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Stefan M Constantinescu, Natacha Driessens, Aurélie Lefebvre, Raluca M Furnica, Bernard Corvilain, and Dominique Maiter


Intravenous etomidate infusion is effective to rapidly lower cortisol levels in severe Cushing’s syndrome (CS) in the intensive care unit (ICU). Recently, etomidate treatment has also been proposed at lower doses in non-ICU wards, but it is not yet clear how this approach compares to ICU treatment.


We compared data from patients with severe CS treated with high starting doses of etomidate (median: 0.30 mg/kg BW/day) in ICU or with lower starting doses (median: 0.025 mg/kg BW/day) in non-ICU medical wards.


Fourteen patients were included, among which ten were treated with low starting doses (LD) and four with high starting doses etomidate (HD). All patients had severe and complicated CS related to adrenal carcinoma (n = 8) or ectopic ACTH secretion (n = 6). Etomidate was effective in reducing cortisol levels below 500 nmol/L in a median of 1 day in the HD group compared to 3 days in the LD group (P = 0.013). However, all patients of the HD group had etomidate-induced cortisol insufficiency and needed frequent monitoring, while no patient from the LD group required hydrocortisone supplementation. No patient in either group died from complications of CS or etomidate treatment, but final outcome was poor as six patients in the LD group and all four patients in the HD group died from their cancer during follow-up.


Our study suggests that, for patients with severe CS who do not require intensive organ-supporting therapy, the use of very low doses of etomidate in medical wards should be considered.

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Athanasia Stoupa, Ghada Al Hage Chehade, Dulanjalee Kariyawasam, Celine Tohier, Christine Bole-Feysot, Patrick Nitschke, Helene Thibault, Marie-laure Jullie, Michel Polak, and Aurore Carré

Background: Among patients with congenital hypothyroidism, 35% have dyshormonogenesis (DH) with thyroid gland in situ with or without goiter. The majority of DH cases are due to mutations in genes involved in thyroid hormone production as TG, TPO, SLC5A5/NIS, SLC26A4/PDS, IYD/DEHAL1, DUOX2, and DUOXA2, and are usually inherited on an autosomal recessive basis. Most previously reported cases of fetal hypothyroidism and goiter were related to TG or TPO mutations and recently DUOXA2.

Patient: In a male patient with antenatal goiter treated with intraamniotic levothyroxine injections, whose long-term follow-up is described in detail, two novel NIS mutations were detected. Mutations of NIS were located in exon 1 (c.52G>A, p.G18R) and exon 13 (c.1546C>T, p.R516X), each mutation was inherited from parents, who are healthy carriers. The p.G18R mutation affecting the first transmembrane domain of the protein can be responsible for deficient iodide uptake. However, the second is a nonsense mutation leading probably to mRNA degradation. In addition, the patient has undergone a thyroidectomy and we have studied the thyroid tissue. The thyroid histology showed heterogeneity with large follicles, epithelial hyperplasia and many areas of fibrosis. Immunohistochemistry with NIS specific antibody showed NIS staining at the basolateral plasma membrane of the thyrocytes.

Conclusions: We report the first case of fetal goitrous hypothyroidism due to two novel NIS mutations with access to thyroid tissue of the patient, specific histology studies and long-term follow-up. This case expands our knowledge and provides further insights on molecular causes of fetal goiter in humans.

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Daniel G Bichet

For an endocrinologist, nephrogenic diabetes insipidus (NDI) is an end-organ disease, that is the antidiuretic hormone, arginine-vasopressin (AVP) is normally produced but not recognized by the kidney with an inability to concentrate urine despite elevated plasma concentrations of AVP. Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. For a geneticist, hereditary NDI is a rare disease with a prevalence of five per million males secondary to loss of function of the vasopressin V2 receptor, an X-linked gene, or loss of function of the water channel AQP2. These are small genes, easily sequenced, with a number of both recurrent and private mutations described as disease causing. Other inherited disorders with mild, moderate or severe inability to concentrate urine include Bartter’s syndrome and cystinosis. MAGED2 mutations are responsible for a transient form of Bartter’s syndrome with severe polyhydramnios. The purpose of this review is to describe classical phenotype findings that will help physicians to identify early, before dehydration episodes with hypernatremia, patients with familial NDI. A number of patients are still diagnosed late with repeated dehydration episodes and large dilations of the urinary tract leading to a flow obstructive nephropathy with progressive deterioration of glomerular function. Families with ancestral X-linked AVPR2 mutations could be reconstructed and all female heterozygote patients identified with subsequent perinatal genetic testing to recognize affected males within 2 weeks of birth. Prevention of dehydration episodes is of critical importance in early life and beyond and decreasing solute intake will diminish total urine output.

