistar albino rats, on postnatal day 21, were assigned into two groups female (n=24) and male (n=24). Groups were divided into four groups Control, and Carob-150, Carob-300, and Carob-600. Ceratonia siliqua L. extract was given to rats in a 0.5% carboxymethylcellulose (CMC) solution. CMC (0.5%) was given to the control, Ceratonia siliqua L. extract was given 150 mg/kg/day to the Carob-150, 300 mg/kg/day to the Carob-300, 600 mg/kg/day to the Carob-600 by oral gavage. The treatments were performed once daily until the first sign of puberty. Serum follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, total testosterone, leptin, glutathione, glutathione peroxidase (GPx), and malondialdehyde were measured by commercial rat-specific ELISA kits. Testis, uterus and ovarian tissue were examined histologically.
RESULTS: The median time of preputial separation in male rats was 38th, 31st, 31st, and 31st days in the Control, Carob-150, Carob-300, and Carob-600 groups, respectively (p=0.004). The median day of vaginal opening day was the 39th, 31st, 34th, and 31st days in the Control, Carob-150, Carob-300, and Carob-600 groups, respectively (p=0.059). FSH, LH, testosterone (male), estradiol (female) and leptin levels of the groups were similar. However, GPx levels were higher in male and female animals given C. siliqua extract compared to the Control (male p=0.001 and female p=0.008). Testicular and ovarian tissues were concordant with the pubertal period in all groups. As the dose of Ceratonia siliqua extract increased, it induced spermatogenesis and spermiogenesis, causing abnormal changes, such as ondulation in the basement membrane, capillary dilatation, and increased congestion in males. In females, edema in the medulla gradually increased with increased dosage, and granulosa cell connections were separated in Carob-300 and Carob-600 groups.
DISCUSSION AND CONCLUSION: This study demonstrated that C. siliqua caused early puberty and increased spermiogenesis and folliculogenesis. Antioxidant mechanisms were impaired with increasing dose, possibly leading to tissue damage at high doses.

INTRODUCTION: Menarche is the endpoint of a sequence of maturational events of female puberty. The timing of menarche is a strongly heritable trait. However, secular trends suggest that lifestyle and environmental factors are important. To assess the trend in age at menarche (AAM), and its associated factors in Ýstanbul over the last 12 years.
METHODS: A cross-sectional study was carried out between March and April 2022 on schoolgirls aged 9-18 years. A predesigned and self-administered questionnaire was filled out anonymously by the students. The data of AAM was included in the statistical analysis if the time of AAM is remembered in both months and years. A probit model was used to calculate the median AAM. The findings were compared with those from a study performed 12 years ago in the same region of Ýstanbul.
RESULTS: Among 9000 girls to whom the questionnaire was distributed, 1749 (19.5%) responded. The median AAM of 1374 girls whose AAM information was considered valid was 12.04 years (95% confidence interval: 12.01-12.13), 0.7 years lower than was reported 12 years ago (p<0.0001). AAM was correlated positively with maternal AAM, and negatively with body mass index (BMI) standard deviation score and maternal educational status (p<0.0001, p<0.0001 and p=0.002), respectively. There was no correlation between the AAM and birth weight. Girls with BMI percentile ≥85% (n=251) had earlier menarche than the ones with BMI percentile <85% (n=1072) (11.5 vs. 12.1 years, p<0.0001). Among the mother-daughter pairs (n=1162), AAM of girls was 0.91 years (median 0.94 years) earlier than their mothers.
DISCUSSION AND CONCLUSION: The present study demonstrates a significant downward trend in the menarcheal age in Ýstanbul over the last twelve years. These findings support a strong contribution from genetic factors and BMI on AAM.

