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Open access

Brien Mehmet, Steve Gillard, Channa N Jayasena, and Sofia Llahana

Objective

Klinefelter syndrome (KS) is the second-most prevalent chromosomal disorder in men, though late diagnosis is very common and 50–75% of men remain undiagnosed. Evidence suggests that men with KS have impaired quality of life (QoL) but research on how the diagnosis of KS is associated with different QoL domains and what factors influence patients’ QoL is limited. This study aimed to provide a systematic review of the published evidence on factors that influence QoL in men with KS.

Design

Systematic review and meta-analysis with narrative synthesis.

Methods

Medline, Cochrane, Embase, Psychinfo, CINAHL, BASE and relevant publication reference lists were searched in January 2021. Eligible studies included randomised control trials, cohort studies, cross-sectional studies and epidemiology studies on KS and its effect on QoL and all domains of World Health Organisation (WHO) Quality of Life 100 (WHOQOL-100). Clinical studies with no date restriction published in English were included.

Results

Thematic analysis was completed on 13 studies, with a meta-analysis of intelligence quotient completed on 7 studies. Twelve out of the 13 studies suggested that KS negatively affected the QoL outcomes and KS was associated with impairments in physical, psychological, level independence and social relationship domains of WHOQOL-100. Meta-analysis suggested that men with KS have significantly lower full-scale Intelligence Quotient vs controls (P < 0.00001).

Conclusions

This is the first evidence synthesis of QoL in men with KS. Current evidence suggests that combined physical and psychological impairments affect men with KS who also experience impairments in relationships and independence in society. Further research is needed to identify factors that influence the QoL in men with KS.

Restricted access

Nicholas Russell, Ali Ghasem-Zadeh, Rudolf Hoermann, Ada S Cheung, Jeffrey D Zajac, Cat Shore-Lorenti, Peter R Ebeling, David J Handelsman, and Mathis Grossmann

Objective

In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T.

Design

This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling.

Methods

78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers.

Results

For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm3 (95% CI: −0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm3 (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers.

Conclusion

Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.

Free access

Clifford J Rosen

Understanding the development and regulation of marrow adiposity, as well as its impact on skeletal remodeling has been a major challenge for our field and during my career as well. The story behind this unique phenotype and its relationship to bone turnover is highlighted in my own quest to defining the physiology and pathophysiology of marrow adipocytes.

Restricted access

Elisabeth Laurer, Antonio Sirovina, Alexandra Blaschitz, Katharina Tischlinger, Rodrigo Montero-Lopez, Thomas Hörtenhuber, Marlene Wimleitner, and Wolfgang Högler

Objective

Children diagnosed with idiopathic isolated growth hormone deficiency (IGHD) are frequently observed to no longer be GH-deficient at a later stage of growth as a result of ‘GHD reversal’. Reevaluation of GH status by stimulation test is currently incorporated into management guidelines at attainment of final height (FH). Over the past three decades, numerous studies have evaluated reversal rates using different methodologies including crucial parameters like GHD aetiology, GH cut-off and retesting time point, with heterogeneous results.

We aimed to systematically analyse the reversibility of childhood-onset IGHD dependent on retesting GH cut-offs and retesting time points.

Methods

PubMed, Cochrane Library, TRIP database and NHS Evidence were searched for publications investigating the reversibility of IGHD from database initiation to 30 June 2020 following PRISMA recommendations. Study cohorts were pooled according to retesting GH cut-off and time point. Reversal rates were calculated using random-effects models.

Results

Of the 29 studies initially identified, 25 provided sufficient detail for IGHD analysis, resulting in 2030 IGHD patient data. Reversal rates decreased significantly as the retesting GH cut-off increased (P  = 0.0013). Pooled (95% CI) reversal rates were 80% (59–92%, n  = 227), 73% (62–81%, n  = 516) and 55% (41–68%, n  = 1287) for cohorts using retesting GH cut-offs of 3–4 ng/mL, 5–6 ng/mL and 7.7–10 ng/mL, respectively. Individuals retested at FH (n  = 674) showed a pooled reversal rate of 74% (64–82%) compared to 48% (25–71%) when retested before FH (n  = 653).

Conclusion

Provided evidence supports reevaluation of current IGHD management guidelines. The high reversal rates should instigate consideration of early retesting.

