EndoBridge 2023: highlights and pearls.

EndoBridge 2023 took place on October 20-22, 2023, in Antalya, Turkey. Accredited by the European Council, the 3-day scientific program of the 11th Annual Meeting of EndoBridge included state-of-the-art lectures and interactive small group discussion sessions incorporating interesting and challenging clinical cases led by globally recognized leaders in the field and was well attended by a highly diverse audience. Following its established format over the years, the program provided a comprehensive update across all aspects of endocrinology and metabolism, including topics in pituitary, thyroid, bone, and adrenal disorders, neuroendocrine tumors, diabetes mellitus, obesity, nutrition, and lipid disorders. As usual, the meeting was held in English with simultaneous translation into Russian, Arabic, and Turkish. The abstracts of clinical cases presented by the delegates during oral and poster sessions have been published in JCEM Case Reports. Herein, we provide a paper on highlights and pearls of the meeting sessions covering a wide range of subjects, from thyroid nodule stratification to secondary osteoporosis and from glycemic challenges in post-bariatric surgery to male hypogonadism. This report emphasizes the latest developments in the field, along with clinical approaches to common endocrine issues. The 12th annual meeting of EndoBridge will be held on October 17-20, 2024 in Antalya, Turkey.

Inspiring New Science to Guide Healthcare in Turner Syndrome: Rationale, design, and methods for the InsighTS Registry.

Inspiring New Science to Guide Healthcare in Turner Syndrome (InsighTS) Registry is a national, multicenter registry for individuals with Turner syndrome (TS) designed to collect and store validated longitudinal clinical data from a diverse cohort of patients with TS. Herein, we describe the rationale, design, and approach used to develop the InsighTS registry, as well as the demographics of the initial participants to illustrate the registry's diversity and future utility. Multiple stakeholder groups have been involved from project conceptualization through dissemination, ensuring the registry serves the priorities of the TS community. Key features of InsighTS include recruitment strategies to facilitate enrollment of participants that appropriately reflect the population of individuals with TS receiving care in the US, clarity of data ownership and sharing, and sustainability of this resource. The registry gathers clinical data on diagnosis, treatment, comorbidities, health care utilization, clinical practices, and quality of life with the goal of improving health outcomes for this population. Future directions include multiple patient-centered clinical-translational research projects that will use the InsighTS platform. This thorough and thoughtful planning will ensure InsighTS is a valuable and sustainable resource for the TS community for decades to come.

Correction: Variation in early number skills and mathematics achievement: Implications from cognitive profiles of children with or without Turner syndrome.

[This corrects the article DOI: 10.1371/journal.pone.0239224.].

Karyotype is associated with timing of ovarian failure in women with Turner syndrome.

OBJECTIVE: To characterize the age of ovarian failure in Turner Syndrome (TS) patients by karyotype. METHODS: Retrospective cohort study of individuals with TS at an academic university hospital. Subjects were seen in TS Clinic at UNC Hospital between 2014 and 2018. Individuals were analyzed by karyotype category (45X, 45X/46XX mosaicism, miscellaneous) and percentage of 45X cells. Age at follicle-stimulating hormone> 30 was defined as the age at loss of ovarian function. RESULTS: A total of 79 patients were identified after excluding individuals with unknown ovarian function and those with Y chromosome material. Thirty-eight percent were 45X monosomic, 62% were 45X/46XX mosaic or miscellaneous karyotypes. Fifty-five of 79 (70%) patients had evidence of ovarian failure, median age of failure 11 years (IQR: 4,12). Ovarian failure was more prevalent among individuals with 45X karyotype (100%). The median age of ovarian failure for 45X patients (n=30) was 10 years old, which is significantly younger than other karyotypes (n=49), with a median of 15 years, p<0.01. Linear regression analysis found that 1 percentage point increase in 45X cells in the peripheral karyotype is associated with a 0.09 year decrease in age of ovarian failure (p value=0.01). Only 9% of individuals were referred for fertility counseling. CONCLUSIONS: There is a lower prevalence of ovarian failure among individuals with mosaic TS karyotypes, and referral rate for fertility counseling of patients with TS is low. These findings are in line with published literature. The finding that percentage of 45X cells in peripheral karyotype is associated with earlier age of ovarian failure is novel and warrants further investigation in a larger prospective cohort.

