Classification of follicular cell tumors of the thyroid gland: analysis involving Japanese patients from one institute.

Prognostic analyses of thyroid carcinomas of follicular cell origin were carried out on patients treated at Kuma Hospital, Kobe, Japan. A new histopathological classification based on the prognostic evidence is proposed in this study, and it is applicable to the patients treated curatively. Major histological types of papillary carcinoma, follicular carcinoma and poorly differentiated carcinoma were combined into one single entity of follicular cell adenocarcinoma because (i) they have the same cell origin (follicular cell); (ii) clear-cut separation of papillary and follicular carcinoma is not always possible, and 10 year cause-specific survival was essentially similar when the patients were treated curatively; and (iii) poorly differentiated carcinoma usually has a background of either papillary or follicular carcinoma. This adenocarcinoma together with undifferentiated carcinoma was stratified into four prognostic groups using pure morphological criteria of the degree of cellular differentiation and histological grade. They are termed well-differentiated adenocarcinoma, moderately differentiated adenocarcinoma, poorly differentiated carcinoma and undifferentiated carcinoma of the thyroid. The 10 year disease-free survival rates were 86.3-93.1%, 65.4-78.7%, and 43.0-53.8%, and 0%, respectively. The 10 year cause-specific survival rates were 97.2-100%, 91.5-97.4%, and 71.2-80.0%, and 0%, respectively.

A novel homozygous missense mutation of the dual oxidase 2 (DUOX2) gene in an adult patient with large goiter.

OBJECTIVE: To describe the first adult case of large goiter associated with a novel R1110Q mutation in the dual oxidase 2 (DUOX2) gene. She was initially euthyroid, and developed hypothyroidism later in her forties. DUOX2 is an essential enzyme in iodine organification of thyroid hormone biosynthesis. Only infant cases of congenital hypothyroidism due to mutations of the DUOX2 gene have been reported. Biallelic mutation of DUOX2 is thought to lead to total iodine organification defect. PATIENTS AND MEASUREMENT: This 57-year-old woman became first aware of goiter around the age of 20 years. Since the goiter had enlarged gradually, she consulted us at the age of 32 years. Goiter was soft, and thyroid function was normal. Antithyroid antibodies were negative. Both physical and mental development was normal. Three of her nine siblings and her mother had large goiters. At the age of 44 years, thyroid function demonstrated subclinical hypothyroidism. She started to take levo-thyroxine at a dose of 100 mug/day to reduce goiter. At the age of 56 years, goiter size remained the same. The perchlorate discharge rate was 72.8%, suggesting partial iodine organification defect. Thus, thyroid peroxidase (TPO) gene and DUOX2 gene were analyzed. RESULTS: There was no mutation in the TPO gene, but a novel homozygous mutation (R1110Q) in the DUOX2 gene was identified. The same heterozygous mutation was detected in her two sons and two grandchildren. This mutation was not detected in 104 control alleles and was located at a site differing from any other reported mutations in the DUOX2 gene. CONCLUSIONS: This homozygous missense mutation can be associated with thyroid dysfunction and goiter formation of an enlarged thyroid gland.

A novel thyrotropin receptor germline mutation (Asp617Tyr) causing hereditary hyperthyroidism.

Constitutively activating germline mutations of the thyrotropin receptor (TSHR) gene have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. We describe here a Japanese kindred with two affected individuals who showed overt hyperthyroidism and mild goiter in the absence of TSHR antibodies. A novel heterozygous germline point mutation, identified in both individuals, resulted in an amino acid substitution of aspartic acid for tyrosine at codon 617 (Asp617Tyr) in the third intracellular loop of the TSHR. Screening of 7 additional family members led to the identification of the same mutation in 4 relatives: 1 had undergone thyroidectomy due to hyperthyroidism but 3 were asymptomatic with subclinical hyperthyroidism. In vitro functional studies of the Asp617Tyr TSHR demonstrated a constitutive activation of the cyclic adenosine monophosphate pathway, but not of the inositol phosphate cascade, with data similar to those of Asp619Gly, the first constitutively activating mutant TSHR identified. Treatment with inorganic iodine for 7 months successfully relieved all symptoms of hyperthyroidism in both patients.

Risk factors for recurrence to the lymph node in papillary thyroid carcinoma patients without preoperatively detectable lateral node metastasis: validity of prophylactic modified radical neck dissection.

