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Open access

Xiaoya Zheng, Shanshan Yu, Jian Long, Qiang Wei, Liping Liu, Chun Liu, and Wei Ren

Objective

Both primary thyroid lymphoma (PTL) and diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC) are two rare malignant tumours with different therapies and prognoses. This study compared their clinical features.

Methods

From a retrospective review of the pathologic database at our institute between January 2015 and August 2020, 52 PTL patients and 40 DSVPTC patients were included. Demographic, clinical, laboratory and ultrasound data were extracted from electronic medical records. Statistical analyses were performed using GraphPad Prism 5.0.

Results

Both PTL and DSVPTC were more likely to occur in women (83.7 and 67.5%, respectively), but DSVPTC patients were younger (median age: 36 vs 64.5), had fewer compressive symptoms, and more frequently had neck lymph node metastasis than PTL patients. The prevalence of Hashimoto’s thyroiditis (HT) and hypothyroidism was significantly higher in PTL patients than in DSVPTC patients (31% vs 17.5%). Hyperthyroidism could only be found in DSVPTC patients, which accounted for 7.5%. Heterogeneous echogenicity and irregular edges were frequently observed in both PTL and DSVPTC. However, compared with PTL, DSVPTC exhibited smaller lesion sizes, higher frequencies of diffuse sonographic patterns and calcification and lower frequencies of hypoechoic features and internal blood flow signal. The overall survival rate with PTL was 77.23%, which was lower than that with DSVPTC (90.91%), but this difference was not significant (P  = 0.096).

Conclusion

Clinical characteristics such as age, compression symptoms, and sonographic features such as a large mass with heterogeneous echogenicity, hypoechoic, irregular edges, and calcification are helpful for impression diagnosis of PTL and DSVPTC before surgery.

Open access

Debra M Gordon, Pablo Beckers, Emilie Castermans, Sebastian J C M M Neggers, Liliya Rostomyan, Vincent Bours, Patrick Petrossians, Vinciane Dideberg, Albert Beckers, and Adrian F Daly

Objective

Screening studies have established genetic risk profiles for diseases such as multiple endocrine neoplasia type 1 (MEN1) and pheochromocytoma–paraganglioma (PPGL). Founder effects play an important role in the regional/national epidemiology of endocrine cancers, particularly PPGL. Founder effects in the Netherlands have been described for various diseases, some of which established themselves in South Africa due to Dutch emigration. The role of Dutch founder effects in South Africa has not been explored in PPGL.

Design

We performed a single-center study in South Africa of the germline genetic causes of isolated/syndromic neuroendocrine tumors.

Methods

Next-generation panel, Sanger sequencing and multiplex ligand-dependent probe amplification for endocrine neoplasia risk genes.

Results

From a group of 13 patients, we identified 6 with PPGL, 4 with sporadic or familial isolated pituitary adenomas, and 3 with clinical MEN1; genetic variants were identified in 9/13 cases. We identified the Dutch founder exon 3 deletion in SDHB in two apparently unrelated individuals with distinct ethnic backgrounds that had metastatic PPGL. Asymptomatic carriers with this Dutch founder SDHBexon 3 deletion were also identified. Other PPGL patients had variants in SDHB, and SDHD and three MEN1variants were identified among MEN1 and young-onset pituitary adenoma patients.

Conclusions

This is the first identification of a Dutch founder effect for PPGL in South Africa. Awareness of the presence of this exon 3 SDHB deletion could promote targeted screening at a local level. Insights into PPGL genetics in South Africa could be achieved by studying existing patient databases for Dutch founder mutations in SDHx genes.

Open access

Lanping Jiang, Xiaoyan Peng, Bingbin Zhao, Lei Zhang, Lubin Xu, Xuemei Li, Min Nie, and Limeng Chen

Purposes

This study was conducted to identify the frequent mutations from reported Chinese Gitelman syndrome (GS) patients, to predict the three-dimensional structure change of human Na–Cl co-transporter (hNCC), and to test the activity of these mutations and some novel mutations in vitro and in vivo.

Methods

SLC12A3 gene mutations in Chinese GS patients previously reported in the PubMed, China National Knowledge Infrastructure, and Wanfang database were summarized. Predicted configurations of wild type (WT) and mutant proteins were achieved using the I-TASSER workplace. Six missense mutations (T60M, L215F, D486N, N534K, Q617R, and R928C) were generated by site-directed mutagenesis. 22Na+ uptake experiment was carried out in the Xenopus laevisoocyte expression system. In the study, 35 GS patients and 20 healthy volunteers underwent the thiazide test.

