Paediatric Endocrinology

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Hongbo Yang Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Meiping Chen Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Lingjuan Jiang State Key Laboratory of Complex Severe and Rare Diseases, Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Linjie Wang Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Lian Duan Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Fengying Gong Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Huijuan Zhu Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Hui Pan Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Purpose

Patients with adult growth hormone deficiency (AGHD) are at an increased risk of metabolic syndrome. Despite extensive research efforts in recent decades, the lipid metabolism pattern of AGHD has yet to be thoroughly characterized.

Methods

In this study, we used lipidomics analysis of fasting serum samples from 30 AGHD patients with intracranial germ cell tumors (iGCTs) and 30 age-, gender- and body mass index (BMI)-matched healthy controls to investigate the serum lipidomic pattern of AGHD patients with iGCTs. We meticulously quantified 534 serum lipids from 29 classes using high-coverage targeted lipidomics technology in conjunction with a robust bioinformatics pipeline.

Results

Our results revealed an AGHD-specific dynamic change in the serum lipidomic profile, manifested by higher overall levels of many lipid subclasses, including triacylglycerols (TAGs), diacylglycerols (DAGs), phosphatidylglycerols, phosphatidylethanolamines (PE), phosphatidylcholines (PC), phosphatidylinositols, ceramides and bis(monoacylglycerol)phosphates, than in healthy controls and a distinct lower level for alkyl PE (PE-O) and alkyl PC (PC-O). AGHD individuals with nonalcoholic fatty liver disease showed specific changes in higher TAG and DAG subclass levels. Alterations in lipid profiles may contribute to metabolic dysregulation in AGHD patients. TAGs, PCs and PE fatty acids positively correlated with BMI, fasting insulin, insulin resistance index and adverse lipid parameters. In contrast, ether-linked PE-O, PC-O and LysoPE-O showed a negative correlation.

Conclusions

This study has significantly expanded the current understanding of lipid dysregulation in AGHD patients with iGCT. These findings can potentially guide future research and development of monitoring and intervention strategies.

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Yamei Yang Department of Ultrasound, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Yong Yao Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Kan Deng Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Bin Xing Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Wei Lian Department of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Hui You Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Feng Feng Department of Radiology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Xin Lian Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Xinxin Mao Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Fengying Gong Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Linjie Wang Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Meiping Chen Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Xiaoan Ke Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Hui Miao Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Lian Duan Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Huijuan Zhu Department of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, The Translational Medicine Center, Key Laboratory of Endocrinology of National Health Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China

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Background

Somatic GNAS mutations are acknowledged as a significant etiological factor for acromegaly. However, the relationship between GNAS mutation status, clinical characteristics and gender has not been adequately investigated. This study aims to address these gaps by examining GNAS mutations and delineating the detailed clinical profile of affected patients within a Chinese acromegaly cohort.

Methods

Our study encompassed 97 individuals newly diagnosed with acromegaly who underwent surgical treatment between May 2015 and January 2022. We obtained DNA from frozen pituitary adenomas to screen for GNAS hotspot mutations and assessed the associated clinical characteristics.

Results

In our cohort, 44.3% (43/97) of patients exhibited somatic GNAS mutations. Patients with mutations were predominantly male (58.1 vs 33.3%, P = 0.015), experienced longer diagnosis delays (72.0 (48.0, 120.0) vs 36.0 (21.0, 75.0) months, P = 0.002), had smaller maximum tumor diameters (1.75 ± 0.83 vs 2.23 ± 0.89 cm, P = 0.008) and demonstrated higher rates of growth hormone (GH) secretion per unit tumor volume (18.93 (9.67, 30.12) vs 10.91 (2.80, 20.40) ng/mL cm−3, P = 0.005). Regarding gender-specific differences, GNAS mutations in male patients were linked to significantly higher baseline GH levels (24.40 (14.40, 36.30) vs 10.55 (5.25, 16.95) ng/mL, P = 0.002), while female patients with mutations had notably smaller tumor sizes (1.55 ± 0.55 cm vs 2.32 ± 0.85 cm, P < 0.001).

Conclusion

GNAS mutations are prevalent among Chinese acromegaly patients, correlating with reduced pituitary tumor sizes and enhanced GH secretion functions. Our findings underscore the influence of gender on the clinical manifestations of GNAS mutations. Accordingly, we recommend that future clinical and foundational research studies on acromegaly give heightened consideration to gender-specific differences.

