Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene

Congenital hyperthyroidism is usually caused by maternal-to-fetal transfer of thyroid-stimulating antibodies from a mother with autoimmune thyroid disease. Very recently, activating thyrotropin (TSH) receptor germline mutations were detected in a few patients with sporadic nonautoimmune congenital hyperthyroidism, as well as in familial forms of nonautoimmune hyperthyroidism defining a new pathophysiological entity of hyperthyroidism. In this report, we describe a nonidentical twin girl with severe congenital hyperthyroidism. The twin brother and the mother were euthyroid. Skull radiographs revealed premature synostosis of the sagittal sutures. Hyperthyroidism was inadequately controlled with antithyroid drugs and radioiodine therapy. After a near-total thyroidectomy performed at age 3, the patient became hypothyroid and required thyroid hormone replacement. At age 14, hyperthyroidism recurred. A hyperplastic remnant of the right upper lobe was removed surgically, resulting in euthyroidism. Over the following years, thyroid hormone levels increased gradually and at age 19 she was again hyperthyroid. There was no clinical or biochemical evidence of an autoimmune process. The patient's neurologic development was impaired and her intelligence is subnormal. Direct sequencing of the TSH receptor gene revealed a heterozygous mutation resulting in a substitution of threonine(632) by isoleucine in the sixth transmembrane segment, an amino acid change known to result in constitutive activation of the cyclic adenosine monophosphate (cAMP) pathway. The mutation was absent in the parer;ts and the twin brother, indicating a de novo germline mutation. Early recognition of this disorder is important because of the resistance to standard treatment, special therapeutic implications, and the possibility of familial transmission.