The RET protooncogene is constitutively activated by point mutations in hereditary medullary thyroid carcinomas (MTCs). RET somatic point mutations have also been reported in 40-50% of sporadic MTCs. Several single nucleotide polymorphisms of the RET gene have been described in the general population as well as in patients with MTC. These allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET gene. Because the exon 11 RET polymorphism determines an important aminoacidic variation (G691S), we studied its frequency in 212 subjects, 106 sporadic MTC patients and 106 normal age-, sex-, race-, and geographic origin-matched controls. In 46 cases of sporadic MTCs, we also studied the cosegregation of somatic RET gene mutation and G691S polymorphism as well as the linkage of the polymorphism with RET germline mutation in 60 members of eight multiple endocrine neoplasia type 2 families. The influence of this polymorphism on the RET gene transcription has also been studied. In parallel we analyzed the frequencies of another three neutral polymorphisms (L769L, S836S, S904S). We found a statistically significant (P = 0.029) higher allelic frequency of G691S polymorphism in MTCs (27.83%) than that found in normal controls (18.86%), at variance with the three neutral polymorphisms whose frequencies were not different in patients and controls. With this study we excluded the influence of the G691S polymorphism on RET mRNA expression, the development of the somatic RET mutation, the linkage with the germline RET mutation, the younger onset of the MTCs, and the clinical outcome of the disease. A putative role of the G691S polymorphism as genetic modifier in the normal subjects remains to be established.

To assess the significance of a single serum thyroglobulin (Tg) determination on and off thyroid suppressive therapy, serum Tg measurements have been performed in 349 serum samples from 82 patients with differentiated thyroid cancer. All samples were collected after total thyroidectomy with or without subsequent ablation of residual thyroid tissue by radioiodine. One hundred and fifty-three samples were obtained while the patients were on thyroid suppressive therapy and 196 after withdrawal of medication. The results of serum Tg assays were analysed in relation to the presence or absence of residual or metastatic thyroid tissue, as assessed by clinical and laboratory evaluation, including 131I whole body scan. In patients with thyroid residue but no metastases, undetectable serum Tg (false negative results) occurred in 45% of cases off therapy and in 92.9% of cases during therapy. In the presence of metastases no undetectable serum Tg result was found in patients off therapy, while four (6.9%) out of 58 samples from patients with bone and/or lung metastases and seven (31.8%) out of 22 samples from patients with lymph node metastases alone were undetectable (falsely negative) during suppressive therapy. Serum Tg was undetectable in sera from patients with no evidence of thyroid residue or metastatic disease in all but one (1.7%) of 59 samples on and three (5.4%) of 56 samples off suppressive therapy. These Tg results were confirmed to be truly rather than falsely positive, since evidence of metastatic disease was obtained by whole body scan after the administration of therapeutic doses of 131I.(ABSTRACT TRUNCATED AT 250 WORDS)

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The goitrogenic role of autoimmune phenomena in endemic goiter is still uncertain. Scanty and discrepant results have been reported in different areas of the world. This prompted us to evaluate the prevalence of circulating thyroid antibodies in an area of North-Western Tuscany during a survey for endemic goiter. The survey was carried out according to the P.A.H.O. criteria in a stable community. In all schoolchildren (n = 142, age range 7-15 yr) and in most of their parents (n = 159), thyroid size was evaluated and urine was collected for iodine determination. Blood was drawn for determination of circulating thyroid microsomal (MAb) and thyroglobulin antibodies (TgAb), TT3, TT4 and TSH. Prevalence of goiter in schoolchildren was 77.9% and 94.8% in their parents. Mean (+/- SD) urinary iodine excretion was 55.0 +/- 2.1 micrograms/24 h. The overall frequency of TgAb and MAb in the adult population was 14.4%, statistically higher than that of control subjects matched for sex and age. The frequency in schoolchildren was 4.3%. The presence of goiter in children was unrelated to the presence of thyroid antibodies in parents, whether goitrous or nongoitrous. A higher prevalence of goiter was found in children with goitrous parents as compared to children with nongoitrous parents (p less than 0.005). In conclusion, the frequency of thyroid autoantibodies in the adult population of the endemic area studied was increased, but showed no relation with the presence of goiter. The prevalence of goiter in children was associated with the presence of goiter but not of thyroid autoantibodies in parents. These data suggest that autoimmune phenomena are of limited importance in the development of endemic goiter.

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The value of serum thyroglobulin (Tg) determination in the differential diagnosis of congenital hypothyroidism was assessed by serum Tg measurements in 14 patients with proven congenital hypothyroidism, in 3 subjects with transient perinatal hypothyroidism, in 3 newborns with congenital thyroxine binding globulin (TBG) deficiency and in 34 normal controls. Serum Tg was undetectable in all 6 cases with thyroid agenesis, normal or moderately elevated in the 4 cases with ectopic thyroid, markedly increased in the 4 cases with dyshormonogenic goiter and normal in the 3 cases with transient hypothyroidism and in the 3 with TBG deficiency. The present data indicate that serum Tg measurements may be useful in the differentiation of athyreotic hypothyroidism from other conditions of congenital hypothyroidism.

Serum thyroglobulin (Tg) was measured in the cord blood of 635 newborns and serum thyroxine (T4) reverse triiodothyronine (rT3), TSH and T3 were measured in about 200 of them. Cord Tg was detectable in all newborns with a mean +/- SE value (50 +/- 1.3 ng/ml) higher than that found in the serum of adult subjects (n = 144; Tg = 13 +/- 1.1; p less than 0.0001). Cord Tg had a log-normal distribution. A low, but positive correlation was found between cord Tg and cord TSH (n = 242; r = 0.17; p less than 0.05) but not with cord T4 or cord rT3. Gestational age was negatively correlated with cord Tg or cord rT3 (rS = 0.97; p less than 0.01; rS = -0.89; p less than 0.02, respectively) while was positively correlated with cord T4 or cord TSH (rS = 0.85; p less than 0.05; rS = 0.86; p less than 0.01, respectively). Birth weight, maternal diabetes, induction of labor with oxitocin, cesarian section and newborns' illness showed no influence on cord Tg levels when considered alone, but decreased cord Tg levels were found in ill newborns delivered by cesarian section. On the contrary, increased cord Tg levels were present in cord blood of newborns who developed hypoglycemia soon after birth and in small for gestational age newborns. In 24 newborns studied daily for the first 6 days of life, serum Tg was always detectable with mean values not different from those found in the cord blood.(ABSTRACT TRUNCATED AT 250 WORDS)