Korcan Demir

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.

Spontaneous intestinal perforation after oral ibuprofen treatment of patent ductus arteriosus in two very-low-birthweight infants.

Aim: To discuss intestinal side effects of ibuprofen in the treatment of patent ductus arteriosus, after having observed two cases of spontaneous intestinal perforation following ibuprofen treatment. Methods: Clinical and laboratory records of two preterm infants, who developed intestinal perforation after ibuprofen administration, were evaluated. Results: Gestational ages of infants were 29 wk (male) and 30 wk (female). Both infants developed intestinal perforations without signs of necrotizing enterocolitis. The perforations cured with Penrose drainage alone.

Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.

Objective  Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2‐5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG.

Thyroid dyshormonogenesis is mainly caused by TPO mutations in consanguineous community

In this study, we aimed to investigate the genetic background of thyroid dyshormonogenesis (TDH).

Diabetes care, glycemic control, complications, and concomitant autoimmune diseases in children with type 1 diabetes in Turkey: a multicenter study.

Objective: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries. The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control. The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence. The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey. Methods: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood. Epidemiological and clinical characteristics of the patients were recorded. Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated. Results: Mean age, diabetes duration, and hemoglobin A1c level were 12.5±4.1 years, 4.7±3.2 years, and 8.5±1.6%, respectively. Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%. Chronic lymphocytic thyroiditis was noted in 12%, Graves’ disease in 0.1%, and celiac disease in 4.3% of the patients. Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively. Diabetic nephropathy was not present in any of the patients. Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01). A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively). Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese. Conclusions: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered. Conflict of interest:None declared.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11Yod/+ mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.

TSHR is the main causative locus in autosomal recessively inherited thyroid dysgenesis.

Abstract Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and results in mental retardation if untreated. Eighty-five percent of CH cases are due to disruptions in thyroid organogenesis and are mostly sporadic, but about 2% of thyroid dysgenesis is familial, indicating the involvement of genetic factors in the aetiology of the disease. In this study, we aimed to investigate the Mendelian (single-gene) causes of non-syndromic and non-goitrous congenital hypothyroidism (CHNG) in consanguineous or multicase families. Here we report the results of the second part (n=105) of our large cohort (n=244), representing the largest such cohort in the literature, and interpret the overall results of the whole cohort. Additionally, 50 sporadic cases with thyroid dysgenesis and 400 unaffected control subjects were included in the study. In familial cases, first, we performed potential linkage analysis of four known genes causing CHNG (TSHR, PAX8, TSHB, and NKX2-5) using microsatellite markers and then examined the presence of mutations in these genes by direct sequencing. In addition, in silico analyses of the predicted structural effects of TSHR mutations were performed and related to the mutation specific disease phenotype. We detected eight new TSHR mutations and a PAX8 mutation but no mutations in TSHB and NKX2-5. None of the biallelic TSHR mutations detected in familial cases were present in the cohort of 50 sporadic cases. Genotype/phenotype relationships were established between TSHR mutations and resulting clinical presentations. Here we conclude that TSHR mutations are the main detectable cause of autosomal recessively inherited thyroid dysgenesis. We also outline a new genetic testing strategy for the investigation of suspected autosomal recessive non-goitrous CH.

Metabolic Alterations During Valproic Acid Treatment: A Prospective Study

We prospectively examined the effects of valproic acid on the endocrine system and metabolic variables in epileptic children. Patients with newly diagnosed idiopathic epilepsy were included in the study. Laboratory and clinical variables were assessed before and after 6 and 12 months of treatment. In total, 30 patients (mean age, 8.6 +/- 4.4 years S.D.) were investigated. Body mass index and body mass index standard deviation scores of patients increased significantly during treatment. Although there was no statistical significance regarding fasting glucose, serum insulin, triglyceride, and high-density lipoprotein cholesterol levels and the insulin resistance index, a statistically significant increase in total and low-density lipoprotein cholesterol levels had occurred after 12 months of valproic acid treatment. At the end of the study period, four patients were obese, and six patients were overweight. There was a significant correlation between serum levels of valproic acid and body mass index at month 6 of treatment. There was no significant change in androgen hormone levels during treatment in the prepubertal group. Body mass index and body mass index standard deviation scores increased during the first 6 months of valproic acid treatment. Patients treated with valproic acid should be regularly followed for obesity.

The Role of Initial Clinical and Laboratory Findings in Infants With Hyperthyrotropinemia to Predict Transient or Permanent Hypothyroidism

Objective: Studies on the clinical course of children with hyperthyrotropinemia are scarce. We aimed to evaluate the role of presentation findings in such infants to predict eventual outcome. Methods: Files of infants diagnosed as suspicious congenital hypothyroidism (CH) in the neonatal or early infancy period in the past ten years were analyzed retrospectively, and 37 patients (M/F: 20/17) with hyperthyrotropinemia diagnosed at a median age of 3.2 months were included in the study. Criteria for inclusion were: normal free thyroxine (fT4) levels and thyrotropin (TSH) levels between 10-20 μIU/mL during the initial neonatal screening (or TSH<10μIU/mL afterwards). Cases with permanent CH (Group 1) were compared to those with transient hyperthyrotropinemia (Group 2) regarding age at the time of diagnosis, sex, gestational age, birth weight, symptoms, ultrasonographic and scintigraphic findings, initial thyroid function tests, and state of mental and motor development. Results: Of the total group, 20 patients (54%) were eventually diagnosed as permanent CH. T4 doses that maintained normal thyroid function tests were significantly higher at the end of the first and second years of life in this group. Age, TSH and fT4 levels at the time of diagnosis, sex, gestational age, birth weight, symptoms, ultrasonographic and scintigraphic findings, and the state of mental and motor development were similar in the two groups. Conclusions: T4 dose required to maintain a euthyroid state was the only parameter which distinguished between transient and permanent CH. Conflict of interest:None declared.

Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations

CONTEXT Recently several patients with resistance to thyroid hormone (RTH)-α due to T3 receptor-α (TRα) mutations were identified. The phenotype of these patients consists of varying degrees of growth impairment, delayed bone, mental and motor development, constipation, macrocephaly, and near-normal thyroid function tests. OBJECTIVE The objective of the study was to describe the clinical phenotype of three new families with RTHα and thereby gain more detailed knowledge on this novel syndrome. DESIGN, SETTING, AND PARTICIPANTS RTHα was suspected in three index patients from different families. Detailed clinical and biochemical assessment and imaging and genetic analyses were performed in the patients and their relatives. In addition, functional consequences of TRα mutations were investigated in vitro. RESULTS We studied 22 individuals from three families and identified 10 patients with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental, and motor development, whereas the seven patients in family 3 had only mild clinical features. The most frequent abnormalities were anemia, constipation, and a delay in at least one of the developmental milestones. Serum free T3 ranged from high-normal to high and serum free T4 and rT3 from normal to low. TSH levels were normal in all patients. CONCLUSIONS This large case series underlines the variation in the clinical phenotype of RTHα patients. RTHα should be suspected in subjects when even mild clinical and laboratory features of hypothyroidism are present along with high/high-normal free T3, low/normal free T4, and normal TSH.