Restricted access

Kara E Boodhansingh, Zhongying Yang, Changhong Li, Pan Chen, Katherine Lord, Susan A Becker, Lisa J States, N Scott Adzick, Tricia Bhatti, Show-Ling Shyng, Arupa Ganguly, Charles A Stanley, and Diva D De Leon

Objective

Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI.

Design

The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined.

Methods

We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK).

Results

Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic.

Conclusion

These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

Open access

Catherine Peters and Nadia Schoenmakers

Transient congenital hypothyroidism (TCH) refers to congenital hypothyroidism which spontaneously resolves in the first few months or years of life. Currently, there is a paucity of reliable markers predicting TCH at diagnosis, and the diagnosis is established following the withdrawal of levothyroxine therapy around 3 years of age. The incidence of TCH is increasing, and it is a major contributor to the overall increase in the incidence of CH in recent studies. Both genetic factors, in particular mutations affecting DUOX2 and DUOXA2, and environmental factors, for example, iodine deficiency and excess, anti- TSHR antibodies and exposure to antithyroid or iodine-rich medications, may cause TCH. Resolution of TCH in childhood may reflect both normal thyroid physiology (decreased thyroid hormone biosynthesis requirements after the neonatal period) and clearance or cessation of environmental precipitants. The relative contributions and interactions of genetic and environmental factors to TCH, and the extent to which TCH may be prevented, require evaluation in future population-based studies.

Restricted access

Hans Olav Ueland, Grethe Åstrøm Ueland, Kristian Løvås, Lars Ertesvåg Breivk, Alexander Stanley Thrane, Ann-Elin Meling Stokland, Eyvind Rødahl, and Eystein Sverre Husebye

Purpose

The aim of this study is to identify biochemical inflammatory markers predicting the presence or risk of developing thyroid eye disease (TED) in patients with Graves’ disease (GD).

Methods

Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ-Specific Diseases. Serum samples were analysed for 92 different inflammatory biomarkers using the proximity extension assay. Biomarker levels were compared between groups of patients with and without TED and healthy subjects (HS) (n = 120).

Results

TED was found in 36 of 100 GD patients. Significant (P < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and HS were compared (42 elevated and 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL6) (P = 0.022) and macrophage colony-stimulating factor (CSF1) (P = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significantly elevated levels of Fms-related tyrosine kinase 3 ligand (FLT3LG) (P = 0.009). Furthermore, fibroblast growth factor 21 (FGF21) was significantly increased (P = 0.008) in patients with GD who had no signs of TED at baseline but developed TED later.

Conclusion

We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation-related proteins were elevated, while others were decreased. Distinctly increased levels of IL6, CSF1, FLT3LG, and FGF21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore potential new biomarkers for clinical use.

Restricted access

Patricia Sandqvist, Anders Sundin, Inga-Lena Nilsson, Per Grybäck, and Alejandro Sanchez-Crespo

Objective

Successful preoperative image localisation of all parathyroid adenomas (PTA) in patients with primary hyperparathyroidism (pHPT) and multiglandular disease (MGD) remains challenging. We investigate whether a machine learning classifier (MLC) could predict the presence of overlooked PTA at preoperative localisation with 99mTc-Sestamibi-SPECT/CT in MGD patients.

Design

This study is a retrospective study from a single tertiary referral hospital initially including 349 patients with biochemically confirmed pHPT and cured after surgical parathyroidectomy.

Methods

A classification ensemble of decision trees with Bayesian hyperparameter optimisation and five-fold cross-validation was trained with six predictor variables: the preoperative plasma concentrations of parathyroid hormone, total calcium and thyroid-stimulating hormone, the serum concentration of ionised calcium, the 24-h urine calcium and the histopathological weight of the localised PTA at imaging. Two response classes were defined: patients with single-gland disease (SGD) correctly localised at imaging and MGD patients in whom only one PTA was localised on imaging. The data set was split into 70% for training and 30% for testing. The MLC was also tested on a subset of the original data based on CT image-derived PTA weights.

Results

The MLC achieved an overall accuracy at validation of 90% with an area under the cross-validation receiver operating characteristic curve of 0.9. On test data, the MLC reached a 72% true-positive prediction rate for MGD patients and a misclassification rate of 6% for SGD patients. Similar results were obtained in the testing set with image-derived PTA weight.

