2024 European Thyroid Association Guidelines on diagnosis and management of genetic disorders of thyroid hormone transport, metabolism and action

Abstract

Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism, and resistance to hormone action. Mediated by heritable single-gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with the identification of pathogenic variants in causal genes, and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarizing key clinical features and useful investigations, criteria for molecular genetic diagnosis, and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

Keywords: clinical practice guideline; deiodinase; diagnosis and management; impaired sensitivity to thyroid hormones; resistance to thyroid hormone; selenoprotein; thyroid hormone receptor; thyroid hormone transporter.

Figure 1

Algorithm for differential diagnosis, showing stepwise approach to the investigation of raised thyroid hormones (T4 and/or T3) with non-suppressed TSH. Key: ALB, albumin; ASU, alpha subunit; CH, congenital hypothyroidism; DIO1, deiodinase type 1; ICTP, serum carboxy-terminal telopeptide of type 1 collagen; L-T3, liothyronine; MCT8, monocarboxylate transporter 8; MRI, magnetic resonance imaging; NTI, non-thyroidal illness; PET, positron emission tomography; RTHα, resistance to thyroid hormone alpha; RTHβ, resistance to thyroid hormone beta; SECISBP2, selenocysteine insertion sequence binding protein 2; SHBG, sex hormone binding globulin; SRL, somatostatin receptor ligand; T3, triiodothyronine; T4, thyroxine; TBG, thyroxine binding globulin; THRB, thyroid hormone receptor beta gene; TRH, thyrotropin releasing hormone; TRU-TCA1-1, tRNA selenocysteine (anticodon TCA) 1-1; TSH, thyrotropin; TTR, transthyretin.