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Ute I Scholl

Germline mutations in the chloride channel gene CLCN2 have been described as cause of familial hyperaldosteronism type II. In this issue, Dutta and colleagues in a groundbreaking study identify a somatic (tumor-specific) CLCN2 mutation in an aldosterone-producing adenoma, expanding the disease spectrum associated with CLCN2 mutations.

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Warrick J Inder

While the ACTH1-24 test has some well documented short comings, it is the most widely used test to diagnose primary and secondary adrenal insufficiency. However, this synthetic ACTH preparation is not readily available in some countries. Research from India has demonstrated that using a long acting porcine sequence ACTH has similar diagnostic performance to ACTH1-24 at around 25% of the cost. This may allow access to a robust test for adrenal insufficiency to developing countries and potentially allow thousands of patients to be identified and appropriately treated.

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Luigi Maione, Giovanna Pala, Claire Bouvattier, Séverine Trabado, Georgios Papadakis, Philippe Chanson, Jerome Bouligand, Nelly Pitteloud, Andrew A Dwyer, Mohamad Maghnie and Jacques Young

Context: Congenital hypogonadotropic hypogonadism/Kallmann Syndrome (CHH/KS) is a rare condition characterized by gonadotropin deficiency and pubertal failure. Adult height (AH) in patients with CHH/KS has not been well studied.

Objective: To assess AH in a large cohort of patients with CHH/KS.

Patients: A total of 219 patients (165 males, 54 females). Parents and siblings were included.

Methods: AH was assessed in patients and family members. AH was compared to the general French population, parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered the difference between AH and parental TH. ∆H was compared between patients and siblings, normosmic CHH and KS (CHH+anosmia or hyposmia), and according to underlying genetic defect. We examined correlations between ∆H and age at diagnosis and therapeutically-induced individual statural gain.

Results: Mean AH in men and women with CHH/KS was greater than in the French general population. Patients of both sexes had statural gain (AH>TH). Males with CHH/KS were significantly, albeit moderately, taller than their brothers. ∆H was higher in CHH/KS compared to unaffected siblings (+6.2±7.2 cm versus +3.4±5.2 cm, p<0.0001). ∆H was positively correlated with age at diagnosis (r=0.22, p=0.002). Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual therapeutically induced growth gain inversely correlated with the age at initiation of hormonal treatment (r=-0.57, p<0.0001). Patients starting treatment prior to age 16 gained more height with therapy compared to delayed treatment (16.6±5.9 versus 4.1±5.2 cm, p<0.0001).

Conclusions: CHH/KS is associated with a significant statural gain compared to the general population, mid-parental TH and same sex siblings. Greater height in CHH/KS than siblings indicates that those differences are independent of an intergenerational effect on statural gain.

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Julia Vergier, Frederic Castinetti, Alexandru Saveanu, Nadine Girard, Thierry Brue and Rachel Reynaud

Pituitary stalk interruption syndrome (PSIS) is a congenital pituitary anatomical defect. This syndrome is an antenatal developmental defect belonging to the holoprosencephaly phenotype spectrum. It is heterogeneous regarding clinical, biological and radiological presentation and is characterized by the following triad: thin (<1 mm) or interrupted pituitary stalk connecting the hypothalamus to the pituitary gland, no eutopic posterior lobe, and hypoplasia or aplasia of the anterior lobe. This review reports current knowledge about the composite pathogenesis, for which underlying mechanisms remain unclear. Current data suggest genetic origins involving early developmental gene mutations with complex inheritance patterns and environmental influence, placing PSIS at the crossroads between Mendelian and multifactorial diseases. The phenotype associated with PSIS is highly heterogeneous with a high incidence of various combinations of hormonal deficiencies, sometimes associated with extra-pituitary birth defects. The age at onset is variable, but typical presentation is evolutive combined anterior pituitary hormone deficiencies at pediatric age, which progress even during adulthood to panhypopituitarism. Therefore, patients’ follow-up throughout life is essential for adequate management.

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Oluwatoyosi Bello, Meera Ladwa, Olah Hakim, Chinmay Marathe, Fariba Shoajee-Moradie, Geoff Charles-Edwards, Janet L Peacock, Margot A Umpleby, Stephanie Amiel and Louise Goff

Objectives: In men of black west African (BAM) and white European (WEM) ethnicity, we aimed to 1) compare adipose tissue, peripheral and hepatic insulin sensitivity, and 2) investigate associations between ectopic fat and insulin sensitivity by ethnicity.

Design and Methods: In overweight BAM (n=21) and WEM (n=23) with normal glucose tolerance, we performed a two-step hyperinsulinaemic–euglycaemic clamp with infusion of [6,6 2H2]-glucose and [2H5]-glycerol to measure whole body, peripheral, hepatic and adipose tissue insulin sensitivity (lipolysis). Visceral adipose tissue (VAT), intrahepatic lipids (IHL) and intramyocellular (IMCL) lipids were measured using magnetic resonance imaging and spectroscopy. Associations between insulin sensitivity and ectopic fat were assessed using Pearson’s correlation coefficient by ethnicity and regression analysis.