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M Deandrea, P Trimboli, A Creanza, F Garino, A Mormile, S Bertolino, R Garberoglio, P Limone, and M Zingrillo

Background and aim. Cystic thyroid nodules (CNs), although generally benign, can cause compressive or aesthetic problems. Percutaneous ethanol injection (PEI) can represent an alternative to surgery. The present retrospective study evaluates: 1) the long-term outcome of CNs after PEI; 2) the differences between two different PEI protocols; 3) the CNs response according to the liquid component.

Materials and methods. The study comprises 358 nodules post-PEI followed for at least two years. PEI was performed according two different treatment protocols with a single (Foggia) or double (Turin) alcohol injection. CNs were divided according to their composition: cystic (CYS) > 90%, mainly cystic (M-CYS) 75-90%, mixed (MIX) 50-75%, solid-mixed (S-MIX) 35-50%. The volume reduction rate (VRR) was defined as nodule volume (ml) after PEI/nodule volume (ml) before PEI x 100.

Results. The 1-year VRR was significantly higher than that at 6 months (89.5% vs. 72.9%, p=0.0005), no differences were observed after one year. A significant difference between Turin and Foggia was observed only in VRR at early visit (79% vs. 86%, respectively, p=0.002) and recurrence rate (14% vs. 24%, respectively, p=0.001). Minor side-effects were infrequent. In 192 nodules with a 10-year follow-up CYS showed higher VRR than MIX and S-MIX nodules (p<0.001).

Conclusion. Our study reported that the long-term outcome of CNs treated with PEI is excellent regardless of the PEI technique utilized; the larger the cystic amount, the higher the VRR. Based on present results, PEI can be considered as the first-line choice for treating thyroid CNs

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Mariacarolina Salerno, Nicola Improda, and Donatella Capalbo

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

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Christine Poitou, Héléna Mosbah, and Karine Clemént

Obesity, defined by an excess of body fat impacting on health, is a complex disease resulting from the interaction between many genetic/epigenetic factors and environmental triggers. For clinical situations with severe obesity, it has been possible to classify these obesity forms according to the molecular alterations. These include: i) syndromic obesity, which associates severe early-onset obesity with neurodevelopmental disorders and/or polymalformative syndrome, and, ii) non-syndromic monogenic obesity, due to gene variants most often located in the leptin-melanocortin pathway. In addition to severe obesity, patients affected by these diseases display complex somatic conditions, eventually including obesity comorbidities, neuropsychological and psychiatric disorders. These conditions render the clinical management of these patients particularly challenging. Patients’ early diagnosis is critical to allow specialized and multidisciplinary care, with a necessary interaction between the health and social sectors. Up to now, the management of genetic obesity was only based, above all, on controlling the patient's environment, which involves limiting access to food, ensuring a reassuring daily eating environment that limits impulsiveness, and the practice of adapted, supported, and supervised physical activity. Bariatric surgery has also been undertaken in genetic obesity cases with uncertain outcomes. The context is rapidly changing, as new innovative therapies are currently being tested both for syndromic and monogenic forms of obesity. This review focuses on care management and new therapeutic opportunities in genetic obesity, including the use of the melanocortin 4 agonist, setmelanotide. The results from ongoing trials will hopefully pave the way to a future precision medicine approach for genetic obesity.

Open access

John P. Bilezikian, Daniel Bikle, Martin Hewison, Marise Lazaretti-Castro, Anna Maria Formenti, Aakriti Gupta, Mahesh V Madhavan, Nandini Nair, Varta Babalyan, Nicholas James Hutchings, Nicola Napoli, Domenico Accili, Neil Binkley, Donald W Landry, and Andrea Giustina

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.

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Victoria S Sprung, Kelly A Bowden Davies, Juliette A Norman, Andrew Thompson, Katie L Mitchell, John P H Wilding, Graham J Kemp, and Daniel J Cuthbertson


Data suggest that metabolic health status, incorporating components of metabolic syndrome (MetS), predicts cardiovascular disease (CVD) risk better than BMI. This study explored the association of MetS and obesity with endothelial function, a prognostic risk factor for incident CVD.