BACKGROUND: Although papillary carcinoma usually shows mild characteristics, it metastasizes and shows recurrence to the lymph node in high incidences. Of the two representative lymph node compartments to which papillary carcinoma metastasizes, the central compartment can be routinely dissected via the surgical incision made for thyroidectomy. However, the routine application of prophylactic lateral node dissection (modified radical neck dissection [MND]) remains controversial. In this study, we investigated risk factors for lymph node recurrence of papillary carcinoma to determine the appropriate application of prophylactic MND. METHODS: We investigated risk factors for lymph node recurrence in 1,231 patients without preoperatively detectable lateral node metastasis who underwent thyroidectomy, central node dissection, and prophylactic MND for papillary carcinoma between 1987 and 1995. RESULTS: The incidence of lateral node metastasis and the number of metastatic lateral nodes significantly increased with carcinoma size. The lymph node disease-free survival (LN-DFS) was also significantly worse in carcinoma with a maximal diameter greater than 3 cm. Massive extrathyroid extension, male gender, and age 55 years or older also reflected a poorer LN-DFS. The 10-year LN-DFS rates of patients with carcinoma having two and three or four of these features were low at 88.5% and 64.7%, respectively, although the rates of those with carcinoma having no or only one characteristic were better than 95%. CONCLUSIONS: Prophylactic MND is recommended for cases of papillary carcinoma demonstrating two or more of the following four characteristics; male gender, age 55 years or older, maximal tumor diameter larger than 3 cm, and massive extrathyroid extension.

S100A10 expression in thyroid neoplasms originating from the follicular epithelium: contribution to the aggressive characteristic of anaplastic carcinoma.

BACKGROUND: S100A10, a member of the S100 family, forms a heterotetramer with annexin IIH and promotes carcinoma invasion and metastasis by plasminogen activation. In this study, S100A10 and annexin II expression in thyroid neoplasms were demonstrated. PATIENTS AND METHODS: The expression levels of S100A10 and annexin II in 193 thyroid neoplasms were immunohistochemically investigated. RESULTS: S10A10 and annexin II were not expressed in normal follicular cells or any follicular adenomas. Cells stained positively in 14.6% and 20.8% of follicular carcinomas for S100A10 and annexin II, respectively, but their expression levels were always low. S100A10 and annexin II were expressed in all papillary carcinomas, but 88.2% and 82.8% ofpapillary carcinomas were classified in the low group. These expression levels were not linked to any clinicopathological features. S100S10 and annexin II were also expressed in all anaplastic carcinomas, with 83.3% of these lesions were classified in the high group. CONCLUSION: These findings suggest that S100A10 and annexin II contribute to the aggressive characteristics of anaplastic carcinoma, while playing a constitutive role in papillary carcinoma.

Prognosis of patients with benign thyroid diseases accompanied by incidental papillary carcinoma undetectable on preoperative imaging tests.

BACKGROUND: Despite the recent wide availability of ultrasonography and fine-needle aspiration biopsy, endocrine surgeons often encounter incidental papillary carcinoma (IPC), that is a papillary carcinoma that had gone undetected by preoperative imaging studies but was identified by pathological examination of surgical specimens resected for benign thyroid diseases. METHODS: The present study was developed to investigate the prognoses of 317 patients who underwent surgery for benign diseases involving IPC in comparison with the prognoses of 1,674 patients with clinically apparent papillary carcinoma detected preoperatively and diagnosed. RESULTS: None of the patients underwent further surgery such as completion total thyroidectomy and node dissection immediately after the diagnosis of IPC. To date, 7 patients (2.2%) have had recurrences; 6 of those were locoregional recurrences and one was a bone metastasis. None of the patients have died of thyroid carcinoma. The disease-free survival of IPC patients was significantly better than that of clinically apparent papillary carcinoma patients and was similar to that of the subset of patients with papillary microcarcinoma without clinically apparent metastasis. CONCLUSIONS: Because IPC is associated with good prognosis, further surgery, such as completion total thyroidectomy or lymph node dissection immediately after the diagnosis of IPC is not necessary.

Prognosis and prognostic factors of follicular carcinoma in Japan: importance of postoperative pathological examination.

