Hyperthyroidism, Nonautoimmune

A number sign (#) is used with this entry because of evidence that nonautoimmune hyperthyroidism is caused by heterozygous mutation in the thyroid-stimulating hormone receptor gene (TSHR; 603372) on chromosome 14q31.

Mutation in the TSHR gene can also cause thyrotropin resistance and nonautoimmune hypothyroidism (275200).

Congenital nonautoimmune hyperthyroidism is distinct from autoimmune hyperthyroidism, or Graves disease (275000), and from transient neonatal hyperthyroidism due to passive transfer of maternal autoantibodies.

Clinical Features

Graves disease in the neonate is usually described as a transient disorder in the newborn offspring of women who have or have had hyperthyroidism. Hollingsworth and Mabry (1976) reported a subset of patients with 'congenital Graves disease' in whom the disorder was not caused by immunoglobulins. The authors favored autosomal dominant inheritance with female predilection. They quoted an experience of Dr. A. M. DiGeorge (Philadelphia) who had seen affected father and son. The father had symptoms from age 3 years and the son from birth; both had required antithyroid medication.

Thomas et al. (1982) reported a large family in which 9 of 34 members had hyperthyroidism associated with diffuse goiter. Exophthalmos was absent, and there were no antithyroid antibodies. Examination of thyroid tissue showed rare lymphocytic infiltration and absence of immune complexes.

Kopp et al. (1995) described a boy in whom hyperthyroidism was suspected at birth because of tachycardia, tachypnea, and a diffuse goiter. Laboratory tests confirmed the diagnosis and did not demonstrate any antithyroid antibodies. The patient was initially treated with propylthiouracil, and later had a subtotal thyroidectomy at the age of 8 years. Although almost all thyroid tissue was removed, the patient remained hyperthyroid after surgery and radioiodine therapy was administered at the age of 9 years. Thereafter, the patient became euthyroid. Neuropsychologic testing revealed hyperactivity and mental retardation with an IQ between 75 and 85. The patient's mother was euthyroid, and repeated tests for thyroid antibodies were always negative.

De Roux et al. (1996) reported a newborn who presented with severe hyperthyroidism, diffuse goiter, eyelid retraction, and possibly proptosis. The absence of thyroid pathology in the parents and the lack of antithyroid antibodies in the mother and the patient suggested a nonimmune etiology.

In a review, Paschke and Ludgate (1997) noted that the thyroid gland was enlarged in most patients with nonautoimmune hyperthyroidism, but that features of Graves disease, such as thyroid-associated ophthalmopathy, pretibial myxedema, lymphocytic infiltration of the thyroid, and thyroid antibodies, were absent. Hyperthyroidism occurred at any time from the neonatal period to adulthood; the variability in age at onset probably resulted from other genetic components and environmental factors such as iodine intake and dietary goitrogens. Patients required ablative treatment (surgery or radioiodine) because there had been reports in many families of recurrent hyperthyroidism after subtotal thyroidectomy, mandating a second thyroidectomy or radioiodine treatment.

Molecular Genetics

In affected members of 2 large unrelated kindreds from northern France with autosomal dominant nonautoimmune hyperthyroidism, Duprez et al. (1994) identified 2 different heterozygous mutations in the TSHR gene (603372.0019; 603372.0020). One of the families had been reported by Thomas et al. (1982).

In a boy with nonautoimmune congenital hyperthyroidism, Kopp et al. (1995) identified a heterozygous mutation in the TSHR gene (603372.0004) that resulted in constitutive activation of the receptor.

In an infant with nonautoimmune hyperthyroidism, de Roux et al. (1996) identified a heterozygous mutation in the TSHR gene (603372.0007).