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 threonine632 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 parents 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.