BACKGROUND: Follicular carcinoma is known to show a worse prognosis than papillary carcinoma because of distant metastasis in higher incidence. However, few studies have been published regarding the prognosis of follicular carcinoma patients in Japan, which prompted us to investigate this issue. METHODS: We examined the prognosis and whether and how various clinicopathological features have affected disease-free survival (DFS) and cause-specific survival (CSS) of 334 patients who underwent initial surgery for follicular carcinoma. RESULTS: In 18 patients (5.4%), curative surgery could not be achieved because of distant metastasis at surgery in 17 patients and local extension in 1 patient. For 316 patients who underwent curative surgery, 5-year and 10-year DFS rates were 88.4% and 75.3%, respectively. Poorly differentiated carcinoma and widely invasive carcinoma, together with some conventional prognostic factors, predicted poorer DFS of patients. On multivariate analysis, poorly differentiated carcinoma was an independent prognostic factor for DFS. The 5-year and 10-year CSS rates for these 334 patients were 96.4% and 90.4%, respectively. Curative surgery and poorly differentiated carcinoma were recognized as independent prognostic factors. CONCLUSIONS: We can hypothesize that follicular carcinoma in Japan is generally a nonaggressive disease with a good prognosis. However, because poorly differentiated or widely invasive carcinomas showed a worse prognosis, postoperative pathological examination is important in predicting patient prognosis.

Long-term follow-up for patients with papillary thyroid carcinoma treated as benign nodules.

BACKGROUND: The recent prevalence of ultrasonography and fine-needle aspiration biopsy (FNAB) has facilitated the detection and diagnosis of papillary thyroid carcinoma. However, there are still cases that are preoperatively misdiagnosed and treated as benign nodules because ultrasonographic and FNAB findings do not provide sufficient evidence for a malignant diagnosis. In this study, we investigated the clinical outcomes of patients with papillary carcinoma that had not been recognized preoperatively. PATIENTS AND METHODS: We investigated the prognoses of 56 patients with papillary carcinoma who underwent thyroidectomy without node dissection under a diagnosis of benign nodules. RESULTS: None of the patients underwent further surgery such as completion total thyroidectomy and node dissection after the pathological diagnosis of papillary carcinoma was established. However, to date, only 3 patients (5.3%) showed recurrence 116, 133 and 148 months after the initial surgery, respectively. Two patients showed recurrence in the remnant thyroid and one showed recurrence in the bone. None of the patients have died of thyroid carcinoma. CONCLUSION: Papillary carcinomas misdiagnosed as benign nodules on ultrasonography and FNAB are indolent and very slow-growing. Immediate further surgery is not needed for such cases, even if they were resected as benign nodules at the initial surgery.

Extranodal tumor extension to adjacent organs predicts a worse cause-specific survival in patients with papillary thyroid carcinoma.

BACKGROUND: We previously reported that massive extrathyroid extension has an independent prognostic value in patients with thyroid papillary carcinoma. However, tumor extension to adjacent organs can be observed not only in primary tumor but also in metastatic nodes. In this study we investigated the clinical significance of extranodal tumor extension to adjacent organs (nodal ex) in papillary thyroid carcinoma. METHODS: We classified all cases into three categories based on the degree of nodal ex: nodal ex0, no apparent extranodal tumor extension; nodal ex1, hard metastatic nodes with perinodal growth extending to adjacent organs, which require separation of the nodes from the organs; and nodal ex2, metastatic nodes with perinodal growth completely invading the adjacent organs and requiring excision of nodes together with these organs. We investigated the clinical significance of each grade in 1,692 patients who underwent initial surgery for papillary carcinoma between 1987 and 1995. RESULTS: The presence of nodal ex was significantly linked to various clinicopathological features such as male gender, N1b, large number of metastatic nodes, pT4a, and distant metastasis. On univariate analysis, patients with either nodal ex1 or ex2 showed significantly worse disease-free and cause-specific survival rates, although these rates did not differ between patients with nodal ex1 and those with nodal ex2. Furthermore, multivariate analysis demonstrated that nodal ex independently predicts worse cause-specific survival of these patients. CONCLUSIONS: Presence of nodal ex significantly reflects the biologically aggressive behaviors of papillary carcinoma and has a prognostic value, especially for cause-specific survival of patients.

