INTRODUCTION:Since the first description of Turner syndrome (TS), both genotypic spectrum and phenotypic presentation have evolved. This study aimed to examine trends in this evolution over the past three decades and provides an overview of current genetic and clinical features in a large nationwide multicenter cohort of girls with TS. METHODS:We analyzed data from growth hormone (GH)-treated girls with TS included in BELGROW, the national GH registry of the BELux Society for Pediatric Endocrinology and Diabetology, between 1985 and 2022. Karyotype, age at diagnosis, and phenotype were studied in 716 girls. Two periods were compared: 1991-2002 (group 1, n = 250) and 2003-2017 (group 2, n = 270). RESULTS:The annual number of girls with TS starting GH remained stable (mean n = 19/year). In the entire cohort, monosomy 45,X was the most frequent karyotype (44%), followed by structural anomalies of the X chromosome (27%), 45,X/46,XX mosaicism (13%), triple X mosaicism (4%), 45,X/46,XY or complex Y anomalies (6%), and others (6%). The proportion of 45,X decreased between the two periods (46%-38%, p < 0.05). Overall, median age at diagnosis was 6.4 years with 7.6% of girls diagnosed prenatally, 24% before age 1, 49% in childhood, and 19% after 12 years. Prenatal diagnoses increased from 2.5% (group 1) to 15% (group 2) (p < 0.001). Girls with a 45,X karyotype were diagnosed earlier than girls with other genotypes (median 2.2 vs. 8 years, p < 0.001). Skeletal (73%), neurosensory (60%), and cardiac (29%) systems were most affected. Skeletal and cardiac malformations were more frequent in girls with a 45,X karyotype (p < 0.05 and p < 0.01, respectively). CONCLUSION:Genotype distribution and timing of TS diagnosis have significantly changed since 1991, while the annual number of girls starting GH therapy has remained stable. A 45,X karyotype is associated with earlier diagnosis and more comorbidities.

CONTEXT:Real-world data add value to outcomes from randomized controlled trials on the use of hybrid closed-loop systems in the management of children and adolescents with type 1 diabetes. OBJECTIVE:This multicenter prospective observational cohort study assessed real-world changes in glycemic and person-reported outcomes 1 year after Control-IQ initiation in children and adolescents with type 1 diabetes. METHODS:Between December 2021 and December 2022, all children aged 6-18 years who started Control-IQ at 13 Belgian centers were consecutively recruited. Data were collected at start of Control-IQ and after 4, 8, and 12 months. Person-reported outcomes were evaluated through questionnaires (Diabetes Quality of Life for Youth [DQOLY], Hypoglycemia Fear Survey [HFS], HAPPI-D). Data are reported as mean ± SD or least-squares mean (95% CI). RESULTS:A total of 114 children were included, with a mean age of 12.0 ± 3.2 years and of whom 61.4% were girls. Time in range (3.9-10.0 mmol/L) increased from start (51.6% [47.6-55.5]) to 12 months (64.4% [61.2-67.5]) (P < 0.001). After 12 months, HbA1c decreased from 62 mmol/mol (60-65) (7.8% [7.6-8.1]) to 54 mmol/mol (52-57) (7.1% [6.9-7.3]) and time <3.9 mmol/L from 3.9% (3.1-4.8) to 2.7% (1.9-3.5) (all P < 0.001). Children scored better on DQOLY satisfaction (70.4 [67.8-73.0] vs 74.0 points [71.3-76.6]) and DQOLY impact (54.6 [50.9-58.3] vs 51.3 points [47.4-55.1]), and parents on HAPPI-D (22.5 [21.1-23.9] vs 19.6 points [18.2-21.0]) and HFS worry (25.0 [21.6-28.4] vs 20.3 points [17.0-23.5]) (all P < 0.001). Children missed fewer days of school (287 vs 30 days/100 person-years, P < 0.001) and parents missed fewer days of work (247 vs 47 days/100 person-years, P < 0.001). CONCLUSION:One-year use of Control-IQ was associated with improved glycemic management, more diabetes-related quality of life and fewer school/work absences.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Introduction: A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity, and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods: Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no-mutation group). Results: After a median (P10; P90) duration of 5.4 (2.2; 10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.1; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype, and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (beta = 0.90, p < 0.001), mid-parental height SDS (beta = 0.27; p = 0.005), birth weight SDS (beta = 0.15; p = 0.051), age at start (beta = 0.07; p = 0.032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p < 0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion: Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

