Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism.

Defects in genes mediating thyroid hormone biosynthesis result in dyshormonogenic congenital hypothyroidism (CH). Here, we report homozygous truncating mutations in SLC26A7 in 6 unrelated families with goitrous CH and show that goitrous hypothyroidism also occurs in Slc26a7-null mice. In both species, the gene is expressed predominantly in the thyroid gland, and loss of function is associated with impaired availability of iodine for thyroid hormone synthesis, partially corrected in mice by iodine supplementation. SLC26A7 is a member of the same transporter family as SLC26A4 (pendrin), an anion exchanger with affinity for iodide and chloride (among others), whose gene mutations cause congenital deafness and dyshormonogenic goiter. However, in contrast to pendrin, SLC26A7 does not mediate cellular iodide efflux and hearing in affected individuals is normal. We delineate a hitherto unrecognized role for SLC26A7 in thyroid hormone biosynthesis, for which the mechanism remains unclear.

An InDel in Phospholipase-C-B-1 Is Linked with Euthyroid Multinodular Goiter.

BACKGROUND: Euthyroid multinodular goiter (MNG) is common, but little is known about the genetic variations conferring predisposition. Previously, a family with MNG of adolescent onset was reported in which some family members developed papillary thyroid carcinomas (PTC). METHODS: Genome-wide linkage analysis and next-generation sequencing were conducted to identify genetic variants that may confer disease predisposition. A multipoint nonparametric LOD score of 3.01 was obtained, covering 19 cM on chromosome 20p. Haplotype analysis reduced the region of interest to 10 cM. RESULTS: Analysis of copy number variation identified an intronic InDel (∼1000 bp) in the PLCB1 gene in all eight affected family members and carriers (an unaffected person who has inherited the genetic trait). This InDel is present in approximately 1% of "healthy" Caucasians. Next-generation sequencing of the region identified no additional disease-associated variant, suggesting a possible role of the InDel. Since PLCB1 contributes to thyrocyte growth regulation, the InDel was investigated in relevant Caucasian cohorts. It was detected in 0/70 PTC but 4/81 unrelated subjects with MNG (three females; age at thyroidectomy 27-59 years; no family history of MNG/PTC). The InDel frequency is significantly higher in MNG subjects compared to controls (χ2 = 5.076; p = 0.024. PLCB1 transcript levels were significantly higher in thyroids with the InDel than without (p < 0.02). CONCLUSIONS: The intronic PLCB1 InDel is the first variant found in familial multiple papilloid adenomata-type MNG and in a subset of patients with sporadic MNG. It may function through overexpression, and increased PLC activity has been reported in thyroid neoplasms. The potential role of the deletion as a biomarker to identify MNG patients more likely to progress to PTC merits exploration.

Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake.

BACKGROUND: The Chernobyl accident caused an unprecedented increase in papillary thyroid carcinoma (PTC) incidence with a surprisingly short latency and unusual morphology. We have investigated whether unexpected features of the PTC incidence after Chernobyl were radiation specific or influenced by iodine deficiency. METHODS: PTCs from children from Belarus, Ukraine, and the Russian Federation exposed to fallout from Chernobyl were compared with PTCs from children not exposed to radiation from the same countries, from England and Wales (E&W) and from Japan. The degree and type of differentiation, fibrosis, and invasion were quantified. RESULTS: There were no significant differences between PTCs from radiation-exposed children from Belarus, Ukraine, and the Russian Federation and PTCs from children from the same countries who were not exposed to radiation. Childhood PTCs from Japan were much more highly differentiated (p < 0.001), showed more papillary differentiation (p < 0.001) and were less invasive (p < 0.01) than "Chernobyl" tumors, while tumors from E&W generally showed intermediate levels of degree and type of differentiation and invasion. There was a marked difference between the sex ratios of children with PTCs who were radiation exposed and those who were not exposed (F:M exposed vs. unexposed 1.5:1 vs. 4.2:1; chi(2) = 7.90, p < or = 0.01005). CONCLUSIONS: The aggressiveness and morphological features of Chernobyl childhood PTCs are not associated with radiation exposure. The differences found between tumors from the Chernobyl area, E&W, and Japan could be influenced by many factors. We speculate that dietary iodine levels may have wide implications in radiation-induced thyroid carcinogenesis, and that iodine deficiency could increase incidence, reduce latency, and influence tumor morphology and aggressiveness.

Thyroid implants after surgery and blunt trauma.