INTRODUCTION: Idiopathic hypogonadotropic hypogonadism (IHH) is classified into two groups-Kalman syndrome and normosmic IHH (nIHH). Half of all cases can be explained by mutations in >50 genes. Targeted gene panel testing with nexrt generation sequencing (NGS) is required for patients without typical phenotypic findings. The aim was to determine the genetic etiologies of patients with IHH using NGS, including 54 IHH-associated genes, and to present protein homology modeling and protein stability analyzes of the detected variations.
METHODS: Clinical and demographic data of 16 patients (eight female), aged between 11.6-17.8 years, from different families were assessed. All patients were followed up for a diagnosis of nIHH, had normal cranial imaging, were without anterior pituitary hormone deficiency other than gonadotropins, had no sex chromosome anomaly, had no additional disease, and underwent genetic analysis with NGS between the years 2008-2021. Rare variants were classified according to the variant interpretation framework of the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology. Changes in protein structure caused by variations were modeled using RoseTTAFold and changes in protein stability resulting from variation were analyzed.
RESULTS: Half of the 16 had no detectable variation. Three (18.75%) had a homozygous (pathogenic) variant in the GNRHR gene, one (6.25%) had a compound heterozygous [likely pathogenic-variants of uncertain significance (VUS)] variant in PROK2 and four (25%) each had a heterozygous (VUS) variant in HESX1, FGF8, FLRT3 and DMXL2. Protein models showed that variants interpreted as VUS according to ACMG could account for the clinical IHH.
DISCUSSION AND CONCLUSION: The frequency of variation detection was similar to the literature. Modelling showed that the variant in five different genes, interpreted as VUS according to ACMG, could explain the clinical IHH.

INTRODUCTION: With the diagnosis of chronic illness in children, a stressful period is likely to begin for both the affected child and their families. The aim of this study was to investigate the factors affecting chronic disease management by the parents of children diagnosed with type 1 diabetes mellitus (T1DM).
METHODS: The sample consisted of 110 children, aged between 4-17 years and their mothers. The patients had been diagnosed with T1DM for at least one year, and had attended pediatric endocrinology outpatients or were hospitalized in a single center. First, sociodemographic information about the child with T1DM were obtained. Then, the “Family Management Measure” (FaMM) was applied. The FaMM is constructed to measure family functioning and management in families who have a child with a chronic illness.
RESULTS: Paternal years of education (p=0.036), family income (p=0.008), insulin pump use (p=0.011), and time elapsed after diagnosis (p=0.048) positively affected both the management of T1DM and the child’s daily life. However, presence of chronic diseases in addition to T1DM (p=0.004) negatively affected diabetes management. Higher maternal education year (p=0.013) and family income level (p=0.001) increased parental mutuality scores. However, as the time after diagnosis increased, parental mutuality scores decreased.
DISCUSSION AND CONCLUSION: It is important to evaluate the child with chronic disease with a biopsychosocial approach. This approach aims to evaluate the problems of the child and his/her family who experience the disease with a holistic approach.

INTRODUCTION: Genetic studies of familial central precocious puberty (CPP) have suggested that makorin ring finger protein 3 (MKRN3) is the primary inhibitor of gonadotropin-releasing hormone secretion. Obesity in girls can cause early puberty by affecting the hypothalamic-pituitary-gonadal axis. This study evaluated serum MKRN3 levels of patients with CPP and its relationship with body mass index (BMI).
METHODS: The study included 92 CPP and 86 prepubertal healthy controls (HC) aged 6-10 years. The CPP and HC groups were divided into obese and non-obese subgroups to evaluate whether BMI affects MKRN3. Patients’ presenting complaints, chronological age, height age, bone age, Tanner stage, standard deviation scores for weight, height, and BMI, levels of follicle-stimulating hormone, luteinizing hormone, estradiol, and MKRN3, and pelvic ultrasonography findings were recorded.
RESULTS: Serum MKRN3 levels were lower in the CPP group and lowest in the CPP-obese subgroup. There were significant differences in MKRN3 levels between the CPP-obese and CPP-normal weight (p=0.02), CPP-obese and HC-obese (p<0.001), and CPP-obese and HCnormal weight (p=0.03) groups. MKRN3 and BMI were negatively correlated in all cases (r=-0.326, p<0.001).
DISCUSSION AND CONCLUSION: The negative correlation between BMI and MKRN3, and lower MKRN3 levels in CPP-obese patients, suggests that adipose tissue has a role in the onset of puberty. More comprehensive studies are needed to determine the relationship between MKRN3 and adipose tissue.