Conclusions

Artificial intelligence can aid in identifying patients with MGD for whom 99mTc-Sestamibi-SPECT/CT failed to visualise all PTAs.

Restricted access

Jacob Volmer Stidsen, Diana Hedevang Christensen, Jan Erik Henriksen, Kurt Højlund, Michael Hecht Olsen, Reimar Wernick Thomsen, Lotte Brix Christensen, Jens Steen Nielsen, Thomas Bastholm Olesen, and Henning Beck-Nielsen

Objective

Hyperglycaemia in type 2 diabetes is caused by varying degrees of two defects: low insulin sensitivity and beta-cell dysfunction. We assessed if subgrouping of patients into three pathophysiological phenotypes according to these defects could identify individuals with high or low risk of future cardiovascular events.

Design

This is a prospective cohort study.

Methods

We assessed estimates of insulin sensitivity and beta-cell function from the homeostasis model assessment-2 in 4209 individuals with recently diagnosed type 2 diabetes enrolled from general practitioners and outpatient clinics in Denmark. Individuals were followed for a composite cardiovascular endpoint (either atherosclerotic outcomes (myocardial infarction, unstable angina pectoris, stroke, coronary or peripheral revascularization), heart failure, or cardiovascular death) and all-cause mortality.

Results

Totally 417 individuals with the insulinopenic phenotype (high insulin sensitivity and low beta-cell function) had substantially lower risk of cardiovascular events (5-year cumulative incidence: 4.6% vs 10.1%; age-/sex-adjusted hazard ratio (aHR): 0.49; 95% CI: 0.30–0.82) compared with 2685 individuals with the classical phenotype (low insulin sensitivity and low beta-cell function), driven by atherosclerotic events. Conversely, 1107 individuals with the hyperinsulinaemic phenotype (low insulin sensitivity and high beta-cell function) had more cardiovascular events (5-year cumulative incidence: 12.6%; aHR: 1.33; 95% CI: 1.05–1.69), primarily driven by increased heart failure and cardiovascular death and increased all-cause mortality.

Conclusions

Simple phenotyping based on insulin sensitivity and beta-cell function predicts distinct future risks of cardiovascular events and death in patients with type 2 diabetes. These results suggest that precision medicine according to underlying type 2 pathophysiology potentially can reduce diabetes complications.

Open access

Elin Pettersen Sørgjerd, Robin Mjelle, Vidar Beisvåg, Arnar Flatberg, Valdemar Grill, and Bjørn O Åsvold

Objective

Diabetes is a heterogeneous disease and a precise diagnosis of diabetes subgroups is necessary to initiate proper early treatment and clinical management of the disease. Circulating small RNAs (sRNAs) are potentially diagnostic biomarkers in diseases, including diabetes. Here we aimed to examine whether profiles of circulating sRNAs differed between patients with autoimmune and non-autoimmune diabetes and non-diabetic controls.

Design

This cross-sectional case–control study included participants from the third survey of the HUNT study.

Methods

We performed sRNA sequencing in serum from adult-onset type 1 diabetes (n = 51), type 2 diabetes (n = 50) and latent autoimmune diabetes in adult (LADA, n  = 51), as well as non-diabetic HUNT3 participants as control group (n = 51). Differential expression analysis of the sRNAs was performed in R using limma-voom.

Results

We identified differences in sRNA expression between autoimmune (type 1 diabetes and LADA) and non-autoimmune diabetes (type 2 diabetes) and between patients with diabetes and non-diabetic controls. Focusing on miRNA, we identified 10 differentially expressed mature miRNAs and 30 differentially expressed miRNA variants (isomiRs). We also identified significant changes within other sRNA classes, including a pronounced downregulation of a tRNA fragment in patients with diabetes compared to non-diabetic controls. We created cross-validated sRNA signatures based on the significant sRNAs that distinguished patients with diabetes from non-diabetic controls, and autoimmune from non-autoimmune diabetes, with high specificity and sensitivity. sRNA profiles did not distinguish between type 1 diabetes and LADA.

Conclusions

Circulating sRNAs are differentially expressed between patients with diabetes and non-diabetic controls and between autoimmune and non-autoimmune diabetes.