Results: There were no ethnic differences in whole body or tissue-specific insulin sensitivity (all p>0.05). Suppression of lipolysis was inversely associated with VAT and IHL in WEM but not BAM (VAT: WEM r=-0.68, p<0.01; BAM r=0.07, p=0.79. IHL: WEM r=-0.52, p=0.01; BAM r=-0.12, p=0.63). IMCL was inversely associated with skeletal muscle insulin sensitivity in WEM but not BAM (WEM r=-0.56,p<0.01; BAM r=-0.09, p=0.75) and IHL was inversely associated with hepatic insulin sensitivity in WEM but not BAM (WEM r=-0.53, p=0.02; BAM r=-0.13, p=0.62).

Conclusions: Ectopic fat deposition may play a lesser role in reducing insulin sensitivity in men of black African ethnicity, and may not be driven by lipolysis. Resistance to storing VAT, IHL and IMCL may enable men of black African ethnicity to maintain comparable insulin sensitivity to white Europeans.

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Haixia Guan, Nathalie Silva de Morais, Jessica Stuart, Sara Ahmadi, Ellen Marqusee, Mathew I Kim and Erik K. Alexander

Objective

To investigate the concordance of serologic and sonographic evidence of Hashimoto’s thyroiditis with its gold standard histopathologic identification.

Design

We performed a retrospective analysis on a cohort of 825 consecutive patients in whom TPOAb and thyroid ultrasound were performed, and in whom thyroid nodule evaluation led to surgical and histopathologic analysis. The presence or absence of Hashimoto’s thyroiditis on histopathology was correlated with serologic and sonographic markers. We further assessed the impact of low versus high titers of TPOAb upon this concordance.

Results

Of 825 patients, 277 (33.5%) had histologic confirmation of Hashimoto’s thyroiditis, 235 patients (28.4%) had elevated serum levels of TPOAb, and 197 (23.8%) had sonographic evidence of diffuse heterogeneity. Of those with histopathologic evidence, only 64% had elevated TPOAb (sensitivity: 63.9%; specificity: 89.4%), while only 49% were sonographically diffusely heterogeneous (sensitivity: 49.1%; specificity: 88.9%). A subset of only 102 of 277 (37%) with histologically proven Hashimoto’s thyroiditis was positive for both TPOAb and diffusely heterogeneous. Concordance analysis demonstrated that TPOAb and histopathology had higher agreement (κ = 0.55) than did ultrasound and histopathology (κ = 0.40) for the diagnosis of Hashimoto’s thyroiditis. Higher titers of TPOAb correlated with a higher likelihood of Hashimoto’s thyroiditis, with a best cutoff of 2.11-fold the upper normal level of TPOAb.

Conclusion

Only moderate concordance exists between serological evidence of Hashimoto’s thyroiditis and histopathologic findings, though it increases with higher TPOAb concentration. Diffuse heterogeneity on ultrasound is a less-sensitive diagnostic tool than elevated TPOAb.

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Liron Yoffe, Avital Polsky, Avital Gilam, Chen Raff, Federico Mecacci, Agostino Ognibene, Fatima Crispi, Eduard Gratacós, Hannah Kanety, Shali Mazaki-Tovi, Noam Shomron and Moshe Hod

Design

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications and its prevalence is constantly rising worldwide. Diagnosis is commonly in the late second or early third trimester of pregnancy, though the development of GDM starts early; hence, first-trimester diagnosis is feasible.

Objective

Our objective was to identify microRNAs that best distinguish GDM samples from those of healthy pregnant women and to evaluate the predictive value of microRNAs for GDM detection in the first trimester.

Methods

We investigated the abundance of circulating microRNAs in the plasma of pregnant women in their first trimester. Two populations were included in the study to enable population-specific as well as cross-population inspection of expression profiles. Each microRNA was tested for differential expression in GDM vs control samples, and their efficiency for GDM detection was evaluated using machine-learning models.

Results

Two upregulated microRNAs (miR-223 and miR-23a) were identified in GDM vs the control set, and validated on a new cohort of women. Using both microRNAs in a logistic-regression model, we achieved an AUC value of 0.91. We further demonstrated the overall predictive value of microRNAs using several types of multivariable machine-learning models that included the entire set of expressed microRNAs. All models achieved high accuracy when applied on the dataset (mean AUC = 0.77). The significance of the classification results was established via permutation tests.

Conclusions

Our findings suggest that circulating microRNAs are potential biomarkers for GDM in the first trimester. This warrants further examination and lays the foundation for producing a novel early non-invasive diagnostic tool for GDM.

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Urszula Razny, Anna Polus, Joanna Goralska, Anna Zdzienicka, Anna Gruca, Maria Kapusta, Maria Biela, Aldona Dembinska-Kiec, Bogdan Solnica and Malgorzata Malczewska-Malec

Objective

To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance.

Design

Cross-sectional study.

Methods

Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls.

Results

Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling – β catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load.

Conclusions

Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.

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Mehtap Derya Aydemirli, E Kapiteijn, Kaylee R.m. Ferrier, Nelleke Ottevanger, Thera P Links, Anouk N.a. van der Horst-Schrivers, Karen Esther Broekman, Rolf H.h. Groenwold and Juliette Zwaveling

Objective: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial.

Methods: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care, were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies.

Results: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n=11, 28%), diarrhoea (n=7, 18%), vomiting (n=4, 10%), and gallbladder disease (n=3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI), 4.0-15.5) and 18.3 (95% CI, 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (p=0.04).

Conclusions: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real life population and the SELECT study population regarding patient characteristics should be taken into account.