Endocrine Abstracts

JOINT3799

Resistance to thyroid hormones due to mutations in THRA (RTHα) is a very rare disease, of which only 40 cases have been described so far in the literature (27 in children and 13 in adults). However, its incidence could be much higher than currently estimated: in fact, many affected relatives with a mild phenotype were only diagnosed by genetic screening after initial diagnosis of the index cases. Twenty-five variants in THRA gene have been identified so far, but likely there are many more we have not discovered yet. Both our patients first came to our attention due to short stature when they were starting pubertal development; however, failure to growth was associated to other clinical features of which some could possibly be associated with untreated hypothyroidism (e.g. neurodevelopmental delay, delayed tooth eruption, constipation) while others were not directly related with hypothyroidism but anyway suggestive for a syndromic disease (e.g. dysmorphic features of the face and trunk, several nevi, ligaments’ hyperlaxity, redundant skin, clinodactyly). Thyroid function tests in both patients were typical for RTHα, but they were not recognised as such: the first showed fT4 levels at the lower limits of normal associated with normal TSH values, but fT3 was never measured; the second patient had two other central hormonal deficits (GH and ACTH), therefore low fT4 levels were attributed to a form of central hypothyroidism, which can be tricky to distinguish from RTHα. Definitive diagnosis was made with exome sequencing, which revealed de novo heterozygous variants in both patient: in the first a variant of unknown significance (c.G802C, protein p.Asp268His), while in the second the variant c.1204_1215del causes deletion of four amino acids in the protein p.(Leu402_Phe405del). After the diagnosis, we repeated thyroid function tests and we calculated fT3/fT4 ratio, which was above mean reference values in both patients. After the start of therapy with L-T4, both our patients had immediate amelioration of symptoms such as constipation. To conclude, it is crucial to keep in mind RTHα in the differential diagnosis for children with growth failure, dysmorphic features, and delayed psychomotor development. fT3/fT4 ratio is of fundamental importance in not-straightforward cases. Early diagnosis would allow children to start treatment with L-T4 and thus possibly avoid severe neurodevelopmental outcomes, together with the amelioration of constipation leading to better quality of life for the patient and the family.