Early-onset Chronic Keratitis as the First Presenting Component of Autoimmune Polyendocrinopathy Syndrome Type 1 (APS-1): A Case Report and Review of the Literature.

Autoimmune polyendocrine syndrome type 1 (APS-1), also referred to as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a rare monogenic autosomal recessive autoimmune disease. It is caused by mutations in the autoimmune regulator (AIRE) gene. APS-1 is diagnosed clinically by the presence of two of the three major components: chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenocortical insufficiency. A 3.3-year-old girl was presented with a carpopedal spasm to the pediatric emergency clinic. She had a history of recurrent keratitis, and chronic candidiasis as urinary tract infections and oral thrashes. Hypoparathyroidism (HPT) was diagnosed based on low serum concentrations of calcium and parathyroid hormone and elevated serum concentrations of phosphate, and treatment with calcium and calcitriol supplementation was started. Genetic testing revealed homozygosity for nonsense c.769C>T (p.R257X) mutation in exon 6 in the AIRE gene which was reported previously. At the age of 5.6 years, she was presented with an adrenal crisis, and treatment with hydrocortisone and fludrocortisone was started. The reported case highlights that unexplained chronic keratitis in children may be the first and most severe component of this syndrome. The classic triad of APS-1 may also appear in the first decade of life.

Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus.

Objective: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. Materials and Methods: The presence of clinical features of MODY and negative results for three autoantibody markers of T1DM in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Results: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). A 12 variants were classified as P/LP while 12 were interpreted as variant of unknown significance (VUS). Nine of the pathogenic or likely pathogenic variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All of the variants, except one, showed heterozygotic inheritance. Conclusion: This study screened mutations in the 14 MODY-related genes and the regulatory factor X6 (RFX6) gene in Turkish children diagnosed with autoantibody-negative type 1 diabetes mellitus (T1DM). The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes.

Comparison of Makorin Ring Finger Protein 3 Levels Between Obese and Normal Weight Patients with Central Precocious Puberty

Objective: 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). 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.

PLXNB1 mutations in the etiology of idiopathic hypogonadotropic hypogonadism.

Idiopathic hypogonadotropic hypogonadism (IHH) comprises a group of rare genetic disorders characterized by pubertal failure caused by gonadotropin-releasing hormone (GnRH) deficiency. Genetic factors involved in semaphorin/plexin signaling have been identified in patients with IHH. PlexinB1, a member of the plexin family receptors, serves as the receptor for semaphorin 4D (Sema4D). In mice, perturbations in Sema4D/PlexinB1 signaling leads to improper GnRH development, highlighting the importance of investigating PlexinB1 mutations in IHH families. In total, 336 IHH patients (normosmic IHH, n = 293 and Kallmann syndrome, n = 43) from 290 independent families were included in the present study. Six PLXNB1 rare sequence variants (p.N361S, p.V608A, p.R636C, p.V672A, p.R1031H, and p.C1318R) are described in eight normosmic IHH patients from seven independent families. These variants were examined using bioinformatic modeling and compared to mutants reported in PLXNA1. Based on these analyses, the variant p.R1031H was assayed for alterations in cell morphology, PlexinB1 expression, and migration using a GnRH cell line and Boyden chambers. Experiments showed reduced membrane expression and impaired migration in cells expressing this variant compared to the wild-type. Our results provide clinical, genetic, molecular/cellular, and modeling evidence to implicate variants in PLXNB1 in the etiology of IHH.

Inactivating NHLH2 variants cause idiopathic hypogonadotropic hypogonadism and obesity in humans.