Results

T60M, T163M, D486N, R913Q, R928C, and R959frameshift were frequent SLC12A3 gene mutations (mutated frequency >3%) in 310 Chinese GS families. The protein’s three-dimensional structure was predicted to be altered in all mutations. Compared with WT hNCC, the thiazide-sensitive 22Na+ uptake was significantly diminished for all six mutations: T60M 22 ± 9.2%, R928C 29 ± 12%, L215F 38 ± 14%, N534K 41 ± 15.5%, Q617R 63 ± 22.1%, and D486N 77 ± 20.4%. In thiazide test, the net increase in chloride fractional excretion in 20 healthy controls was significantly higher than GS patients with or without T60M or D486N mutations.

Conclusions

Frequent mutations (T60M, D486N, and R928C) and novel mutations (L215F, N534K, and Q617R) lead to protein structure alternation and protein dysfunction verified by 22Na+ uptake experiment in vitro and thiazide test on the patients.

Open access

Luis Eduardo Barbalho de Mello, Thaise Nayane Ribeiro Carneiro, Aline Neves Araujo, Camila Xavier Alves, Pedro Alexandre Favoretto Galante, Vanessa Candiotti Buzatto, Maria das Graças de Almeida, Karina Marques Vermeulen-Serpa, Sancha Helena de Lima Vale, Fernando José de Pinto Paiva, José Brandão-Neto, and Janete Maria Cerutti

The genetics underlying non-syndromic familial non-medullary thyroid carcinoma (FNMTC) is still poorly understood. To identify susceptibility genes for FNMTC, we performed whole-exome sequencing (WES) in a Brazilian family affected by papillary thyroid carcinoma (PTC) in three consecutive generations. WES was performed in four affected and two unaffected family members. Manual inspection in over 100 previously reported susceptibility genes for FNMTC showed that no variants in known genes co-segregated with disease phenotype in this family. Novel candidate genes were investigated using PhenoDB and filtered using Genome Aggregation (gnomAD) and Online Archive of Brazilian Mutations (ABraOM) population databases. The missense variant p.Ile657Met in the NID1 gene was the only variant that co-segregated with the disease, while absent in unaffected family members and controls. The allele frequency for this variant was <0.0001 in the gnomAD and ABbraOM databases. In silico analysis predicted the variant to be deleterious or likely damaging to the protein function. Somatic mutations in NID1 gene were found in nearly 500 cases of different cancer subtypes in the intOGen platform. Immunohistochemistry analysis showed NID1 expression in PTC cells, while it was absent in normal thyroid tissue. Our findings were corroborated using data from the TCGA cohort. Moreover, higher expression of NID1 was associated with higher likelihood of relapse after treatment and N1b disease in PTCs from the TCGA cohort. Although replication studies are needed to better understand the role of this variant in the FNMTC susceptibility, the NID1 variant (c.1971T>G) identified in this study fulfills several criteria that suggest it as a new FNMTC predisposing gene.

Open access

Wenjun Long, Tuo Zhou, Xiuping Xuan, Qiuli Cao, Zuojie Luo, Yingfen Qin, Qin Ning, Xiaoping Luo, and Xuemei Xie

Intrauterine growth restriction combined with postnatal accelerated growth (CG-IUGR) could lead to long-term detrimental metabolic outcomes characterized by insulin resistance. As an indispensable co-receptor of Wnt signaling, LRP6 plays a critical role in the susceptibility of metabolic disorders. However, whether LRP6 is involved in the metabolic programing is still unknown. We hypothesized that CG-IUGR programed impaired insulin sensitivity through the impaired LRP6-mediated Wnt signaling in skeletal muscle. A CG-IUGR rat model was employed. The transcriptional and translational alterations of the components of the Wnt and the insulin signaling in the skeletal muscle of the male CG-IUGR rats were determined. The role of LRP6 on the insulin signaling was evaluated by shRNA knockdown or Wnt3a stimulation of LRP6. Compared with controls, the male CG-IUGR rats showed an insulin-resistant phenotype, with impaired insulin signaling and decreased expression of LRP6/β-catenin in skeletal muscle. LRP6 knockdown led to reduced expression of the IR-β/IRS-1 in C2C12 cell line, while Wnt3a-mediated LRP6 expression increased the expression of IRS-1 and IGF-1R but not IR-β in the primary muscle cells of male CG-IUGR rats. The impaired LRP6/β-catenin/IGF-1R/IRS-1 signaling is probably one of the critical mechanisms underlying the programed impaired insulin sensitivity in male CG-IUGR.