Background:Adults with obesity may display disturbed cardiac chronotropic responses during cardiopulmonary exercise testing,which relates to poor cardiometabolic health and an increased risk for adverse cardiovascular events.It is unknown whether cardiac chronotropic incompetence（CI） during maximal exercise is already present in obese adolescents and,if so,how that relates to cardiometabolic health.Methods:Sixty-nine obese adolescents（body mass index standard deviation score=2.23±0.32,age=14.1±1.2 years;mean±SD） and 29lean adolescents（body mass index standard deviation score=-0.16±0.84,age=14.0±1.5 years） performed a maximal cardiopulmonary exercise testing from which indicators for peak performance were determined.The resting heart rate and peak heart rate were used to calculate the maximal chronotropic response index.Biochemistry（lipid profile,glycemic control,inflammation,and leptin） was studied in fasted blood samples and during an oral glucose tolerance test within obese adolescents.Regression analyses were applied to examine associations between the presence of CI and blood or exercise capacity parameters,respectively,within obese adolescents.Results:CI was prevalent in 32 out of 69 obese adolescents（46%） and 3 out of 29 lean adolescents（10%）.C-reactive protein was significantly higher in obese adolescents with CI compared to obese adolescents without CI（p=0.012）.Furthermore,peak oxygen uptake and peak cycling power output were significantly reduced（p ＜0.05） in obese adolescents with CI vs.obese adolescents without CI.The chronotropic index was independently related to blood total cholesterol（standardized coefficient β=-0.332;p=0.012） and C-reactive protein concentration（standardized coefficient β=-0.269;p=0.039）.Conclusion:CI is more common in the current cohort of obese adolescents,and is related to systemic inflammation and exercise intolerance.