Metabolism has a role in determining the time of pubertal development and fertility. Nonetheless, molecular/cellular pathways linking metabolism/body weight to puberty/reproduction are unknown. The KNDy (Kisspeptin/Neurokinin B/Dynorphin) neurons in the arcuate nucleus of the hypothalamus constitute the GnRH (gonadotropin-releasing hormone) pulse generator. We previously created a mouse model with a whole-body targeted deletion of nescient helix-loop-helix 2 (Nhlh2; N2KO), a class II member of the basic helix-loop-helix family of transcription factors. As this mouse model features pubertal failure and late-onset obesity, we wanted to study whether NHLH2 represents a candidate molecule to link metabolism and puberty in the hypothalamus. Exome sequencing of a large Idiopathic Hypogonadotropic Hypogonadism cohort revealed obese patients with rare sequence variants in NHLH2, which were characterized by in-silico protein analysis, chromatin immunoprecipitation, and luciferase reporter assays. In vitro heterologous expression studies demonstrated that the variant p.R79C impairs Nhlh2 binding to the Mc4r promoter. Furthermore, p.R79C and other variants show impaired transactivation of the human KISS1 promoter. These are the first inactivating human variants that support NHLH2's critical role in human puberty and body weight control. Failure to carry out this function results in the absence of pubertal development and late-onset obesity in humans.

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: Outcomes of Extended Pilot Study in 241,083 Infants

Objective: Turkish Directorate of Public Health introduced the first pilot screening program for congenital adrenal hyperplasia (CAH) in four Turkish cities in 2017, and in 2018 extended the program, with a slight change in screening strategy, to fourteen cities. To evaluate the performance of the extended study and update previously reported outcomes. Methods: Retrospective, descriptive study. Neonates of ≥32 gestational weeks and ≥1500 gr birth weight from fourteen cities, born between May-December 2018, were included. Screening protocol included one sample, two-tier testing as applied in the previous pilot study. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. Cases with positive initial screening underwent second tier testing by steroid profiling in DBS using liquid chromatographyt-andem mass spectrometry to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.7 (increased from ≥0.5 in the earlier pilot study) were referred to pediatric endocrinology clinics for diagnostic assessment. Results: In the evaluated period, 241,083 newborns were screened. 12,321 (5.11%) required second-tier testing and 880 (0.36%) were referred for clinical assessment, twenty of whom were diagnosed with CAH (10 females, 10 males). Sixteen were diagnosed as classical 21-hydroxylase deficiency (21-OHD) CAH (12 with salt-wasting and four with simple virilising CAH), and four cases were identified with 11ß-OHD CAH. No case of salt-wasting CAH was missed by neonatal screening (sensitivity was 100%). The incidence of classical 21-OHD and 11ß-OHD in the screened population was 1:15,067 and 1:60,270, respectively. Conclusion: Turkish neonatal CAH screening effectively led to earlier diagnosis of 21-OHD and 11ß-OHD, using steroid profiling as a second-tier test. This will result in improved care of these patients in the future.

Quality-of-life Evaluation of Healthy Siblings of Children with Chronic Illness

Background: Chronic disease of children can cause changes in the health-related quality of life (HrQoL) of the family members. Aims: To evaluate the HrQoL of healthy siblings of children with chronic disease. Study Design: Cross-sectional study. Methods: The study included healthy sibling of children with chronic disease (cerebral palsy, epilepsy, diabetes, celiac disease, hematologic/oncologic disease, or asthma) and healthy sibling of healthy children to evaluate the quality of life. We used the Pediatric Quality of Life Inventory questionnaire; the physical health and psychosocial health scores were calculated using the responses of the sibling and parent. The primary endpoint was the comparison of HrQoL scores of healthy siblings of children with chronic disease and that of healthy siblings of healthy children. Results: This study included a respective healthy sibling of 191 children with chronic disease and healthy sibling of 100 healthy children. The physical health, psychosocial health, and total health scores of healthy siblings of children with chronic disease were significantly lower than that of healthy siblings of healthy children (p<0.001). Among the healthy siblings of children with chronic disease, the lowest psychosocial health score was found in the siblings of children with cerebral palsy, hematologic/oncologic disease, and asthma (p<0.001). The global impact on the quality of life for healthy siblings of children with chronic disease was significantly higher in the self-report of the children than that of the parents (30.4% versus 15.1%, p<0.05). Conclusion: Most healthy siblings of children with chronic disease are physically and psychosocially affected and there is low parental awareness of this condition. This can increase the risk of emotional neglect and abuse of these children. Therefore, special support programs are needed for the families of children with chronic diseases.

