Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
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Background
Radiofrequency ablation (RFA) is effective in the treatment of thyroid nodules, leading to a 50–90% reduction with respect to baseline. Current guidelines indicate the need for a benign cytology prior to RFA, though, on the other side, this procedure is also successfully used for the treatment of papillary microcarcinomas. No specific indications are available for nodules with an indeterminate cytology (Bethesda III/IV).
Aim
To evaluate the efficacy of RFA in Bethesda III nodules without genetic alterations as verified by means of a custom panel.
Methods
We have treated 33 patients (mean delivered energy 1069 ± 1201 J/mL of basal volume) with Bethesda III cytology, EU-TIRADS 3-4, and negative genetic panel. The mean basal nodular volume was 17.3 ± 10.7 mL.
Results
Considering the whole series, the mean volume reduction rate (VRR) was 36.8 ± 16.5% at 1 month, 59.9 ± 15.5% at 6 months, and 62 ± 15.7% at 1-year follow-up. The sub-analysis done in patients with 1 and 2 years follow-up data available (n = 20 and n = 5, respectively) confirmed a progressive nodular volume decrease. At all-time points, the rate of reduction was statistically significant (P < 0.0001), without significant correlation between the VRR and the basal volume. Neither cytological changes nor complications were observed after the procedure.
Conclusion
RFA is effective in Bethesda III, oncogene-negative nodules, with reduction rates similar to those obtained in confirmed benign lesions. This procedure represents a good alternative to surgery or active surveillance in this particular class of nodules, regardless of their initial volume. A longer follow-up will allow to evaluate further reduction or possible regrowth.
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Department of Medicine, Kuma Hospital, Kobe
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What Is Known about This Topic? • Iodide transport defect (ITD) is a dyshormonogenetic congenital hypothyroidism caused by sodium/iodide symporter (NIS) gene mutations. In the lactating mammary gland, iodide is concentrated by NIS
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, and postoperative findings detected up to 4 months after surgery. Furthermore, for PTC, some molecular markers, such as BRAF and TERT promoter gene mutations, have been identified. Although BRAF mutations are frequently detected in PTC, studies
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, the first identified patients were not suspected of having a THRA gene mutation initially. The first patient was identified via exome sequencing [ 24 ]. Around the same time, 2 additional patients were identified by a candidate gene approach after
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suggestive of a hereditary form (QOE = +++; SOR = score 1). (b) If the diagnosis of MTC is made preoperatively, apparently sporadic MTC patients must be investigated for the presence of RET gene mutations (see the following paragraph) and, if positive
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stability of the thyroid tissue ( 13 ). Indeed, several thyroid pathologies, some deriving from Tg gene mutations, are associated with anomalous follicular size (e.g. goitre). In addition, Tg leaking and lymphocytic infiltrations are related to the
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Objectives
The pathogenesis of Graves’ orbitopathy (GO) remains to be fully elucidated. Here we reviewed the role of genetics and epigenetics.
Design
We conducted a PubMed search with the following key words: Graves’ orbitopathy, thyroid eye disease; or Graves’ ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome and methylome analysis were performed were chosen.
Results
The different prevalence of GO in the two sexes as well as racial differences suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and of patient-derived orbital fibroblasts suggest a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated.
Conclusions
Although pathogenetic gene variants have not been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.
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Departments of Pediatrics, Chicago, IL, USA
Departments of Committee on Genetics, The University of Chicago, Chicago, IL, USA
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Background: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). Objective: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. Methods: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T<sub>4</sub>. Although her serum TSH normalized, her serum T<sub>4</sub> remained low. Affected family members had low total T<sub>4</sub> and T<sub>3</sub>, but a normal free T<sub>4</sub> index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T<sub>4</sub> and T<sub>3</sub>. His brother had a similar thyroid phenotype. Results: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T<sub>4</sub>. Conclusions: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T<sub>4</sub> resulting in low serum T<sub>4</sub>. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.
Departments of Pediatrics, The University of Chicago, Chicago, Ill., USA
Genetics, The University of Chicago, Chicago, Ill., USA
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Fondazione Ca' Granda Policlinico, Milan, Italy
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Istituto Auxologico Italiano, Milan, Italy
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Departments of Pediatrics, The University of Chicago, Chicago, Ill., USA
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action in different tissues may coexist. During the First International Workshop on Resistance to Thyroid Hormone in Cambridge, United Kingdom in 1993, a consensus statement was issued to establish a unified nomenclature of THRB gene mutations in RTH
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cancers with RET gene mutations or fusions ( 3 , 4 ). In MTC patients, phase I/II studies with RET inhibitors reported overall response rates of 73% and phase III studies are ongoing ( 5 , 6 ). Here, we describe the case of a patient with metastatic
