ESPE Abstracts (2015) 84 P-2-570

Goitrous Hypothyroidism of Pubertal Onset Caused by a Novel Mutation in DEHAL1 Gene

Esther Schulza, Ainhoa Iglesiasb, Halit Ilker Akkurta, Knut Helmkea & José Carlos Morenob


aAltonaer Children’s Hospital, Hamburg, Germany; bThyroid Molecular Laboratory, Institute for Medical and Molecular Genetics (INGEMM), La Paz University Hospital, Madrid, Spain


Background: Iodotyrosine deiodinase (DEHAL1) is a thyroidal enzyme that deiodinates mono- and diiodtyrosines (MIT, DIT) and recycles iodine, essential for synthesis of thyroid hormone. Iodotyrosine deiodinase deficiency leads to hypothyroidism, goiter and variable mental retardation. The age for clinical onset was reportedly very diverse, allegedly related to individual iodine nutrition.

Clinical case: We report on a boy, offspring of consanguineous parents from Lebanon, who presented at the age of 11 years with a very large goiter, rapidly developed within the previous 3 weeks, without other clinical signs. Hormonal investigations revealed severe primary hypothyroidism (TSH>150 mU/l, fT4 0.2 ng/dl, fT3 2.4 ng/l, Thyroglobulin 8828 ng/ml, no anti-thyroid autoantibodies). Two weeks after 75 μg/day levothyroxine treatment, goiter volume shrank to a volume of 30 ml (n<5.4 ml), as measured by ultrasonography (US). In further course, adherence to therapy was poor, and goiter re-increased to a volume 150 ml in the setting of relapsed biochemical hypothyroidism. US showed high perfusion of the gland and irregular structure of the thyroid parenchyma. After improved adherence to treatment, the goiter reduced to 110 ml in 4 months. Genetic investigations identified a novel homozygous mutation in DEHAL consisting in the insertion of one nucleotide in exon 1 (c.168-169insA), present in heterozygosity in apparently asymptomatic parents. This pathogenic deletion causes a frameshift leading to a early stop-codon at amino acid 62 (p.A57SfsX62) of the protein.

Conclusion: Full DEHAL1 defects may remain asymptomatic for many years after birth in iodine-sufficient environments, and clinically present at puberty with dramatic severity. Goiter size is very sensitive to correction of hypothyroidism. The novel mutation is the most amino-terminally located so far in DEHAL1, and completely deletes the functional nitroreductase domain of the enzyme. Early urine MIT/DIT determinations in deserve investigation as possible biomarkers for pre-clinical diagnosis of DEHAL1 defects.

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