Skeletal dysplasia and growth failure in congenital hypothyroidism due to a novel form generalized thyroid hormone resistance.

Background: Thyroid hormone exerts systemic actions mediated by its specific receptors. These actions encompass a wide array of functions, including energy homeostasis, skeletal growth, neural development, cardiac function, and gastrointestinal function. There are two thyroid hormone receptors, thyroid hormone receptor alpha (THRA) and thyroid hormone receptor beta (THRB) which are encoded by genes on two different chromosomes and with differing tissue distributions. Only mutations in THRB were known until recently with a reported incidence of 1 in ~40,000. Mutations in thyroid receptor THRA have recently been discovered and are is exceedingly rare, with 14 cases documented in the past five years. We report a case of a patient with generalized thyroid hormone resistance due to THRA mutation. Clinical Case: Patient was born to non-consanguineous parents at term and was appropriate for gestational age. Prenatal ultrasound was suspect for shortened long bones. Congenital heart disease (ASD and VSD) were detected at birth. Genetics consultation confirmed ultrasound concern with finding of mild rhizomelia. Patient had coarse facial features, macroglossia, and dysmorphic appearance. Initial genetics work-up showed normal chromosomes, normal newborn screening, and normal metabolic studies. Genetics was concerned for possible mucopolysaccharidosis, but further testing ordered did not show definite results of this diagnosis. Patient exhibited post-natal growth failure after birth with length well below 3rdpercentile by 18 months old. Delayed developmental milestones (verbal [greater than] motor) was seen. Thyroid function tests between birth and 11 months old were normal. Thyroid function testing at 11 months old were suspect for central hypothyroidism with free T4 0.6 ng/dl (0.6-1.3) and TSH 1.07 uIU/ml (0.71-5.81). Cranial MRI scan showed no abnormalities in hypothalamic-pituitary area. Levothyroxine 37.5 mcg was started, and thyroid function tests normalized. However, little change was seen clinically in patient’s growth pattern or development. Whole exome screening performed in 2013 demonstrated a heterozygous mutation in the THRA gene consistent with generalized thyroid hormone resistance from this mutation. Liothyronine treatment was added in 2014. Growth has continued to be extremely slow with current height standard deviation score of -4.2. Patient is developmentally delayed and non-verbal. Conclusions: A constellation of findings including post-natal growth failure, skeletal findings, and prominent verbal developmental delays are seen in generalized thyroid hormone resistance due to THRA mutation. The subtle presentation of this condition is different from congenital hypothyroidism or generalized thyroid hormone resistance due to THRB mutation. This case will help geneticists and endocrinologist recognize this condition.