Bone age is one of biological indicators of maturity used in clinical practice and it is a very important parameter of a child’s assessment, especially in paediatric endocrinology. The most widely used method of bone age assessment is by performing a hand and wrist radiograph and its analysis with Greulich-Pyle or Tanner-Whitehouse atlases, although it has been about 60 years since they were published. Due to the progress in the area of Computer-Aided Diagnosis and application of artificial intelligence in medicine, lately, numerous programs for automatic bone age assessment have been created. Most of them have been verified in clinical studies in comparison to traditional methods, showing good precision while eliminating inter- and intra-rater variability and significantly reducing the time of assessment. Additionally, there are available methods for assessment of bone age which avoid X-ray exposure, using modalities such as ultrasound or magnetic resonance imaging.

Objective: Neutropenia can occur in untreated autoimmune hyperthyroidism (AIH) or in association with treatment with the anti-thyroid drug, methimazole (MMI). Starting MMI in children and adolescents with AIH and pre-existing neutropenia could thus be worrisome. The aim was to describe the prevalence of neutropenia in pediatric AIH, prior to antithyroid drug therapy and to assess the effect of antithyroid drugs on neutrophil count.
Methods: Patients with AIH attending a pediatric endocrinology clinic were retrospectively reviewed. Absolute neutrophil count (ANC) data at presentation and during anti-thyroid treatment for up to 24 weeks was collected. AIH was defined as elevated free thyroxine (fT4) or free tri-iodothyronine (fT3), suppressed thyroid stimulating hormone, and positive thyroid autoantibodies. Neutropenia was defined as ANC <1500 cells/µL.
Results: Thirty-one patients (71% female) were included with a median interquartile range (IQR) age of 14.71 (11.89-17.10) years. Neither fT4 nor fT3 levels correlated with ANC at presentation (rs=0.22, p=0.24 and rs=0.13, p=0.54, respectively). 26/31 (84%) had normal baseline ANC. None developed neutropenia with thionamides. 5/31 (16%) had baseline neutropenia (median ANC 1,200/µL; IQR 874-1200). Four of these five started MMI at diagnosis while one was started on propranolol only but MMI was started one week later. All five normalized ANC within 24 weeks.
Conclusion: In this cohort, 16% of AIH patients had neutropenia at presentation, but this resolved in the short term and did not worsen with thionamides. Thionamides may be used with caution in these patients with close monitoring of blood counts.

Objective: Initial high-dose sodium levothyroxine (Na-LT4) (10-15 µg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 risks iatrogenic hyperthyroidism. The aim of this study was to investigate the normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels.
Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH, based on initial free thyroxine (fT4) levels. Time taken to achieve target hormone levels was compared within groups.
Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 µg/kg/day. Serum fT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit of 14.8±6 days (range 1-36). There was no significant difference in terms of time to achieve target fT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), eight (72.7%) and eight (57.1%) patients experienced hyperthyroxinemia (serum fT4 >1.94 ng/dL) in the mild, moderate, and severe CH groups at the first visit, respectively (p=0.016).
Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4. Initial dose of Na-LT4 may be selected on the basis of pretreatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroxinemia even though the dose was close to the lower limit of the recommended range in guidelines. We suggest that lower initial doses may be appropriate with closer follow-up within the first week.

Objective: We aimed to evaluate the clinical, radiological and pathological findings of children and adolescents with thyroid nodules.
Methods: Data of 121 children and adolescent with thyroid nodules and had fine needle aspiration (FNA) were examined retrospectively. Concomitant thyroid disease, ultrasonography (US) features of the nodule, FNA and histopathological results were recorded. FNA results were assessed according to The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).
Results: Median (range) age of the cases was 14 (3-18) years and 81% were female. FNA results of patients were: insufficient in 1 (0.8%); benign in 68 (56.2%); indeterminate in 44 (36.4%); and malignant in 8 (6.6%) patients. Among 39 patients who underwent surgery, 10 (25.6%) had differentiated thyroid cancer (DTC) and the overall malignancy rate was 10.0% (10/100). Follow-up FNA results showed progress based on TBSRTC in 18.7% of benign results and 4/75 patients had DTC on surgical excision. Two of 22 patients with atypia of undetermined significance (AUS) who continued follow-up was diagnosed with DTC. Male gender, presence of Hashimoto thyroiditis and US findings of uninodularity, hypoechogenicity, increased blood flow, irregular margins, solid structure, microcalcification and presence of abnormal cervical lymph nodes were associated with malignancy.
Conclusion: In this study 10% of thyroid nodules were malignant in children and adolescents. Patients with AUS have a 9% potential for malignancy. Patients with initially benign FNA result may have changes on repeat FNA when assessed with TBSTRC indicating a 5.3% false negative rate.