STUDY QUESTION:What is the long-term outcome of individuals born with bilateral testicular regression (BTR) in relation to its underlying etiology? SUMMARY ANSWER:Statural growth and pubertal development are adequate with incremental doses of testosterone replacement therapy (TRT); however, penile growth is often suboptimal, especially in those with a suspected genetic etiology (i.e. heterozygous DHX37 variants) or a micropenis at birth. WHAT IS KNOWN ALREADY:BTR is a rare and poorly understood condition. Although a vascular origin has been postulated, heterozygous missense variants in DHX37 have been attributed to the phenotype as well. How these various etiologies impact the clinical phenotype, gonadal histology and outcome of BTR remains unclear. STUDY DESIGN SIZE DURATION:For this cross-sectional study, individuals with BTR were recruited in eight Belgian pediatric endocrinology departments, between December 2019 and December 2022. A physical exam was performed cross-sectionally in all 17 end-pubertal participants and a quality of care questionnaire was completed by 11 of them. Exome-based panel testing of 241 genes involved in gonadal development and spermatogenesis was performed along with a retrospective analysis of presentation and management. A centralized histological review of gonadal rests was done for 10 participants. PARTICIPANTS/MATERIALS SETTING METHODS:A total of 35 participants (33 with male, 1 with female, and 1 with non-binary gender identity) were recruited at a mean age of 15.0 ± 5.7 years. MAIN RESULTS AND THE ROLE OF CHANCE:The median age at presentation was 1.2 years [0-14 years]. Maternal gestational complications were common (38.2%), with a notably high incidence of monozygotic twin pregnancies (8.8%). Heterozygous (likely) pathogenic missense variants in DHX37 (p.Arg334Trp and p.Arg308Gln) were found in three participants. No other (likely) pathogenic variants were found. All three participants with a DHX37 variant had a microphallus at birth (leading to female sex assignment in one), while only six of the remaining 31 participants without a DHX37 variant (19.4%) had a microphallus at birth (information regarding one participant was missing). Testosterone therapy during infancy to increase penile growth was more effective in those without versus those with a DHX37 variant. The three participants with a DHX37 variant developed a male, female, and non-binary gender identity, respectively; all other participants identified as males. TRT in incremental doses had been initiated in 25 participants (median age at start was 12.4 years). Final height was within the target height range in all end-pubertal participants; however, 5 out of 11 participants (45.5%), for whom stretched penile length (SPL) was measured, had a micropenis (mean adult SPL: 9.6 ± 2.5). Of the 11 participants who completed the questionnaire, five (45.5%) reported suboptimal understanding of the goals and effects of TRT at the time of puberty induction. Furthermore, only 6 (54.5%) and 5 (45.5%) of these 11 participants indicated that they were well informed about the risks and potential side effects of TRT, respectively. Histological analysis of two participants with DHX37 variants suggested early disruption of gonadal development due to the presence of Müllerian remnants in both and undifferentiated gonadal tissue in one. In eight other analyzed participants, no gonadal remnants were found, in line with the BTR diagnosis. LIMITATIONS REASONS FOR CAUTION:The limitations of this study include the relatively small sample size (n = 35) and the few individuals with DHX37 variants (n = 3). Furthermore, data on the SPL were often missing, due to this being undocumented or refused by participants. WIDER IMPLICATIONS OF THE FINDINGS:TRT provides adequate statural growth, even when initiated in late adolescence, thus providing time for physicians to explore the patients' gender identity if needed. However, sufficient and understandable information regarding the effects and side effects of TRT is required throughout the management of these patients. SPL remains suboptimal in many individuals and could be improved by TRT during infancy to mimic the physiological mini-puberty. An environmental origin in some participants is supported by the high incidence of gestational complications (38.2%) and by the three monozygotic twin pregnancies discordant for the BTR phenotype. Individuals with a heterozygous DHX37 variant have a more severe phenotype with severely restricted penile growth until adulthood. Histological analysis confirmed DHX37 as a gonadal development, rather than a BTR-related, gene. STUDY FUNDING/COMPETING INTERESTS:Funding was provided by the Belgian Society for Pediatric Endocrinology and Diabetology (BESPEED) and by Ghent University Hospital under the NucleUZ Grant (E.D.B.). M.C. and E.D.B. are supported by an FWO senior clinical investigator grant (1801018N and 1802220N, respectively). The authors report no conflicts of interest. TRIAL REGISTRATION NUMBER:N/A.