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Mireille N M van Poppel Institute of Human Movement Sciences, Sport and Health, University of Graz, Graz, Austria

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Christopher J Nolan Department of Endocrinology at The Canberra Hospital and the Australian National University School of Medicine and Psychology, Canberra, ACT, Australia

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Gernot Desoye Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria

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Pancreas agenesis is a rare condition underlying a variant of permanent neonatal diabetes mellitus. Neonates with this condition are born small for gestational age, but less is known about which components of growth are impacted, the timing of the growth restriction and potential sex differences. Our objective was to assess in which periods in gestation complete pancreas agenesis restricts fetal growth and possible sex differences in susceptibility. Published cases (n = 49) with pancreas agenesis providing relevant data (gestational age, fetal sex, birth weight, birth length, head circumference, placental weight) were identified by MEDLINE and secondary literature search covering the years 1950–January 2023. Semiquantitative analysis of these case reports used centiles based on Intergrowth-21 reference charts. Neonates with pancreas agenesis were severely growth restricted; however, median centiles for birth weight, birth length, and head circumference of those born before week 36 were significantly higher compared to those born from 36 weeks. Similar results were found when data were separated by before and from 38 weeks. Head circumference was less affected than birth weight or birth length. No sex differences were found. In conclusion, pancreas agenesis severely restricts fetal length and head circumference in addition to weight growth, with stronger effects evident from 36 weeks of gestation. In addition to the well-known effects of insulin on growth of fetal fat mass, the pronounced effect on birth length and head circumference indicates effects of insulin on fetal lean body growth as well. Lack of power may account for failure to find sex differences.

Significance statement

Neonates with complete pancreas agenesis are born small, but the details of their growth deviation, timing, and potential sex differences remain uncertain. All neonates with pancreas agenesis in our study had reduced birth weight, length, and head circumference, with milder effects in those born before 36 weeks compared to after 36 weeks. This trend persisted when data were separated into before and after 38 weeks, with no discernible sex differences. The absence of the pancreas, and therefore insulin, significantly reduces fetal growth, especially after 36 weeks of gestation. In addition to insulin’s known role in fetal fat mass, our findings suggest it has a substantial influence on birth length and head circumference, underscoring its impact on fetal lean body growth.

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Claire L Wood Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Kieren G Hollingsworth Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Edrina Bokaie Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Eric Hughes Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Robert Muni-Lofra Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Anna Mayhew Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Rod T Mitchell MRC Centre for Reproductive Health, The University of Edinburgh, Queens Medical Research Institute, Edinburgh, UK

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Michela Guglieri Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Joseph McElvaney Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK

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Timothy D Cheetham Department of Paediatric Endocrinology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

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Volker Straub Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK

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Glucocorticoids (GCs) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD) but cause pubertal delay. Pubertal induction with testosterone is recommended but longer-term outcome is unknown.

Objective

To assess hypothalamic–pituitary–gonadal axis, muscle volume and function 5 years after pubertal induction.

Methods

A prospective observational follow-up of a clinical study was conducted. 15 GC-treated males with DMD were treated with incremental testosterone for 2 years (end of regimen +2 years) then evaluated at +2.5 years and +5 years (final follow-up ~3 years after last injection). Data collected included testicular volume (TV), gonadotrophin, testosterone, inhibin B, muscle function, and limb muscle MRI.

Results

Participants were 18.7 years (s.d. 1.6) at the final follow-up and had been on GC for 11.2 years (s.d. 2.2). Testosterone levels were similar at +2.5 years (8.6 nmol/L (s.d. 3.4) and 5 years (11.0 nmol/L (s.d. 6.1). TV increased from 2.8 mL (s.d. 0.9) at +2 years to 7.1 mL (s.d. 1.8) then 10.6 mL (s.d. 3.5) at +2.5 years and +5.0 years (P < 0.001). Inhibin B levels increased from 55.6 pg/mL (s.d. 47.0) at baseline to 158.2 pg/mL (s.d.87.6), P =0.004 at 5 years but remained lower than reference values (mean 305 pg/mL). Muscle contractile bulk decreased.

Interpretation

Pubertal induction with testosterone in DMD is associated with HPG axis activation and ongoing increases in inhibin B, TV, and testosterone concentrations. Some patients have normal levels which is promising regarding future fertility. Given the beneficial impact of testosterone on bone health, muscle, and well-being, monitoring testosterone levels in this population and supplementation of sub-optimal levels is important.

