Thyroid nodules (and goitre) also occur in individuals without exposure to iodine deficiency, and not all individuals in an iodine- deficient region develop goitre. A familial clustering for nodular goitre is well documented and family and twin pair studies in endemic and non- endemic goitre regions have underscored a gen etic predisposition for goitre development. For example, twin studies show a concordance rate of 80% for monozygotic twins and of 42% for dizygotic twins in endemic and of 40– 50% and 13% in non- endemic regions, respectively, strongly suggesting interplay between genetic and environmental factors. On the basis of twin studies, the contribution of genetic susceptibility to goitre development has been calculated to be 39% in endemic regions and 82% in a non- endemic area.
Genetic defects in enzymes involved in thyroid hormone syn thesis (e.g. thyroglobulin (TG), thyroperoxidase (TPO), sodium- iodide symporter (NIS) typically result in hypothyroid goitres, but in some rare cases genetic variations in the TG, TPO, and NIS gene have also been reported in association with (diffuse or) nodular euthyroid goitre. Furthermore, alterations in the pendrin gene account for the syndromic occurrence of euthyroid nodular goitre and con genital sensorineural hearing loss.
Since these monogenetic defects are exceptionally rare, linkage studies have been performed to identify susceptibility loci for non- toxic goitre (NTG) on a broader scale. A locus on chromosome 14 (termed MNG- 1 locus) has been identified in a Canadian and a German study and was found to cosegregate with familial NTG. In an Italian pedigree with euthyroid goitre an X- linked autosomal pat tern of inheritance with a putative genetic defect in the Xp22 region was suggested (termed MNG- 2 locus). Moreover, in a study by the European Thyroid Association working group on the ‘Genetics of euthyroid goitre’ 18 extended Danish, German, and Slovakian families were analysed in a genome- wide scan. Further putative candidate loci for NTG were identified on chromosomes 3p, 2q, 7q, and 8p emphasizing the genetic heterogeneity of euthyroid goitre.
The first association of germline DICER1 mutations with NTG was shown 2011. DICER1 is an important enzyme in the maturation of microribonucleic acid (RNA), which have substantial impact in gene expression at the posttranscriptional level. The DICER1 gene is located in the MNG- 1 locus and loss- of- function mutations were identified in 33 members of five families. Besides NTG, mutations in DICER1 are associated with several benign and malignant tumours (e.g. pleuropulmonary blastoma, cystic nephroma, and ovarian Sertoli- Leydig cell tumour). The incidence of multinodular goitre in individuals with DICER1 mutations by age 20 years is 32% in females and 13% in males and also the risk of developing thyroid cancer is increased. Thus, for the majority of euthyroid goitres, a complex, multifactorial pathogenesis including interactions between various environmental factors, gender- specific components, and the genetic background has to be assumed.