Objectives To improve adult height in pubertal girls with a poor height prediction, treatment with growth hormone (GH) can be used in combination with a gonadotropin releasing hormone agonist (GnRHa), to delay closure of the growth plates. However, there are few studies to support this practice, and they show conflicting results. The objective of this trial is to assess the safety and efficacy of this combination treatment in early pubertal girls with a short predicted height, in comparison with matched controls. Design, patients, and methods We designed an open-label, multicenter, interventional case-control study. Early pubertal girls with predicted adult height (PAH) below -2.5 SDS, were recruited in tertiary care centers in Belgium. They were treated for four years with GH and GnRHa. The girls were followed until adult height (AH) was reached. AH vs PAH, AH vs Height at start, and AH vs Target Height (TH) were evaluated, as well as safety parameters. Control data were assembled from historical patient files or from patients who preferred not to participate in the study. Results Sixteen girls with mean age ( ± SD) at start of 11.0 years (± 1.3) completed the study protocol and follow-up. Their mean height ( ± SD) increased from 131.3 ± 4.1 cm (-2.3 ± 0.7 SDS) at start of treatment to 159.8 ± 4.7 cm (-1.1 ± 0.7 SDS) at AH. In matched controls, height increased from 132.3 ± 4.2 cm (-2.4 ± 0.5 SDS) to 153.2 ± 3.4 cm (-2.1 ± 0.6 SDS) (p<0.001). AH surpassed initial PAH by 12.0 ± 2.6 cm in treated girls; and by 4.2 ± 3.6 cm in the controls (p<0.001). Most treated girls reached normal adult height (>-2SD) (87.5%) and 68.7% reached or superseded the target height (TH), which was the case in only a minority of the controls (37.5% and 6.2%, respectively) (p= 0.003 and 0.001). A serious adverse event possibly related to the treatment, was a fracture of the metatarsals. Conclusion A four-year GH/GnRHa treatment in early pubertal girls with a poor PAH seems safe and results in a clinically relevant and statistically significant increase in AH compared with matched historical controls. Clinical trial registration ClinicalTrials.gov , identifier NCT00840944.

Objective Real-time continuous glucose monitoring (RT-CGM) can improve metabolic control and quality of life (QoL), but long-term real-world data in children with type 1 diabetes (T1D) are scarce. Over a period of 24 months, we assessed the impact of RT-CGM reimbursement on glycemic control and QoL in children/adolescents with T1D treated with insulin pumps. Research design and methods We conducted a multicenter prospective observational study. Primary endpoint was the change in HbA1c. Secondary endpoints included change in time in hypoglycemia, QoL, hospitalizations for hypoglycemia and/or ketoacidosis and absenteeism (school for children, work for parents). Results Between December 2014 and February 2019, 75 children/adolescents were followed for 12 (n = 62) and 24 months (n = 50). Baseline HbA1c was 7.2 ± 0.7% (55 ± 8mmol/mol) compared to 7.1 ± 0.8% (54 ± 9mmol/mol) at 24 months (p = 1.0). Participants with a baseline HbA1c ≥ 7.5% (n = 27, mean 8.0 ± 0.3%; 64 ± 3mmol/mol) showed an improvement at 4 months (7.6 ± 0.7%; 60 ± 8mmol/mol; p = 0.009) and at 8 months (7.5 ± 0.6%; 58 ± 7mmol/mol; p = 0.006), but not anymore thereafter (endpoint 24 months: 7.7 ± 0.9%; 61 ± 10mmol/mol; p = 0.2). Time in hypoglycemia did not change over time. QoL for parents and children remained stable. Need for assistance by ambulance due to hypoglycemia reduced from 8 to zero times per 100 patient-years (p = 0.02) and work absenteeism for parents decreased from 411 to 214 days per 100 patient-years (p = 0.03), after 24 months. Conclusion RT-CGM in pump-treated children/adolescents with T1D showed a temporary improvement in HbA1c in participants with a baseline HbA1c ≥ 7.5%, without increasing time in hypoglycemia. QoL was not affected. Importantly, RT-CGM reduced the need for assistance by ambulance due to hypoglycemia and reduced work absenteeism for parents after 24 months. Clinical trial registration [ClinicalTrials.gov], identifier [NCT02601729].

