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Objectives Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by isolated glucocorticoid deficiency. Melanocortin receptor 2 (MC2R) mediates the functions of adrenocorticotropic hormone (ACTH) in the adrenal cortex. MC2R accessory protein (MRAP) is a transmembrane protein involved in the trafficking of MC2R to the cell surface. Mutations in MC2R and MRAP genes cause FGD type 1 and 2. In the present case series, we evaluate the clinical characteristics and long-term follow-up of six cases with FGD due to mutations in MC2R and MRAP. Case presentation Data of six cases with FGD (five with mutations in MC2R and one with a mutation in MRAP) who were being followed at our paediatric endocrine centre was evaluated. Diagnosis of FGD was considered in case of elevated ACTH and inappropriately low cortisol level, and exclusion of other aetiologies. The main presenting complaints were hyperpigmentation and hypoglycaemic convulsion in all cases. During a follow-up period of 26–115 months, one patient with homozygous 560delT mutation in MC2R, one female with G226R mutation in MC2R and one female with IVS3ds+1delG mutation in MRAP had a neurodevelopmental delay (NDD), while the other three patients had normal neurodevelopment. Conclusions FGD patients due to MC2R and MRAP mutations with early diagnosis and compliance to the hydrocortisone therapy had normal neurodevelopment, while delay in diagnosis and poor compliance was associated with severe hypoglycaemic convulsions and subsequent complications NDD.

Objective Bi-allelic mutations in wolframin gene (WFS1) cause Wolfram syndrome 1 (WS1 or DIDMOAD) characterized with non-autoimmune diabetes mellitus (DM), optic atrophy (OA), diabetes insipidus (DI), sensorineural deafness (SND), urinary tract abnormalities, and neuropsychiatric disorders. We evaluated patients presented with an incomplete phenotype of WS1 using homozygosity mapping and subsequent whole-exome sequencing. Patients and methods Four unrelated consanguineous Turkish families (7 affected children), and their unaffected parents and siblings were evaluated. Homozygosity mapping (HZM) was performed, followed by whole-exome sequencing of WFS1. Mutations were classified according to results of "in silico" analyses, protein prediction, and functional consequences. Results Homozygosity mapping confirmed shared homozygous regions on chromosome 4 (chr4p16.1) between the affected individuals, and absent from their unaffected siblings. Exome sequencing identified three novel (c.1215T>A, c.554G>A, c.1525_1540dup) and one known (c. 1522_1523delTA) mutations in WFS1 gene. All mutations were predicted to cause stop codon leading to early termination of protein synthesis and complete loss-of-function. All patients were found to be homozygous for the change, with parents and other unaffected siblings being carriers. Conclusion Our study expands the mutation spectrum of WSF1 mutations with three novel mutations. Homozygosity mapping may provide enrichment for molecular genetic analysis and early diagnosis of WS1 patients with incomplete phenotype, particularly in consanguineous pedigrees.

Context Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. Objective To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. Setting Twelve tertiary pediatric endocrine referral centers. Patients Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. Main Outcome Measures Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. Results Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation. Conclusion We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Objective: The tendency to reduce thyroid stimulating hormone (TSH) referral cut-off values in congenital hypothyroidism (CH) neonatal screening programs has resulted in an increase in the incidence of CH, but also the referral of infants with mild transient elevation of TSH. Therefore, there is a need to develop markers for differentiation of transient elevated TSH and permanent CH as early as safely possible to avoid unnecessary treatment. The aim was to evaluate sixth-month L-thyroxine (LT4) dose as a predictive marker for differentiation of transient elevated TSH and permanent CH. Methods: Data of patients who had been followed after referral from the neonatal screening programme between the year 2010 and 2019 in a tertiary pediatric endocrine centre were examined retrospectively. Results: There were 226 cases referred, of whom 186 (82.3%) had eutopic thyroid gland, and 40 (17.7%) had dysgenetic gland. In patients with a dysgentic gland there was a non-significant tendency to have lower diagnostic free thyroxine concentration but significantly higher TSH compared with those with eutopic gland (p=0.44 and p=0.023, respectively). Patients with thyroid dysgenesis required higher initial and six month LT4 doses compared with those with eutopic glands (p=0.001). Receiver operator curve analysis showed the optimum cut-off value for LT4 at six months for transient vs. permanent CH was 2 μg/kg/day (sensitivity 77% and specificity 55%), regardless of etiology. Similarly, in patients with eutopic glands the optimum cut-off value for LT4 dose at six months for permanent vs. transient patients was 2 μg/kg/day (sensitivity 72% and specificity 54%). Conclusion: Results suggest that LT4 requirement at six months of therapy may be a good marker for predicting transient TSH elevation in patients with eutopic thyroid gland, thus facilitating the decision to halt LT4 therapy.

Objective The aim was to determine the final adult height (FAH) achieved by recombinant human growth hormone (rhGH) treatment, the factors affecting FAH and the success of attaining the genetic potential. Methods Data of 133 patients treated with rhGH therapy were reviewed retrospectively. Patients were grouped according to diagnosis, either isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD), and by sex, and pubertal status at the beginning of treatment. Results The mean age of initiation of treatment was 12.3±2.18 years, and the mean duration of rhGH treatment was 3.65±1.5 years. The mean height standard deviation score (SDS) at diagnosis was -3.11±0.75 SD. All patients received a standardized GH dose of 0.033 mg/kg/day. Mean FAH-SDS was -1.8±0.77 and delta height-SDS (the change in height SDS between the beginning and end of treatment) was 1.28±0.94 SD. FAH-SDS was -1.79±0.86 SD in males; -1.82±0.64 in females (p=0.857); -1.94±0.71 at the beginning of treatment in pubertal patients and -1.68±0.81 in prepubertal patients (p=0.056); -1.84±0.89 in patients with IGHD and -0.47±0.2 in patients with MPHD (p˃0.05). In multiple regression analysis, First year delta height-SDS was the most predictive factor for both FAH-SDS and delta height-SDS. Conclusion The majority of our patients achieved a final height compatible with their genetic potential as well as population standards when treated with rhGH even having started at a relatively late age. First year delta height-SDS was a predictive factor for FAH.