Risk factors contributing to a poor prognosis of papillary thyroid carcinoma: validity of UICC/AJCC TNM classification and stage grouping.

BACKGROUND: In 2002, the UICC/AJCC TNM classification for papillary thyroid carcinoma was revised. In this study, we examined the validity of this classification system by investigating the predictors of disease-free survival (DFS) and cause-specific survival (CSS) in patients. METHODS: We examined various clinicopathological features, including the component of the TNM classification, for 1,740 patients who underwent initial and curative surgery for papillary carcinoma between 1987 and 1995. RESULTS: Clinical and pathological T4a, clinical N1b in the TNM classification, and patient age were recognized as independent predictors of not only DFS, but also CSS of patients. Tumor size, male gender, and central node metastasis independently affected DFS only. There were 1,005 pathological N1b patients, but pathological N1b did not independently affect either DFS or CSS. Regarding the stage grouping, clinical stage IVA including clinical N1b more clearly affected DFS and CSS than pathological stage IVA including pathological N1b. CONCLUSION: Clinical stage grouping was more useful than pathological stage grouping for predicting the prognosis of papillary carcinoma patients possibly because pathological stage overestimates the biological characteristics of many pathological N1b tumors.

Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients.

CONTEXT: Recently, non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total cholesterol minus HDL-C, has emerged as a predictor of cardiovascular disease. OBJECTIVE: We evaluated the effect of L-T4 replacement on non-HDL-C levels in patients with primary hypothyroidism. METHODS: Thirteen patients with overt hypothyroidism and 26 patients with subclinical hypothyroidism participated in the study. The lipid profiles, including non-HDL-C, were measured in patients with hypothyroidism before and 3 months after L-T4 replacement was started. RESULTS: After L-T4 replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with overt hypothyroidism. In patients with subclinical hypothyroidism, the serum concentrations of total cholesterol, non-HDL-C, remnant-like particle cholesterol, and apolipoprotein B (Apo B) were significantly decreased, whereas no significant changes in the serum concentrations of low-density lipoprotein cholesterol, HDL-C, triglycerides, apolipoprotein A-I, and Lp(a) were observed. In all 39 patients, the reduction in the non-HDL-C levels correlated with the reduction in the low-density lipoprotein cholesterol, remnant-like particle cholesterol, and Apo B levels. However, the reduction in the non-HDL-C levels did not correlate with the reduction in the HDL-C, Lp(a), and apolipoprotein A-I levels. CONCLUSIONS: This study is the first to show that L-T4 replacement may reduce serum concentrations of non-HDL-C in patients with hypothyroidism. The study also suggests that such altered serum concentrations of non-HDL-C in hypothyroidism may be related to the disturbed metabolism of low-density lipoprotein, remnant lipoprotein, and Apo B.

Clinical significance of lymph node metastasis of thyroid papillary carcinoma located in one lobe.

BACKGROUND: Previous studies have shown that lymph node metastasis can be of prognostic value. In this study, we investigated the clinical significance of node metastasis focusing on metastasis in the central compartment for patients with papillary carcinoma located in one lobe. PATIENTS AND METHODS: We investigated the frequency of lymph node metastasis in 759 patients with papillary carcinoma to determine whether and how such metastasis affects disease-free survival (DFS). RESULTS: Central node metastasis was observed in 63% of patients, and the frequency was increased in relation to tumor size. The frequency of lateral node metastasis was 62.0%, which was also directly related to tumor size. On multivariate analysis of cases showing tumor larger than 1 cm, central node metastasis was recognized as an independent prognostic factor of DFS. The frequency of metastasis to the paratracheal nodes contralateral to the tumor was drastically elevated for tumors larger than 1 cm, but metastasis to this region did not independently predict worse DFS. CONCLUSION: Central node metastasis independently predicts a worse DFS for patients with papillary carcinoma larger than 1 cm.

Inverse relationships between the expression of MMP-7 and MMP-11 and predictors of poor prognosis of papillary thyroid carcinoma.

