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Luigi Maione, Giovanna Pala, Claire Bouvattier, Séverine Trabado, Georgios Papadakis, Philippe Chanson, Jérôme 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, mid parental target height (TH) and between patients and same-sex siblings. Delta height (∆H) was considered as the difference between AH and parental TH. ∆H was compared between patients and siblings, normosmic CHH and KS (CHH with anosmia/hyposmia), and according to underlying genetic defect. We examined the 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 that in the French general population. Patients of both sexes had 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 vs +3.4 ± 5.2 cm, P < 0.0001). ∆H was positively correlated with age at diagnosis. Neither olfactory function (normosmic CHH vs KS) nor specific genetic cause impacted ∆H. Individual growth during replacement therapy inversely correlated with the age at initiation of hormonal treatment (P < 0.0001).

Conclusions

CHH/KS is associated with higher AH compared to the general population and mid-parental TH. Greater height in CHH/KS than siblings indicates that those differences are in part independent of an intergenerational effect.

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M D Aydemirli, E Kapiteijn, K R M Ferrier, P B Ottevanger, T P Links, A N A van der Horst-Schrivers, K E Broekman, R H H Groenwold and J 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.

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Nicole Jacqueline Jensen, Malin Nilsson, Jonas Schultz Ingerslev, Dorte Aalund Olsen, Mogens Fenger, Mads Svart, Niels Møller, Mette Zander, Kamilla Woznica Miskowiak and Jørgen Rungby

Objective

Cognitive impairment in type 2 diabetes is associated with cerebral glucose hypometabolism. Providing a glucose substitute such as ketone bodies might restore metabolic balance in glucose-compromised neurones and improve cognitive performance. We aimed to investigate if β-hydroxybutyrate (ketone body) infusion acutely affects cognitive performance, measured by a neuropsychological test battery, in patients with type 2 diabetes.

Design

Randomised, placebo-controlled, double-blind cross-over trial.

Methods

Eighteen patients with type 2 diabetes received i.v. ketone body (β-hydroxybutyrate) and placebo (saline) infusion in a randomised order on two separate occasions. On both days of examination, blood glucose was clamped at 7.5 mmol/L and a neuropsychological test battery was used to assess global cognitive performance (primary outcome) and specialized cognitive measures of verbal memory, working memory, executive function, psychomotor speed, and sustained attention.

Results

During neurocognitive testing, β-hydroxybutyrate concentrations were 2.4 vs 0.1 mmol/L. Working memory assessed by Wechsler Adult Intelligence Scale letter-number-sequencing significantly improved by 1.6 points (95% CI: 0.7, 2.4; non-adjusted P < 0.001) corresponding to a 17% increase in performance during ketone infusion compared to placebo. There was no change for global cognitive performance or any other cognitive measure after adjusting for multiple comparisons. Blood concentrations of β-hydroxybutyrate and glycaemic status did not associate with test performance; however, insulin resistance measured by HOMA was related to improved working memory performance during ketone infusion (β = 4%; 95% CI: 1.1, 7.7; P = 0.012).

Conclusions

Ketone infusion specifically improved working memory performance in patients with type 2 diabetes in the absence of changes in global cognition.

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Edoarda Vasco de Albuquerque Albuquerque, Mariana Ferreira de Assis Funari, Elisângela Pereira de Souza Quedas, Rachel Sayuri Honjo Kawahira, Raquel Soares Jallad, Thaís Kataoka Homma, Regina Matsunaga Martin, Vinicius Nahime Brito, Alexsandra Christianne Malaquias, Antonio Marcondes Lerario, Carla Rosenberg, Ana Cristina Victorino Krepischi, Chong Ae Kim, Ivo Jorge Prado Arnhold and Alexander Augusto de Lima Jorge

Context

Patients with tall stature often remain undiagnosed after clinical investigation and few studies have genetically assessed this group, most of them without a systematic approach.

Objective

To assess prospectively a group of individuals with tall stature, with and without syndromic features, and to establish a molecular diagnosis for their growth disorder.

Design

Screening by karyotype (n = 42), chromosome microarray analyses (CMA) (n = 16), MS-MLPA (n = 2) targeted panel (n = 12) and whole-exome sequencing (n = 31).

Patients and methods

We selected 42 patients with tall stature after exclusion of pathologies in GH/IGF1 axis and divided them into syndromic (n = 30) and non-syndromic (n = 12) subgroups.

Main outcome measures

Frequencies of pathogenic findings.