Clinical, Histochemical, and Molecular Study of Three Turkish Siblings Diagnosed with H Syndrome, and Literature Review.

BACKGROUND: The term "H syndrome" was coined to denote the major clinical findings, which include hyperpigmentation, hypertrichosis, hearing loss, hepatosplenomegaly, hyperglycaemia, hypogonadism, hallux flexion contractures, and short height. OBJECTIVE: To report the clinical, endocrinological, histochemical, and genetic findings of three siblings. METHODS: Skin and liver biopsies were taken to investigate the histochemical characteristics of hyperpigmented hypertrichotic skin lesions and massive hepatomegaly. The levels of basal serum thyroid hormones, oestradiol, total testosterone, follicle-stimulating hormone, luteinising hormone, and stimulated growth hormone (GH) were measured to investigate the endocrine aspects of the syndrome. Mutation analysis was carried out in all six exons and exon-intron boundaries of SLC29A3 by direct sequencing. RESULTS: Physical examination of the patients revealed common charac-teristic findings of H syndrome. Additional clinical findings were sectorial iris atrophy in the younger sister. Laboratory evaluation revealed microcytic anaemia, markedly increased erythrocyte sedimentation rate and C-reactive protein levels, and humoral immune deficiency in the younger siblings, who presented with recurrent fever and sinopulmonary infection. Two different GH stimulation tests revealed GH deficiency in the younger sister with short stature. Liver and skin biopsies revealed polyclonal lymphohistiocytic and plasma cell infiltration. Sequencing of SLC29A3 in the three siblings revealed a novel homozygous mutation in exon 6, which caused the transition of arginine to tryptophan. CONCLUSION: This study not only extended the clinical and mutation spectrum of SLC29A3 in H syndrome, but also showed that short children should be assessed according to the guidelines for short stature in children.

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: A Pilot Study with 38,935 Infants

Objective: Congenital adrenal hyperplasia (CAH) is the most common form of primary adrenal insufficiency in children. Neonatal screening for CAH is effective in detecting the salt-wasting (SW) form and in reducing mortality. In this study, our aim was to estimate the incidence of CAH in Turkey and to assess the characteristics and efficacy of the adopted newborn CAH screening strategy. Methods: A pilot newborn CAH screening study was carried out under the authority of the Turkish Directorate of Public Health. Newborn babies of ≥32 gestational weeks and ≥1500 gr birth weight from four cities, born between March 27-September 15, 2017 were included in the study. Screening protocol included one sample two-tier testing. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. The cases with positive initial screening were tested by steroid profiling in DBS using a liquid chromatography-tandem mass spectrometry method to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione as a second-tier test. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.5 were referred to pediatric endocrinology clinics for diagnostic assessment. Results: 38,935 infants were tested, 2265 (5.82%) required second-tier testing and 212 (0.54%) were referred for clinical assessment, six of whom were diagnosed with CAH (four males, two females). Four cases were identified as SW 21-hydroxylase deficiency (21-OHD) (two males, two females). One male baby had simple virilizing 21-OHD and one male baby had 11-OHD CAH. The incidence of classical 21-OHD in the screened population was 1:7,787. Conclusion: The incidence of CAH due to classical 21-OHD is higher in Turkey compared to previous reports. We, therefore, suggest that CAH be added to the newborn screening panel in Turkey. The use of steroid profiling as a second-tier test was found to improve the efficacy of the screening and reduce the number of false-positives.

