Current Therapeutic Approaches for Graves' Orbitopathy - are Targeted Therapies the Future? / Aktuelle Therapieansätze der endokrinen Orbitopathie ­ sind die zielgerichteten Therapien die Zukunft?

Graves' orbitopathy is an autoimmune disease of the orbit that most frequently occurs with Graves' hyperthyroidism. The occurrence of autoantibodies directed against the TSH receptor (TRAb) is of central importance for the diagnosis and pathogenesis. These autoantibodies are mostly stimulating, and induce uncontrolled hyperthyroidism and tissue remodelling in the orbit and more or less pronounced inflammation. Consequently, patients suffer to a variable extent from periocular swelling, exophthalmos, and fibrosis of the eye muscles and thus restrictive motility impairment with double vision. In recent decades, therapeutic approaches have mainly comprised immunosuppressive treatments and antithyroid drug therapy for hyperthyroidism to inhibit thyroid hormone production. With the recognition that TRAb also activates an important growth factor receptor, IGF1R (insulin-like growth factor 1 receptor), biological agents have been developed. Teprotumumab (an inhibitory IGF1R antibody) has already been approved in the USA and the therapeutic effects are enormous, especially with regard to the reduction of exophthalmos. Side effects are to be considered, especially hyperglycaemia and hearing loss. It is not yet clear whether the autoimmune reaction (development of the TRAb/attraction of immunocompetent cells) is also influenced by anti-IGF1R inhibiting agents. Recurrences after therapy show that the inhibition of antibody development must be included in the therapeutic concept, especially in severe cases.

Activating TSH-receptor mutation (Met453Thr) as a cause of adenomatous non-autoimmune hyperthyroidism in a 3-year-old boy.

Several mutations of the TSH-receptor gene have been described in a variety of thyroid diseases. Particularly in children and adolescents, somatic or germ cell mutations may lead to hyperthyroidism. In these cases, molecular analysis of the TSHR gene provides important information for further clinical management. We report a 3-year-old boy with a rare somatic TSHR mutation causing autonomous adenoma of the thyroid gland in order to illustrate how the genetic analysis of the lesion impacted on the surgical strategy. The patient presented with a left neck mass, negative thyroid autoantibodies, and unifocal autonomy on thyroid scan. He underwent local resection of the adenoma. Genetic workup demonstrated a somatic mutation of TSHR. Exons 9 and 10 of the TSHR gene (chromosome 14q3) from peripheral blood DNA and toxic thyroid adenoma tissue DNA were amplified by PCR and analyzed by denatured gradient gel electrophoresis (DGGE). DGGE from the EDTA blood sample showed no difference compared to the wild-type, whereas material extracted from the tissue sample showed a mutation in exon 10. Direct sequencing of the PCR product from the tissue demonstrated a heterozygous mutation in codon 453 (ATG-->ACG), leading to a substitution of methionine by threonine. The genetic appraisal of resected thyroid tissue in cases with nonautoimmune hyperthyroidism is important to formulate surgical and medical treatment plans. In cases with somatic mutations of the TSHR, simple resection of the adenoma is sufficient, whereas total thyroidectomy should be considered in patients with germ cell mutations.