COVID-19 infection and thyroid function.

Context: COVID-19 is a new viral infection affecting mainly the respiratory system with involvement of many other organs. Thyroid dysfunction has been described in COVID-19 but data are still unclear and conflicting on its frequency, severity and relationship with the outcome. Patients and methods: We assessed thyroid function tests (TFT) in 50 patients admitted to our institution with confirmed COVID-19 infection. We excluded patients known to have thyroid diseases or taking drugs that may affect thyroid function. Serum free thyroxine (FT4), thyrotropin (TSH) and triiodothyronine (T3) were measured once or more during the first 10 days after admission. In about 50 % of the cases, a follow up TFT was obtained during the first year after discharge (at a median follow up of 6 months). Results: We included 50 patients, 29 males (58 %) and 21 females (42 %). The median age was 47 years (range 25-89). Overall, TFTs were completely normal in all patients except for minor transient abnormalities in 5 patients (10 %) as follows: three patients had a mild transient elevated TSH, one had a mild transient suppressed TSH and one patient had a mildly low FT4 with normal TSH. There were no differences between the follow up TFTs obtained after discharge and TFTs obtained during admission in the acute phase. Conclusion: In this study, thyroid dysfunction during acute COVID-19 infection was rare, mild and transient. However, the study might not be powered enough to detect an association between thyroid dysfunction and the severity of illness and further studies are needed to assess this issue. Late-onset thyroid dysfunction does not seem to occur in COVID-19 infection during the next year after discharge.

A Unique Mechanism of a Novel Synonymous PHEX Variant Causing X-Linked Hypophosphatemia.

CONTEXT: Synonymous mutations are usually nonpathogenic. OBJECTIVE: We report here a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. METHODS: We studied a 4-member family (a mother, a son, and 2 daughters), all affected with XLH. Genomic DNA was extracted from peripheral leucocytes. Whole exome sequencing (WES) was used to identify the underlying genetic variant in the proband (the son). Sanger sequencing was used to confirm this variant in the proband and his family members. RT-PCR and sequencing of the cDNA revealed the effect of this variant on the PHEX structure and function. RESULTS: A synonymous variant in the PHEX gene (c.1701A>C) was identified in all affected members. This variant changes the first nucleotide of exon 17 from adenine to cytosine. Using RT-PCR, this variant was shown to interfere with splicing of exons 16 with 17 resulting in a single shorter PHEX transcript in the proband compared to normal control. Sanger sequencing of the cDNA revealed a complete skipping of exon 17 and direct splicing of exons 16 and 18. This led to a frameshift and an introduction of a new stop codon in the next codon (codon 568), which ultimately led to truncation and loss of the final 183 amino acids of PHEX. CONCLUSION: This novel variant shows how a synonymous exonic mutation may induce a complex series of changes in the transcription and translation of the gene and causes a disease, a mechanism that is not commonly recognized.

Case Report: Severe Gonadal Dysgenesis Causing 46,XY Disorder of Sex Development Due to a Novel NR5A1 Variant.

Mutations in the nuclear receptor subfamily 5 group A member 1 (NR5A1) are the underlying cause of 10-20% of 46,XY disorders of sex development (DSDs). We describe a young girl with 46,XY DSD due to a unique novel mutation of the NR5A1 gene. An 11-year-old subject, raised as a female, was noticed to have clitromegly. She looked otherwise normal. However, her evaluation revealed a 46,XY karyotype, moderate clitromegly but otherwise normal female external genitalia, undescended atrophied testes, rudimentary uterus, no ovaries, and lack of breast development. Serum testosterone and estradiol were low, and gonadotropins were elevated. Adrenocortical function was normal. DNA was isolated from the peripheral leucocytes and used for whole exome sequencing. The results were confirmed by Sanger sequencing. We identified a novel mutation in NR5A1 changing the second nucleotide of the translation initiation codon (ATG>ACG) and resulting in a change of the first amino acid, methionine to threonine (p.Met1The). This led to severe gonadal dysgenesis with deficiency of testosterone and anti-Müllerian hormone (AMH) secretion. Lack of the former led to the development of female external genitalia, and lack of the latter allowed the Müllerian duct to develop into the uterus and the upper vagina. The patient has a female gender identity. Bilateral orchidectomy was performed and showed severely atrophic testes. Estrogen/progesterone therapy was initiated with excellent breast development and normal cyclical menses. In summary, we describe a severely affected case of 46,XY DSD due to a novel NR5A1 mutation involving the initiation codon that fully explains the clinical phenotype in this subject.

Natural Course of the American Thyroid Association Response to Therapy Statuses (Dynamic Risk Stratification) in Differentiated Thyroid Cancer.