Clinical and Laboratory Characteristics of Hyperprolactinemia in Children and Adolescents: National Survey

Objective: We aimed to report the characteristics at admission, diagnosis, treatment, and follow-up of cases of pediatric hyperprolactinemia in a large multicenter study. Methods: We reviewed the records of 233 hyperprolactinemic patients, under 18 years of age, who were followed by different centers. The patients were divided as having microadenomas, macroadenomas, drug-induced hyperprolactinemia and idiopathic hyperprolactinemia. Complaints of the patients, their mode of treatment (medication and/or surgery) and outcomes were evaluated in detail. Results: The mean age of the patients with hyperprolactinemia was 14.5 years, and 88.4% were females. In terms of etiology, microadenomas were observed in 32.6%, macroadenomas in 27%, idiopathic hyperprolactinemia in 22.7% and drug-induced hyperprolactinemia in 6.4%. Other causes of hyperprolactinemia were defined in 11.3%. Common complaints in females (n=206) were sorted into menstrual irregularities, headaches, galactorrhea, primary or secondary amenorrhea and weight gain, whereas headache, gynecomastia, short stature and blurred vision were common in males (n=27). Median prolactin levels were 93.15 ng/mL, 241.8 ng/mL, 74.5 ng/mL, 93.2 ng/mL, and 69 ng/mL for microadenomas, macroadenomas, idiopathic hyperprolactinemia, drug-induced hyperprolactinemia, and other causes of hyperprolactinemia, respectively. Of 172 patients with hyperprolactinemia, 77.3% were treated with cabergoline and 13.4% with bromocriptine. 20.1% of the patients with pituitary adenomas underwent pituitary surgery. Conclusion: We present the largest cohort of children and adolescents with hyperprolactinemia in the literature to date. Hyperprolactinemia is more common in females and cabergoline is highly effective and practical to use in adolescents, due to its biweekly dosing. Indications for surgery in pediatric cases need to be revised.

The Role of Umbilical Cord Blood Concentration of IGF-I, IGF-II, Leptin, Adiponectin, Ghrelin, Resistin, and Visfatin in Fetal Growth.

OBJECTIVE: Herein, we measured the concentration of insulinlike growth factor I (IGF-I), IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin in the umbilical cord blood of newborns categorized as "small for gestational age" (SGA), "appropriate for gestational age" (AGA), and "large for gestational age" (LGA). Our aim was to elucidate the link between the levels of these proteins and fetal growth. STUDY DESIGN: A total of 96 term infants were included and categorized into three weight categories. Their venous cord blood samples were collected to measure the levels of IGF-I, IGF-II, leptin, adiponectin, ghrelin, resistin, and visfatin. RESULTS: IGF-I, visfatin, and leptin levels showed significant differences among the groups. Pairwise comparisons showed that adiponectin (p = 0.023), resistin (p = 0.025), and ghrelin (p = 0.005) levels were significantly lower in the SGA group than in the LGA group. Correlation analyses showed a strong association of IGF-1, IGF-II, and leptin levels with birth weight (r = 0.644, p < 0.001; r = 0.441, p < 0.001; and r = 0.404, p < 0.001, respectively). CONCLUSION: SGA newborns showed a significantly higher visfatin concentration and lower ghrelin, leptin, resistin, and adiponectin levels than the AGA and LGA newborns did.

Effectiveness of Two Different Methods for Pain Reduction During Insulin Injection in Children With Type 1 Diabetes: Buzzy and ShotBlocker.