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, 17 alpha-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 chromatography-tandem 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 11 beta-OHD CAH. No case of salt-wasting CAH was missed by neonatal screening (sensitivity was 100 %). The incidence of classical 21-OHD and 11 beta-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 11 beta-OHD, using steroid profiling as a second-tier test. This will result in improved care of these patients in the future.

A novel heterozygous IVS11-2A>C(c.1957-2A>C) mutation in the GLI2 gene is reported. There was an extremely distinct phenotypical expression in two siblings and their father. The index case was a boy who developed cholestasis and hypoglycaemia in the neonatal period. He had bilateral postaxial polydactyly, mid-facial hypoplasia, high palatal arch, micropenis, and bilateral cryptorchidism. Laboratory examination revealed a diagnosis of multiple pituitary hormone deficiency. There was severe anterior pituitary hypoplasia, absent pituitary stalk and ectopic posterior pituitary on magnetic resonance imaging which suggested pituitary stalk interruption syndrome with no other midline structural abnormality. Molecular genetic analysis revealed a novel heterozygous splicing IVS11-2A>C(c.1957-2A>C) mutation detected in the GLI2 gene. His father and a six-year-old brother with the identical mutation also had unilateral postaxial polydactyly and mid-facial hypoplasia although there was no pituitary hormone deficiency. This novel heterozygous GLI2 mutation detected appears to present with an extremely variable clinical phenotype, even in related individuals with an identical mutation, suggesting incomplete penetrance of this GLI2 mutation.

Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes presenting within the first 6 months of life. INS gene promoter mutations have been shown to cause both remitting/relapsing and permanent NDM. We, herein, present three interesting patients with INS gene promoter mutations. Two cousins with an identical homozygous c.-331C > G mutation presented with NDM. The first cousin had nonremitting diabetes and still requires multidose insulin injections at the current age of 6.1 years. However, the other cousin's diabetes remitted at the age of 9 months, and she is still in remission at the age of 3 years with no medication or dietary intervention required (latest HbA1c was 4.9%). The third patient had NDM also due to a homozygous INS promoter c.-331C>A mutation. Her diabetes remitted at the age of 2 months and relapsed at the age of 2.6 years with severe diabetic ketoacidosis (DKA). Distinct clinical phenotype and relapse with severe DKA in one of the three cases suggest that INS promotor mutations can cause a heterogeneous phenotype and even cases exhibiting remission can relapse unpredictably. Therefore, as the age of relapse is unpredictable, close follow-up and family education on diabetes symptoms are essential for cases with remitting/relapsing diabetes due to INS gene mutations.

Backgrounds Limitations in the evaluation of the pituitary size and changes according to pubertal status make its validity questionable. Recently, in a small-scale study, pons ratio (PR) has been suggested as a more sensitive tool for diagnosis and etiological evaluation of growth hormone deficiency (GHD). The aim of the study is to evaluate the diagnostic value of PR in the diagnosis of GHD. Methods We retrospectively evaluated the pituitary magnetic resonance imaging (MRI) of 133 patients with a diagnosis of GHD. Primary axis (PA) was assigned as a line crossing the mid-sagittal dorsum sella and fourth ventricle. PR was defined as the pons height above the PA divided by total pons height. The PR of patients with GHD was compared to subjects without GHD. Results Study included 133 patients with GHD and 47 controls. In total, 121 (91%) patients had isolated GHD and 12 (9%) patients had multiple pituitary hormone deficiency. The PR of the patient group (mean: 0.32 ± 0.89; range: 0.14–0.63) was significantly higher than controls (mean: 0.26 ± 0.067; range 0.19–0.44) (p: 0.000). The optimal cut-off value of PR for GHD diagnosis was 0.27 (sensitivity 71% specificity 56%). There was a negative correlation between anterior pituitary height (APH)-SDS and PR (p: 0.002; r: −0.27). APH was increased, but PR remained unchanged in pubertal patients (p: 0.089). Conclusions PR measurement is a noninvasive, practical method with a cost-benefit clinical value. As it is not affected by pubertal status, PR is potentially a more sensitive tool for evaluation of pituitary gland in GHD patients compared to APH.

Background Aldosterone synthase deficiency (ASD) caused by mutations in the CYP11B2 gene is characterized by isolated mineralocorticoid deficiency. Data are scarce regarding clinical and biochemical outcomes of the disease in the follow-up. Objective Assessment of the growth and steroid profiles of patients with ASD at the time of diagnosis and after discontinuation of treatment. Design and method Children with clinical diagnosis of ASD were included in a multicenter study. Growth and treatment characteristics were recorded. Plasma adrenal steroids were measured using liquid chromatography-mass spectrometry. Genetic diagnosis was confirmed by CYP11B2 gene sequencing and in silico analyses. Results Sixteen patients from 12 families were included (8 females; median age at presentation: 3.1 months, range: 0.4 to 8.1). The most common symptom was poor weight gain (56.3%). Median age of onset of fludrocortisone treatment was 3.6 months (range: 0.9 to 8.3). Catch-up growth was achieved at median 2 months (range: 0.5 to 14.5) after treatment. Fludrocortisone could be stopped in 5 patients at a median age of 6.0 years (range: 2.2 to 7.6). Plasma steroid profiles revealed reduced aldosterone synthase activity both at diagnosis and after discontinuation of treatment compared to age-matched controls. We identified 6 novel (p.Y195H, c.1200 + 1G > A, p.F130L, p.E198del, c.1122-18G > A, p.I339_E343del) and 4 previously described CYP11B2 variants. The most common variant (40%) was p.T185I. Conclusions Fludrocortisone treatment is associated with a rapid catch-up growth and control of electrolyte imbalances in ASD. Decreased mineralocorticoid requirement over time can be explained by the development of physiological adaptation mechanisms rather than improved aldosterone synthase activity. As complete biochemical remission cannot be achieved, a long-term surveillance of these patients is required.