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A Bergougnoux Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France

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L Gaspari Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France

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M Soleirol Département de Pediatrie, CHU Nîmes, France, Université de Montpellier Faculté de Médecine Montpellier-Nîmes, Montpellier, France

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N Servant Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France

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S Soskin Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France

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S Rossignol Département de Pédiatrie, Centre Hospitalier Universitaire Hautepierre de Strasbourg, Strasbourg, France

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K Wagner-Mahler Département de Pédiatrie, CHU Nice, Hôpitaux Pédiatriques de Nice CHU-Lenval, Nice, France

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J Bertherat Department of Endocrinology, French Reference Center for Rare Adrenal Disorders, Hôpital Cochin, Université Paris Cité, Institut Cochin, Assitance Publique-Hôpitaux de Paris, Paris, France

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C Sultan Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France

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N Kalfa Department of Pediatric Urological Surgery, French Reference Center for abnormalities of Genital Development (DevGen), CHU Lapeyronie, Montpellier University, Montpellier, France

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F Paris Service de Génétique Moléculaire et de Cytogénétique, Centre Hospitalier Universitaire de Montpellier, Université de Montpellier, Montpellier, France
Département d'Endocrinologie et de Gynécologie Pédiatrique, Hôpital Arnaud de Villeneuve, Université de Montpellier, Montpellier, France
INSERM Unité 1203 (DEFE), Université de Montpellier, Montpellier, France

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Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

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Rebeca Esquivel-Zuniga Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA

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Alan D Rogol Department of Pediatrics, University of Virginia, Charlottesville, Virginia, USA

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Hypogonadism is a clinical syndrome resulting from failure to produce physiological concentrations of sex steroid hormones with accompanying symptoms, such as slowed growth and delayed pubertal maturation. Hypogonadism may arise from gonadal disease (primary hypogonadism), dysfunction of the hypothalamic–pituitary axis (secondary hypogonadism) or functional hypogonadism. Disrupted puberty (delayed or absent) leading to hypogonadism can have a significant impact on both the physical and psychosocial well-being of adolescents with lasting effects. The diagnosis of hypogonadism in teenagers can be challenging as the most common cause of delayed puberty in both sexes is self-limited, also known as constitutional delay of growth and puberty (CDGP). Although an underlying congenital cause should always be considered in a teenager with hypogonadism, acquired conditions such as obesity, diabetes mellitus, other chronic diseases and medications have all been associated with low sex steroid hormone levels. In this review, we highlight some forms of functional hypogonadism in adolescents and the clinical challenges to differentiate normal variants from pathological states.

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Lukas Plachy Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Lenka Petruzelkova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Petra Dusatkova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Klara Maratova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Dana Zemkova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Lenka Elblova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Vit Neuman Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Stanislava Kolouskova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Barbora Obermannova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Marta Snajderova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Zdenek Sumnik Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Jan Lebl Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Stepanka Pruhova Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

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Familial short stature (FSS) describes vertically transmitted growth disorders. Traditionally, polygenic inheritance is presumed, but monogenic inheritance seems to occur more frequently than expected. Clinical predictors of monogenic FSS have not been elucidated. The aim of the study was to identify the monogenic etiology and its clinical predictors in FSS children. Of 747 patients treated with growth hormone (GH) in our center, 95 with FSS met the inclusion criteria (pretreatment height ≤−2 SD in child and his/her shorter parent); secondary short stature and Turner/Prader–Willi syndrome were excluded criteria. Genetic etiology was known in 11/95 children before the study, remaining 84 were examined by next-generation sequencing. The results were evaluated by American College of Medical Genetics and Genomics (ACMG) guidelines. Nonparametric tests evaluated differences between monogenic and non-monogenic FSS, an ROC curve estimated quantitative cutoffs for the predictors. Monogenic FSS was confirmed in 36/95 (38%) children. Of these, 29 (81%) carried a causative genetic variant affecting the growth plate, 4 (11%) a variant affecting GH–insulin-like growth factor 1 (IGF1) axis and 3 (8%) a variant in miscellaneous genes. Lower shorter parent’s height (P = 0.015) and less delayed bone age (BA) before GH treatment (P = 0.026) predicted monogenic FSS. In children with BA delayed less than 0.4 years and with shorter parent’s heights ≤−2.4 SD, monogenic FSS was revealed in 13/16 (81%) cases. To conclude, in FSS children treated with GH, a monogenic etiology is frequent, and gene variants affecting the growth plate are the most common. Shorter parent’s height and BA are clinical predictors of monogenic FSS.

