Our results suggest a previously unknown role of NKX2-5 in the pathogenesis of TD.

Thyroid hormones (TH) are bound to three major serum transport proteins, thyroxin-binding globulin (TBG), transthyretin (TTR) and human serum albumin (HSA). TBG has the strongest affinity for TH, whereas HSA is the most abundant protein in plasma. Individuals harboring genetic variations in TH transport proteins present with altered thyroid function tests, but are clinically euthyroid and do not require treatment. Clinical awareness and early recognition of these conditions are important to prevent unnecessary therapy with possible untoward effects. This review summarizes the gene, molecular structure and properties of these TH transport proteins and provides an overview of their inherited abnormalities, clinical presentation, genetic background and pathophysiologic mechanisms.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; = 0.020; 80% vs 50% at 10 years; = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

Autologous dendritic cells pulsed with HPV E7 protein can induce T cell responses in a portion of late stage cervical cancer patients. Boosting of immune responses by adjuvants and vaccination of tumor HLA-positive patients will be mandatory in future trials.

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We report three new subjects, from two families, in whom RTH was associated with homozygous mutations in the THRB gene. They represent an important addition to the single known patient homozygous for a mutant TRβ. The clinical and laboratory abnormalities indicate a strong dominant-negative effect and are in agreement with data obtained from mice expressing a mutant Thrb in both alleles. This report strengthens the concept that the mutated TRβ interferes with the function of the TRα1 in humans.

Key Points Question Is cortical-sparing adrenalectomy associated with increased pheochromocytoma-specific morbidity and mortality for patients with bilateral pheochromocytomas compared with total adrenalectomy? Findings In this cohort study of 625 patients with bilateral pheochromocytomas, most had hereditary syndromes, but 36% initially presented with unilateral pheochromocytoma. Bilateral total adrenalectomy resulted in a high rate of adverse effects from glucocorticoid replacement therapy, whereas cortical-sparing surgery was not associated with a worse outcome. Meaning These findings suggest that cortical-sparing surgery may be the preferred approach for patients at risk for, or diagnosed with, bilateral pheochromocytomas, especially those harboring a germline mutation in one of the known predisposition genes.