Changes to care delivery at nine international pediatric diabetes clinics in response to the COVID-19 global pandemic.

BACKGROUND: Pediatric diabetes clinics around the world rapidly adapted care in response to COVID-19. We explored provider perceptions of care delivery adaptations and challenges for providers and patients across nine international pediatric diabetes clinics. METHODS: Providers in a quality improvement collaborative completed a questionnaire about clinic adaptations, including roles, care delivery methods, and provider and patient concerns and challenges. We employed a rapid analysis to identify main themes. RESULTS: Providers described adaptations within multiple domains of care delivery, including provider roles and workload, clinical encounter and team meeting format, care delivery platforms, self-management technology education, and patient-provider data sharing. Providers reported concerns about potential negative impacts on patients from COVID-19 and the clinical adaptations it required, including fears related to telemedicine efficacy, blood glucose and insulin pump/pen data sharing, and delayed care-seeking. Particular concern was expressed about already vulnerable patients. Simultaneously, providers reported 'silver linings' of adaptations that they perceived as having potential to inform care and self-management recommendations going forward, including time-saving clinic processes, telemedicine, lifestyle changes compelled by COVID-19, and improvements to family and clinic staff literacy around data sharing. CONCLUSIONS: Providers across diverse clinical settings reported care delivery adaptations in response to COVID-19-particularly telemedicine processes-created challenges and opportunities to improve care quality and patient health. To develop quality care during COVID-19, providers emphasized the importance of generating evidence about which in-person or telemedicine processes were most beneficial for specific care scenarios, and incorporating the unique care needs of the most vulnerable patients.

Variation in early number skills and mathematics achievement: Implications from cognitive profiles of children with or without Turner syndrome.

Individuals with Mathematics Learning Disabilities have persistent mathematics underperformance but vary with respect to their cognitive profiles. The present study examined mathematics ability and achievement, and associated mathematics-specific numerical skills and domain-general cognitive abilities, in young children with Turner syndrome compared to their matched peers. We utilized two independent peer groups so that group comparisons would account for verbal skills, a hypothesized strength of girls with Turner syndrome, and nonsymbolic magnitude comparison skills, a hypothesized difference of girls with Turner syndrome. This individual matching approach afforded characterization of mathematics profiles of girls with Turner syndrome and girls without Turner syndrome that share potential key features of the Turner syndrome phenotype. Results indicated differences in mathematics ability and nonsymbolic magnitude comparison tasks between girls with Turner syndrome and peers with similar levels of verbal skill. Mathematics ability and mathematics achievement scores of girls with Turner syndrome did not differ significantly from their peers with similar levels of accuracy on a nonsymbolic magnitude comparison task. Cognitive correlates of mathematics outcomes showed disparate patterns across groups. These quantitative and qualitative differences across profiles enhance our understanding of variation in mathematics ability in early childhood and inform how mathematics skills develop in young children with or without Turner syndrome.

Insight Into the Ontogeny of GnRH Neurons From Patients Born Without a Nose.