Objective: Hypoglycemia is a common acute complication of type 1 diabetes (T1D), which may cause seizure, loss of consciousness, and temporary motor or sensory impairment. Glucagon administration is an effective way of treating severe hypoglycemia, especially in a free-living setting. Nonetheless, families have difficulties in managing severe hypoglycemia due to their anxiety and challenges with current glucagon administration techniques. The aim of the current study was to explore the associations between parental fear of hypoglycemia (FoH) and their general anxiety level, and in particular, their attitudes towards and thoughts on glucagon administration.
Methods: Parents of children with T1D completed questionnaires assessing background and clinical information, FoH, generalized anxiety disorder (GAD) and parental anxiety for glucagon administration (PAGA).
Results: Sixty-eight parents participated. Positive correlations were found between parental GAD-7 score and both FoH and the number of night-time blood glucose measurements and there was a negative correlation with the child’s age. Parents mean self-evaluation score of their competence in glucagon administration was 6 (standard deviation±2.9) on a scale of 0 to 10. Unsurprisingly, this score was negatively correlated with the PAGA scores. There was no significant difference between children using continuous glucose monitoring system and self-monitoring of blood glucose in terms of parental FoH, anxiety and misconceptions about glucagon administration.
Conclusion: The results showed that parents of children with T1D had anxiety and fear connected with hypoglycemia and glucagon administration. Structured and practical training should be implemented to increase parents’ self-confidence including annual refresher training for home glucagon administration.

Objective: This study aimed to assess the role of serum midkine (MK) as a biomarker for early detection of diabetic nephropathy in children with type 1 diabetes mellitus (T1DM) before microalbuminuria emerges.
Methods: A total of 120 children with T1DM, comprising 60 microalbuminuric patients (Group 1), 60 normoalbuminuric patients (Group 2), and 60 healthy participants as a control group (Group 3) were included. Detailed medical history, clinical examination, and laboratory assessment of high-sensitivity C-reactive protein (hs-CRP), hemoglobin A1c percentage (HbA1c%), lipid profile, urinary albumin to creatinine ratio (ACR), serum MK and estimated glomerular filtration rate based on serum creatinine were performed in all participants.
Results: Both Group 1 and Group 2 had significantly higher serum MK compared to controls (p<0.001). Additionally, significantly higher MK concentrations were present in Group 1 compared with Group 2 (p<0.001). Receiver operating characteristic curve analysis revealed that the MK concentration cutoff value of 1512 pg/mL was able to predict microalbuminuria with a sensitivity of 96% and specificity of 92%. Stepwise regression analysis revealed that HbA1c%, hs-CRP, and ACR were independently related to MK levels (p<0.001 for each).
Conclusion: The results of this study suggest that serum MK is a useful, novel, practical marker for the evaluation of renal involvement in children with T1DM, especially in normoalbuminuric children.