Objective To retrospectively evaluate the follow-up data in patients with 46,XX congenital adrenal hyperplasia (CAH) who were raised male. Methods A national database was created. The data of patients were asked to be recorded in the data form. Results The median (range) age of diagnosis was three (0.1-18.3) years in 44 patients. Twenty nine cases were diagnosed after the age of two years. Most (95.4%) cases were stage 4-5 virilized. Hysterectomy and bilateral salpingoopherectomy, at a median age of 7.25 (2.4-25.3) years, was performed in 35 cases. Testicular prostheses were placed in 11 (25%) cases at a median age of 11.2 (2.8-17) years. The median final height was 149.2 (132.8-172) cms in 38 patients, including simple virilizing (n=18), salt-wasting (n=6), and 11-beta hydroxylase (n=12). Of the 16 patients above the age of eighteen, university education was completed in 25%. Conclusion It was seen that most (65.9%) of the 46,XX CAH cases raised male were diagnosed after two years of age. In these cases, hysterectomy and bilateral salpingoopherectomy, genital corrective surgeries and testicular prosthesis operations were performed in a very wide age rage.

Several recent studies have reported that toxic metabolites accumulated in the body as a product of inborn errors of metabolism (IEM) are eliminated more rapidly with continuous venovenous hemodiafiltration (CVVHDF) than with peritoneal dialysis (PD). However, there is still uncertainty about the impacts of dialysis modalities on the short-term outcome. Here, it was aimed to investigate the effects of dialysis modalities on the short-term outcome. This retrospective study included 40 newborn infants who underwent PD (29 patients) or CVVHDF (11 patients) due to inborn errors of metabolism at a tertiary centre, between June 2013 and March 2018. The outcomes and the potential effects of the dialysis modality were evaluated. Of 40 patients, 21 were urea cycle defect, 14 were organic academia, and 5 were maple syrup urine disease. The median 50% reduction time of toxic metabolites were shorter in patients treated with CVVHDF (p 0.05). Catheter blockage was the most common complication observed in PD group (24.1%), whereas in CVVHDF group hypotension and filter blockage were more common. There was no significant difference in mortality between dialysis groups (38% vs. 45.4%, p 0.05). In patients with hyperammonaemia, duration of plasma ammonia 200 μg/dL was the most important factor influencing mortality (OR 1.05, CI 1.01-1.09, p = 0.007).Conclusion: This study showed that CVVHDF is more efficient than PD to rapidly eliminate toxic metabolites caused by IEM in newborn infants, but not in improving survival. What is Known: •Toxic metabolites are eliminated more rapidly with CVVHDF than with PD. •Higher complication rates were reported with rigid peritoneal catheters in PD and catheter blockage in CVVHDF. What is New: •Prolonged duration of plasma ammonia levels above a safe limit (200 μg/dL) was associated with increased mortality. •Lower catheter-related complication rates may have been associated with the use of Tenckhoff catheters in PD and the use of right internal jugular vein in CVVHDF.

It is well-known that in children with type 1 diabetes (T1D), the frequency of Celiac disease (CD) is increased due to mechanisms which are not fully elucidated but include autoimmune injury as well as shared genetic predisposition. Although histopathologic examination is the gold standard for diagnosis, avoiding unnecessary endoscopy is crucial. Therefore, for both clinicians and patients’ families, the diagnosis of CD remains challenging. In light of this, a joint working group, the Type 1 Diabetes and Celiac Disease Joint Working Group, was convened, with the aim of reporting institutional data and reviewing current international guidelines, in order to provide a framework for clinicians. Several controversial issues were discussed: For CD screening in children with T1D, regardless of age, it is recommended to measure tissue transglutaminase-immunoglobulin A (tTG-IgA) and/or endomysial-IgA antibody due to their high sensitivity and specificity. However, the decision-making process based on tTG-IgA titer in children with T1D is still debated, since tTG-IgA titers may fluctuate in children with T1D. Moreover, seronegativity may occur spontaneously. The authors’ own data showed that most of the cases who have biopsy-proven CD had tTG-IgA levels 7-10 times above the upper limit. The decision for endoscopy based solely on tTG-IgA levels should be avoided, except in cases where tTG-IgA levels are seven times and above the upper limit. A closer collaboration should be built between divisions of pediatric endocrinology and gastroenterology in terms of screening, diagnosis and follow-up of children with T1D and suspicious CD., NA

Background Given the rarity of 11β-hydroxylase deficiency (11βOHD), there is a paucity of data about the differences in clinical and biochemical characteristics of classic (C-11βOHD) and nonclassic 11βOHD (NC-11βOHD). Objective To characterize a multicenter pediatric cohort with 11βOHD. Method The clinical and biochemical characteristics were retrospectively retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Results 102 patients (C-11βOHD, n = 92; NC-11βOHD, n = 10) from 76 families (46,XX; n = 53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female adult height was 152 cm [−1.85 SD score (SDS)] and male 160.4 cm (−2.56 SDS).None of the NC-11βOHD girls had ambiguous genitalia (C-11βOHD 100%), and none of the NC-11βOHD patients were hypertensive (C-11βOHD 50%). Compared to NC-11βOHD, C-11βOHD patients were diagnosed earlier (1.33 vs 6.9 years; P 2.2, Conclusion NC-11βOHD can escape from clinical attention due to relatively mild clinical presentation. However, steroid profiles enable the diagnosis, differential diagnosis, and subtyping of 11βOHD.