The concept of response to therapy in differentiated thyroid cancer (DTC) was introduced as a dynamic risk stratification used to assess the status of the disease at the time of the evaluation during the follow-up and the risk of recurrence in the future. Our aim in this study was to evaluate the natural course over time of different response to therapy statuses. METHODS: We studied 501 nonselected DTC patients (102 males and 399 females) with a median age of 37 years (interquartile range [IQR] 29-48). All patients underwent near-total or total thyroidectomy followed by I-131 ablation (initial management). RESULTS: Of the 501 patients, 387 patients (77.2%) did not have any additional therapuetic interventions after the initial management. In this group, the response to therapy status at the time of the first evaluation after I-131 (median 17 months, IQR 14-22) was an excellent response in 258 (66.7%), an indeterminate response in 101 (26.1%), biochemically incomplete in 17 (4.4%), and structurally incomplete in 11 patients (2.8%). The status changed spontaneously without any intervention in many of them. At the last follow-up visit (median duration 101 months, IQR 71-126), 357 patients (92.2%) achieved an excellent response, 4 (1%) an indeterminate response, 8 (2.1%) a biochemically incomplete status, 16 (4.1%) a structurally incomplete status, and 2 (0.5%) died secondary to DTC with a structurally incomplete status. The response to therapy in the other 114 patients who underwent additional interventions changed from before intervention to the last evaluation as follows: excellent response, 0 to 60 patients (52.6%), indeterminate response, 20 (17.5%) to 1 patient (0.9%), biochemically incomplete 25 (21.9%) to 10 patients (9%), and structurally incomplete 69 (60.5%) to 43 patients (37.7%). Overall, at the last evaluation, 417 (83.2%) were in an excellent response, 5 (1%) in an indeterminate response, 18 (3.6%) in a biochemically incomplete status, 50 (10.2%) in a structurally incomplete status, and 11 (2.2%) died secondary to DTC with a structurally incomplete status. CONCLUSIONS: The response to therapy at the initial evaluation is predictive of the long-term outcome. Most patients with the indeterminate response and some in the biochemically incomplete statuses spontaneously regress to an excellent status. Mortality and progression of DTC occur mostly in the structurally incomplete status.

The Impact of COVID-19 Viral Infection on the Hypothalamic-Pituitary-Adrenal Axis.

OBJECTIVE: To study the adrenocortical response to an acute coronavirus disease-2019 (COVID-19) infection. METHODS: Morning plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate levels were measured in 28 consecutive patients with COVID-19 (16 men, 12 women, median age 45.5 years, range 25-69 years) on day 1 to 2 of hospital admission. These tests were repeated twice in 20 patients and thrice in 15 patients on different days. The hormone levels were correlated with severity of the disease. RESULTS: The median morning cortisol level was 196 (31-587) nmol/L. It was <100 nmol/L in 8 patients (28.6%), <200 nmol/L in 14 patients (50%), and <300 nmol/L in 18 patients (64.3%). The corresponding ACTH values had a median of 18.5 ng/L (range 4-38 ng/L), and the ACTH level was <10 ng/L in 7 patients (26.9%), <20 ng/L in 17 patients (60.7%), and <30 ng/L in 23 patients (82.1%). The repeated testing on different days showed a similar pattern. Overall, if a cutoff level of <300 nmol/L is considered abnormal in the setting of acute disease, 9 patients (32%) had cortisol levels below this limit, regardless of whether the test was done only once (3 patients) or 3 times (6 patients). When the disease was more severe, the patients had lower cortisol and ACTH levels, suggesting a direct link between the COVID-19 infection and impaired glucocorticoid response. CONCLUSION: Unexpectedly, the adrenocortical response in patients with COVID-19 infection was impaired, and a significant percentage of the patients had plasma cortisol and ACTH levels consistent with central adrenal insufficiency.

Course and Predictive Factors of Incomplete Response to Therapy in Low- and Intermediate-Risk Thyroid Cancer.

CONTEXT: Controversy surrounds the extent and intensity of the management of American Thyroid Association (ATA) intermediate- and low-risk patients with differentiated thyroid cancer (DTC). Understanding the natural history and factors that predict outcome is important for properly tailoring the management of these patients. OBJECTIVE: This work aims to study the natural course and predictive factors of incomplete response to therapy in low- and intermediate-risk DTC. PATIENTS AND METHODS: We studied a cohort of 506 consecutive patients [418 women (82.6%) and 88 men (17.4%)] with low and intermediate risk with a median age of 35 years (interquartile range [IQR], 27-46 years). We analyzed the natural course and the predictive factors of biochemically or structurally incomplete response. RESULTS: Of 506 patients studied, 297 (58.7%) patients were in the low-risk group and 209 (41.3%) were in the intermediate-risk group. Over a median follow-up of 102 months (IQR, 66-130 months), 458 (90.5%) patients achieved an excellent response, 17 (3.4%) had a biochemically incomplete status, and 31 (6.1%) had a structurally incomplete status. In univariable and multivariable analyses, age (≥ 33 years) (P < .0001, odds ratio 1.06 [1.04-1.08]) and lateral lymph node metastasis (LNM; P < .0001, odds ratio 3.2 [1.7-5.9]) were strong predictive factors for biochemically and structurally incomplete response to therapy. Sex, tumor size, multifocality, extrathyroidal extension, and lymphovascular invasion did not predict incomplete response to therapy. CONCLUSIONS: Patients with low- and intermediate-risk DTC have favorable outcomes. Age and lateral LNM are strong predictors of an incomplete response to therapy. This suggests that older patients and those with LNM should be managed and followed up more actively than younger patients and those without LNM.