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Acute myeloid leukemia (AML) is a highly heterogeneous disease. Although patients can be classified into risk groups based on their genetic changes, the prognosis of disease within these categories varies widely. This situation raises the need to search for new molecular markers related to AML. Serine peptidase inhibitor Kazal type 2 (SPINK2) has recently been reported to be upregulated in AML and associated with poor outcomes by meta-analysis and in a limited number of AML patients. We analyzed SPINK2 mRNA expression in 62 patients (45 adult and 17 pediatric) with AML and 11 cell lines using quantitative Real-Time PCR (qRT-PCR). SPINK2 protein level was determined using ELISA in cell lines. We found that the expression of SPINK2 mRNA and protein levels in AML cell lines (HL60 and NB4) have increased compared to other cell lines (K562, Jurkat and NALM6, MCF7, HeLa, HUVEC, hFOB, 293T, U87). SPINK2 mRNA expression was upregulated in patients with AML compared to controls (p=0.004) and significantly lower in t(8;21)-positive patients compared to negative patients (p=0.0006). Our results suggest that SPINK2 serves an important role in AML development. Further studies are needed to evaluate SPINK2 expression in AML patients with t(8.21) and investigate to clarify its prognostic value in various subgroups of AML. [ABSTRACT FROM AUTHOR]

The aim of this study is to determine the clinical and molecular characteristics enabling differential diagnosis in a group of Turkish children clinically diagnosed with MODY and identify the cut-off value of HbA1c, which can distinguish patients with GCK variants from young-onset type 1 and type 2 diabetes. The study included 49 patients from 48 unrelated families who were admitted between 2018 and 2020 with a clinical diagnosis of MODY. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of ten MODY genes was performed using targeted next-generation sequencing (NGS) panel and the variants were classified according to American Collage of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. A total of 14 (28%) pathogenic/likely pathogenic variants were detected among 49 patients. 11 variants in GCK and 3 variants in HNF1A genes were found. We identified four novel variants in GCK gene. Using ROC analysis, we found that best cut-off value of HbA1c at the time of diagnosis for predicting the subjects with a GCK variant among patients suspected to have MODY was 6.95% (sensitivity 90%, specificity 86%, AUC 0.89 [95% CI: 0.783–1]). Most of the cases without GCK variant (33/38 [86%]) had an HbA1c value above this cutoff value. We found that among participants suspected of having MODY, family history, HbA1c at the time of diagnosis, and not using insulin therapy were the most differentiating variables of patients with GCK variants. Family history, HbA1c at the time of diagnosis, and not receiving insulin therapy were found to be the most distinguishing variables of patients with GCK variants among subjects suspected to have MODY. [ABSTRACT FROM AUTHOR]

Large cell calcifying Sertoli cell tumours (LCCSCTs) are one of the infrequent causes of prepubertal gynaecomastia. Most of these tumours are in the content of Peutz–Jeghers syndrome (PJS) or other familial syndromes (Carney complex). Here, we report a long-term follow-up of an 8.5-year-old prepubertal boy with a diagnosis of PJS, who presented with bilateral gynaecomastia, advanced bone age and accelerated growth velocity, and were found to have bilateral multifocal testicular microcalcifications. As the findings were compatible with LCCSCT, anastrozole was initiated. Gynaecomastia completely regressed and growth velocity and pubertal development were appropriate for age during follow-up. Testicular lesions slightly increased in size. After four years of medication, anastrozole was discontinued but was restarted due to the recurrence of gynaecomastia after six months. Testicular tumour should be investigated in a patient with PJS who presents with prepubertal gynaecomastia. When findings are consistent with LCCSCT, aromatase inhibitors may be preferred in the treatment. [ABSTRACT FROM AUTHOR]