Introduction: Diabetic ketoacidosis (DKA) is the most common cause of acute morbidity and mortality in children and adolescents with type 1 diabetes mellitus (T1DM). Because DKA management is associated with complications, endocrine communities have published guidelines and attempted to set standards for DKA diagnosis and management worldwide. In this study, for the patients followed up in the intensive care unit who have been treated according to DKA protocols, clinical and laboratory characteristics, differences between new and old diagnosed patients, and results of treatment were evaluated. Methods: The records of 67 patients hospitalized in the pediatric intensive care unit for the past two years were reviewed retrospectively. Patients were grouped as newly diagnosed and old diagnosed diabetics. Results: The mean age of the patients was 8.66 ± 5.0 years (3 months to 17.9 years) and 39 (58.2%) were male. Forty-five patients (67.1%) presented with mild DKA and 22 (33.9%) with severe DKA. Fourteen (63.6%) of the severe DKA cases were newly diagnosed with T1DM. Six patients had hyponatremia (corrected serum Na level 145 mmol/L). Only one of the hyponatremic patients had severe acidosis, while four of the hypernatremic patients had severe acidosis. At the 14th hour, blood glucose levels were below 200 mg/dl, blood ketones became negative in 5.8 hours, and at 9.1 hours, blood pH and/or HCO3 levels were normalized, recovery criteria were completed, and subcutaneous (SC) insulin injection was started. Of the patients, 38 (56.7) were newly diagnosed with T1DM. The mean age of newly diagnosed T1DM patients was smaller (7.40 ± 4.96) than those with old diagnosis, respiratory rates (RRs) were higher and pCO2 levels were lower on admission. Blood glucose, blood ketone negativity, acidosis, and Glasgow coma score (GCS) scores of the newly diagnosed T1DM patients improved later than the previous diagnoses. Only one patient under two years of age with a pH of 6.89 was given HCO3. None of the patients had symptomatic brain edema and death. Conclusions: As a result, DKA is an acute and serious complication of diabetes, whose results are promising when managed only with minimal individual changes according to guidelines. Bicarbonate administration is not needed except in patients with very severe acidosis. Bedside blood ketone monitoring seems to be important because it allows for early enteral feeding.

Objective: The prevalence of celiac disease (CD) varies between 1% and 10% in patients with type 1 diabetes mellitus (T1DM). This study aimed to determine the frequency of spontaneous recovery of celiac serology and the biopsy-proven CD (BPCD) frequency in patients with T1DM. Methods: The data of 668 patients with available celiac serology tests from a total of 779 patients who were followed for the last 10 years with the diagnosis of T1DM were retrospectively evaluated. Results: Positive serology was detected in 103 out of 668 (15.4%) patients. There was spontaneous normalization in 24 (23.3%), fluctuation in 11 (10.7%) and permanently positive serology in 68 (66%). In 46 out of 53 (86.8%) patients with positive serology and biopsy, CD diagnosis was confirmed by biopsy (BPCD). The frequency of BPCD was 6.9%, and the serology in 76.1% was positive at the time of diagnosis of T1DM. The weight, height and body mass index-standard deviation score at diagnosis were lower in patients with BPCD compared to the group without CD. An anti-tissue transglutaminase-IgA (anti-TTG-IgA) level of 11.8 times the upper limit of normal was the most sensitive (93%) and specific (90%) cut-off for BPCD (area under the curve: 0.95; 95% confidence interval: 0.912-1; p

Background: Given the rarity of 11β-hydroxylase deficiency (11βOHD), there is a paucity of the data about the differences in clinical and biochemical characteristics of classic (C-11βOHD) and non-classic 11βOHD (NC-11βOHD).Objective: To characterize a multicenter pediatric cohort with 11βOHD. Method: The clinical and biochemical characteristics were retrieved. CYP11B1 gene sequencing was performed. Seventeen plasma steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Results: 102 patients (C-11βOHD; n=92, NC-11βOHD; n=10) from 76 families (46,XX; n=53) had biallelic CYP11B1 mutations (novel 9 out of 30). Five 46,XX patients (10%) were raised as males. Nineteen patients (19%) had initially been misdiagnosed with 21-hydroxylase deficiency. Female final height was 152 cm (-1.85SDS) and male 160.4 cm (-2.56SDS). None of the NC-11βOHD girls had ambiguous genitalia (C-11βOHD 100%) and none of the NC-11βOHD patients were hypertensive (C-11βOHD 50%). Compared to NC-11βOHD, C-11βOHD patients were diagnosed earlier (1.33 vs. 6.9 years, p 2.2

Sirolimus has been reported to be effective in the treatment of the diffuse form of congenital hyperinsulinism (CHI), unresponsive to diazoxide and octreotide, without causing severe side effects. Two newborns with CHI due to homozygous ABCC8 gene mutations were started on sirolimus aged 21 and 17 days, due to lack of response to medical treatment. A good response to sirolimus was observed. At follow-up after ten and two months of treatment, liver enzymes were found to be increased [serum sirolimus level 1.4 ng/mL (normal range: 5-15), aspartate aminotransferase (AST): 298U/L, alanine aminotransferase (ALT): 302U/L and serum sirolimus level: 9.9 ng/mL, AST: 261U/L, ALT: 275U/L, respectively]. In Case 1, discontinuation of the drug resulted in normalization of liver enzymes within three days. Two days after normalization, sirolimus was restarted at a lower dose, which resulted in a repeated increase in transferases. In Case 2, a reduction of sirolimus dose caused normalization of liver enzymes within ten days. When the dose was increased, enzymes increased within three days. Sirolimus was discontinued in both cases. The rapid normalization of liver enzyme levels after sirolimus withdrawal or dose reduction; elevation of transaminases after restart or dose increase and rapid normalization after sirolimus withdrawal were findings strongly suggestive of sirolimus-induced hepatitis. To the best of our knowledge, this is the first report of sirolimus-induced hepatitis in CHI. Sirolimus is a promising drug for CHI patients who are unresponsive to medical treatment, but physicians should be vigilant for adverse effects on liver function.

Çalışmada 24 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. Objective: Hypophosphatemic rickets (HR) is a rare renal phosphate-wasting disorder, which is usually X-linked and is commonly caused by PHEX mutations. The treatment and follow-up of HR is challenging due to imperfect treatment options. Methods: Here we present nationwide initial and follow-up data on HR. Results: From 24 centers, 166 patients were included in the study. Genetic analysis (n = 75) showed PHEX mutation in 80% of patients. The mean follow-up period was 6.7 +/- 2.4 years. During the first 3-years of treatment (n = 91), mild increase in phosphate, decrease in alkaline phosphatase and elevation in parathyroid hormone (PTH) levels were detected. The height standard deviation scores were -2.38, -2.77, -2.72, -2.47 at initial, 1st, 2nd and 3rd year of treatment, respectively (p > 0.05). On follow-up 36% of the patients showed complete or significant improvement in leg deformities and these patients had similar phosphate levels at presentation with better levels in 1st and 2nd years of treatment; even the treatment doses of phosphate were similar. Furthermore, 27 patients developed nephrocalcinosis (NC), the patients showed no difference in biochemical differences at presentation and follow-up, but 3rd year Pill was higher. However, higher treatment doses of phosphate and calcitriol were Found in the NC group. Conclusion: HR treatment and follow-up is challenging and our results showed higher treatment doses were associated with NC without any change in serum phosphate levels, suggesting that giving higher doses led to increased phosphaturia, probably through stimulation of fibroblast growth factor 23. However, higher calcitriol doses could improve bone deformities. Safer and more efficacious therapies are needed.

