Thyrotoxicosis can lead to thyrotoxic periodic paralysis (TPP), an endocrine channelopathy, and is the most common cause of acquired periodic paralysis. Typically, paralytic attacks cease when hyperthyroidism is abolished, and recur if hyperthyroidism returns. TPP is often underdiagnosed, as it has diverse periodicity, duration and intensity. The age at which patients develop TPP closely follows the age at which thyrotoxicosis occurs. All ethnicities can be affected, but TPP is most prevalent in people of Asian and, secondly, Latin American descent. TPP is characterized by hypokalemia, suppressed TSH levels and increased levels of thyroid hormones. Nonselective β adrenergic blockers, such as propranolol, are an efficient adjuvant to antithyroid drugs to prevent paralysis; however, an early and definitive treatment should always be pursued. Evidence indicates that TPP results from the combination of genetic susceptibility, thyrotoxicosis and environmental factors (such as a high-carbohydrate diet). We believe that excess T(3) modifies the insulin sensitivity of skeletal muscle and pancreatic β cells and thus alters potassium homeostasis, but only leads to a depolarization-induced acute loss of muscle excitability in patients with inherited ion channel mutations. An integrated etiopathophysiological model is proposed based on molecular findings and knowledge gained from long-term follow-up of patients with TPP.

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Our data demonstrate that a dynamic risk stratification system that uses response to therapy variables to adjust risk estimates over time provides more useful clinical prognostic information than static initial anatomic staging in MTC thyroid cancer.

Accurate interpretation of germline mutations of the rearranged during transfection (RET) proto-oncogene is vital for the proper recommendation of preventive thyroidectomy in medullary thyroid carcinoma (MTC)-prone carriers. To gain information regarding the most disputed variant of RET, ATA-A Y791F, we sequenced blood DNA samples from a cohort of 2904 cancer-free elderly individuals (1261 via Sanger sequencing and 1643 via whole-exome/genome sequencing). We also accessed the exome sequences of an additional 8069 individuals from non-cancer-related laboratories and public databanks as well as genetic results from the Catalogue of Somatic Mutations in Cancer (COSMIC) project. The mean allelic frequency observed in the controls was 0.0031, with higher occurrences in Central European populations (0.006/0.008). The prevalence of RET Y791F in the control databases was extremely high compared with the 40 known RET pathogenic mutations (P=0.00003), while no somatic occurrence has been reported in tumours. In this study, we report new, unrelated Brazilian individuals with germline RET Y791F-only: two tumour-free elderly controls; two individuals with sporadic MTC whose Y791F-carrying relatives did not show any evidence of tumours; and a 74-year-old phaeochromocytoma patient without MTC. Furthermore, we showed that the co-occurrence of Y791F with the strong RET C634Y mutation explains the aggressive MTC phenotypes observed in a large affected family that was initially reported as Y791F-only. Our literature review revealed that limited analyses have led to the misclassification of RET Y791F as a probable pathogenic variant and, consequently, to the occurrence of unnecessary thyroidectomies. The current study will have a substantial clinical influence, as it reveals, in a comprehensive manner, that RET Y791F only shows no association with MTC susceptibility.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.