Forty-four participants were phenotyped according to BMI as non-obese vs obese (<30 or >30 kg/m2) and according to the International Diabetes Federation criteria of MetS: ≤2 criteria MetS (MetS−) vs ≥3 criteria MetS (MetS+); (1.)non-obese MetS− vs (2.) non-obese MetS+ and (3.) obese MetS vs (4.) obese MetS+. Flow-mediated dilation (FMD), body composition including liver fat (MRI and spectroscopy), dietary intake, intensities of habitual physical activity and cardio-respiratory fitness were determined. Variables were analysed using a one-factor between-groups ANOVA and linear regression; mean (95% CI) are presented.


Individuals with MetS+ displayed lower FMD than those with MetS−. For non-obese individuals mean difference between MetS+ and MetS− was 4.1% ((1.0, 7.3); P = 0.004) and obese individuals had a mean difference between MetS+ and MetS− of 6.2% ((3.1, 9.2); P < 0.001). Although there was no association between BMI and FMD (P = 0.27), an increased number of MetS components was associated with a lower FMD (P = 0.005), and after adjustment for age and sex, 19.7% of the variance of FMD was explained by MetS, whereas only 1.1% was explained by BMI.


In this study cohort, components of MetS, rather than obesity per se, contribute to reduced FMD, which suggests a reduced bioavailability of nitric oxide and thus increased risk of CVD.

Open access

Friso de Vries, Mees Bruin, Angelica Cersosimo, Charlotte N van Beuzekom, S Faisal Ahmed, Robin P Peeters, Nienke R Biermasz, Olaf Hiort, and Alberto M Pereira


Given that volumes of patients and interventions are important criteria to qualify as a reference centre (RC) for the European Reference Network on Rare Endocrine Conditions (Endo-ERN), the present study aimed to evaluate the data that were reported in the original application against subsequent assessments of activity and review the criteria that may define RCs using two main thematic groups (MTGs): Pituitary and Thyroid, as examples.


Review of content in application forms and continuous monitoring data and of a survey distributed to RCs. A list of ‘key procedures’ for the assessment of performance of RCs was composed with the help of the Pituitary and Thyroid MTG chairs.


In the original application, the number of undefined procedures ranged from 20 to 5500/year (Pituitary) and from 10 to 2700/year (phyroid) between applicants. In the survey, the number of key procedures per centre ranged from 18 to 150/year (Pituitary) and from 20 to 1376/year (Thyroid). The median numbers of new patients reported in the continuous monitoring program were comparable with the application and survey; however, some centres reported large variations.


Monitoring of clinical activity in an ERN requires clear definitions that are optimally aligned with clinical practice, diagnosis registration, and hospital IT systems. This is a particular challenge in the rare disease field where the centre may also provide expert input in collaboration with local hospitals. Application of uniform definitions, in addition to condition-specific clinical benchmarks, which can include patient-reported- as well as clinician-reported outcome measures, is urgently needed to allow benchmarking of care across Endo-ERN.

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Flavia Magri, Spyridon Chytiris, Laura Croce, Martina Molteni, Giulia Bendotti, Giovanni Gruosso, Samuel Ngnitejeu Tata, Manuela Agozzino, Mario Rotondi, and Luca Chiovato

Objective The ultrasonographic scores EU TI-RADS and ACR TI-RADS were introduced to give the clinicians indications for fine-needle-aspiration-cytology (FNAC). The predictive role of these scores was never evaluated and compared in a surgical series of patients. The aim of this study was to evaluate the ex-post diagnostic accuracy of EU TI-RADS and ACR TI-RADS in a real-life series of thyroidectomized patients and to evaluate the “missing” thyroid cancer following the operational indications of these scores.

Design retrospective monocentric cohort study. Methods 255 patients (harboring 304 nodules) undergoing thyroidectomy for benign and malignant thyroid conditions were enrolled. The prevalence of thyroid malignancy for each class of ACR TI-RADS and EU TI-RADS, their diagnostic accuracy, the number of “unnecessary” FNAC and the number of “missed” cancers were evaluated.

Results ACR TI-RADS and EU TI-RADS score had similar and satisfactory accuracy values for predicting thyroid malignancy (AUC: 0.835 for ACR TI-RADS vs 0.827 for EU TI-RADS). The ACR TI-RADS and EU TI-RADS categories (suspicious vs non-suspicious), age, sex and presence of a single nodule significantly and independently predicted the presence of malignancy in a logistic regression model. An ex post-analysis according to the indications for FNAC for each score indicated that 31 and 16 cases of cancer would have been missed by ACR TI-RADS and EU TI-RADS scores, respectively.

Conclusions ACR TI-RADS and EU TI-RADS display a good performance in predicting thyroid cancer when histology is taken as reference standard, but additional clinical judgement is required to decide the indication for FNAC.