ESPE Abstracts (2015) 84 P-1-128

Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor [alpha] Mutations

Korcan Demira,b, Anja van Guchtc, Muammer Büyükinand, Gönül Catlid, Yavuz Ayhane, Veysel Nijat Basf, Bumin Nuri Dündarg, Behzat Ozkana, Marcel E Meimac, W Edward Visserc, Robin P Peetersc & Theo J Visserc

aDivision of Pediatric Endocrinology, Dr Behçet Uz Children’s Hospital, Izmir, Turkey; bDivision of Pediatric Endocrinology, Dokuz Eylül University, Izmir, Turkey; cDepartment of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; dDivision of Pediatric Endocrinology, Tepecik Education and Research Hospital, Izmir, Turkey; eDepartment of Psychiatry, Hacettepe University, Ankara, Turkey; fDivision of Pediatric Endocrinology, Eskisehir State Hospital, Eskisehir, Turkey; gDivision of Pediatric Endocrinology, Katip Çelebi University, Izmir, Turkey

Background: Recently, T3 receptor alpha (TRα) mutations have been identified in a number of patients with varying degrees of growth impairment, delayed development, constipation, increases in serum T3 and decreases in T4 and rT3.

Objective: To determine the spectrum of clinical and functional consequences of novel TRα mutations.

Method: Clinical assessment and biochemical, imaging, and genetic analyses were performed in the three index patients and their relatives. Functional consequences of TRα mutations were investigated in vitro.

Results: We studied 22 individuals from three families and identified nine patients (five children, four adults; five females, four males; age range 11 months–55 years) with heterozygous TRα mutations: C380fs387X, R384H, and A263S, respectively. These mutations were associated with decreasing severity of the clinical phenotype: the patient in family 1 showed severe defects in growth, mental and motor development, whereas the six patients in family three had only mild clinical features. The patient in family 1 had been treated with LT4 from the age of 2 years without obvious benefit. The most frequent abnormalities were thickened skull vault (100%), normocytic normochromic anemia, constipation, a delay in at least one of the developmental milestones (78% each). Only two patients (22%) had short stature and three cases (33%) demonstrated disproportionate body ratios. Serum (F)T3 ranged from high-normal to elevated, and serum (F)T4 and rT3 from normal to decreased. TSH levels were all normal. Creatinine kinase levels were elevated only in affected children. The frame-shift mutation completely inactivated TRα, whereas the missense mutations produced milder defects.

Conclusion: We report the largest case series with TRα mutations expanding the clinical spectrum. Lateral cranial x-ray findings, normocytic normochromic anemia, and, particularly in children, high creatinine kinase levels strengthen the diagnosis when clinical signs of hypothyroidism are present along with near-normal thyroid hormone levels.