Esra Döğer

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Vitamin D status in children with Hashimoto thyroiditis.

Abstract Objective: To investigate vitamin D status in children with Hashimoto thyroiditis. Subjects and methods: The study group consisted of 78 children recently diagnosed as Hashimoto thyroiditis and 74 subjects as the control group. Parameters of calcium metabolism, thyroid function tests, and 25-hydroxyvitamin D [25(OH)D] levels were measured. Results: Vitamin D deficiency rate was significantly higher in the Hashimoto group compared with the control subjects (73.1% vs. 17.6%, p<0.0001). In the Hashimoto group, mean 25(OH)D levels were significantly lower compared with the control group (31.2±11.5 vs. 57.9±19.7 nmol/L, p<0.001) and was inversely correlated with the anti-thyroid peroxidase (anti-TPO) levels (r=–0.30, p=0.007). Conclusion: The higher vitamin D deficiency rates besides lower vitamin D levels in the Hashimoto group together with the inverse correlation between vitamin D and anti-TPO suggest that vitamin D deficiency may have a role in the autoimmune process in Hashimoto thyroiditis in children.

Octreotide-Induced Long QT Syndrome in a Child with Congenital Hyperinsulinemia and a Novel Missense Mutation (p.Met115Val) in the ABCC8 Gene

Background/Aims: Congenital hyperinsulinism (CHI) denotes an inappropriate secretion of insulin from pancreatic β-cells in the presence of a low blood glucose level due to various genetic causes. Diazoxide is the first-line medical treatment for CHI. In case of failure, a somatostatin analogue called octreotide is used. A prolonged QT interval is an unusual side effect of octreotide which can be lethal if unrecognized. Case Presentation: We report on a 35-day-old infant who was diagnosed with CHI on the 3rd day of his life and underwent pancreatectomy due to failure of medical treatment at 8 months. His genetic analysis revealed a compound heterozygosity for a novel missense mutation (p.Met115Val) and a nonsense mutation (p.Trp1339X) in the ABCC8 gene. Furthermore, at the 6th month of follow-up, a long QT (0.49 s) was determined by ECG examination, which was normalized following discontinuation of octreotide treatment after pancreatectomy. Thus, the long QT was considered to be secondary to octreotide medication. Conclusion: We recommend ECG monitoring before and during octreotide treatment in order to recognize a prolonged QT interval and to prevent related complications in cases with congenital hyperinsulinemia.

PREVALENCE OF ZnT8 ANTIBODY IN TURKISH CHILDREN AND ADOLESCENTS WITH NEW ONSET TYPE 1 DIABETES

Objective: Zinc transporter 8 protein (ZnT8A) is a transmembrane protein which functions to transfer zinc to insulin vesicles. Antibodies formed against ZnT8A (ZnT8A) are regarded as an independent autoimmunity demonstrator in type 1 diabetes (T1D). The aim of this study was to investigate the prevalence of ZnT8A in Turkish children with new onset T1D. Method: Eighty four patients between 1-18 years of age diagnosed with T1D between February 2015-March 2016 and the control group consisting of 50 healthy children without any autoimmune diseases were included in the study. Serum samples for ZnT8A testing were taken from the patient group within a week of diagnosis. A ZnT8A enzyme-linked immunosorbent assay was used in the analyses. Results: ZnT8A positivity was detected in 58% of the patients with new onset T1D and 8% of the control group. ZnT8A were demonstrated in 5 of 11 patients with negative results for classical diabetes antibodies [insulinoma antigen-2 antibody (IA-2A), glutamic acid decarboxylase (GAD) or insulin autoantibodies]. No association was found between ZnT8A positivity and age, gender, presence or degree of ketoacidosis at presentation, hemoglobin A1c, insulin or C-peptide concentration, or the presence of either thyroid or celiac antibodies. Conclusion: ZnT8A prevalence in children with T1D in Turkey was compatible with the literature. The ratio of patients who are clinically considered to have T1D but have negative routine diabetes auto-antibodies were observed to decrease nearly by 50% when ZnT8 antibodies were added to the panel. ZnT8 measurement should be more widespread for clarifying the etiology in T1D.