Congenital adrenal hyperplasia (CAH) is an autosomal recessive genetic disorder due to presence of mutations in the genes involved in the metabolism of steroid hormones in adrenal gland. There are two main forms of CAH, classic form and non-classic form. While classic form stands for the severe form, the non-classic form stands for the moderate and more frequent form of CAH. The enzyme deficiencies such as 21-hydroxylase, 11-beta-hydroxylase, 3-beta-hydroxysteroid dehydrogenase, 17-alpha-hydroxylase deficiencies are associated with CAH. In this study, we aimed to investigate CYP21A2, CYP11B1, HSD3B2 genes which are associated with 21-hydroxylase, 11-beta-hydroxylase and 3-beta-hydroxysteroid dehydrogenase enzyme deficiencies, respectively, in 365 individuals by using Sanger sequencing method. We emphasized the classification of variants according their disease causing potential, and evaluated variants' frequencies including newly discovered novel variants. As a result, 32 variants of CYP21A2 including 10 novel variants, 9 variants of CYP11B1 including 3 novel variants and 6 variants of HSD3B2 including 4 novel variants were identified. The conclusions of our study showed that in Anatolia, discovery of novel variants is quite common on account of tremendous ratios of consanguineous marriages which increases the frequency of CAH. These results will contribute to the understanding of molecular pathology of the disease.

Background Despite implementation of a controlled diet, children with classical galactosemia (CG) may develop a variety of developmental and cognitive problems. In this study, we examined the early developmental status of, as well as the neurological and neuroradiological findings for, children with CG. Methods We retrospectively evaluated 46 galactosemia patients who were followed between 2003 and 2017. We included those who exhibited CG and p.gln188arg homozygous mutation without concomitant disease and who had undergone detailed neurological examination, brain magnetic resonance imaging (MRI), and Denver II developmental testing. Results The mean ages at the time of the most recent neurological examination and Denver II testing were 48.5 ± 28.5 months and 34.4 ± 18.2 months, respectively. Developmental delay was defined as developmental age ≥ 20% lower than chronological age. The results were normal in 25 patients and delayed ≥ 20% in least in one domain, primarily in language development, in 21 patients. Brain MRI was abnormal in 22 patients. Conclusions This analysis of the youngest children with the same genetic mutation reported thus far showed that, despite treatment, developmental delays and abnormalities on brain MRI may begin at an early age.

Objective Deficiency of sex steroids has a negative impact on bone mineral content. In studies conducted on postmenopausal women and animal studies, elevated follicle-stimulating hormone (FSH) levels were found to be correlated with a decrease in bone mineralization and osteoporosis. The aim of the present study was to evaluate bone mineral density (BMD) in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism and also to investigate the correlation between FSH level and BMD. Methods The study group included 33 adolescent girls with hypogonadism (14 with hypogonadotropic hypogonadism and 19 with hypergonadotropic hypogonadism). FSH, luteinizing hormone, estradiol levels, and BMD (using dual energy x-ray absorptiometry) were measured. Results There were no statistically significant differences between the chronological age and bone age of the two patient groups, namely, with hypogonadotropic and hypergonadotropic hypogonadism. There was also no significant difference between BMD z-score values obtained from measurements from the spine and the femur neck of patients in the two groups (p-values were 0.841 and 0.281, respectively). In the hypergonadotropic group, a moderately negative correlation was detected between FSH level and BMD z-score measured from the femur neck (ρ=-0.69, p=0.001), whilst no correlation was observed between FSH levels and height adjusted BMD-z scores measured from the spine (ρ=0.17, p=0.493). FSH level was not found to be an independent variable affecting BMD z-score. Conclusion BMD z-scores were detected to be similar in adolescent girls with hypogonadotropic and hypergonadotropic hypogonadism, and FSH levels were not found to have a clinically relevant impact on BMD.

PubMedID: 29353264 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). Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. 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

Baran RT, Sürer-Adanır A, Karakurt MN, Dündar M, Aydın M, Özbek MN, Demirbilek H. Evaluation of psychological characteristics of Turkish children with type 1 diabetes mellitus from two demographically and geographically distinct regions. Turk J Pediatr 2018; 60: 554-561. Type 1 diabetes mellitus (T1DM), patients have an increased risk of psychiatric morbidity compared to their healthy counterparts. The aim of the present study is to evaluate the demographic and laboratory data and psychological characteristics of children with T1DM from two geographical regions of Turkey. The study included 98 pediatric T1DM patients followed in pediatric endocrinology clinics from Diyarbakir (n=50), an eastern city and Antalya (n=48) a western city, and 43 healthy subjects from Diyarbakir (n=20) and Antalya (n=23). The sociodemographic data, duration of diabetes and the glycated hemoglobin levels (HbA1c) were also noted. For the evaluation of emotional and behavioral problems in children, Turkish version of The Child Behavior Checklist (CBCL) 6-18, and for depression, Child depression inventory (CDI) was used. Patients from the Diyarbakır Diabetes Mellitus (DDM) group had a longer duration of diabetes compared to those of the Antalya Diabetes Mellitus (ADM) group, while HbA1c levels were not statistically different. Children with T1DM from Diyarbakır reported higher problem scores in CBCL in majority of domains and both internalizing and externalizing subscores compared to the controls and in all domains compared to the patients from Antalya. The CDI scores of the DDM group were also significantly higher than those of the ADM group. In conclusion, diabetic children from Diyarbakır had more problems in emotional, social and behavioral domains compared to the healthy peers and patients from Antalya, indicating that T1DM brought more psychosocial burden to these patients independently from the metabolic control. Pediatric specialists working in the eastern region should be more precautious with diabetic patients in terms of comorbid psychiatric conditions and psychiatric referral when needed.