Objective: Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disease caused by a mutation in the transient receptor potential melastatin 6 (TRPM6) gene and is characterized by selective magnesium malabsorption. Affected cases are usually diagnosed during infancy and usually present with seizures due to hypocalcemia and hypomagnesemia. Irreversible neurological deficits and arrhythmias can be observed without appropriate treatment. The aim was to evaluate the long-term follow-up of patients with genetically confirmed HSH.
Methods: A total of six patients with HSH, two of whom were siblings, were included. Age at diagnosis, clinical, laboratory and follow-up data on admission were recorded. All 39 exons of the TRPM6 gene and flanking exon-intron junctions from genomic DNA were amplified and sequenced in all cases.
Results: The median (range) follow-up duration was 12.1 (7.6-21.7) years. All cases were diagnosed in infancy. Four different mutations, three of which had not been previously reported, were detected in the TRPM6 gene. Treatment compliance was good and there were no severe complications in the long-term follow-up of cases. However, mental retardation, specific learning difficulty and attention deficit/hyperactive disorder were observed as comorbidities.
Conclusion: Of the four different TRPM6 mutations in this small cohort, three had not been previously reported. The long-term prognosis of HSH appears to be good, given early diagnosis and good treatment compliance. This long-term follow-up and prognostic data and the three novel mutations will contribute to the published evidence concerning this rare condition, HSH, and it is hoped will prevent negative outcomes.

Objective: To investigate clinical characteristics and response to growth hormone (GH) treatment in patients with Prader-Willi syndrome (PWS) in Turkey.
Methods: The data of 52 PWS patients from ten centers was retrospectively analyzed. A nation-wide, web-based data system was used for data collection. Demographic, clinical, genetic, and laboratory data and follow-up information of the patients were evaluated.
Results: The median age of patients at presentation was 1.5 years, and 50% were females. Genetic analysis showed microdeletion in 69.2%, uniparental disomy in 11.5%, imprinting defect in 1.9% and methylation abnormality in 17.3%. Hypotonia (55.7%), feeding difficulties (36.5%) and obesity (30.7%) were the most common complaints. Cryptorchidism and micropenis were present in 69.2% and 15.3% of males, respectively. At presentation, 25% had short stature, 44.2% were obese, 9.6% were overweight and 17.3% were underweight. Median age of obese patients was significantly higher than underweight patients. Central hypothyroidism and adrenal insufficiency were present in 30.7% and 4.7%, respectively. Hypogonadism was present in 75% at normal age of puberty. GH treatment was started in 40% at a mean age of 4.7±2.7 years. After two years of GH treatment, a significant increase in height SDS was observed. However, body mass index (BMI) standard deviation (SDS) remained unchanged.
Conclusion: The most frequent complaints were hypotonia and feeding difficulty at first presentation. Obesity was the initial finding in 44.2%. GH treatment was started in less than half of the patients. While GH treatment significantly increased height SDS, BMI SDS remained unchanged, possibly due to the relatively older age at GH start.

Objective: The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey.
Methods: A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses.
Results: In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel.
Conclusion: This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.

Objective: The aim was to evaluate the results of diagnosis, follow-up and treatment of the patients who recieved growth hormone (GH) treatment for the last 10 years and to determine the differences in the process and results over the years.
Methods: Anthropometric, clinical, laboratory data, treatment adherence and side effects were evaluated retrospectively in 767 patients who recieved GH treatment between 2009-2018. Patients were grouped as isolated GH deficiency (IGHD), multiple pituitary hormone deficiency (MPHD), small for gestational age (SGA), and Turner syndrome (TS) depending on diagnosis.
Results: GH treatment was started in 689 cases (89.8%) with IGHD, 24 (3.1%) with MPHD, 26 (3.4%) with SGA and 28 (3.7%) with TS. Median age of GH treatment onset was the earliest in SGA (8.4 years) and the latest in the IGHD group (12.0 years). At the time of treatment cessation, height standard deviation score (SDS) in IGHD and MPHD was significantly higher than treatment initiation time, whereas there was no significant difference in TS and SGA. One hundred eighty-nine cases reached the final height. Final heights for girls/boys were: IGHD 154/164.9 cm; MPHD 156.2/163.5 cm; TS 146.7 cm; and SGA 145.7/-cm, respectively. Target height SDS-final height SDS median values were IGHD: 0.1, MPHD: 0.6, SGA: 0.5, TS: 2.4 respectively. The patients’ treatment compliance was high (92%) and the incidence of side effects was low (2.7%).
Conclusion: In our cohort, GH treatment start age was late and no difference in this was observed in the last 10 years. The improvement in the height SDS was most marked in the IGHD and MPHD groups, the least in the TS and SGA groups.