Endoglin and obestatin levels, cardiometabolic risk factors and subclinical atherosclerosis in children aged 10–18 years

Abstract Background: The aim of this study was to investigate the early signs of atherosclerosis and to evaluate serum endoglin and obestatin levels as predictors of subclinical atherosclerosis in obese children. Methods: A total of 95 children (60 obese and 35 controls) aged 10–18 years were included in the study. Their endoglin and obestatin levels and biochemical parameters were measured. The carotid intima media thickness (cIMT) and brachial artery flow-mediated dilatation (FMD) responses were evaluated. Results: The cIMT values were higher (p < 0.001) and FMD responses were lower (p = 0.003) in the obese group than in the control group. A logistic regression multivariate analysis revealed that cIMT was independently associated with the body mass index (BMI) Z-score (β = 0.323, p = 0.003) and low density lipoprotein (LDL) (β = 0.29, p = 0.008), while FMD % was independently associated with waist circumference (β = −0.36, p = 0.002). The obese and control groups were similar in endoglin (p = 0.67) and obestatin levels (p = 0.70). The endoglin level was inversely correlated with the cholesterol and LDL levels (r = −0.23, p = 0.032; rho = −0.25, p = 0.019). Conclusions: The cIMT and brachial artery FMD response in obese children are significantly different compared to healthy controls. Circulating endoglin and obestatin levels are not predictive markers for subclinical atherosclerosis in obese children aged 10–18 years old.

Gonadoblastoma with Dysgerminoma in a Phenotypically Turner-Like Girl with 45,X/46,XY Karyotype.

Individuals with 45,X/46,XY karyotype are at increased risk for germ cell tumor development. We report a case with a diagnosis of 45,X/46,XY gonadal dysgenesis who presented with short stature, physical stigmata of Turner syndrome. Her pubertal development was at Tanner stage 3. At follow-up, bilateral prophylactic gonadectomy was performed when considering the risk factors. Pathological assessment was consistent with gonadoblastoma in the left gonad, and dysgerminoma and gonadoblastoma in neighboring areas in the right gonad. The karyotype analysis of the right and left gonadal tissues reveled 45,X[97,3]/46,XY[2,7] and 45,X[92,7]/46,XY[4,5]/47,XYY [2,8] mosaic, respectively. The clinical management of such patient should be individualized according to the present risk factors. Additionally, signs of estrogenization like advanced breast development always suggest the possible presence of germ cell tumor.

The relationship between diet quality and insulin resistance in obese children: adaptation of the Healthy Lifestyle-Diet Index in Turkey

Abstract Background: Childhood obesity and its complications are serious health problems and diet/lifestyle changes can be beneficial for the prevention of diseases. Adaptation of the Healthy Lifestyle-Diet (HLD) Index in accordance with the dietary guidelines for Turkey (TR) and determination of the relationship between metabolic syndrome risk factors in obese children were the aims of this study. Methods: This study was conducted on 164 overweight or obese children (87 male, 77 female) aged 9–13 years. For all participants, the HLD-TR Index and a 24-h dietary recall were performed and the mean adequacy ratio (MAR) was calculated. Anthropometric measurements and the body composition of the children were taken. Metabolic syndrome risk factors and insulin resistance were assessed. Results: The mean age of the male and female children was 11.2±1.49 and 11.0±1.40 years, respectively. The majority of the children were obese in both genders. There were no statistically significant differences in the HLD-TR scores between the genders. As the index scores increased, a decrease in the energy intake and an increase in the MAR were observed. Negative correlations between the index scores and body mass, waist circumference and body fat mass were observed. Furthermore, a one-unit increase in the index score decreases the insulin resistance risk by 0.91 times after adjustments for age and gender (odds ratio: 0.91 [0.85–0.97]). Conclusions: The HLD-TR Index is a valid tool that can give an idea about the quality of the diet in obese children. Furthermore, with the increase in the compliance with recommendations for diet/lifestyle changes, indicators of obesity and metabolic syndrome were decreased.