AIMS: Matrix metalloproteinases (MMPs) have various functions that play roles in carcinoma development. In this study, we investigated the expression of two representative MMPs, MMP-7 and MMP-11, in papillary thyroid carcinomas. METHODS: We immunohistochemically investigated the expression of these MMPs in 196 cases of papillary carcinoma. RESULTS: A high level of MMP-7 expression was observed in 56 cases (28.3%). The expression level was significantly decreased in cases showing large tumour, N positivity, large pT and poor differentiation. MMP-11 expression was high in 119 cases (60.1%). The expression level was inversely related to tumour size, N factor, pT factor, pN factor, extrathyroid extension, and poor differentiation. CONCLUSIONS: In contrast to other MMPs, MMP-7 and MMP-11 are inversely linked to aggressive characteristics of papillary thyroid carcinoma and their down-regulations may even be a marker of poor prognosis in patients.

Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient.

Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. We here describe a Japanese woman who had presented with severe hyperthyroidism and advanced bone age as a neonate. She underwent neurosurgical intervention for craniosynostosis, and presented with perodactylia and mild mental retardation with hydrocephalus. Hyperthyroidism has been refractory to antithyroid drug therapy in the absence of antithyrotropin receptor antibodies during follow-up of 20 years, resulting in an enlarged goiter. Analysis of the patient's genomic DNA showed a heterozygous thymine-to-adenine point mutation in exon 10 of TSHR at position 1535 which was not present in the parents' DNA. This mutation, changing leucine to glutamine in codon 512 in the third transmembrane region, was previously identified as a somatic mutation in toxic thyroid nodules and was shown to increase basal cAMP production in vitro. To our knowledge, this is the first report of a germline mutation of TSHR causing sporadic congenital nonautoimmune hyperthyroidism in a Japanese patient.

Two-day thionamide withdrawal prior to radioiodine uptake sufficiently increases uptake and does not exacerbate hyperthyroidism compared to 7-day withdrawal in Graves' disease.

The appropriate period of antithyroid drug (ATD) discontinuation before radioiodine therapy is the most critical problem in Graves' disease patients under going treatment with ATD. To determine the optimal period that does not alter the outcome of radioiodine therapy or exacerbate hyperthyroidism, we compared serum FT4 levels at radioiodine uptake (RAIU) and therapy outcomes between a 2-day withdrawal group and 7-day withdrawal group. We prospectively recruited 43 patients for the 2-day withdrawal protocol and retrospectively reviewed 49 patients treated with radioiodine following the protocol of 7-day withdrawal. There was no significant difference in RAIU between the 2 groups. The mean serum FT4 level measured on the first day of 24-h RAIU of the 7-day group was significantly higher than that in the 2-day group. There were no significant differences in the outcomes at each point (6 months, 1 year, and 2 years after therapy) between the 2 groups. Our results indicated that withdrawal of ATD for 2 days is superior to 7 days in that 2 days discontinuation did not exacerbate hyperthyroidism. In order to prevent serum thyroid hormone increase after ATD withdrawal and radioiodine therapy, a 2-day ATD withdrawal period before radioiodine therapy may be useful for high-risk patients such as the elderly and patients with cardiac complications. We believe that the 2-day ATD withdrawal method may be useful for patients undergoing treatment with ATD who are to undergo radioiodine therapy.

Sensitivity and specificity of intraoperative recurrent laryngeal nerve stimulation test for predicting vocal cord palsy after thyroid surgery.

INTRODUCTION: Recurrent laryngeal nerve (RLN) palsy after thyroidectomy, although infrequently encountered, can decrease quality of life. In addition to the hoarseness that occurs with unilateral RLN palsy, bilateral RLN palsy leads to dyspnea and often to life-threatening glottal obstruction. Therefore, intraoperative awareness of the nerve's status is of great importance. This study examined the sensitivity and specificity of a palpation technique to detect contraction of the posterior cricoarytenoid muscle (PCA) through the posterior hypopharyngeal wall while the RLN was being stimulated with a disposable nerve stimulator during thyroid surgery (the laryngeal palpation test) to predict postoperative RLN deficits. METHODS: A total of 2197 RLNs in 1376 patients were identified to be at risk of injury during thyroidectomy performed between July 2003 and August 2004. Postoperative RLN integrity was assessed using direct laryngoscopy or laryngofiberoscopy to visualize vocal fold mobility. RESULTS: Altogether, 76 RLNs failed to elicit a PCA contraction in response to nerve stimulation, and 80 cases of temporary vocal cord palsy and 21 cases of permanent vocal cord palsy were recognized on postoperative evaluation. For postoperative vocal cord palsy, the sensitivity and specificity of the laryngeal palpation test were 69.3% and 99.7%, respectively, with a positive predictive value of 92.1% and negative predictive value of 98.5%. For permanent vocal cord palsy, the sensitivity and specificity were 85.7% and 97.3%, respectively, with a positive predictive value of 23.7% and negative predictive value of 99.8%. CONCLUSIONS: The laryngeal palpation test is not a particularly useful method for predicting the level of RLN function after thyroidectomy. All patients must be examined postoperatively by direct laryngoscopy or laryngofiberoscopy to check vocal cord mobility. Even if there is no contraction of the PCA and we detect vocal cord palsy immediately after surgery, vocal cord palsy often recovers within 1 year when visual preservation of RLN is successful.