This study aimed to determine the prevalence and predictors of euthyroid sick syndrome (ESS) in pediatric intensive care, and to establish a link between thyroid function tests and mortality. Between January 2015 and March 2020, children admitted to our pediatric intensive care unit (PICU) and tested for free triiodothyronine (fT3), free thyroxine (fT4), and thyrotropin (TSH) levels were included. Patients with decreased fT3, with normal or decreased fT4, and normal or decreased TSH levels were assigned to the ESS group. The association between biochemical indicators and ESS, as well as the relationship between fT3 and mortality, were examined. A total of 141 (36%) of 386 children included to study were classified in the ESS group. The ESS group had a higher rate of 28-day mortality (12 [8.5%] vs. 9 [3.7%]). Blood urea nitrogen (BUN), albumin, platelet, lactate, and pediatric index of mortality 3 [PIM3 (%)] were significantly associated with ESS (odds ratios in order: 1.024, 0.422, 0.729, 1.208, 1.013). Multivariate regression analysis showed that BUN, albumin, platelet, and lactate were independently associated with ESS progression. The area under curve (AUC [95%CI]) for fT3 was 0.644 (0.555–0.789) to detect mortality. Children with a fT3 level lower than 2.31 pg/mL had significantly higher 28-day mortality (log rank test, p=0.001). Our study identified BUN, albumin, lactate, and platelet count as independent risk factors for ESS progression in children. Furthermore, our findings indicated a correlation between fT3 and mortality, which makes fT3 an ideal candidate to be included in mortality indices. [ABSTRACT FROM AUTHOR]

The exact mechanism of partial clinical remission in type 1 diabetes mellitus (T1DM) has not been elucidated yet. The severity of the inflammation at the time of diagnosis may affect the occurrence or duration of this phase. We aimed to investigate the relationship between hematological inflammatory parameters at the time of diagnosis in T1DM and (i) daily insulin requirement during the follow-up and (ii) the presence of partial clinical remission period, which was determined according to insulin dose-adjusted HbA1c levels. A single-center retrospective study was conducted, including children who were diagnosed with T1DM, were positive for at least one autoantibody, and were followed up for one year in our clinic between 2010 and 2020. Sixty-eight patients (55.9% female, 64.7% prepubertal) were included in the study, whose mean age was 8.4 ± 4.2 years. A total of 38 patients (55.9%) had partial clinical remission. None of the initial hematological indices were associated with the occurrence of partial remission. Initial neutrophil/lymphocyte ratio (NLR) and derived-NLR (d-NLR) levels were significantly lower (p=0.011 and 0.033, respectively) and lymphocyte/monocyte ratio (LMR) levels were significantly higher (p=0.005) in patients who showed an insulin requirement of <0.5 IU/kg/day at the 3rd month after diagnosis. Initial hematological parameters were not found as a predictor of partial clinical remission period in T1DM in children. However, a lower NLR and d-NLR, or a higher LMR at the time of diagnosis can be used as an indicator of a low daily insulin need at the 3rd month of T1DM. [ABSTRACT FROM AUTHOR]

Background: Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods: Mutation analysis of MODY genes (GCK, HNF1A, HNF4A, HNF1B, ABCC8, INS and KCNJ11) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results: A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK, six in HNF4A, four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions: While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel. [ABSTRACT FROM AUTHOR]

Objectives: Variants in fibroblast growth factor receptor-1 (FGFR1) may either cause isolated hypogonadotropic hypogonadism (IHH) or Kallmann syndrome (KS). Although the relationship of genes classically involved in IHH with combined pituitary hormone deficiency (CPHD) is well established, variants in FGFR1 have been presented as a rare cause of this phenotype recently. Case presentation: Herein, we report an adopted 16-year-old male presented with delayed puberty and micropenis. He had undergone surgery for bilateral undescended testes in childhood. He was normosmic, and the pituitary imaging was normal. However, hypogonadotropic hypogonadism and growth hormone deficiency were detected, associated with a heterozygous nonsense variant (c.1864 C>T, p.R622X) in FGFR1. Conclusions: FGFR1 variants are among the causes of IHH and KS, which are inherited in an autosomal dominant manner and can be associated with midline defects. It should also be kept in mind that CPHD may be associated with FGFR1 variants in a subject with normal olfactory function. [ABSTRACT FROM AUTHOR]