CONTEXT: The reproductive axis is controlled by a network of gonadotropin-releasing hormone (GnRH) neurons born in the primitive nose that migrate to the hypothalamus alongside axons of the olfactory system. The observation that congenital anosmia (inability to smell) is often associated with GnRH deficiency in humans led to the prevailing view that GnRH neurons depend on olfactory structures to reach the brain, but this hypothesis has not been confirmed. OBJECTIVE: The objective of this work is to determine the potential for normal reproductive function in the setting of completely absent internal and external olfactory structures. METHODS: We conducted comprehensive phenotyping studies in 11 patients with congenital arhinia. These studies were augmented by review of medical records and study questionnaires in another 40 international patients. RESULTS: All male patients demonstrated clinical and/or biochemical signs of GnRH deficiency, and the 5 men studied in person had no luteinizing hormone (LH) pulses, suggesting absent GnRH activity. The 6 women studied in person also had apulsatile LH profiles, yet 3 had spontaneous breast development and 2 women (studied from afar) had normal breast development and menstrual cycles, suggesting a fully intact reproductive axis. Administration of pulsatile GnRH to 2 GnRH-deficient patients revealed normal pituitary responsiveness but gonadal failure in the male patient. CONCLUSIONS: Patients with arhinia teach us that the GnRH neuron, a key gatekeeper of the reproductive axis, is associated with but may not depend on olfactory structures for normal migration and function, and more broadly, illustrate the power of extreme human phenotypes in answering fundamental questions about human embryology.

Alcohol consumption patterns in young adults with type 1 diabetes: The SEARCH for diabetes in youth study.

AIMS: The objective of this study is to describe alcohol consumption behaviors of young adults with T1D and to examine associations between alcohol consumption and diabetes-related clinical markers. METHODS: Data from 602 SEARCH for Diabetes in Youth Study participants age ≥ 18 yrs. with T1D were collected from 12/2011 to 6/2015 (50% female, mean age 21.3(SD 2.4), 22% race/ethnic minority). Participants were characterized as alcohol non-drinkers (n = 269), drinkers but non-binge drinkers (n = 167), or binge drinkers (n = 166) based on reported consumption in the past 30 days. Analyses were conducted using one-way ANOVAs, chi-square tests, and logistic regression modeling to examine associations between drinking and clinical markers. RESULTS: Fifty-five percent of participants reported alcohol consumption; 27.6% of participants reported binge drinking. After adjusting for demographic characteristics, neither binge drinking nor non-binge drinking were associated with HbA1c or severe hypoglycemic events relative to non-drinkers. Binge drinking was associated with higher HDL (p = 0.008), lower systolic blood pressure (p = 0.011), and a lower waist:height ratio compared to non-drinkers (p = 0.013). CONCLUSIONS: Young adults with T1D in the SEARCH cohort reported similar alcohol use but higher rates of binge drinking compared to the general United States population and previously reported rates in adults with T1D.

Understanding antagonism and synergism: A qualitative assessment of weight management in youth with Type 1 diabetes mellitus.

AIMS: No current clinical guidelines focus on weight management in youth with type 1 diabetes mellitus (T1DM). Our aim was to characterize the patient-perceived experience and barriers to weight management in youth with T1DM. METHODS: Participants were recruited from the University of North Carolina (n = 16, 56% female, 60% White, 50% insulin pump users, mean age 14.8 years, mean HbA1c 8.5% (69 mmol/mol)) and the University of Colorado (n = 18, 50% female, 80% white, 53% pump users, mean age 15.3 years, mean HbA1c 9.3% (78 mmol/mol)). Focus groups were stratified by sex and weight status (BMI cutoff = 25). Discussions were guided by a standardized set of questions, audio-taped, transcribed, and analyzed thematically using inductive qualitative methods. RESULTS: Youth with T1DM expressed four interrelated themes of antagonism between type 1 diabetes and weight management: dysregulated appetite, disruption of blood glucose levels associated with changing diet/exercise, hypoglycemia as a barrier to weight loss, and the overwhelming nature of dual management of weight and glycemic control, and two interrelated themes of synergism: improvement in shared, underlying heath behaviors and exercise as a tool for weight and glycemic control. Variation in emphasis of specific thematic elements was greatest across sex. Youth identified five major components of a weight management program for T1DM: intensified glucose management, healthy diet with known carbohydrate content, exercise, individualization and flexibility, and psychosocial and peer support. CONCLUSIONS: There is critical need for personalized, T1DM-specific weight recommendations to overcome disease-specific barriers to weight management in the context of T1DM.