Autoimmune Limbic Encephalitis Associated with Type 1 Diabetes Mellitus

A 16-year-old boy was admitted to our emergency department with confusion and headache. Electroencephalography revealed temporal slowing, cerebral magnetic resonance imaging demonstrated hyperintense signal of the right mesiotemporal lobe, and positron emission tomography demonstrated increased activity in the right temporal lobe. Blood glutamic acid decarboxylase antibody (anti-GAD) level was 2114 IU/mL (0–10) and the cerebrospinal fluid anti-GAD level was 4.07 nmol/L (<0.02). These findings led to a consideration of autoimmune LE as a possible diagnosis. Pulse methylprednisolone was administered over five days. After steroid treatment, symptoms improved, but hyperglycemia occurred on the third day of treatment. Glycemia level reached 502 mg/dL. Concurrent insulin level was 42 μIU/mL. Hyperglycemia improved after cessation of steroid treatment. Glycated hemoglobin was 5.6%. The possibility of a steroid-induced hyperglycemia was considered. Six months later, the patient was readmitted with dyspnea and abdominal pain. The family reported occurrence of polyuria and polydipsia during the previous two months. Blood anti-GAD level was >2000 IU/mL. The patient was diagnosed to have T1D. With treatment, the ketoacidosis improved in 10 h. After being educated for diabetes, the patient was discharged. Two months later, he presented with a headache and confusion again. Intravenous immunoglobulin (IVIG) 1 g/kg/d for two days every month was administered. Neurological symptoms improved and the daily insulin dose was decreased.

Soluble Endoglin Level Increase Occurs Prior to Development of Subclinical Structural Vascular Alterations in Diabetic Adolescents

Objective: Soluble endoglin (S-endoglin) has been implicated as a potential marker of endothelial dysfunction (ED) and was reported to be elevated in diabetic adults, correlating with the severity of diabetic vasculopathy. However, circulating S-endoglin and its association with other markers of ED have not been formerly analyzed in the first decade of diabetes onset in adolescents with type 1 diabetes mellitus (T1DM). Methods: Fifty-eight adolescents with moderately/poorly controlled T1DM were included in this study and twenty-nine healthy adolescents served as controls. The diabetic group was divided into two groups based on the presence of microalbuminuria, as the microalbuminuria group (n=15) and the normoalbuminuria group (n=43). Functional vascular alterations were evaluated by measuring serum S-endoglin and plasma nitric oxide (NO) concentrations, the flow-mediated dilatation (FMD) of the brachial artery. Carotid intima media thickness (CIMT) was measured for evaluation of structural vascular alterations. Results: The S-endoglin and NO levels of both microalbuminuria and normoalbuminuria groups were higher than those of the control group (for S-endoglin, p=0.047 and p<0.001; for NO, p=0.004 and p=0.006, respectively). The FMD percent was lower in the microalbuminuria group compared to the normoalbuminuria and control groups (p=0.036 and p=0.020, respectively). There were negative correlations between S-endoglin concentration and FMD percent (r=-0.213, p=0.051) and between serum S-endoglin concentration and albumin excretion rate (r=-0.361, p=0.005). No significant differences were found in CIMT among any of the groups (p=0.443). Conclusion: In adolescents with T1DM, S-endoglin concentrations might increase in parallel to the deterioration in endothelial function before subclinical structural vascular alterations become evident.

Assessment of bone turnover markers and bone mineral density in normal short boys.

Abstract Aim: To investigate whether there is a change in bone turnover-related biochemical markers and bone mineral density of children with constitutional delay of growth and puberty (CDGP) in the prepubertal period. Methods: We measured serum calcium, phosphorus, alkaline phosphatase, parathormone, 25-OH vitamin D, osteocalcin, osteoprotogerin and urinary deoxypyridinoline levels (D-pyd), and bone mineral density (BMD) in 31 prepubertal boys with CDGP. These children were compared with 22 prepubertal boys with familial short stature (FSS) and 27 normal prepubertal boys. Results: Urinary D-pyd was significantly high in CDGP group as compared to control group (p=0.010). Volumetric BMD did not significantly differ between CDGP, FSS, and control groups (p=0.450). Volumetric BMD and urinary D-pyd levels of FSS and control groups were similar. Mean or median levels of calcium, phosphorus, alkaline phosphatase, parathormone, and osteoprotegerin did not significantly differ between CDGP, FSS, and control groups. Conclusions: Our data suggest that prepubertal boys with CDPG have normal bone turnover. However, their significantly higher urinary D-pyd levels relative to those of FSS and control groups might be an indicator of later development of osteoporosis. Therefore, long-term follow-up studies monitoring bone mineral status of prepubertal boys with CDPG from prepuberty to adulthood are needed to better understand bone metabolism of these patients.