The differential diagnosis of thyroid tissue found laterally in the neck includes several conditions: lymph node deposits of thyroid carcinoma, "benign metastatic thyroidosis," detached thyroid nodules, and true ectopic thyroid tissue. We have studied nine cases with thyroid deposits in the soft tissues of the neck that do not conform to these diagnoses. We present evidence that they represent surgical or traumatic implantation of thyroid neoplasms. Eight of the nine cases presented one to 26 years after initial surgery. Adequate information of the operative procedure was available in seven cases, one patient underwent subtotal lobectomy and six subtotal thyroidectomy for a nodular gland. The nodules occurred within the operation field with no evidence that they were within lymph nodes. In six cases, birefringent particles consistent with talc from the earlier operation were found adjacent to the nodules. Three cases showed implants of colloid nodules, three of follicular adenoma, one of oncocytic (Hürthle) cell adenoma and one of follicular carcinoma. In the ninth case, infiltrating thyroid tissue in muscle and fibrous tissue presented 3 years after major blunt trauma to the neck. The tissue resembled that in a disrupted thyroid nodule present in the gland itself and was regarded as traumatically implanted. The observation that surgery or trauma to a nodular thyroid can occasionally lead to multiple subcutaneous thyroid implants has implication for management of thyroid disease. Therapy may be difficult; recurrence followed surgical removal of the nodules in three cases, and radioiodine may be a more effective therapy. Recognition of this entity is important for accurate pathologic diagnosis. It is apparently limited to implantation of tumor. The absence of implantation of normal or hyperplastic thyroid, despite the high frequency of partial thyroidectomy in Graves' disease, has pathobiological implications. These findings also support the generally held view that lobectomy rather than nodulectomy is the operation of choice for a solitary nodule.

Modulation of N-methyl-N-nitrosourea-induced crypt restricted metallothionein immunopositivity in mouse colon by a non-genotoxic diet-related chemical.

Red meat consumption is associated with endogenous metabolic generation of mutagenic N-nitroso compounds (NOC) and may be implicated in causation of colorectal cancer. Assessment of a biologically relevant dose of NOCs is hampered by imperfect understanding of NOC interactions with other dietary components. This study tests the hypothesis that NOC effects upon mutational biomarkers in mouse colon may be modulated by a non-genotoxic diet-related compound. N-methyl-N-nitrosourea (MNU) and undegraded lambda carrageenan (lambdaCgN) were selected as test chemicals, representing a NOC and a non-genotoxic agent, respectively. Study end-points included (i) DNA adduct formation and (ii) metallothionein (MT) crypt restricted immunopositivity indices (MTCRII) which are considered representative of crypt stem cell mutations. Frequency and size of MT immunopositive foci as well as total number of MT immunopositive crypts were assessed. Biologically effective doses of MNU and lambdaCgN were determined in model validation studies and the agents were then tested alone and in combination. Continuous lambdaCgN treatment for 10 weeks induced significantly greater colonic mucosal injury than a drinking water control. In combined treatment regimens, lambdaCgN treatment did not significantly affect MNU-induced DNA adduct formation. However, combinations of lambdaCgN with MNU significantly increased MTCRII in excess of those induced by MNU alone. Recurrent or continuous lambdaCgN regimens had greater interactive effects with MNU upon MTCRII than short-term lambdaCgN treatment. This study has shown that exposure to a non-genotoxic diet-related compound (lambdaCgN) modulates the effective NOC dosimetry for induction of MT crypt restricted immunopositivity.

Pathology of the autonomously functioning (hot) thyroid nodule.

We describe the pathologic findings of 73 clinically and scintigraphically confirmed hot nodules. In general, hot nodules from an unselected group primarily treated by surgery were smaller and the sex ratio was closer to equality compared with the ample female predominance in the referral, pre-, and post-prophylaxis groups. Malignancy was observed in six cases (8.2%) (5 follicular, 1 papillary). Of the 67 benign tumors, 48 (71.6%) were adenomas which showed the cytoarchitectural features of hot nodules described previously, and 19 (28.3%) were less well-differentiated adenomas that included a few oxyphil tumors. Intracolloid oxalate crystals from background thyroid tissue were present in 59 assessable cases (83%) overall, the majority showed more than occasional crystals that had a tendency to increase in number with decreasing morphologic activity of the thyroid epithelium. Thyroglobulin protein and mRNA stainings tended to be more pronounced in cell cytoplasm of the tumors than in background thyroid. This study shows that hot nodules may show a wide morphologic spectrum of follicular neoplasms and can be occasionally malignant. It is inferred from the morphologic and other findings that it is likely that some, if not all, of the primary follicular cancers associated with hyperfunction arise by clonal progression from benign hot nodules. This progression is rare, probably because most hot nodules present with the symptoms of hyperfunction and receive early treatment.