ESPE Yearbook of Paediatric Endocrinology

Thyroid. 2021;31:202–207. doi: 10.1089/thy.2020.0253.

This study describes a new genetic thyroid disease that might be unnoticeable in individuals with normal thyroid synthetic capacity, but may cause harm in all patients who are dependent on levothyroxine substitution such as congenital hypothyroidism, acquired hypothyroidism, or post-thyroidectomy.

Three iodothyronine deiodinases (D1, D2, D3) are known. They modulate the availability of thyroid hormones. D1 is encoded by the DIO1 gene. D1 regulates thyroid hormone metabolism in two ways: first, it regulates serum levels of T3 by T4 outer ring deiodination and second, deiodinates the inactive reverse T3 (rT3, a product of T4 deiodination by D3) to inactive T2. Thus, the production of active T3 or inactive rT3 from T4 depends on the balance of D1+D2 and D3 activities, a regulation level of serum T3 already active in utero protecting the fetus from too high maternal T3 [1].

Franca et al. report a novel genetic thyroid disorder associated with heterozygous mutations in the Iodothyronine Deiodinase Type 1 (DIO1) gene. The index patients presented with slightly elevated TSH values and elevated rT3 levels but were otherwise healthy in the context of further family members with the same biochemical constellation. Functional studies in vitro and study of dio1 knock-out mice confirmed the human phenoytpe.

Of much more relevance than these otherwise healthy patients was a DIO1 mutation in siblings with thyroid dyshormonogenesis due to TPO mutations in a more recent publication of the same authors. Two of three siblings affected by TPO mutations had an additional heterozygous DIO1 mutation. These two siblings showed significantly worse neurological outcomes than the sibling without the additional DIO1 mutation, suggesting a phenotype modifier role of the DIO1 mutation. On a biochemical level, the additional DIO1 mutation resulted in reduced enzyme activity causing decreased T3 production from the substituted levothyroxine. Consecutively, more levothyroxine was inactivated by physiological D3 enzyme activity to rT3, resulting in unrecognizable underdosing of patients, if T4 but not rT3 levels are measured.

Reference: 1. Szinnai G, Polak M. Chapter 62: The maturation of thyroid function in the fetus, in the perinatal period and during childhood. Werner and Inbar’s The Thyroid. A Fundamental and Clincal Text, 11th Edition. Editors: L.E. Braverman, D.S. Cooper, P.A. Kopp. Philadelphia, Woulters Kluwer, 2020, pp. 839–854.2. Furman AE, Hannoush Z, Barrera Echegoyen FX, Dumitrescu AM, Refetoff S, Weiss RE. Novel DIO1 gene mutation acting as phenotype modifier for novel compound heterozygous TPO gene mutations causing congenital hypothyroidism. Thyroid. 2021. doi: 10.1089/thy.2021.0210.