Mattia Barbot

Background: Resistance to TSH is defined as reduced sensitivity to normal, biologically-active TSH, and abnormally high levels of TSH are needed to achieve normal levels of thyroid hor-mones. Case Presentation: A 15-year-old female patient, having been treated since childhood with levothyrox-ine for hyperthyrotropinemia was referred to our institution complaining of tachycardia after the levothy-roxine therapy had been increased. Thyroid ultrasound features were normal, and thyroid antibodies were negative. The therapy was gradually tapered in light of the symptoms, although subclinical hypothyroid-ism was evident at thyroid function tests. First-degree relatives were tested for thyroid function, and the father was also found to have a previously-unknown subclinical hypothyroidism. The patient underwent genetic testing for TSH receptor (TSHR) gene mutations, which revealed a gene variant hitherto not described: p.C598R (c.1792T>C). The father was also tested and was found to carry the same mutation, while other first-degree relatives were wild-type for the TSHR gene. An in-silico analysis was performed, which revealed a loss-of-function phenotype corresponding to the described variant, suggesting a novel loss-of-function TSH receptor gene mutation. Conclusion: In this case report, we present a novel loss-of-function gene mutation in the TSH receptor gene associated with a TSH resistance phenotype.

Context Diagnostic accuracy of testing currently used for the differential diagnosis of Cushing disease (CD) vs ectopic adrenocorticotropic hormone secretion (EAS) is difficult to interpret. Objective The present study aimed to identify and evaluate the diagnostic accuracy of the corticotropin-releasing hormone (CRH) test, the desmopressin test, and the high-dose dexamethasone suppression test (HDDST) when used to establish a CD or EAS diagnosis. Methods This study is a systematic review of the literature and meta-analysis. MEDLINE, OVID, and Web of Science databases were searched for articles published between 1990 and 2021. Articles included described at least 1 test(s) (CRH, desmopressin, or HDDST) and the diagnostic reference standard(s) (histopathology, petrosal sinus sampling, surgical remission, imaging, and long-term follow-up) used to establish a CD or EAS diagnosis. Results Sixty-two studies were included: 43 reported the use of the HDDST; 32, the CRH test; and the 21, the desmopressin test. The CRH test was found to have the highest sensitivity in detecting CD (ACTH 86.9%, 95% CI 82.1-90.6, cortisol 86.2%, 95% CI 78.3-91.5) and the highest specificity in detecting EAS (ACTH 93.9%, 95% CI 87-98.3, cortisol 89.4%, 95% CI 82.8-93.7). This resulted in a high diagnostic odds ratio (58, 95% CI 43.25-77.47), large area under the curve, and a receiver operating characteristic of 0.934. The diagnostic accuracy of the HDDST and desmopressin test was lower than that of the CRH test. Conclusion The meta-analysis indicates that a patient with a positive ACTH response after a CRH test is highly likely to have CD. Further studies analyzing role of dynamic testing in addition to imaging are needed.