ESPE2023 Free Communications Thyroid (6 abstracts)
Thyroid hormone resistance due to THRB gene mutations: neonatal manifestations in two cases
Séverine Labey 1 , Frédérique Savagner 2 , Aline Rideau 3 , Amalia Sertedaki 4 , Maria Dolianiti 4 , Sofia Sakka 4 , Sultana Siahanidou 4 , Juliane Léger 1 , Jean-Claude Carel 1 & Christina Kanaka-Gantenbein 4
1Department of Pediatric Endocrinology and Diabetology & Reference center for Growth and Development Endocrine diseases, Assistance Publique-Hôpitaux de Paris, Robert Debré University Hospital, Paris, France. 2Laboratory of Biochemistry and Molecular Biology, IFB-CHU, Toulouse, France. 3Neonatal Intensive Care Unit, Assistance Publique Hôpitaux de Paris, Robert-Debré Paediatric Hospital, Paris, France. 4Division of Endocrinology, Diabetes and Metabolism and Aghia Sophia ENDO-ERN center for rare pediatric endocrine disorders, First Department of pediatrics, Medical School, National and Kapodistrian University of Athens, Aghia Sophia Children’s Hospital, Athens, Greece
Introduction: Thyroid hormone resistance (THR) is a rare disease (≈ 1/50000) mainly due to thyroid hormone receptor beta gene (THRB) mutations, generally identified in late childhood and adulthood. We report 2 atypical cases of neonatal diagnosis of THR.
Case 1: The newborn presented with neonatal respiratory distress due to a voluminous compressive goiter, requiring invasive ventilation. Thyroid function tests (TFT) showed very high TSH and free THs levels (see table). He also presented supra-ventricular tachycardia, managed by adenosine, β-blockers and digoxin. Tiratricol, a T3-analog, reduced TSH levels and decreased goiter size allowing spontaneous ventilation at day 17. Clinical and biological evolution remains satisfactory at the age of 18 months.
Case 2: The patient was referred after positive neonatal screening for congenital hypothyroidism. TFT revealed elevated levels of TSH and THs, and clinical symptoms are detailed in table. Tachycardia was treated with β-blocker and then with α-blocker. High doses of T3 given every other day decreased TSH values with a slight reduction of the goiter, although goiter size increased again upon follow-up.
Genetic results: Both patients had a de novo heterozygous mutations in the exon 10 of THRB, classified as pathogenic according to ACMG criteria, but not previously reported. Given the unusual neonatal presentation, we further evaluated genes involved in thyroid development and function through whole exome sequencing or targeted NGS. In case 1, we found an heterozygous missense mutation in the TSHR gene c.1703T>A, p.I568N, inherited from the father. Functional tests confirmed the constitutional activation of the mutated receptor. In case 2, no other pathogenic or likely pathogenic variant was detected.
| Case 1 | Case 2 | |
| Family history | None | None |
| Diagnosis circumstances | Neonatal respiratory distress | CH screening result |
| TFT | ||
| TSH (mUI/L) | 73.8 | >75 |
| fT4 (pmol/l) | 77.1 | >77.3 |
| Thyroid size (N<1.53ml) | 9.7ml (compressive) | 5.1ml |
| Clinical symptoms | Supra-ventricular tachycardia Premature dental eruption Insufficient weight gain | Tachycardia Brain Ventriculomegaly Hearing loss Insufficient weight gain |
| THRB mutation | c.1352_1353delinsAA p.F451Stop | c.1301_1301delG p.C434Sfs*9 |
| Second genetic event | TSHR c.1703T>A | None identified |
| Treatment | Tiratricol | T3 every other day |
| Evolution | Marked reduction in goiter size | Increased goiter size |
Conclusion: Neonatal manifestations of THR are very rare and are likely due to genetic or epigenetic events occurring in addition to THRB mutations. We have identified a likely such event in the form of an activating TSHR mutation. Therapeutic management is challenging.
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