Background: Similar autoimmune processes (defective T-cell function) take place during the pathogenesis of aplastic anemia (AA) and Graves' disease (GD). Antithyroid drugs used for the management of GD may induce AA and GD may occur following treatment of severe aplastic anemia (SAA). Case presentation: Clinical and laboratory investigations were performed for an 11-year-and-2-month-old girl who was referred for bilateral exophthalmus and abnormal thyroid function tests. She had been diagnosed as having severe acquired AA at the age of 8 years and had been treated with allogenic hematopoietic stem cell transplantation from her healthy human leukocyte antigen-matched sibling donor. Clinical examination revealed a weight of 32.6 kg (−0.88 standard deviation [SD] score); height, 145.7 cm (−0.14 SD score); body mass index 15.5 kg/m2 (−1.01 SD score); heart rate, 110/min; blood pressure, 128/74 mmHg; bilateral exophthalmos and an enlarged thyroid gland. The laboratory workup showed hemoglobin of 11.1 g/dL; white blood cells, 7500/mL; platelets, 172,000/mL; free thyroxine (FT4), 4.80 ng/dL (normal, 0.5–1.51); free triiodothyronine (FT3), 17.7 pg/mL (normal, 2.5–3.9); thyrotropin (TSH), 0.015 mIU/mL (normal, 0.38–5.3); antithyroglobulin peroxidase (TPO) antibody, 61.7 IU/mL (normal, 0–9); antithyroglobulin (TG) antibody, <0.9 IU/mL (normal, 0–4) and thyrotropin (TSH) receptor antibodies 14 U/L (normal, 0–1). Doppler ultrasonography showed diffuse enlargement of the thyroid gland and increased vascularity. She was treated with methimazole (0.6 mg/kg/day). L-thyroxine treatment was also needed (50 μg/day). Thrombocytopenia developed during follow-up. A thyroidectomy was performed for definitive treatment at the 14th month of treatment. Conclusions: The association of hyperthyroidism and AA in the pediatric age group is rare. The long-term use of antithyroid drugs and radioactive iodine should be avoided due to their hematologic toxic side effects. [ABSTRACT FROM AUTHOR]

Background: Fetuin A is an inhibitor of insulin action and have been found to be related with subcutaneous lipid accumulation and insulin resistance. The relation of cardiac lipid accumulation, fetuin A and insulin resistance parameters in obese children is not well-known. The aim of the study was to evaluate the relation of serum fetuin A levels with subcutaneous and cardiac lipid accumulation, and insulin resistance parameters in Turkish obese children. Methods: Serum fetuin A levels, cardiac and subcutaneous lipid accumulation parameters of 42 obese (10.9±2.3 years, 19 female) and 40 control group subjects (11.2±2.7) were compared. Cardiac lipid accumulation measured by subepicardial adipose tissue thickness. Insulin resistance was assessed using homeostasis model assessment (HOMA-IR) index. Results: There were significant correlations serum fetuin A levels with BMI-SDS, circumferences of waist, hip and midarm, SATT and HOMA-IR (r=0.362, p=0.018, r=0.728, p=0.001, r=0.662, p=0.0001, r=0.713, p=0.0001, r=0.477, p=0.001, and r=0.330, p=0.038 as, respectively). Conclusions: Fetuin A was correlated well with cardiac and subcutaneous lipid accumulation, insulin resistance parameters, which may be related with early pathogenetic mechanisms of metabolic obesity complications in children. [ABSTRACT FROM AUTHOR]

Background: The aim of this study is to determine the relationship between oxidative stress marker (8-iso-prostaglandine F2α) and glycemic indices computed from daily glucose monitoring data in children with type 1 diabetes mellitus (T1DM). Methods: Thirty-one children and adolescents with T1DM (median age 12.2 years) and healthy subjects (median age 11.7 years) were enrolled into the study. Anthropometric data were recorded for the entire group before the study. In addition, diabetes duration, insulin requirement, lipid values, microalbuminuria, HbA1c were recorded in T1DM subjects. T1DM subjects performed self-monitoring of blood glucose (SMBG) for a month (at least four times a day) for calculating glycemic indices. Twenty-four-hour urine 8-iso-prostoglandine F2α levels were studied at the end of the study period in the both groups. Results: Median diabetes duration was 5 years, hemoglobin A1c (HbA1c) was 7.3%. Standard deviation (SD) of the blood glucose (BG) was determined as 85 mg/dL. Median urinary 8-iso-prostoglandine F2α was found to be significantly higher than that of the healthy subjects (2808.9 and 298 pg/mg creatinine, p < 0.001, respectively). There was no correlation between urinary 8-iso-prostoglandine F2α and age, anthropometric data, diabetes duration, insulin requirement, lipid values, microalbuminuria, HbA1c, or SD of BG in T1DM groups. Conclusions: This study showed that, 8-iso-prostoglandine F2α that is an oxidative stress marker, is significantly higher in T1DM than that of healthy subjects while, no significant relation between glycemic indices and urinary 8-iso-prostoglandine F2α levels were demonstrated. Further studies are needed to assess other factors, and the relationship between glucose fluctuations and oxidative stress markers. [ABSTRACT FROM AUTHOR]