Hepatocellular Carcinoma, Virilization, and Hilus Cell Hyperplasia in a Girl With Turner Syndrome.

Patients with Turner syndrome (TS) are known to be at risk for excess androgen production and virilization associated with gonadoblastoma and Y chromosome mosaicism, and excess androgens are a risk factor for the development of hepatocellular carcinoma. However, virilization and hepatocellular carcinoma have not been described in a patient with TS. A 10-year-old with nonmosaic 45,X TS presented with clitoromegaly, accelerated linear growth velocity, advanced bone age, and elevated testosterone levels as well as a second occurrence of hepatocellular carcinoma. Gonadectomy was performed, and pathology revealed hilus cell hyperplasia. Immunohistochemical staining of both the original and recurrent hepatocellular carcinoma tissues was diffusely positive for androgen receptors. After gonadectomy, testosterone levels were measurable but normal, with no further virilization; however, the liver mass continued to grow. Ovarian hilus cell hyperplasia should be considered a potential etiology for virilization in the TS population. Excess endogenous testosterone exposure in girls and women with TS may be associated with hepatocellular carcinoma expressing the androgen receptor, though normalizing testosterone levels may not lead to tumor regression in these cases.

SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome.

Arhinia, or absence of the nose, is a rare malformation of unknown etiology that is often accompanied by ocular and reproductive defects. Sequencing of 40 people with arhinia revealed that 84% of probands harbor a missense mutation localized to a constrained region of SMCHD1 encompassing the ATPase domain. SMCHD1 mutations cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) via a trans-acting loss-of-function epigenetic mechanism. We discovered shared mutations and comparable DNA hypomethylation patterning between these distinct disorders. CRISPR/Cas9-mediated alteration of smchd1 in zebrafish yielded arhinia-relevant phenotypes. Transcriptome and protein analyses in arhinia probands and controls showed no differences in SMCHD1 mRNA or protein abundance but revealed regulatory changes in genes and pathways associated with craniofacial patterning. Mutations in SMCHD1 thus contribute to distinct phenotypic spectra, from craniofacial malformation and reproductive disorders to muscular dystrophy, which we speculate to be consistent with oligogenic mechanisms resulting in pleiotropic outcomes.

Evaluating Substance Use and Insulin Misuse in Adolescents With Type 1 Diabetes.

PURPOSE: Substance use behaviors often emerge during adolescence, and adolescents with type 1 diabetes (T1D) may be at risk for engaging in traditional substance use (eg, alcohol, tobacco, and illicit substances) as well as a unique form of substance use: insulin misuse. The purpose of this exploratory study was to examine substance use and insulin misuse in adolescents with T1D. METHODS: Sixty adolescents aged 12 to 20 years with T1D (n = 60) completed surveys on substance use, insulin misuse, and diabetes self-management during a routine diabetes appointment. Demographic measures were summarized by mean (SD) or percentage. Prevalence of substance use and insulin misuse was calculated and stratified by demographic and clinical characteristics. Two-sample t test (continuous variables) and chi-square analysis (categorical variables) determined statistically significant differences. RESULTS: The prevalence of ever using substances was 36.7%, and that for ever misusing insulin was 19%. Older participants (17.1 ± 1.8 vs 15.6 ± 1.9 years; P < .01) and those with depression (31.8% vs 7.9%; P = .02) were more likely to use substances. Disordered eating behaviors were the most frequently reported reason for insulin misuse. Self-harm intent was reported by one-third of insulin misusers. Substance use and insulin misuse were not related to glycemic control or diabetes self-management behaviors. CONCLUSIONS: The diabetes care team should be aware that substance use and insulin misuse are common in adolescents with T1D. Screening for these risky behaviors is critical in those who are older or have mental health disorders. Effective education, prevention, and treatment strategies targeted at these behaviors are needed to improve the overall health of this population.

