MON-264 Familial Neonatal Nonautoimmune Hyperthyroidism Due To A Thyrotropin Receptor Gene Mutation (A619G).

Abstract

Activating germline mutations of the TSH receptor are responsible for a rare form of non-autoimmune hyperthyroidism transmitted as an autosomal dominant trait. We describe the case of a patient and her mother presenting with neonatal non-autoimmune hyperthyroidism associated with a heterozygous A619G mutation previously described in one patient who presented in adolescence. Our patient is a 6 year old African-American female diagnosed with hyperthyroidism at 2 weeks of age. Thyroid tests were being followed in the NICU due to maternal history of hyperthyroidism. The mother had a history of hyperthyroidism and had thyroidectomy at age 4 years. The patient was thought to have neonatal Graves disease due to maternal history of hyperthyroidism. She was initially started on Propranolol at an outside hospital. She presented to the Children’s Hospital of Michigan Emergency Department at 7 weeks of age with tachycardia and constant crying. Her thyroid tests at that time revealed elevated free thyroxine and free T3 levels at 2.7 ng/mL (0.8-1.8) and 8.8 pg/mL (1.4- 4.4) respectively. TSH level was less than 0.008 µIU/mL (0.800-4.400). She had diffuse goiter. She was started on Methimazole and the dose was adjusted to keep her FT4 and T3 within normal range; TSH remained suppressed despite normalizing FT4 and T3 levels. Thyroid antibodies were repeatedly negative including Thyroid peroxidase, thyroid microsomal, thyroglobulin antibodies, thyrotropin receptor antibodies (TRab) and thyroid stimulating immunoglobulins (TSI). The patient also had bilateral exotropia and required strabismus surgery at 13 and at 17 months of age. She also has global developmental delay requiring physical, occupational, and speech therapy. Chromosomal microarray and fragile X DNA testing were normal. She is currently growing at 1.7 SDS for height and 0.8 SDS for weight and is on Methimazole 7.5 mg orally daily. TSHR sequencing and deletion/duplication analysis revealed that she is heterozygous for a missense variant: c.1856A>G; p.Asp619Gly. We report a case of a patient and her mother with non-autoimmune hyperthyroidism with a heterozygous c.1856A>G (p.Asp619Gly) missense variant in the TSHR gene. This variant has been previously identified in one individual in the compound heterozygous state and was considered to be the primary contributing mutation. Functional studies suggest that the variant leads to constitutive activity of the TSH receptor, supporting the pathogenicity of the variant. In our patient, the mutation was found to be inherited from the mother who also has a history of goiter and hyperthyroidism and unlike the previously reported case, our patient presented in the neonatal period. We describe the clinical course and associated findings in this family and discuss the evaluation and management of this interesting condition.