Aim: To perform molecular analysis of pediatric maturity onset diabetes of the young (MODY) patients by next-generation sequencing, which enables simultaneous analysis of multiple genes in a single test, to determine the genetic etiology of a group of Turkish children clinically diagnosed as MODY, and to assess genotype-phenotype relationship. Methods: Forty-two children diagnosed with MODY and their parents were enrolled in the study. Clinical and laboratory characteristics of the patients at the time of diagnosis were obtained from hospital records. Molecular analyses of GCK, HNF1A, HNF4A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, and BLK genes were performed on genomic DNA by using next-generation sequencing. Pathogenicity for novel mutations was assessed by bioinformatics prediction software programs and segregation analyses. Results: A mutation in MODY genes was identified in 12 (29%) of the cases. GCK mutations were detected in eight cases, and HNF1B, HNF1A, PDX1, and BLK mutations in the others. We identified five novel missense mutations - three in GCK (p.Val338Met, p.Cys252Ser, and p.Val86Ala), one in HNF1A (p.Cys241Ter), and one in PDX1 (p.Gly55Asp), which we believe to be pathogenic. Conclusion: The results of this study showed that mutations in the GCK gene are the leading cause of MODY in our population. Moreover, genetic diagnosis could be made in 29% of Turkish patients, and five novel mutations were identified. [ABSTRACT FROM AUTHOR]

Disorders of sex development (DSD) are a generic definition including any problem noted at birth where the genitalia are atypical in relation to the chromosomes or gonads. The most important clinical problems in DSD comprise physical and psychological disturbances and the risk of gonadal tumor development. Germ cell tumor risk is lowest (< 5%) in patients with defects in androgene action or synthesis (such as complete androgen insensitivity syndrome, 5a-reductase deficiency), whereas the highest risk (15%-60%) is observed in 46,XY gonadal dysgenesis. The presence of Y chromosomal material in the karyotype increases the risk for the development of gonadal tumors. The reported age of tumor development varies based on the etiology of DSD (gonadal dysgenesis, androgen insensitivity syndrome, androgen synthesis defects, mixed gonadal dysgenesis, etc.). In the past, early gonadectomy was recommended for all cases of 46,XY DSD, however, according to current approaches, gonadal tumor risk is predicted based on the molecular diagnosis and the timing of the gonadectomy depends on the result of molecular analysis. Until now, optimal protocol in the management of DSD is still controversial. In addition to that, safe and well-accepted guidelines are needed. There is limited number of prospective studies on timing of a gonadectomy in childhood and adolescence. Therefore, evidence-based data on timing and indications of gonadectomy in patients with DSD are needed. In this review, recent data regarding gonadal malignancy risk in DSD and recommendations on timing of gonadectomy are presented. [ABSTRACT FROM AUTHOR]

Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders characterized by autosomal dominantly inherited non-insulin dependent form of diabetes classically presenting in adolescence or young adults before the age of 25 years. MODY is a rare cause of diabetes (1% of all cases) and is frequently misdiagnosed as Type 1 diabetes (T1DM) or Type 2 diabetes (T2DM). A precise molecular diagnosis is essential because it leads to optimal treatment of the patients and allows early diagnosis for their asymptomatic family members. Mutations in the glucokinase ( GCK) (MODY 2) and hepatocyte nuclear factor ( HNF)1A/4A (MODY 3 and MODY 1) genes are the most common causes of MODY. GCK mutations cause a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment. However, mutations in the HNF1A and HNF4A cause a progressive pancreatic β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in these patients by acting on adenosine triphosphate (ATP)-sensitive potassium channels, although insulin therapy may be required later in life. Mutations in the HNF1B (MODY 5) is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction. Compared to MODY 1, 2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. In this review, we summarize the main clinical and laboratory characteristics of the common and rarer causes of MODY. [ABSTRACT FROM AUTHOR]

