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Cretinism is marked by irreversible mental and growth retardation. We describe here an entirely new case of cretinism showing combined pituitary hormone deficiencies of thyrotropin, growth hormone and prolactin that appears to be caused by homozygosity for a nonsense mutation in the gene for the pituitary specific transcription activator, Pit-1/GHF-1 (designated PIT1 in humans for pituitary specific factor 1). This is the first report in humans of a defect in a transcription activator causing deficiency of multiple target genes.

Postmortem histological examination of the thyroid gland and measurement of serum antithyroid antibodies were performed in 70 patients without overt thyroid disease. Lymphocytic infiltration, antithyroglobulin hemagglutination antibody (TGHA), and antithyroid microsomal hemagglutination antibody (MCHA) were found in 12, 2, and 9 cases, respectively. The incidence of lymphocytic infiltration in females was three times that in males. Ten of the 12 cases with lymphocytic infiltration had positive antibodies (either TGHA or MCHA), while 10 of 11 patients with positive antibodies showed lymphocytic infiltration. Thus, the correlation between morphological and serological findings was highly significant at P less than 0.001. The incidence of a small thyroid gland of less than 15 g in weight was higher in patients with lymphocytic infiltration and/or positive antibodies than in patients with a normal thyroid gland. These data suggest that positive serum antithyroid antibodies in subjects without overt thyroid disease may indicate the existence of lymphocytic infiltration in the thyroid gland, that is presumably subclinical autoimmune thyroiditis.

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The effect of pregnancy on the clinical course of Graves' disease was examined by studies on 41 pregnancies in 35 patients with Graves' disease, who were considered to be in a state of remission or near remission and were not receiving antithyroid drugs, during and after delivery. Eighteen of the 41 cases (44%) showed transient increases in the serum free T4 index (FT4 index) during weeks 10--15 of pregnancy, but normal thyroid function in the second and third trimesters. Similar transient increases in the serum free T3 index (FT3 index) were observed in early pregnancy in these patients. These early increases in the FT4 and FT3 indexes were specific to Graves' disease and were not observed in Hashimoto's disease. Two to 4 months postpartum, 32 cases (78%) developed various degrees of thyrotoxicosis, which was divided into 3 types: 1) persistent thyrotoxicosis with high radioactive iodine (RAIU) (10 cases), 2) transient thyrotoxicosis with normal or high RAIU) (10 cases), and 3) destruction-induced thyrotoxicosis with low RAIU (12 cases). An increase in the FT4 index in early pregnancy was significantly (P less than 0.001) associated with relapse of stimulation-induced thyrotoxicosis of either the persistent or transient type. Patients who developed destruction-induced thyrotoxicosis after delivery had significantly higher titers of antithyroid microsomal antibodies (P less than 0.001) and a longer euthyroid period before pregnancy (P less than 0.01) than patients who had recurrent persistent thyrotoxicosis. These data indicate that Graves' disease is aggravated in early pregnancy and after delivery and ameliorates in the latter half of pregnancy. Postpartum relapse of persistent hyperthyroidism could be predicted from an early increase in the FT4 index during pregnancy.

Congenital isolated thyroid‐stimulating hormone (TSH) deficiency is an autosomal recessive disease that manifests as hypothyroidism (cretinism), causing severe mental and growth retardations. Patients were found to have a single base substitution in the codon for the 29th amino acid of the TSH beta subunit gene. The alteration is in the center of the so‐called CAGYC region, which consists of an amino acid sequence conserved among all of the known glycoprotein hormone beta subunits. No other nucleotide substitutions have been found in the gene thus far sequenced. Microinjection of the mutated beta mRNAs into Xenopus laevis oocytes led to the formation of conformationally altered beta polypeptides that could not associate with alpha subunits. The mutation created a new recognition site for the enzyme MaeI. Southern blot hybridization of genomic DNA digested with MaeI showed that the patients were homozygous and their parents were heterozygous for the mutation. This test was also used to examine other family members for the disease.

Clinical thyrotoxicosis is caused by circulating hCG with higher biological activity in pregnant women with hyperemesis. A new clinical entity of 'gestational thyrotoxicosis' is proposed and tentative characteristics are discussed.

The serum ratios of T3 to T4, and T4-binding globulin (TBG) and calcitonin concentrations were studied in cases of thyrotoxic Graves' disease and destruction-induced thyrotoxicosis. In 272 patients with Graves' disease, 209 of 240 (87%) untreated patients without complications had high T3 to T4 ratios (nanograms per micrograms) of more than 20. Six of 32 (19%) patients with Graves' disease who had complications (15 with pregnancy, 14 with increased TBG, and 3 with conditions associated with a low T3 syndrome) had high T3 to T4 ratios. Eleven of 74 (15%) patients with destruction-induced thyrotoxicosis (24 with subacute thyroiditis, 39 with postpartum transient thyrotoxicosis, and 11 with spontaneous transient thyrotoxicosis) had high T3 to T4 ratios. Patients who had serum T4 levels of more than 30 micrograms/dl and/or T3 levels of more than 800 ng/dl had Graves' disease. There was no significant correlation between the T3 to T4 ratio and activities of thyroid-stimulating immunoglobulins in thyrotoxic patients with Graves' disease who had no complications. The average serum levels of TBG in destruction-induced thyrotoxicosis and thyrotoxic Graves' disease were 20.7 +/- 4.3 micrograms/ml (mean +/- SD; n = 22), and 19.9 +/- 4.0 (n = 41), respectively, which were significantly lower than that in healthy subjects (22.7 +/- 4.4 micrograms/ml; n = 165), but there was no difference between the values in the two groups of thyrotoxicosis patients. The average serum level of calcitonin in destruction-induced thyrotoxicosis patients was 96.7 +/- 66.7 pg/ml (n = 21), which was significantly (P less than 0.05) higher than the values in patients with thyrotoxic Graves' disease (62.0 +/- 44.7 pg/ml; n = 26) and in healthy subjects (63.9 +/- 31.2 pg/ml; n = 29), but the difference in values in the two groups of thyrotoxicosis was not clinically useful because of considerable overlap of individual values. The T3 to T4 ratio is a simple and helpful index for the differentiation of the two types of thyrotoxicosis. A T3 to T4 ratio less than 20 in thyrotoxic patients before therapy is a laboratory signal of destruction-induced thyrotoxicosis or Graves' disease with complications, but final differentiation should be confirmed by measuring radioactive iodine uptake.