CLINICAL STUDY High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis Magdalena Avbelj, Husref Tahirovic 1 , Marusa Debeljak, Maria Kusekova 2 , Alma Toromanovic 1 , Ciril Krzisnik and Tadej Battelino University Medical Centre, University Children’s Hospital, Vrazov trg 1, SI-1000 Ljubljana, Slovenia 1 Department of Pediatrics, University Clinical Center Tuzla, 75000 Tuzla, Bosnia and Herzegovina, and 2 1st Department of Paediatrics, University Children’s Hospital, 04001 Kosice, Slovakia (Correspondence should be addressed to T Battelino; Email: tadej.battelino@mf.uni-lj.si) Abstract Objective: Thyroid dyshormonogenesis is a genetically heterogeneous group of inherited disorders in the enzymatic cascade of thyroid hormone synthesis that result in congenital hypothyroidism (CH). Thyroid peroxidase gene (TPO) mutations are one of the most common causes of thyroid dyshormonogenesis. The aim of this study was to identify TPO gene defects in a cohort of patients with thyroid dyshormonogenesis from Slovenia, Bosnia, and Slovakia. Design and methods: Forty-three patients with permanent CH and orthoptic thyroid glands from 39 unrelated families participated in the study. Mutational analysis of the TPO gene and part of its promoter consisted of single-stranded conformation polymorphism analysis, sequencing, and restriction fragment length polymorphism (RFLP) analysis. Results: TPO gene mutations were identified in 46% of participants. Seven different mutations were identified, four mutations of these being novel, namely 613COT (R175X), 1519_1539del (A477_N483del), 2089GOA (G667S), and 2669GOA (G860R). Only a single allele mutation was identified in 65% of the TPO mutation carriers. Conclusions: The results showed a higher prevalence of TPO gene mutations in thyroid dyshormonogenesis when compared with published studies. The high percentage of single allele mutations implied possible intronic or regulatory TPO gene mutations or monoallelic expression. European Journal of Endocrinology 156 511–519 Introduction Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, occurring in 1:3000– 4000 newborns (1). The serious detrimental effect on the child’s cognitive and motor development, which used to be a major feature of the disease, is now mostly prevented by newborn screening detection and early treatment (2). In Slovenia, neonatal screening for CH was intro- duced in 1981 (3). The present incidence of permanent CH in Slovenia is approximately 1:3100 newborns, based on 58 patients identified among 181 264 new- borns in a 10-year period from 1994 to 2003 (data obtained from the National Registry of the Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, Ljubljana, which is the nationwide referral center for CH). The neonatal thyroid-stimulat- ing hormone (TSH) screening program in the Federa- tion of Bosnia and Herzegovina (major part of Bosnia and Herzegovina) has been implemented since March 2005. The Federal Minister of Health accredited the implementation of the neonatal screening program for CH and phenylketonuria to the Laboratory for the Detection of Congenital Metabolic Diseases at the Department of Pediatrics, University Hospital, Tuzla (4). There were 30 068 newborns screened and 12 patients identified with CH from 1st March 2005 to 31st December 2006 (data obtained from the Federal Registry for CH of the Division for Endocrinology, Diabetes and Metabolism, Department of Pediatrics, University Hospital, Tuzla). The recent population- based studies showed Slovene adolescents and Bosnian schoolchildren to be iodine sufficient (5, 6). The majority of sporadic CH is due to developmental disorders, referred to as thyroid dysgenesis, which include the complete absence of thyroid tissue (agenesis) and a small-sized thyroid (hypoplasia) with or without associated ectopy. The less common causes of CH are hereditary defects in the enzymatic cascade of thyroid hormone synthesis, which share a common name, thyroid dyshormonogenesis. In this entity, the thyroid gland is found in the normal anatomical position; it is often enlarged, but with adequate levothyroxine (LT 4 ) substitution therapy it may also be of normal size. In a 10-year period from 1994 to 2003, 34% of Slovene European Journal of Endocrinology (2007) 156 511–519 ISSN 0804-4643 q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0037 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 06/03/2020 02:50:41AM via free access