Prepubertal unilateral gynecomastia is an extremely rare condition. At present, its etiology and management strategy are not well known. Two unrelated prepubertal boys of ages 8 and 9 who presented with complaints of unilateral enlargement of breast tissue are reported. Physical examination, biochemical, hormonal and oncologic work-up findings were normal. Both patients were treated with peripheral liposuction successfully. Histopathological and immunohistochemical examinations showed benign fibroglandular gynecomastia and intensive (3+) estrogen receptor expression in 100\% of periductal epithelial cells. Although an extremely rare and generally benign condition, patients with prepubertal unilateral gynecomastia should have a full endocrine and oncologic work-up.

A number of factors may lead to inaccuracy in measurement of capillary blood glucose with a glucometer. Measurement of other carbohydrate molecules such as galactose and fructose along with glucose can potentially be a cause of error. We report a newborn patient who was referred to our hospital with conjugated bilirubinemia, hepatomegaly and high capillary blood glucose levels measured with a glucometer. Simultaneous biochemical measurements revealed normal blood glucose levels. Further investigation led to a diagnosis of classical galactosemia. Capillary blood glucose level measured with glucometer also dropped to normal values following cessation of breastfeeding and initiation of feeding with a lactose-free formula.

WOS: 000380224800019, PubMed ID: 27144933, Context: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. Objective: We aimed to study natural history and disease burden of various subtypes of CGL. Design: We attempted to ascertain nearly all patients with CGL in Turkey. Setting: This was a nationwide study. Patients or Other Participants: Participants included 33 patients (22 families) with CGL and 30 healthy controls. Main Outcome Measure(s): We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. Results: Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316 + 1G > T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C > T, c. 631delG, c. 62A > T, and c. 465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c. 259C > T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. Conclusions: CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

ABALI, SAYGIN/0000-0001-6552-2801; Gurbuz, Fatih/0000-0003-2160-9838; Hatun, Sukru/0000-0003-1633-9570; Abaci, Ayhan/0000-0002-1812-0321; Turan, Serap/0000-0002-5172-5402; Buyukinan, Muammer/0000-0002-2937-823X; yuksel, bilgin/0000-0003-4378-3255; Ozgen, Ilker Tolga/0000-0001-6592-9652; binay, cigdem/0000-0002-7749-8818; ozkan, Behzat/0000-0002-9153-8409; Demir, Korcan/0000-0002-8334-2422; Eren, Erdal/0000-0002-1684-1053 WOS: 000373099300016 PubMed: 26788866 To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P

Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.). Copyright © 2012 Massachusetts Medical Society.

The aim of this study was to elucidate the role of adiponectin, leptin, TNF-α and IL-6 on the early detection of the microvascular complications of type I diabetes.A total of 88 children were included in the study. There were 60 type I diabetic patients and 28 healthy control children.The gender, age, weight, height, BMI and puberty status characteristics were similar in the patient and control groups (p0.05). The serum leptin, TNF-α and IL-6 levels were similar between the patient and control groups (p0.05) and the only difference was in the serum adiponectin level which was higher in the patient group (p:0.042). We also found no association between the adiponectin, leptin, TNF-α and IL-6 levels and diabetes duration (p0.05). Leptin was high in the pubertal period (p:0.016), while adiponectin TNF-α and IL-6 levels were similar in the prepubertal and pubertal periods (p0.05). The serum leptin level was high in microalbuminuria patients (p0.041). The serum adiponectin, TNF-α, and IL-6 levels were not different in patients with and without microalbuminuria (p0.05). The serum adiponectin level was lower in diabetic retinopathy patients (p:0.003), while the serum leptin level was higher (p:0.003). The TNF-α and IL-6 levels were similar in patients with and without retinopathy (p0.05).We found increased serum adinopectin levels in children and adolescents with type I diabetes mellitus and low levels in diabetic retinopathy patients. Patients with low serum adiponectin levels and high leptin levels should be more closely monitored for chronic complication development and better metabolic control should be aimed for.Bu çalışmada tip I diyabetin mikrovasküler komplikasyonlarının erken saptanması ve bu komplikasyonların erken tanınmasında adiponektin, leptin, TNF-α ve IL-6’nın rolünün ortaya çıkarılması amaçlanmıştır.Çalışmaya toplam 88 çocuk alınmıştır. Bunların 60’ı tip I diyabet’li hasta, 28’i sağlıklı kontrol çocuktan oluşmaktaydı.Hasta ile kontrol grubu arasında cinsiyet, yaş, ağırlık, boy, VKİ, puberte durumları benzerdi (p0.05). Hasta ile kontrol grubu arasında sadece serum adiponektin düzeyinin hasta grubunda daha yüksek olduğu saptanırken (p:0.042), hasta ile kontrol grubu arasında serum leptin, TNF-α ve IL-6 düzeyleri benzerdi (p0.05). Diyabet süreleri ile adiponektin, leptin, TNF-α ve IL-6 düzeyleri arasında da bir ilişki saptanmadı (P0.05). Puberte döneminde leptin yüksekliği saptanırken (p:0.016), adiponektin, TNF-α ve IL-6 düzeyleri prepubertal ve pubertal dönemde benzerdi (p0.05). Mikroalbuminürili hastalarda serum leptin yüksekliği saptanırken (p0.041), serum adiponektin, TNF-α ve IL-6 düzeyleri mikroalbuminüri olan ve olmayan hastalarda benzerdi (p0.05). Diyabetik retinopatili hastalarda serum adiponektin düzeyi daha düşük (P:0.003), serum leptin düzeyi daha yüksek saptandı (p:0.003). TNF-α ve IL-6 düzeyleri retinopati olan ve olmayan hastalarda benzerdi (p0.05).Tip 1 diyabetli çocuk ve adolesanlarda serum adinopektin düzeyini artmış olarak bulurken diyabetik retinopatili hastalarda ise bu düzeyi düşük bulduk. Serum adiponektin düşüklüğü ve leptin yüksekliği olan hastalar kronik komplikasyonların gelişimi açısından daha yakın takip edilmeli ve daha iyi bir metabolik kontrol sağlanmaya çalışılmalıdır.