BACKGROUND: Repeated injections may prevent children from performing insulin administration (skip dosing) and may cause anxiety. AIMS: To compare the effect of ShotBlocker and the combination of vibration and cold application (Buzzy) in reducing pain during insulin administration in children. METHODS: This research was designed as a randomized controlled experimental study. The study sample consisted of 60 children aged between 6 and 12 years who were diagnosed as having type 1 diabetes and received insulin from the Child Endocrinology Department of the medical faculty in Eskisehir Osmangazi University between May 2015 and June 2017. The children were randomized into the Buzzy (n = 20), ShotBlocker (n = 20), and control (n = 20) groups. Three instruments were used to obtain the research data: Interview and Observation Form, Children's Anxiety and Pain Scale (CAPS), and Faces Pain Scale-Revised (FPS-R). RESULTS: The mean age of the children was 9.43 ± 2.18 years (range 6-12 years). There were no significant differences among preprocedural anxiety levels of the study groups in terms of self-, parent-, and observer-reported levels (p = .935, p = .374, and p = .680, respectively). Children in the control group had higher levels of pain than children in the Buzzy and ShotBlocker groups (p = .008, p = .007, and p > .001, respectively). There was a significant difference between the groups with procedural anxiety levels reported by the family and observer (p = .006 and p = .002, respectively), favoring the intervention groups. LINKING EVIDENCE TO ACTION: Nurses should be aware of pain during insulin injection and use methods for pain relief accordingly. ShotBlocker is recommended as a helpful option in cases where a pain control method is required.

SLC4A4 compound heterozygous mutations in exon-intron boundary regions presenting with severe proximal renal tubular acidosis and extrarenal symptoms coexisting with Turner's syndrome: a case report.

BACKGROUND: Congenital NBCe1A deficiency with the SLC4A4 mutation causes severe proximal renal tubular acidosis, which often comprises extrarenal symptoms, such as intellectual disability and developmental delay, glaucoma, cataract and band keratopathy. To date, almost all mutations have been found to be homozygous mutations located in exons. CASE PRESENTATION: We performed direct nucleotide sequencing analysis of exons and exon-intron boundary regions of the SLC4A4 in a patient presenting with severe renal proximal tubule acidosis, glaucoma and intellectual disability and her parents without these signs. The examination revealed compound heterozygous mutations in exon-intron boundary regions, c.1076 + 3A > C and c.1772 - 2A > T, neither of which have been reported previously. While the former mutation was found in the mother, the latter was found in the father. The transcript of the SLC4A4 gene was almost undetectable, and the patient was also diagnosed with Turner's syndrome. CONCLUSIONS: We identified two novel SLC4A4 mutations, c.1076 + 3A > C and c.1772 - 2A > T. When presented in a compound heterozygous state, these mutations caused a phenotype of severe renal proximal tubular acidosis along with glaucoma and mental retardation. This is the first report of congenital proximal renal tubular acidosis carrying compound heterozygous SLC4A4 mutations in exon-intron boundary regions. We suggest that an mRNA surveillance mechanism, nonsense-mediated RNA decay, following aberrant splicing was the reason that the SLC4A4 transcript was almost undetectable in the proband.

Severe consumptive hypothyroidism caused by multiple infantile hepatic haemangiomas.

Background Infantile hepatic haemangiomas (IHHs) produce an excess of the thyroid hormone inactivating enzyme type-3 iodothyronine deiodinase (D3), leading to rapid degradation of thyroid hormones and consumptive hypothyroidism. The L-thyroxine replacement dose in patients with consumptive hypothyroidism is inappropriately higher than that in congenital hypothyroidism. Case presentation A 4-month-old boy presented with abdominal distention. Thyroid function tests (TFTs) revealed an elevated thyroid-stimulating hormone (TSH) level of 177 mU/L, normal free thyroxine (fT4) of 1.23 ng/dL, low free tri-iodothyronine (fT3) of 1.55 pg/mL and increased reverse T3 (rT3) of 1240 ng/dL. Abdominal ultrasound and magnetic resonance imaging (MRI) revealed multiple IHHs. Based on his TFTs, ultrasonography and MRI evidence, he was diagnosed with consumptive hypothyroidism, and L-thyroxine replacement at 15 µg/kg/day was started. The L-thyroxine dose was increased gradually to 35 µ/kg/day until a stabilising euthyroid status was achieved. By the age of 8 months, the TSH concentration was decreased to normal levels; the L-thyroxine dose was gradually reduced and finally discontinued at the age of 12 months. Repeat abdominal ultrasound and MRI revealed a reduction in the number and size of the haemangiomas. The TFTs were at normal reference levels. The patient remains in active follow-up. Conclusions Neonatal screening for congenital hypothyroidism is usually negative in cases of IHH, as seen in our case. A high index of suspicion is necessary to diagnose hypothyroidism in cases of IHH. The present case required very high doses of levothyroxine to achieve a euthyroid status. In cases of hypothyroidism in the first year of life with consumptive hypothyroidism caused by hepatic haemangioma, aggressive L-thyroxine replacement is required with no upper limit. The dose should be increased gradually until a stabilising euthyroid status is achieved.