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Yijun Tang Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Yao Chen Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Jiayi Wang Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Qianwen Zhang Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Yirou Wang Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Yufei Xu Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Xin Li Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Jian Wang International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Xiumin Wang Department of Endocrinology and Metabolism, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

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Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

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Alexandra Kiess Department of Pediatric Cardiology, Faculty of Medicine, Heart Center Leipzig, University of Leipzig, Strümpellstraße, Leipzig, Germany
Department of Child and Adolescent Medicine, Section of Pediatric Cardiology, University Hospital Jena, Am Klinikum, Jena, Germany

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Jessica Green Alder Hey Children's NHS Foundation Trust, Pediatric Intensive Care Unit, Eaton Road Liverpool, Great Britain

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Anja Willenberg Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Uta Ceglarek Institute of Laboratory Medicine, Clinical Chemistry, and Molecular Diagnostics (ILM), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Ingo Dähnert Department of Pediatric Cardiology, Faculty of Medicine, Heart Center Leipzig, University of Leipzig, Strümpellstraße, Leipzig, Germany

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Wieland Kiess LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Strasse, Leipzig, Germany
Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Mandy Vogel LIFE Leipzig Research Center for Civilization Diseases, University of Leipzig, Philipp-Rosenthal-Strasse, Leipzig, Germany
Department of Women and Child Health, Hospital for Children and Adolescents and Center for Pediatric Research (CPL), University of Leipzig, Liebigstrasse, Leipzig, Germany

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Background and objectives

As part of the LIFE Child study, we previously described the associations between N-terminal-pro-hormone brain natriuretic peptide (NT-proBNP) and hs-troponin T (hs-TnT) levels and an individual’s sex, age and pubertal status, as well as with body mass index (BMI) and serum lipid levels. For NT-proBNP, we found inverse associations with advancing puberty, increasing BMI and serum lipid levels. These findings led us to further question the putative influences of the developing individual’s metabolic and growth status as represented by levels of insulin-like growth factor-1 (IGF-1) and IGF-1-binding protein-3 (IGF-BP3) as well as hemoglobin A1c (HbA1c) and Cystatin C (CysC).

Material and methods

Serum values, medical history and anthropometric data provided by 2522 children aged 0.25–18 years were collected and analyzed as per study protocol.

Results

A strong negative association between NT-proBNP values and IGF-1, IGF-BP3 and HbA1c levels was identified. For IGF-BP3, this interaction was modulated by sex and age, for HbA1c only by age. For hs-TnT, a positive association was found with IGF-BP3, IGF-1 and CysC. The association between hs-TnT and IGF-1 was sex dependent. The association between CysC and hs-TnT was stronger in girls, but the interaction with age was only seen in boys. Between hs-TnT and HbA1c, the association was significantly negative and modulated by age.

Conclusion

Based on our large pediatric cohort, we could identify age- and sex-dependent interactions between the metabolic status represented by IGF-1, IGF-BP3, CysC and HbA1c levels and the cardiac markers NT-proBNP and hs-TnT.

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Violeta Iotova Department of Pediatrics, Medical University of Varna, Varna, Bulgaria

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Camilla Schalin-Jäntti Department of Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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Charlotte Van Beuzekom Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands

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Petra Bruegmann Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Manuela Broesamle Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands

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Olaf Hiort Department of Paediatric and Adolescent Medicine, Division of Paediatric Endocrinology and Diabetes, University of Lübeck, Lübeck, Germany

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Alberto M Pereira Department of Endocrinology and Metabolism, Amsterdam University Medical Center, Amsterdam, the Netherlands

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The current study aims to assess the development of the knowledge generation program of the European Reference Network on Rare Endocrine Conditions (Endo-ERN) from its start in 2019 until December 2021, with special reference to webinars. We analyzed the number of webinars and live/postevent participants and whether participation and engagement of the attendees changed over time. A total of 30 (86%) self-prepared webinars comprising 300 h of knowledge and competence sharing were broadcasted (2019 – 3; 2020 – 13; 2021 – 14). A total of six webinars were broadcasted live prior to the coronavirus disease 2019 pandemic (https://endo-ern.eu/events/webinars/). The most active main thematic group (MTG) was MTG3 Genetic Disorders of Glucose and Insulin Homeostasis with eight (27%) webinars. Two (25%) MTGs fulfilled the goal to prepare at least two to three webinars per year. Patients were actively involved in 20% of the accounted webinars as both creators and presenters. The total number of live and postevent participants was 3023. The availability of the webinars after the live broadcast increased their outreach with a larger number of postevent viewers (n = 1629, 54%). Within the formal structured evaluation of the webinars, 40–85% of the participants replied on separate occasions and helped improve content. The free webinar access is among the perceived reasons for the rapidly increasing number of total hits to the Endo-ERN website. In conclusion, for its short existence, the Endo-ERN rapidly developed educational outreach, and further efforts to attract creators and learners are warranted.

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