Recently, it was reported that heterozygous PCSK1 variants, causing partial PC1/3 deficiency, result in a significant increased risk for obesity. This effect was almost exclusively generated by the rare p.Y181H (rs145592525, GRCh38.p13 NM_000439.5:c.541T>C) variant, which affects PC1/3 maturation but not enzymatic capacity. As most of the identified individuals with the heterozygous p.Y181H variant were of Belgian origin, we performed a follow-up study in a population of 481 children and adolescents with obesity, and 486 lean individuals. We identified three obese (0.62%) and four lean (0.82%) p.Y181H carriers (p = 0.506) through sanger sequencing and high resulting melting curve analysis, indicating no association with obesity. Haplotype analysis was performed in 13 p.Y181H carriers, 20 non-carriers (10 with obesity and 10 lean), and two p.Y181H families, and showed identical haplotypes for all heterozygous carriers (p < 0.001). Likewise, state-of-the-art literature concerning the role of rare heterozygous PCSK1 variants implies them to be rarely associated with monogenic obesity, as first-degree carrier relatives of patients with PC1/3 deficiency are mostly not reported to be obese. Furthermore, recent meta-analyses have only indicated a robust association for scarce disruptive heterozygous PCSK1 variants with obesity, while clinical significance is less or sometimes lacking for most nonsynonymous variants.

Background. Mechanical efficiency (ME) might be an important parameter evaluating cardiometabolic health and the effectiveness of physical activity interventions in individuals with obesity. However, whether these cardiometabolic risk factors may relate to ME in adolescents with obesity is not known yet. Therefore, this study aims to compare the mechanical efficiency during maximal exercise testing between adolescents with obesity and lean adolescents, and to examine associations with exercise tolerance and metabolic health. Methods. Twenty-nine adolescents with obesity (BMI SDS: 2.11 ± 0.32, age: 13.4 ± 1.1 years, male/female: 15/14) and 29 lean (BMI SDS: −0.16 ± 0.84, age: 14.0 ± 1.5 years, male/female: 16/13) adolescents performed a maximal cardiopulmonary exercise test from which the net mechanical efficiency (MEnet) and substrate oxidation (carbohydrates and lipids) were calculated. Indicators for peak performance were collected. Biochemistry (lipid profile, glycaemic control, inflammation, leptin) was studied in fasted blood samples. Regression analyses were applied to examine relations between MEnet and exercise tolerance or blood variables in the total group. Results. Peak work rate (WRpeak), oxygen uptake (V˙O2peak)/WRpeak, ME, and MEnet were significantly lower (p < 0.05) in adolescents with obesity compared to their lean counterparts (p < 0.05). Furthermore, a reduced MEnet was independently related to a lower WRpeak (SC β = 2.447; p < 0.001) and elevated carbohydrate oxidation during exercise (SC β = −0.497; p < 0.001), as well as to elevated blood low-density lipoprotein cholesterol (SC β = −0.275; p = 0.034) and fasting glucose (SC β = −0.256; p = 0.049) concentration. Conclusion. In adolescents with obesity, the mechanical efficiency is lowered during exercise and this relates to exercise intolerance and a worse metabolic health.

Genome-wide copy number surveys associated chromosome 11q11 with obesity. As this is an olfactory receptor-rich region, we hypothesize that genetic variation in olfactory receptor genes might be implicated in the pathogenesis of obesity. Multiplex Amplicon Quantification analysis was applied to screen for copy number variants at chromosome 11q11 in 627 patients with obesity and 330 healthy-weight individuals. A ± 80 kb deletion with an internally 1.3 kb retained segment was identified, covering the three olfactory receptor genes OR4C11, OR4P4, and OR4S2. A significant increase in copy number loss(es) was perceived in our patient cohort (MAF = 27%; p = 0.02). Gene expression profiling in metabolic relevant tissues was performed to evaluate the functional impact of the obesity susceptible locus. All three 11q11 genes were present in visceral and subcutaneous adipose tissue while no expression was perceived in the liver. These results support the ‘metabolic system’ hypothesis and imply that gene disruption of OR4C11, OR4P4, and OR4S2 will negatively influence energy metabolism, ultimately leading to fat accumulation and obesity. Our study thus demonstrates a role for structural variation within olfactory receptor-rich regions in complex diseases and defines the 11q11 deletion as a risk factor for obesity.

Sleyp, Yoeri; Swillen, Ann; Van Den Bogaert, Kris; Massa, Guy; Aerssens, Peter; Peeters, Hilde Author Information

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)