Context: The steroidogenic acute regulatory protein (StAR) has been shown to be essential for steroidogenesis by mediating cholesterol transfer into mitochondria. Inactivating StAR mutations cause the typical clinical picture of congenital lipoid adrenal hyperplasia.Objective: The objective of the investigation was to study the functional and structural consequences of three novel StAR mutations (p.N148K in an Italian patient; p.P129fs and p.Q128R in a Turkish patient).Methods and Results: Transient in vitro expression of the mutant proteins together with P450 side-chain cleavage enzyme, adrenodoxin, and adrenodoxin reductase yielded severely diminished cholesterol conversion of the p.N148K mutant, the combined p.P129fs and p.Q128R mutant, and the p.P129fs mutant by itself. The p.Q128R mutant led to a higher cholesterol conversion than the wild-type StAR protein. As derived from three-dimensional protein modeling, the residue N148 is lining the ligand cavity of StAR. A positively charged lysine residue at position 148 disturbs the hydrophobic cluster formed by the α4-helix and the sterol binding pocket. The frame shift mutation p.P129fs truncates the StAR protein. Residue p.Q128 is situated at the surface of the molecule and is not part of any functionally characterized region of the protein.Conclusion: The mutations p.N148K and p.P129fs cause adrenal insufficiency in both cases and lead to a disorder of sex development with complete sex reversal in the 46, XY case. The mutation p.Q128R, which is not relevant for the patient’s phenotype, is the first reported variant showing a gain of function. We speculate that the substitution of hydrophilic glutamine with basic arginine at the surface of the molecule may accelerate cholesterol transfer.

WOS: 000360842500004, PubMed: 26831551, Objective: Children with Turner syndrome (TS) have a specific growth pattern that is quite different from that of healthy children. Many countries have population-specific growth charts for TS. Considering national and ethnic differences, we undertook this multicenter collaborative study to construct growth charts and reference values for height, weight and body mass index (BMI) from 3 years of age to adulthood for spontaneous growth of Turkish girls with TS. Methods: Cross-sectional height and weight data of 842 patients with TS, younger than 18 years of age and before starting any therapy, were evaluated. Results: The data were processed to calculate the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentile values for defined ages and to construct growth curves for height-for-age, weight-for-age and BMI-for-age of girls with TS. The growth pattern of TS girls in this series resembled the growth pattern of TS girls in other reports, but there were differences in height between our series and the others. Conclusion: This study provides disease-specific growth charts for Turkish girls with TS. These disease-specific national growth charts will serve to improve the evaluation of growth and its management with growth-promoting therapeutic agents in TS patients., Turkish Pediatric Endocrinology and Diabetes Society [012013], This work was supported by the Turkish Pediatric Endocrinology and Diabetes Society (Grand number: 012013).

Background and Aims: Vitamin D-dependent rickets type I (VDDR1) is an autosomal recessive disorder caused by mutations in the 25-hydroxyvitamin D 1-alpha-hydroxylase gene (CYP27B1). Mutations in CYP27B1 disrupt or lead to a total loss of the 1-α-hydroxylase activity and require treatment with physiological doses of calcitriol. Patients and Methods: A genetic analysis of the CYP27B1 gene was conducted in 22 Turkish patients with VDDR1 from 13 families. Presenting characteristics, biochemical features, treatment, and results from the genetic analysis are described. Results: A splice donor site mutation c.195 + 2T>G was found in 10 patients. The novel missense p.192K>E (c.574A>G) mutation was detected in 5 patients, and a novel missense p.197G>D (c.590G>A) mutation was found in 4 patients. A previously reported 7-bp duplication 1319-1325dupCCCACCC (Phe443Profs*24) in exon 8 was detected in 1 patient, and 1 patient was a compound heterozygote for the novel p.192K>E and the previously described 1319-1325dupCCCACCC mutations. A novel single base pair deletion, c.171_171delG, leading to a frameshift, was found in 1 patient. Conclusions: We identified 3 novel and 2 previously described mutations in the CYP27B1 gene. A marked phenotypical diversity was observed between families that carried identical mutations, suggesting phenotypical heterogeneity.

WOS: 000351307200006, PubMed ID: 25800474, Objective: Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. Methods: A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers. Results: Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin-releasing analogues) to increase final height. Conclusion: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies.

WOS: 000351307200005, PubMed ID: 25800473, Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45, X (50.7%), followed by 45, X/46, XX (10.8%), 46, X, i(Xq) (10.1%) and 45, X/46, X, i(Xq) (9.5%). Mean age at diagnosis was 10.2 +/- 4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45, X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto's thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.

PubMedID: 25500790 To investigate the specific mutations in PROP1, POU1F1, LHX3, and HESX1 genes in patients with combined pituitary hormone deficiency (CPHD) in Turkey. Seventy-six patients with CPHD were included in this study. Based on clinical, hormonal, and neuro-radiological data, relevant transcription factor genes were evaluated by Sanger sequencing and multiplex ligation-dependent probe amplification. Total frequency of mutations was 30.9 % in patients with CPHD. Frequency was significantly higher in familial patients (p = 0.001). Three different types of mutations in PROP1 gene (complete gene deletion, c.301-302delAG, a novel mutation; IVS1+2T>G) were found in 12 unrelated patients (21.8 %). Mutations in PROP1 gene were markedly higher in familial than in sporadic cases (58.8 vs. 5.3 %, p

Biotinidase deficiency is an autosomal recessive inborn error of biotin metabolism. Children with biotinidase deficiency cannot cleave biocytin and, therefore, cannot recycle biotin. Untreated individuals become secondarily biotin deficient, which in turn results in decreased activities of the biotin-dependent carboxylases and the subsequent accumulation of toxic metabolites causing clinical symptoms. Biotinidase deficiency is characterized by neurological, cutaneous manifestations and metabolic abnormalities. The worldwide incidence of profound biotinidase deficiency has been estimated at 1:112,271. The human biotinidase gene is located on chromosome 3p25 and consists of four exons with a total length of 1629 base pairs. To date, more than 100 mutations in the biotinidase gene known to cause biotinidase deficiency have been reported. The vast majority of mutations are homozygous or compound heterozygous. Finding known mutations can be correlated with the biochemical enzymatic results. This report summarizes the demographic features of patients identified as biotinidase deficient from August of 2012 through August of 2013 and mutation analysis results for 20 cases in the southeast region of Turkey.