Response to growth hormone treatment in very young patients with growth hormone deficiencies and mini-puberty.

BACKGROUND: The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). METHODS: Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. RESULTS: The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p<0.001). These differences were not seen in the second year. Δ Length/height standard deviation score (SDS), Δ body weight SDS, length/height SDS, weight SDS in MPHD without hypogonadism for the first year of the GH treatment were found as significantly better than MPHD with hypogonadism. CONCLUSIONS: Early onsets of GH treatment, good weight gain in the first year of the treatment and good weight gain-GH dose in the second year of the treatment are the factors that have the greatest effect on length gain in early onset GHD. The presence of the sex steroid hormones during minipubertal period influence growth pattern positively under GH treatment (closer to the normal percentage according to age and gender).

The effects of short-term use of granulocyte colony-stimulating factor on bone metabolism in child cancer patients.

OBJECTIVE: The granulocyte colony-stimulating factor (G-CSF) is the most commonly used hematopoietic growth factor recombinant DNA technology. It affects bone metabolism by modulating both osteoclast and osteoblast functions. The aim of the present study was to investigate the effects of short-term use of G-CSF on bone metabolism in children with leukemia and solid tumors. METHODS: Thirty-six patients with a malignancy who received G-CSF therapy according to chemotherapy protocols and another 20 growth factor-free cancer patients who were enrolled as controls were included in the study. The serum osteocalcin and urinary free deoxypyridinoline levels were measured before the start of G-CSF therapy, on day 3 after treatment, and 7 days after G-CSF therapy was discontinued. In the control group, the measurements were made during corticosteroid and methotrexate-free chemotherapy. RESULTS: The mean osteocalcin level (8.6±2.3 ng/mL) from before the onset of treatment decreased significantly (7.7±2.3 ng/mL) on day 3 of G-CSF therapy and significantly increased after 7 days of G-CSF therapy (7.9±2.2 ng/mL) (p<0.001 and p<0.001, respectively), which was still significantly lower than the pre-G-CSF values (p<0.001). The urinary free deoxypyridinoline level significantly increased on day 3 of G-CSF treatment (25.6±6.5 nmol/mmol Cr) and significantly decreased after 7 days of G-CSF therapy (22.6±6.4 nmol/mmol Cr) (p<0.001 and p<0.001, respectively), which was still significantly higher than the values recorded before G-CSF therapy (p<0.001). CONCLUSION: The findings show that the short-term use of G-CSF in children with cancer can affect bone metabolism and can play a role in metabolic changes. Decreased osteoblastic activity and increased osteoclastic activity suggest that osteoporosis may be associated with bone pain in these patients.

Evaluation of Coagulation Profile in Children with Type 1 Diabetes Mellitus Using Rotational Thromboelastometry.