Results

We identified two patients with chromosomal abnormalities including SHOX trisomy by karyotype, one 9q22.3 microdeletion syndrome by CMA, two cases of Beckwith–Wiedemann syndrome by targeted MS-MLPA analysis and nine cases with heterozygous pathogenic or likely pathogenic genetic variants by multigene analysis techniques (FBN1 = 3, NSD1 = 2, NFIX = 1, SUZ12 = 1, CHD8 = 1, MC4R = 1). Three of 20 patients analyzed by WES had their diagnosis established. Only one non-syndromic patient had a definitive diagnosis. The sequential genetic assessment diagnosed 14 out of 42 (33.3%) tall patients.

Conclusion

A systematic molecular approach of patients with tall stature was able to identify the etiology in 13 out of 30 (43.3%) syndromic and 1 out of 12 (8.3%) non-syndromic patients, contributing to the genetic counseling and avoiding unfavorable outcomes in the syndromic subgroup.

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Géraldine Vitellius and Marc Lombes

Glucocorticoids (GC) such as cortisol regulate multiple physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene in humans). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, and recruitment of functional transcriptional machinery. Generalized glucocorticoid resistance syndrome, due to GR loss-of-function mutations, may be related to the impairment of one of the GC signaling steps. To date, 31 NR3C1 loss-of-function mutations have been reported in patients presenting with various clinical signs such as hypertension, adrenal hyperplasia, hirsutism or metabolic disorders associated with biological hypercortisolism but without Cushing syndrome signs and no negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Functional characterization of GR loss-of-function mutations often demonstrates GR haploinsufficiency and a decrease of GR target gene induction in relevant cell types. The main signs at presentation are very variable from resistant hypertension, bilateral adrenal hyperplasia likely related to increased ACTH levels but not exclusively, hirsutism to isolated renin-angiotensin-aldosterone system abnormalities in a context of 11βHSD2 deficiency. Some mutated GR patients are obese or overweight together with a healthier metabolic profile that remains to be further explored in future studies. Deciphering the molecular mechanisms altered by GR mutations should enhance our knowledge on GR signaling and ultimately facilitate management of GC-resistant patients. This review also focuses on the criteria facilitating identification of novel NR3C1 mutations in selected patients.

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E Mirallié, F Borel, C Tresallet, A Hamy, M Mathonnet, J C Lifante, L Brunaud, F Menégaux, J B Hardouin, C Blanchard and THYRQOL Group

Objective

This study is to determine the impact of complications after total thyroidectomy on health-related quality of life (HR-QoL) and to identify significant predictive factors of HR-QoL changes. HR-QoL is usually impaired in patients with thyroid diseases compared to the general population. Thyroidectomy is largely performed in the case of benign thyroid benign and can be associated with long-term complications (vocal cord palsy, hypoparathyroidism).

Design

The prospective ThyrQoL multicenter trial (NCT02167529) included 800 patients who underwent total thyroidectomy for benign or malignant non-extensive disease in seven French referral hospitals between 2014 and 2016.

Methods

HR-QoL was assessed using the MOS 36-item short form health survey (SF-36) self-questionnaire with a 6-month follow-up.

Results

We observed a significant improvement of HR-QoL 6 months after surgery (P < 0.0001). Postoperative complications were associated with a non-significant impairment of HR-QoL. In multivariable analysis, Graves’ disease was associated with a significant improvement of HR-QoL (OR = 2.39 [1.49; 3.84]) and thyroid malignant disease with an impairment of HR-QoL (OR = 1.44 [0.99; 2.08]) after thyroidectomy.

Conclusion

We observed a significant improvement of HR-QoL 6 months after total thyroid surgery for benign thyroid disease.

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Zhe Shen, Li Cen, Xufeng Chen, Jiaqi Pan, Youming Li, Weixing Chen and Chaohui Yu

Background

Non-alcoholic fatty liver disease (NAFLD) has been suggested to be a risk factor associated with low BMD (bone mineral density) in several cross-sectional studies. The present longitudinal cohort study aims to explore the effect of NAFLD and its severity on low BMD.

Methods

Between January 2013 and August 2018, individuals who participated in annual comprehensive health examinations were included. BMD was presented using dual-energy X-ray absorptiometry (DXA). These subjects were diagnosed with fatty liver by ultrasound detection.

Results

A total of 1720 subjects were included (1064 subjects with normal BMD and 656 subjects with low BMD) at baseline. Among the 1064 participants with normal BMD at baseline, 399 participants developed low BMD. The multivariable-adjusted hazard ratio for incident low BMD comparing the NAFLD group vs the non-NAFLD group was 2.24 (1.18, 2.81). Increased non-invasive fibrosis markers of NAFLD were positively associated with an increased incidence of low BMD in a graded manner. In addition, obese subjects and women with NAFLD at baseline are more likely to develop low BMD.

