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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. <b><i>Methods:</i></b> 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). <b><i>Results:</i></b> 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. <b><i>Conclusions:</i></b> 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.

Context Controversy surrounds the extent and intensity of the management of the 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 those patients. Objective 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 females [(82.6%) and 88 males (17.4%)] with low and intermediate risk with a median age of 35 years (IQR 27-46). 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 low and 209 (41.3%) in intermediate risk groups. Over a median follow up of 102 months (IQR 66-130), 458 (90.5%) patients achieved an excellent response, 17 (3.4%) were in biochemically incomplete and 31 (6.1%) in a structurally incomplete status. In univariate and multivariate analyses, age (≥ 33 years) (P &lt;0.0001, Odds ratio 1.06 (1.04-1.08) and lateral lymph node metastasis (LNM) (P &lt; 0.0001, 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 outcome. Age and lateral LMN are strong predictors of an incomplete response to therapy. This suggests that older patients and those with LMN should be managed and followed up more proactively than younger patients and those without LMN.

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&gt;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.

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Diffuse sclerosing variant (DSV) is a rare subtype of papillary thyroid cancer (PTC). Whether it represents a higher grade subtype than conventional PTC is not quite clear. Furthermore, there are limited data on its long-term outcome and its molecular genetics. In this report, we studied all cases of DSV PTC seen at our center during the last 20 years. Out of more than 6000 patients (pts) with differentiated thyroid cancer, only 37 were DSV. We reviewed the clinical and histopathological features, management and outcome of these cases. In addition, molecular genetics is partially achieved; 17 out of these 37 cases have been genotyped for BRAFV600E, TERT promotor mutations, NRAS, HRAS and KRAS mutations. The molecular profiling of the other 20 cases is being done. A total of 37 pts were studied {(12 Males:25 Females, median age 21 years (8-89)}. One pt had lobectomy and the other 36 pts (97.3%) had a total thyroidectomy. Central only (4 pts) or central/lateral lymph node dissection (29 pts) were performed. The median tumor size was 4.5 cm (1.5-8.1). The tumor was multifocal in 27 cases (73%), with extrathyroidal invasion in 27 (73%) and lymphovascular invasion in 24 pts (64.8%). A background lymphocytic thyroiditis was present in 12 pts (32.4%). Lymph node metastases were present in 34 pts (92%) and distant metastases in 13 pts (35%). The sites of metastasis are lungs in 12 pts (32.4%) and lungs and bone in 1 pt. Twenty pts (54.1%) were in TNM8 stage 1, 10 pts (27%) in stage 2, 1 (2.7%) in stage 4a, 3 (8.1%) in stage 4b and 3 unstageable. The ATA risk classification for these pts was 4 pts (10.8%) in low, 12 (32.4%) in intermediate, 19 (51.4%) in high-risk groups and 2 could not be assessed. I-131 was administered to 33 pts (89.2%). The median administered activity was 136 mCi (46-218). Fifteen pts (40.5%) received additional therapies (3 surgeries, 7 RAI, 5 surgeries, and RAI). In 17 pts (46%) which were genotyped, only 3 tumors (8.1%) had BRAFV600E mutation, 1 (2.7%) had TERT promotor C228T mutation and none had RAS mutations. At the last follow up, 15 pts (40.5%) achieved an excellent response, 9 (24%) an indeterminate response, 6 (16.2%) with a structural disease, and 7 (19%) were lost for follow up. Conclusion: DSV PTC is a rare variant, occurs mostly in adolescent and young pts, characterized by aggressive histopathological features and high rates of lymph node and distant metastases but the commonly reported mutations in PTC are rare in DSV and mortality is absent.

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Context Although synonymous mutations are usually non-pathogenic, Here, we report a family with X-linked hypophosphatemia (XLH) due to a novel synonymous PHEX variant with a unique mechanism. Methods We studied a four-member family (a mother, a son and two daughters), all are 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&gt;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 658), 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.