The prothrombotic state in type 1 diabetes mellitus (T1DM) has been reported as a plausible cause of vascular complications. Rotational thromboelastometry (ROTEM) assay enables the global assessment of coagulation status. This study aimed to assess hypercoagulability in children with T1DM using ROTEM. A total of 43 T1DM children (20 females and 23 males) aged 2-18 years and age- and sex-matched 30 healthy control subjects were enrolled in the study group. ROTEM assays [intrinsic TEM (INTEM) and extrinsic TEM (EXTEM)] were used to measure and analyze coagulation time (CT), clot formation time, maximum clot firmness (MCF). Glycated hemoglobin levels (HbA1c), diabetic complications, platelet count, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and dimerized plasmin fragment D (D-dimer) were determined in the study group. The mean duration of T1DM diagnosis was 3.15 ± 2.49 years, and the mean HbA1c level was 8.94 ± 1.88% (74.29 ± 20.59 mmol/mol). None of the patients had macrovascular complications. Nephropathy was present in five patients. In the T1DM group, EXTEM-CT [80.00 (66.75-108.50)] was significantly lower, and EXTEM-MCF [65.00 (64.00-70.00)] and INTEM-MCF [65.00 (62.00-68.00)] were significantly higher than in the controls (p < 0.001, p = 0.026, and p = 0.004, respectively). However, the duration of T1DM and the degree of metabolic control had no influence on these parameters. Platelet count, PT, aPTT, fibrinogen and D-dimer levels were comparable between the diabetic patients and the control group. There were statistically significant correlations between fibrinogen level and INTEM-MCF and EXTEM-MCF (p < 0.001, p = 0.002 and r = 0.545, r = 0.454, respectively) This study shows that decreased levels of CT and increased levels of MCF suggest hypercoagulability in patients with T1DM. Further studies are needed to confirm our findings on a larger number of diabetic patients.

WITHDRAWN: Bilateral painless testicular mass, acute uveitis and annular cutaneous lesions: an unusual presentation of sarcoidosis and literature review.

Ahead of Print article withdrawn by publisher.

Horner Syndrome Secondary to Thyroid Surgery.

Horner syndrome (HS), caused by an interruption in the oculosympathetic pathway, is characterised by myosis, ipsilateral blepharoptosis, enophthalmos, facial anhydrosis, and vascular dilation of the lateral part of the face. HS is a rare complication of thyroidectomy. A 15-year-old female patient presented with solitary solid and large nodule in the right thyroid lobe. Ultrasound-guided fine-needle aspiration was performed and the cytological examination results were undefined. The patient underwent a total thyroidectomy. On postoperative day 2, she developed right-sided myosis and upper eyelid ptosis. HS was diagnosed. Interestingly, the patient exhibited an incomplete clinical syndrome with the absence of vasomotor symptoms. We herein report a case of HS in a 15-year-old female patient after total thyroidectomy. The possible causes of HS were ischaemia-induced nerve damage and stretching of the cervical sympathetic chain by the retractor during thyroidectomy. Clinicians should be aware of the possibility of this rare but important surgical complication.

Two Frameshift Mutations in MKRN3 in Turkish Patients with Familial Central Precocious Puberty.

BACKGROUND: Little is known about the genetic causes responsible for idiopathic central precocious puberty (iCPP). More recently, described loss-of-function mutations in the makorin ring finger protein 3 (MKRN3) gene have been demonstrated to be involved in the pathogenesis of familial iCPP. AIM: The objective of this study was to investigate the potential role of MKRN3 in patients with familial iCPP. METHODS: We investigated potential sequence variations in the maternal imprinted MKRN3 gene using Next Generation Sequencing (NGS) analysis in 31 participants from 2 families (6 participants were diagnosed with familial iCPP on the basis of clinical and hormonal findings). Six patients diagnosed with familial iCPP and their unaffected first- and second-degree relatives, including their grandparents, were screened for MKRN3 gene variants. RESULTS: Two heterozygous frameshift mutations (c.441_441delG, p.H148Tfs*23 and c803_803delAT, p.M268Vfs*23) were described in the MKRN3 gene in 2 probands with familial iCPP and in some of their family members. These frameshift mutations create a premature stop codon and result in a truncated protein. CONCLUSIONS: Our report further expands the MKRN3 gene mutation spectrum in patients with familial iCPP. Screening for potential MKRN3 variants should be performed in patients with familial iCPP as well as in patients with sporadic iCPP.