ESPE Abstracts (2019) 92 P1-426

A Rare Case of Familial Heterozygous Thyroid Hormone Receptor Beta (THRB) Mutation Presenting with Dilated Cardiomyopathy

Lucy Hastings1, Vrinda Saraff2, Ashish Chikermane2, Kristien Boelaert3,4, Greta Lyons5,6, Carla Moran5,6, Zainaba Mohamed2


1Birmingham Children's Hospital, Birmingham, United Kingdom. 2Birmingham Women's and Children's Hospital, Birmingham, United Kingdom. 3Queen Elizabeth Hospital, Birmingham, United Kingdom. 4Institute of Metabolism and Systems Research, Birmingham, United Kingdom. 5University of Cambridge Metabolic Research Laboratories, Cambridge, United Kingdom. 6Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom


Background: Resistance to thyroid hormone beta (THRβ) is a clinical spectrum which varies in presentation even between individuals with the same mutation. Life-threatening cardiac dysfunction is recognized in homozygous THRβ state but never reported in cases of inherited heterozygous THRβ defects.

Aim: We report the first case of familial inherited heterozygous (THRB) beta mutation presenting with severe dilated cardiomyopathy.

Case report: Previously well, 9-month-old girl, presented with one-week history of lethargy, respiratory distress and resting tachycardia (HR 170-200bpm). Chest X-ray identified cardiomegaly. Echocardiogram confirmed heart failure with dilated cardiomyopathy. Clinical investigations revealed markedly abnormal thyroid function tests (TFT) with no goiter [TSH 4.81(0.5-3.8mU/L), fT4 50.6(10.8-22.9mU/L), fT3 17.2(3.6-6.8pmol/L)] and vitamin D insufficiency (37nmol/L). Parents were unrelated of Jamaican origin. Infant's father died aged 31years, from sudden cardiac arrest with underlying untreated hyperthyroidism and severe dilated cardiomyopathy of unknown etiology. Father had Thyroid Hormone Resistance (RTH) with (THRβ) heterozygous mutation; c.928A>T, p.M310L. Genetic screening confirmed inheritance of the paternal THRβ mutation in our patient and her older sister aged 3yrs [TSH 2.26(0.5-3.8mU/L), fT45(10.8-22.9pmol/L), fT3 12.4(3.6-6.8pmol/L)], whose echocardiogram is normal to date. Vitamin D insufficiency was treated but did not improve poor cardiac indices.

Over ensuing months, our patient had persistent cardiomyopathy with reduced cardiac function (ejection fraction (EF) 15-20%), required respiratory and inotropic support and was listed for urgent cardiac transplant. It was unclear if the tachycardia was secondary to cardiotoxic hyperthyroxinemia or directly secondary to cardiac failure. Carbimazole was commenced (0.9mg/kg/day) to reduce hyperthyroid additive strain on the heart, despite which fT3/fT4 remained significantly elevated. By week 6of Carbimazole, tachycardia and clinical status improved with elevation in TSH 17.36(0.5-3.8mU/L). To circumvent this, patient was treated with TRIAC (3,5,3'-triiodothyroacetic acid), a centrally acting thyroid hormone analog, effective in the management of childhood THRB. This was associated with simultaneous improvement in cardiac function (EF≧51%). The patient came off the transplant list after 5 months of inpatient care and was discharged home on oral feeds. Genetic cardiomyopathy screens in affected cases were negative.

Conclusion: This is the first case-report of an infant with heterozygous THRB mutation requiring combined Carbimazole and TRIAC treatment for concurrent life-threatening cardiac dysfunction. The critical status of our patient, in-conjunction with sudden death of her untreated father and potential risk of evolution of disease in her sister, demonstrates that heterozygous THRB is a clinical entity that requires ongoing active monitoring and management.

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