Delta Np73 expression in thyroid neoplasms originating from follicular cells.

AIMS: p73, a homologue of p53, is known as a negative regulator of tumour progression. However, delta Np73, an isoform of p73 lacking the NH2-terminal transactivation domain plays an oncogenic role by interfering with the activity of p53 and TA (full-length transactivating isoforms) p73. In this study, we investigated the expression of delta Np73 in human thyroid neoplasms originating from follicular cells. METHODS: We immunohistochemically investigated delta Np73 expression in 223 thyroid neoplasms. Delta Np73 expression level was evaluated as the sum of positivity score and intensity score. RESULTS: Normal follicular cells did not express delta Np73, but 27.3% of follicular adenoma, 85.4% of follicular carcinoma, 99.2% of papillary carcinoma, and 95.7% of anaplastic carcinoma were positive for the transcript. Delta Np73 expression level did not differ between widely invasive and minimally invasive follicular carcinomas. In papillary carcinoma, the level was inversely linked to tumour size, extrathyroid extension, and clinically apparent metastasis. Furthermore, in anaplastic carcinoma, delta Np73 expression level was significantly lower than that in papillary carcinoma. CONCLUSIONS: Our findings indicate that delta Np73 plays a role predominantly in the early phase of papillary carcinoma progression.

A case of hypothyroid Graves' disease following external radiation therapy to the cervical region.

A case of hypothyroid Graves' disease occurred following external radiation therapy to the cervical region is described. Severe hypothyroidism developed in a 56-year-old man 6 months after external radiation therapy for submandibular cancer. Serological evaluation of thyroid autoimmunity revealed the presence of antithyroid antibodies and thyrotropin-binding inhibitory immunogloblins (TBII). Diplopia, limitation of downward gaze, and palpebral edema developed 2 years after levothyroxine replacement therapy. Ocular magnetic resonance imaging revealed marked hypertrophy of the bilateral extraocular muscles with signal hyperintensity on T2-weighted images. This infiltrative ophthalmopathy showed marked improvement after additional treatment with high-dose methylprednisolone and orbital radiation, in parallel with a decrease in TBII. These results suggest that radiation-associated thyroidal injury might be associated with the etiology of hypothyroid Graves' disease.

Haplotype analysis reveals founder effects of thyroglobulin gene mutations C1058R and C1977S in Japan.

CONTEXT: Thyroglobulin (Tg) mutations were previously believed to be rare, resulting in congenital goitrous hypothyroidism. However, an increasing number of patients with Tg mutations, who are euthyroid to mildly hypothyroid, have been identified in Japan. OBJECTIVES: The purpose of this study was to investigate whether the three frequently found Tg mutations, namely C1058R, C1245R, and C1977S, were caused by a founder effect. RESULTS: We found 26 different mutations within the Tg gene in 52 patients from 41 families. Thirty-five patients were homozygous for the mutations, whereas the others were compound heterozygous. The occurrence of Tg mutation within the general Japanese population is one in 67,000. Patients with the C1245R mutation were found throughout Japan, whereas those with the C1058R mutation were confined to a small village on a southern island, and those with the C1977S mutation were restricted to a city. The eight patients with the C1058R mutation and the seven patients with the C1977S mutation all showed the same combinations of 18 single-nucleotide polymorphisms in the coding region of the Tg gene, which would appear in one in 810 million and one in 37 billion, respectively, control subjects. CONCLUSIONS: The frequently found mutations, C1058R and C1977S, were caused by founder effects. This result suggests that Tg mutations may provide a genetic basis for the cause of familial euthyroid goiter.