Cases of neurofibromatosis type 1 (NF1)-associated medullary thyroid carcinoma (MTC) or C-cell hyperplasia are rarely associated with other endocrine tumors or cases with a multiple endocrine neoplasia type 2. In these patients, mutations were detected in the NF1 gene but no mutations were detected in the RET gene. Although vandetanib has been shown to improve progression-free survival in adults with advanced MTC, data in pediatric patients are limited. Herein, we report the use and outcome of vandetanib in a pediatric MTC case in which NF1 gene and RET proto-oncogen mutation were identified together.

We describe a 46,XX girl with Denys-Drash syndrome, showing both kidney disease and genital abnormalities, in whom a misdiagnosis of hyperandrogenism was made. A 15 year-old girl was affected by neonatal nephrotic syndrome, progressing to end stage kidney failure. Hair loss and voice deepening were noted during puberty. Pelvic ultrasound and magnetic resonance imaging showed utero-tubaric agenesis, vaginal atresia and urogenital sinus, with inguinal gonads. Gonadotrophin and estradiol levels were normal, but testosterone was increased up to 285 ng/dL at Tanner stage 3. She underwent prophylactic gonadectomy. Histopathology reported fibrotic ovarian cortex containing numerous follicles in different maturation stages and rudimental remnants of Fallopian tubes. No features of gonadoblastoma were detected. Unexpectedly, testosterone levels were elevated four months after gonadectomy (157 ng/dL). Recent medical history revealed chronic daily comsumption of high dose biotin, as a therapeutic support for hair loss. Laboratory immunoassay instruments used streptavidin-biotin interaction to detect hormones and, in competitive immunoassays, high concentrations of biotin can result in false high results. Total testosterone, measured using liquid chromatography tandem mass spectrometry, was within reference intervals. Similar testosterone levels were detected on repeat immunoassay two weeks after biotin uptake interruption. Discordance between clinical presentation and biochemical results in patients taking biotin, should raise the suspicion of erroneous results. Improved communication among patients, health care providers, and laboratory professionals is required concerning the likelihood of biotin interference with immunoassays

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

Brain abscess formation is extremely rare in patients with osteopetrosis. Herein, we report a case of viridans streptococci brain abscess in an immunocompromised child diagnosed with osteopetrosis. The patient presented with a sudden change in mental status and convulsions. Radiological evaluation revealed a temporal lobe brain abscess, and intravenous antibiotherapy was started immediately. The patient underwent abscess drainage, and laboratory investigation of pus material revealed viridans streptococci.

Steroid 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia (CAH), usually due to biallelic variants in CYP21A2. Classical 21-hydroxylase deficiency is characterised by virilisation of the external genitalia in females and hypocortisolism. Hyponatremia and hyperkalemia are among the common biochemical findings. Familial hypokalemic periodic paralysis (FHPP) is a rare disorder in which affected individuals may experience paralytic episodes associated with hypokalemia, caused by pathogenic variants in SCN4A or CACNA1S. A 14-year-old female, who had been diagnosed with classical 21-hydroxylase deficiency and treated with hydrocortisone and fludrocortisone since early infancy, presented with acute onset weakness. The laboratory results revealed a remarkably low serum potassium level. The family history revealed that both her father and uncle had the same hypokalemic symptoms, which suggested an FHPP diagnosis. We found two previously reported homozygous variants in the CYP21A2 (p.Ile173Asn) and SCN4A (p.Arg672His) genes in the patient. Therefore, diagnoses of simple virilising 21-hydroxylase deficiency and FHPP were genetically confirmed. Here, FPHH and chronic overtreatment with fludrocortisone may explain the presentation of our patient with severe hypokalemia. The family’s medical history, which is always a valuable clue, should be investigated in detail since rare inherited conditions may co-occur in geographies where consanguineous marriages are common and the genetic pool is diverse. In patients with CAH, care should be taken to avoid overtreatment with fludrocortisone. Androgens may have triggered the hypokalemic attack in FHPP, as supported in a previous study.