INTRODUCTION: To determine the clinical significance of serum 25-hydroxy (OH) vitamin D levels in pediatric patients with multisystem inflammatory syndrome in children (MIS-C) and compare the vitamin D levels of these patients with those patients with Coronavirus disease-2019 (COVID-19) and healthy controls.
METHODS: This study was designed for pediatric patients aged 1 month to 18 years and conducted between July 14 and December 25, 2021. Fifty-one patients with MIS-C, 57 who were hospitalized with COVID-19, and 60 controls were enrolled in the study. Vitamin D insufficiency was defined as a serum 25 (OH) vitamin D level of less than 20 ng/mL. Severe MIS-C was classified as necessitating intensive care due to cardiovascular instability, the necessity for non-invasive or invasive mechanical ventilation, and/or a diminishing Glasgow coma scale. World Health Organization definition criteria were used to describe the clinical stages of COVID-19 in children and patients were divided into four groups according to the clinical severity of COVID-19: asymptomatic, mild, moderate, and severe/critical.
RESULTS: The median serum 25 (OH) vitamin D was 14.6 ng/mL in patients with MIS-C, 16 ng/mL in patients with COVID-19, and 21.1 ng/mL in the control group (p<0.001). Vitamin D insufficiency was present in 74.5% (n=38) of patients with MIS-C, 66.7% (n=38) of patients with COVID-19, and 41.7% (n=25) of the controls (p=0.001). The percentage of four or more affected organ systems was 39.2% in patients with MIS-C. The correlation between the number of affected organ systems and serum 25 (OH) vitamin D levels was evaluated in patients with MIS-C and there was a moderate negative correlation (r=-0.310; p=0.027). A weak negative correlation was found between the severity of COVID-19 and serum 25 (OH) vitamin D (r=-0.320, p=0.015).
DISCUSSION AND CONCLUSION: Vitamin D levels were insufficient in both the MIS-C and COVID groups. Furthermore, vitamin D levels correlated with the number of affected organ systems in MIS-C and the severity of COVID-19.

Primary thyroid lymphoma (PTL) is a rare thyroid gland cancer, with diffuse large B-cell lymphomas (DLBCL) being extremely rare in children and adolescents. Thus, optimal therapy is debatable. We describe a rare case of thyroid DLBCL in an adolescent girl with a history of Hashimoto thyroiditis (HT), the difficulty in diagnosis and the outcome of treatment. A 12-year-old girl with a nine-year history of HT was admitted with a right-sided painless progressive swelling of the neck. Physical examination and imaging including ultrasound (US), computed tomography (CT) and positron emission tomography/CT revealed an enlarged thyroid gland with right side lymphadenopathy and no metastasis. Two fine needle aspirations were done showing suspected lymphoblastic lesions for non-Hodgkin lymphoma without precise diagnosis. US guided core needle biopsy was finally performed confirming the diagnosis of DLBCL. She was treated according to LMB 96-group B protocol with no surgical removal of thyroid. The patient responded very well to treatment and 14 months later there is no evidence of relapse or metastases. PTL is an extremely rare cause of thyroid malignancy in children. However, it should be considered in the differential diagnosis of a thyroid mass in adolescents presenting with a rapidly enlarging neck mass and a history of HT. It is a treatable condition with a good prognosis, even in aggressive histological subtypes, with no need for thyroidectomy.

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease.

Hereditary angioedema (HAE) is characterized by recurrent angioedema attacks with no urticaria. This disease has a high mortality due to asphyxia. Level of complement component 4 (C4), C1 esterase inhibitor (C1-INH) level and function, and genetic mutations determine different endotypes of HAE. Clinical presentation and the triggers of vasogenic edema may change according to the endotypes. An adolescent girl with oligomenorrhea, obesity, hirsutism, and acanthosis nigricans was diagnosed with polycystic ovary syndrome and prescribed ethinyl estradiol and cyproterone acetate containing oral contraceptive (OC). On the sixteenth day of treatment, she developed angioedema of the face, neck, and chest leading to dyspnea. Adrenaline, antihistamine, and corticosteroid treatments were ineffective. In the family history, the patient’s mother and two cousins had a history of angioedema. C1-INH concentrate was administered with a diagnosis of HAE. C4 and C1-INH level and activity were normal. Genetic analysis identified a mutation in the factor 12 (F12) gene, and the diagnosis of F12-related HAE was made. OC treatment was discontinued. She has had no additional angioedema attacks in the follow-up period of two years. OC containing estrogen may induce the life-threatening first attack of F12-related HAE even in children. Recurring angioedema attacks in the family should be asked before prescribing estrogen-containing OC pills.

Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is an X-linked disease caused by activating mutations in the arginine vasopressin (AVP) receptor-2 (AVPR2) gene. Affected patients excrete concentrated urine despite very low levels of AVP, and consequently develop euvolemic hyponatremia. Due to its low frequency, patients may be misdiagnosed and treated incorrectly. We report two related male infants with NSIAD that was initially confused with hyporeninemic hypoaldosteronism (HH). First, a 2-month-old male presented with hyponatremia, low plasma osmolality, relatively high urine osmolality, and low plasma renin-aldosterone levels. These clinical and laboratory findings were compatible with syndrome of inappropriate antidiuretic hormone (ADH) secretion without apparent cause. Consequently, fludrocortisone was initiated with a presumptive diagnosis of HH. While correcting hyponatremia, fludrocortisone treatment led to hypertension and was discontinued promptly. The second patient, aged one year, was admitted with a history of oligohydramnios, had been hospitalized four times due to hyponatremia since birth, and had a diagnosis of epilepsy. Similarly, the second infant had clinical and laboratory findings compatible with syndrome of inappropriate ADH secretion with no apparent cause. Fluid restriction normalized his serum sodium despite the plasma AVP level being undetectable. In both infants, AVPR2 gene analysis revealed a known mutation (c.409C>T; p.R137C) and confirmed the diagnosis of NSIAD. In conclusion, NSIAD should be considered in all patients with unexplained euvolemic hyponatremia despite high urine osmolality. If NSAID is not considered, the plasma reninaldosterone profile can be confused with HH, especially in infants.

Transient hypothyroxinaemia of prematurity (THOP) is a disorder encountered particularly in extremely low birth weight and preterm newborns. In recent years, the survival rates of these babies have increased, owing to the advances in neonatal care, thereby increasing the incidence of THOP. Controversies about the management of this disorder still continues while accompanying morbidites may create difficulties in the treatment of these patients. A preterm baby boy, born at 256/7 gestational weeks with a birthweight of 665 g who developed short bowel syndrome after necrotizing enterocolitis surgery and who was treated with rectal levothyroxine, is presented.

Variants of the melanocortin-4 receptor (MC4R) gene are the most common cause of monogenic obesity. It has been shown that, while obesity cannot be controlled with diet and exercise, glucagon-like-peptide-1 receptor agonists (GLP-1 RA) provide weight loss in the short term. In this paper, our experience with liraglutide treatment in an adolescent patient carrying a MC4R gene variant is presented. A female patient was admitted first at the age of 12.5 years with a complaint of progressive weight gain. She had marked excess of appetite since infancy. On physical examination of the pubertal female patient with a body mass index (BMI) of 36.1 kg/m2 (3.48 standard deviation score), there was no pathological finding except diffuse acanthosis nigricans. Laboratory examinations revealed only insulin resistance. Weight loss was not achieved with lifestyle changes, metformin and orlistat treatments. On genetic examination, a sporadic heterozygous c.206T>G(p.I69R) variant that had been reported previously, was found in MC4R gene. Treatment with the GLP-1 RA, liraglutide, was initiated and a 19.2% reduction was achieved in the body weight and BMI at the end of 32 weeks. However, the patient, whose treatment compliance was disrupted due to significant gastrointestinal complaints, returned to her former weight within a few months (13 weeks) after treatment was stopped. In this case with a known pathogenic variant in MC4R gene, decrease of appetite and weight loss were achieved with liraglutide treatment, but side-effects of this treatment led to discontinuation of therapy. In such cases, there is need for effective and tolerable treatment options.