Response to TRIAC therapy in a child with Resistance to Thyroid Hormone beta and behavioural abnormalities

Anand Ramakrishnan; Charlotte Jarvis; Jay Thomas; Suzanne Armitage; Greta Lyons; David Halsall; Krishna Chatterjee; Renuka Ramakrishnan

Introduction: Resistance to thyroid hormone beta, a rare disorder due to mutation in thyroid hormone receptor β, results in raised thyroid hormones with non-suppressed TSH and variable symptoms. Manifestations of RTHb in childhood include failure to thrive, propensity to ENT infections and behavioural abnormalities including ADHD. We report biochemical and behavioural responses to therapy with triiodothyroacetic acid (TRIAC), a centrally-acting thyroid hormone analogue, in a very young child with a novel, pathogenic THRB mutation.

Case report: A 2yr 11month old boy was evaluated for delayed development (predominantly communication, personal social and fine motor) and significant disruptive behaviour with thyroid biochemistry consistent with RTHb. Apart from intermittent episodes of feeling hot and sweaty, he was clinically euthyroid with no goitre. His auxology (Table 1) and bone age were normal. Genetic testing showed heterozygosity for a THRB mutation (c.1328A>C), corresponding to a novel amino acid variant (p.Lys443Thr) at a codon previously associated with RTHb. Behavioural assessment at baseline, using Vineland Adaptive behaviour scale and Age and Stage Questionnaire-3 (ASQ-3) showed marked delay in personal social, communication and fine motor skills with acceptable gross motor skills. He was treated with TRIAC in increasing dosage, showing progressive biochemical improvement (Table 1) accompanied by reduced food intake and slowing of weight gain. Serial behavioural assessments over 9 months of TRIAC therapy showed improvements in communication, social abilities, daily living tasks and inattention/hyperactivity. Whilst difficult to separate these out from his natural development, qualitative testimonies supported a marked improvement in these areas.

Table 1: Serial thyroid biochemistry and auxology following TRIAC therapy
		Duration post treatment (Months)
Parameter/Date	Baseline	1	2	4	5	7
TSH (0.3-3.8 mu/L)	5.3	4.59	3.74	3.14	4.52	2.69
*Total T4 (63-129 nmol/L)**	281			93	126
*Total T3 (1.09-2.24 nmol/L)**	4.5			1.8	1.8
Free T4 (9-19 pmol/L)	27	17.1	16.3	12.0	13.4	14.3
Free T3 (4.29-6.79 pmol/L)	13	9.3	10.2	>30.7	13.0
Height {cm} (SDS)	100 (+1.29)				109.2 (+1.55)
Weight {kg} (SDS)	17.5 (+1.90)			19.9 (+1.85)
BMI {kg/m²} (SDS)	17.5 (+1.40)			16.7 (+1.00)
*Measured by liquid chromatography mass spectrometry to avoid cross reactivity with TRIAC

Conclusion: We report favourable biochemical and behavioural responses to TRIAC therapy in a child with RTHb due to a pathogenic THRB variant. Our report highlights the utility of mass spectrometric T3 measurement in monitoring dosage of TRIAC therapy. To our knowledge this is one of the youngest childhood cases of RTHb being successfully treated with TRIAC.

ESPE Abstracts

P1-291