Association of parental history of diabetes with cardiovascular disease risk factors in children with type 2 diabetes.

AIMS: Determine if parental diabetes (DM) is associated with unhealthier cardiovascular disease (CVD) risk profiles in youth with type 2 diabetes (T2D), and whether associations differed by race/ethnicity. METHODS: Family history was available for 382 youth with T2D from 2001 prevalent and 2002-2005 incident SEARCH for Diabetes in Youth cohorts. Parental DM was evaluated in two ways: two-category-any parent vs. no parent DM (evaluated overall and stratified by race/ethnicity); and four-category-both parents, mother only, father only, or no parent DM (evaluated overall only). Associations with hemoglobin A1c (HbA1c), fasting lipids, blood pressure (BP), and urine albumin:creatinine ratio (ACR) were examined using regression models. RESULTS: Overall, sample characteristics included: 35.9% male, 19.1% non-Hispanic white (NHW), mean T2D duration 26.6±22.2months, mean HbA1c 7.9%±2.5% (62.6±27.8mmol/mol). Unadjusted two-category comparisons showed that youth with parental DM had higher HbA1c, higher DBP, and higher frequency of elevated ACR. Adjusted two-category comparisons showed associations remaining in non-stratified analysis for ACR [OR (95% CI)=2.3 (1.1, 5.0)] and in NHW youth for HbA1c [6.8%±0.4 vs. 8.0±0.4 (51.1±4.8 vs. 63.9±4.2mmol/mol), p=.015], DBP (67.7%±4.5 vs. 76.9±4.4mm Hg, p=.014) and lnTG (4.7±0.3 vs. 5.3±0.3, p=.008). There were no significant findings in the adjusted four-category evaluation. CONCLUSIONS: Parental history of diabetes may be associated with unhealthier CVD risk factors in youth with T2D.

Are HDL levels lower in children with type 1 diabetes and concurrent celiac disease compared with children with type 1 diabetes only?

Celiac disease (CD) is associated with type 1 diabetes mellitus (T1DM), which is known to be associated with abnormal lipid profiles. We aimed to examine the impact of CD on lipid profiles in persons with T1DM. Subjects with T1DM were identified by database and medical record review. Patients were classified as T1DM+CD or T1DM based on CD antibody and endoscopy results. The most recent (before age 20 years) non-fasting lipid panel (NFLP) prior to CD diagnosis for T1DM+CD subjects was compared to the most recent NFLP for T1DM subjects. Adjusted analysis showed T1DM+CD had lower HDL compared with T1DM (T1DM+CD 51.4 mg/dL, T1DM 62.2 mg/dL, p=0.017). There were no other differences in NFLP. In our sample, patients with T1DM+CD had lower HDL levels. Considering the increased cardiovascular disease risk of patients with T1DM, those who also have CD may be at even greater risk due to the association with lower HDL.

The influence of exposure to maternal diabetes in utero on the rate of decline in ß-cell function among youth with diabetes.

Abstract We explored the influence of exposure to maternal diabetes in utero on ß cell decline measured by fasting C-peptide (FCP) among 1079 youth <20 years with diabetes, including 941 with type 1 and 138 with type 2 diabetes. Youths exposed to maternal diabetes had FCP levels that were 17% lower among youth with type 2 diabetes [95% confidence interval (CI): -34%, +6%] and 15% higher among youth with type 1 diabetes (95%CI: -14%, +55%) than their unexposed counterparts, although differences were not statistically significant (p=0.13 and p=0.35, respectively). Exposure to maternal diabetes was not associated with FCP decline in youth with type 2 (p=0.16) or type 1 diabetes (p=0.90); nor was the effect of in utero exposure on FCP modified by diabetes type. Findings suggest that exposure to maternal diabetes in utero may not be an important determinant of short-term ß-cell function decline in youth with type 1 or type 2 diabetes.