Background: Nesfatin-1, a recently discovered anorexigenic peptide, is expressed in several tissues, including pancreatic islet cells and central nervous system. However, its pathophysiological role in the development of obesity and insulin resistance remains unknown. Aim: To investigate the possible involvement of nesfatin-1 in the pathogenesis of childhood obesity, we examined the relationship between fasting and postprandial nesfatin-1 concentrations and metabolic/antropometric parameters in obese children. Material and methods: The study included obese children with a body mass index >95th percentile. Fasting serum glucose, insulin, lipid profile, fasting and postprandial (120th min) nesfatin-1 levels were measured to evaluate the metabolic parameters. Different cutoff values for prepubertal and pubertal stages were used to determine the status of insulin resistance (HOMA-IR) (prepubertal >2.5, pubertal >4). The percentage of body fat was measured using bioelectric impedance analysis. Results: Seventy-one obese children were included in this study. There was no statistically significant difference between fasting and postprandial nesfatin-1 levels in obese subjects (0.70±0.15 and 0.69±0.14 ng/mL, p>0.05, respectively). Insulin resistance was observed in 58% (41/71) of the cases. There was no significant difference in either fasting or postprandial serum nesfatin-1 levels between the insulin-resistant and non-resistant groups (p>0.05). There was no correlation between fasting and postprandial serum nesfatin-1 levels and anthropometric and metabolic parameters in insulin-resistant and non-resistant groups. Conclusions: In this study, there was no significant increase in the postprandial level of nesfatin-1. This observation suggested that oral glucose load in obese children may not be sufficient for nesfatin-1 response and that nesfatin-1 may not have an effect as a short-term regulator of food intake. [ABSTRACT FROM AUTHOR]

Neonatal diabetes mellitus is a rare clinical condition, which develops most commonly secondary to mutations in KCNJ11 and ABCC8 genes encoding ATP-sensitive K+ channels. Patients are typically diagnosed with hyperglycemia-related symptoms in the first 6 months of life and rarely with ketoacidosis. In this article, we report an infant who presented with focal clonic convulsion and thereafter was diagnosed with neonatal diabetes mellitus and thrombi in cerebral venous sinus. In this patient, after a molecular analysis of the ABCC8 gene revealed a novel heterozygous missense mutation (p.D424V), a successful transition from insulin to sulfonylurea treatment was made. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to determine neutrophil gelatinase-associated lipocalin (NGAL) levels in normoalbuminuric and normotensive adolescents with type 1 diabetes and to assess the relationship between NGAL and clinical and laboratory variables. Methods: Forty-six adolescents with type 1 diabetes [male/female (M/F) ratio, 24/22; median age, 14.5 years; range, 12.2-16 years; diabetes duration, 4.8 years; range, 2.6-6.7 years; hemoglobin A1c (HbA1c), 7.9%; range, 7.2%-9.2%] and 21 healthy controls (M/F, 7/14; median age, 14.8 years; range, 13.6-15.5 years) were compared regarding clinical, laboratory, and ambulatory blood pressure monitoring variables. Results: Median blood and urine glucose, HbA1c, urine NGAL/creatinine ratio [13.2 (range, 8.3-43.1) vs. 4.8 (range, 2.9-20.2), p=0.015], and daytime systolic and diastolic blood pressure (BP) standard deviation score and BP loads were found higher in diabetic adolescents. Urine NGAL levels were found to be correlated with albumin/creatinine ratio (r=0.452, p=0.002), whereas plasma NGAL levels were correlated with nighttime systolic BP load (r=0.309, p=0.037). Patients with high-normal albuminuria (n=6) had higher urine NGAL levels [48.7 ng/mL (range, 27.9-149.1 ng/mL) vs. 14.3 ng/mL (range, 3.5-41 ng/mL), p=0.014] and urine NGAL/creatinine ratio [39.3 ng/mg (range, 21.1-126.3 ng/mg) vs. 11.8 ng/mg (range, 6.3-40.9 ng/mg), p=0.03] compared with those of controls and higher urine NGAL levels compared with that of diabetic adolescents with low-normal albuminuria [n=40, 11.2 ng/mL (range, 6-23.4 ng/mL), p=0.004]. Conclusions: Normoalbuminuric and normotensive adolescents with type 1 diabetes have elevated urinary NGAL values, which might indicate kidney injury. [ABSTRACT FROM AUTHOR]