Conclusion

NAFLD and its severity were independently associated with an increased incidence of low BMD. Obesity and female gender are risk factors associated with low BMD. Our findings indicated NAFLD can be a significant contributor to low BMD pathogenesis, requiring further studies to elucidate the potential mechanisms.

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Warrick J Inder

While the ACTH1–24 test has some well-documented shortcomings, 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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Michelle L Kluge, Evan Graber, Kathryn Foley, Lynnette V Hansen, Heidi L Sellers, Dragana Milosevic, Kendall W Cradic and Stefan K Grebe

Introduction

Genotype-phenotype discordance occurs occasionally in congenital adrenal hyperplasia (CAH). Its causes are largely unknown. We describe a case of monochorionic, diamniotic twins with discordant clinical presentations of CAH, and show evidence for this being due to mosaicism resulting from a postzygotic full gene deletion of CYP21A2 prior to twinning.

Case description

A 7-day-old 36-week gestation female infant (Twin A) presented to the emergency department with elevated 17-hydroxyprogesterone (17-OHP). Her identical twin (Twin B) had normal 17-OHP on newborn screening. Both twins showed signs of virilization, more pronounced in Twin B. Molecular genetic testing of both twins and their parents showed a WT paternally-inherited CYP21A2 and a maternally-inherited copy containing the c.293-13C>G mutation. Both twins were also found to have a 5′-CYP21A1P/CYP21A2-3′ hybrid (product of the common 30-kb deletion), derived from the deletion of the paternally-inherited CYP21A2. Neither mother nor father carried the deletion.

Conclusions

The genetic findings are consistent with mosaicism for two CYP21A2 cell lines in both twins. The first cell line is expected, based on parental results, while the second line is due to a postzygotic full gene deletion of the paternally-inherited WT CYP21A2. The resultant genotype, compound heterozygosity for c.293-13C>G and a CYP21A2 full gene deletion, is consistent with a salt-wasting CAH phenotype. Differential distribution of the second cell line between the twins is most likely the cause for their discrepant phenotypes. We believe this is the first report of somatic CYP21A2 mosaicism, and represents a novel cause for discrepant CAH phenotypes in monozygotic twins.

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Abu Saleh Md Moin, Megan Cory, Tatyana Gurlo, Yoshifumi Saisho, Robert A Rizza, Peter C Butler and Alexandra E Butler

Aim

To establish pancreatic alpha-cell mass in lean, non-diabetic humans over the adult lifespan, performed as a follow-up study to beta-cell mass across the adult human lifespan.

Methods

We examined human pancreatic autopsy tissue from 66 lean, non-diabetic individuals aged from 30 to 102 years, grouped into deciles: 3rd (30–39 years), 4th (40–49 years), 5th (50–59 years), 6th (60–69 years), 7th (70–79 years), 8th (80–89 years) and 9th deciles (90+ years). Sections of pancreas were immunostained for glucagon and analyzed for fractional alpha-cell area. Population-based pancreatic volume data were used to calculate alpha-cell mass.

Results

With advanced age, the exocrine pancreas undergoes atrophy demonstrated by increased fat area (as % exocrine area) (0.05 ± 0.01 vs 1.6 ± 0.7% fat area of total exocrine pancreas, 3rd vs 9th decile, P < 0.05). Consequently, islet density increases with age (2.7 ± 0.4 vs 10.5 ± 3.3 islets/mm2, 3rd vs 9th decile, P < 0.05). Alpha-cell fractional area increases with advanced age (0.34 ± 0.05% vs 0.73 ± 0.26%, 3rd vs 9th decile, P < 0.05). However, alpha-cell mass remains constant at ~190 mg throughout the adult lifespan in lean, non-diabetic humans. Within islets, alpha-cell distribution between mantle and core is unchanged across deciles (1862 ± 220 vs 1945 ± 200 vs 1948 ± 139 alpha cells in islet mantle/mm2, 3rd vs 6th vs 9th decile, P = 0.93 and 1912 ± 442 vs 1449 ± 123 vs 1514 ± 168 alpha cells in islet core/mm2, 3rd vs 6th vs 9th decile, P = 0.47), suggesting that human islets retain their structural organization in the setting of age-related exocrine atrophy.

Conclusions

Consistent with our previous findings for beta-cell mass, alpha-cell mass remains constant in humans, even with advanced age. Pancreatic endocrine cells are much more robustly preserved than exocrine cells in aged humans, and islets maintain their structural integrity throughout life.