We aimed to investigate the presence of psychomotor retardation, physical and laboratory examination in infants with megaloblastic anemia. Inclusion criteria for the study were; age 9 to 36 months, refusal of food except for breast and cow milk, loss of appetite, developmental delay, significant pallor, and hypersegmentation neutrophils in the peripheral blood smear. A total of 33 children fulfilling the inclusion criteria were enrolled among 3368 patients attending Pediatric Outpatient Clinics of şirnak-Cizre State Hospital between January 25, 2004 and May 5, 2004. Mean age was 16.4 months. Thirty-two patients had Vitamin B12 deficiency, 1 patient had folate deficiency, and 10 patients had combined vitamin B12 and folate deficiency. Statistically, a positive significant relationship was detected between serum vitamin B12 levels and mean corpuscular volume (P = 0.001, r = 0.56), and between vitamin B12 levels and hemoglobin (P = 0.004, r = 0.49). We believe that preventative measures such as fortification of flour with vitamin B12, nutritional support with vitamin B12 for the mother during pregnancy and nursing, provision of adequate primary preventive health services, and starting complementary food after 6 months of age are important determinants for preventing megaloblastic anemia.

Gunshot injuries (GSI) of the cranial area have an extremely high mortality rate. Herein, we present a girl who has been living with a bullet in the posterior sellar region. A 6-year-old girl was admitted with complaints of headache, polyuria and polydypsia, which started after a GSI. At the time of admission the patient’s anthropometric, physical and neurological examinations were normal. Urine output was 5.5 L/m2/24h. A water deprivation test suggested central diabetes insipidus, which responded to treatment. Evaluation of other pituitary hormones revealed central hypothyroidism and growth hormone deficiency. Pituitary hormone deficiency must be kept in mind in patients injured by a gunshot to the sellar/parasellar region. Conflict of interest:None declared.

Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid.

Multiple sulfatase deficiency is biochemically characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The gene sulfatase-modifying factor 1 (SUMF1), recently identified, encodes the enzyme responsible for post-translational modification of a cysteine residue, which is essential for the activity of sulfatases. We describe clinical findings and mutation analysis of four patients. The patients presented with hypotonia, developmental delay, coarse face, ichthyosis, and hepatosplenomegaly. The diagnosis was made through clinical findings, enzymatic assays, and mutation analysis. We were detected to be homozygous for a novel missense mutation c. 739G > C causing a p.G247R amino acid substitution in the SUMF1 protein.

Mutations in the growth hormone releasing hormone receptor (GHRHR) gene are a relatively rare cause of isolated growth hormone deficiency (IGHD).This study aimed to understand the biochemical basis of hypoglycemia in the index case and the molecular basis of severe short stature in a large consanguineous family with IGHD.The index case presented with a hypoglycemic convulsion, following which eight members in two related consanguineous Turkish families were identified with IGHD. Homozygosity mapping identified the homozygous regions shared only among the affected individuals. Sanger sequencing of GHRHR, which resided in the shared homozygous region, was performed. In silico analysis of the pathogenic GHRHR variant was performed.The clinical presentation and hormonal analysis confirmed GH deficiency in all affected individuals. Magnetic resonance imaging scan of the pituitary gland showed anterior pituitary hypoplasia in five affected individuals in which the youngest was only 0.4 years old, but with normal pituitary size in three affected individuals. Homozygosity mapping showed two large homozygous regions on chromosome 7 shared only among affected individuals. Sanger sequencing of GHRHR gene present in one of these shared regions identified a novel homozygous missense mutation (p.C64G) segregating with the disease phenotype. In silico analysis predicted the mutation to be deleterious and disease causing.We describe a large consanguineous Turkish kindred with IGHD due to a novel homozygous missense GHRHR mutation. This is the first description of presentation with hypoglycemia and the earliest reported occurrence of anterior pituitary hypoplasia in patients with GHRHR mutation.

Infantile Pompe disease (glycogen storage disease type II) is a fatal disease that results from α glycosidase enzyme deficiency. Excessive undegradable intracellular glycogen deposition plays a role in the pathogenesis of the disease. Although excessive glycogen deposition involves many cells, clinical signs are limited mainly to the skeletal and cardiac muscle involvement. Therefore, it is a progressive disease that can cause death in early childhood due to extensive cardiomyopathy and weakness of respiratory muscles. We as well, aimed to present three cases, which had short P-R interval, large QRS complex and the signs of biventricular hypertrophy on ECG and prominent hypertrophic cardiomyopathy on transthoracic echocardiography in addition to respiratory muscle involvement., İnfantil Pompe hastalığı (glikojen depo hastalığı tip 2) alfa-glukozidaz eksikliğinin sebep olduğu ölümcül bir hastalıktır. Hastalığın patogenezinde hücreler içinde yıkılamayan aşırı glikojen birikimi rol oynar. Glikojenin aşırı birikim birçok hücrede olmasına rağmen klinik bulgular başlıca iskelet ve kalp kası tutulumuna sınırlıdır. Bu nedenle yaygın miyopati, kardiyomiyopati ve solunum kaslarının güçsüzlüğü nedeniyle erken süt çocukluğu döneminde ölüme yol açabilen ilerleyici bir hastalıktır. Biz de, solunum kasları tutulumu ile birlikte, EKG'de kısa PR aralığı, uzun QRS, biventriküler hipertrofi bulguları ve ekokardiyografide belirgin hipertrofik kardiyomiyopatisi olan üç olguyu sunmayı amaçladık.