Open access

Josephina G Kuiper, Aline C Fenneman, Anne H van der Spek, Elena Rampanelli, Max Nieuwdorp, Myrthe P P van Herk-Sukel, Valery E P P Lemmens, Ernst J Kuipers, Ron M C Herings, and Eric Fliers

Objective

Whether an association between oral levothyroxine use, leading to supraphysiological exposure of the colon to thyroid hormones, and risk of colorectal cancer exists in humans is unclear. We therefore aimed to assess whether the use of levothyroxine is associated with a reduced risk of colorectal cancer in a linked cohort of pharmacy and cancer data.

Design

Population-based matched case–control study.

Methods

A total of 28,121 patients diagnosed with colorectal cancer between 1998 and 2014 were matched to 106,086 controls. Multivariable logistic regression was used to estimate the association between levothyroxine use and occurrence of colorectal cancer, adjusted for potential confounders. Results were stratified by gender, age, tumour subtype, and staging, as well as treatment duration and dosing.

Results

A total of 1066 colorectal cancer patients (4%) and 4024 (4%) controls had used levothyroxine at any point before index date (adjusted odds ratio 0.95 (0.88–1.01)). Long-term use of levothyroxine was seen in 323 (30%) colorectal cancer patients and 1111 (28%) controls (adjusted odds ratio 1.00 (0.88–1.13)). Stratification by tumour subsite showed a borderline significant risk reduction of rectal cancer, while this was not seen for proximal colon cancer or distal colon cancer. There was no relationship with treatment duration or with levothyroxine dose.

Conclusions

In this study, no reduced risk of colorectal cancer was seen in levothyroxine users. When stratifying by tumour subsite, a borderline significant risk reduction of rectal cancer was found and may warrant further research.

Open access

Georgios Kontogeorgos, Zoi Mamasoula, Emily Krantz, Penelope Trimpou, Kerstin Landin-Wilhelmsen, and Christine M Laine

Objective

Hypoparathyroidism (HypoPT) is a rare endocrine disorder in which insufficient levels of parathyroid hormone (PTH) lead to low serum calcium (S-Ca) levels and muscular cramps. The aim was to study the health-related quality of life (HRQoL) and comorbidities in patients with HypoPT compared with the general population and to estimate the need of treatment with PTH analog.

Design

Patients with HypoPT were identified and compared with a population sample. Short Form-36 (SF-36) and EuroQol-5 Dimensions Visual Analogue Scale questionnaires were used. All patients were followed up at the Sahlgrenska University Hospital outpatient clinic.

Methods

From the medical records between 2007 and 2020, 203 patients with HypoPT were identified and compared with a population sample (n = 414) from the World Health Organization’s (WHO) MONICA project, Gothenburg, Sweden. Of the 203 patients who met the diagnostic criteria, 164 were alive and 65% answered the HRQoL questionnaires.

Results

Patients with HypoPT, 80% postsurgical, and controls had similar age (60 years) and sex distribution (80% women). Patients had lower SF-36 summary component scores for physical (40.0 (interquartile range (IQR): 21) vs 51.2 (IQR: 14.6); P < 0.001) and mental (43.1 (IQR:17.4) vs 56.1(IQR:13.3); P < 0.001) well-being, irrespective of etiology or calcium levels. Individuals with HypoPT had more medications and lower renal function but not higher mortality than controls. Low HRQoL together with low calcium was present in 23% of individuals with HypoPT.

Conclusion

HRQoL was markedly lower in patients with HypoPT than in controls and independent of S-Ca levels. Treatment with PTH analog could be considered at least among patients with both low HRQoL and low calcium levels.

Open access

Caroline Nguyen, Elisabeth Celestin, Delphine Chambolle, Agnès Linglart, Martin Biosse Duplan, Catherine Chaussain, and Lisa Friedlander

Introduction

X-linked hypophosphatemia (XLH) is a rare, hereditary, and lifelong phosphate-wasting disorder characterized by rickets in childhood and impaired teeth mineralization. In the oral cavity, spontaneous abscesses can often occur without any clinical signs of alteration of the causal tooth. The objective of our study was to evaluate the oral care pathway and the oral health-related quality of life (OHRQoL) of patients following in an expert oral medicine department located within a Parisian hospital and working in close collaboration with an endocrinology department expert in this pathology.

Methods

This study employed a qualitative descriptive design including semi-structured interviews using guiding themes.

Results

Twenty-one patients were included in the study. The topics brought up exceeded the initial objectives as the patients mostly addressed the alteration of their oral health-related and general quality of life; a very chaotic oral health care pathway with oral health professionals not aware of their pathology; consequences on their social, professional, and school integration. Patients declared the importance of having a multidisciplinary team around them, including medical and dental professionals.

Conclusions

The variety of manifestations in patients with XLH necessitates high coordination of multidisciplinary patient care to optimize quality of life and reduce disease burden. Oral health care pathways are very chaotic for patients who have difficulty in finding professionals with sufficient knowledge of the disease. OHRQoL is therefore diminished. This situation improves when patients enter a coordinated care network.

Open access

Magdaléna Fořtová, Lenka Hanousková, Martin Valkus, Jana Čepová, Richard Průša, and Karel Kotaška

Background

Fibroblast growth factor 23 (FGF23) is a key regulator of urine phosphate excretion. The aim of the study was to investigate the perioperative (intraoperative and postoperative) changes of plasma intact and C-terminal FGF23 (iFGF23, cFGF23) concentrations in patients with primary hyperparathyroidism (pHPT) submitted to surgery.

Materials and methods

The study involved 38 adult patients with pHPT caused by adenoma. Parathyroid hormone (PTH) levels were investigated intraoperatively (just before the incision and 10 min after adenoma excision). cFGF23, iFGF23, phosphate, estimated glomerular filtration rate (eGFR), and procollagen type 1 N-terminal propetide (P1NP) were measured intraoperatively and postoperatively (next day after the surgery).

Results

PTH levels decreased intraoperatively (13.10 pmol/L vs 4.17 pmol/L, P< 0.0001). FGF23 levels measured intraoperatively were at the upper level of reference interval. cFGF23 decreased postoperatively compared with the values measured just before the incision (cFGF23: 89.17 RU/mL vs 22.23 RU/mL, P< 0.0001). iFGF23 decreased as well, but the postoperative values were low. Postoperative inorganic phosphate values increased (1.03 mmol/L vs 0.8 mmol/L, P= 0.0025). We proved significant negative correlation of perioperative FGF23 with inorganic phosphate (cFGF23: Spearman’s r = −0.253, P= 0.0065; iFGF23: Spearman’s r = −0.245, P= 0.0085). We also found that FGF23 values just before incision correlated with eGFR (cystatin C) (cFGF23: Spearman’s r = −0.499, P= 0.0014; iFGF23: Spearman’s r = −0.413, P= 0.01).

Conclusion

Intraoperative iFGF23 and cFGF23 did not change despite PTH decreased significantly. cFGF23 and iFGF23 significantly decreased 1 day after parathyroidectomy and are associated with increase of inorganic phosphate in pHPT patients. cFGF23 and iFGF23 just before incision correlated with eGFR (cystatin C). Similar results found in both iFGF23 and cFGF23 suggest that each could substitute the other.

Open access

Jean-Philippe Bertocchio, Natalie Grosset, Lionel Groussin, Peter Kamenický, Fabrice Larceneux, Anne Lienhardt-Roussie, Agnès Linglart, Gérard Maruani, Eric Mirallie, François Pattou, Riyad N H Seervai, Coralie Sido, Caroline Silve, Aurélie Vilfaillot, Antoine Tabarin, Marie-Christine Vantyghem, Pascal Houillier, and the investigators of the Épi-Hypo study

Context

Recent guidelines have provided recommendations for the care of patients with chronic hypoparathyroidism. Very little is known about actual physicians’ practices or their adherence to such guidelines.

Objective

To describe the physicians’ practice patterns and their compliance with international guidelines.

Design

The cohort studies included were Épi-Hypo (118 physicians and 107 patients, from September 2016 to December 2019) and ePatients (110 patients, November 2019).

Methods

Internet-based cohorts involving all settings at a nationwide level (France). Participants were (i) physicians treating patients with chronic hypoparathyroidism and patients with chronic hypoparathyroidism either participating in the (ii) Épi-Hypo study (Épi-Hypo 2019 patients), or (iii) Hypoparathyroidism France, the national representative association (ePatients).

Results

The physicians’ specialties were mainly endocrinology (61%), nephrology (28%), family medicine (2.5%), pediatrics (2.5%), rheumatology (2%), or miscellaneous (4%) and 45% were practicing in public universities. The median number of pharmaceutical drug classes prescribed was three per patient. The combination of active vitamin D and calcium salt was given to 59 and 58% of ePatients and Épi-Hypo 2019 patients, respectively. Eighty-five percent of ePatients and 87% of physicians reported monitoring plasma calcium concentrations at a steady state at least twice a year. In 32 and 26% of cases, respectively, ePatients and physicians reported being fully in accordance with international guidelines that recommend targeting symptoms, plasma calcium and phosphate values, and urine calcium excretion.

Conclusions

The care of patients with chronic hypoparathyroidism involves physicians with very different practices, so guidelines should include and target other specialists as well as endocrinologists. Full adherence to the guidelines is low in France.