TGF-ß Physiology as a Novel Therapeutic Target Regarding Autoimmune Thyroid Diseases: Where Do We Stand and What to Expect.

Transforming growth factor beta (TGF-ß), as a master regulator of immune response, is deeply implicated in the complex pathophysiology and development of autoimmune thyroid diseases. Based on the close interplay between thyroid autoimmunity and TGF-ß, scientific interest was shifted to the understanding of the possible role of this molecule regarding the diagnosis, prognosis, and therapy of these diseases. The main aim of this review is to present research data about possible treatment options based on the role of TGF-ß in thyroid autoimmunity. Suggested TGF-ß-mediated therapeutic strategies regarding autoimmune thyroid diseases include either the enhancement of its immunosuppressive role or inhibition of its facilitatory role in thyroid autoimmunity. For example, the application of hr-TGF-ß can be used to bolster the inhibitory role of TGF-ß regarding the development of thyroid diseases, whereas anti-TGF-ß antibodies and similar molecules could impede its immune-promoting effects by blocking different levels of TGF-ß biosynthesis and activation pathways. In conclusion, TGF-ß could evolve to a promising, novel therapeutic tool for thyroid autoimmunity.

Associations of maternal oestradiol, cortisol, and TGF-ß1 plasma concentrations with thyroid autoantibodies during pregnancy and postpartum.

BACKGROUND: Thyroid physiology and autoimmunity are altered in pregnancy. While oestradiol, cortisol, and TGF-ß1 are implicated in these phenomena outside pregnancy, their associations with thyroid autoantibodies during pregnancy and postpartum are not thoroughly examined. This study aimed to unravel their eventual associations during pregnancy and postpartum in the same cohort of 93 pregnant women studied prospectively from 2015 to 2017. METHODS: Blood samples were drawn at the 24th and the 36th gestational week and at the 1st postpartum week for measurements of thyroid hormones, TSH, anti-TPO, anti-Tg, oestradiol, cortisol, and TGF-ß1. RESULTS: Serum anti-TPO was greater (P < 0.05) at the 1st postpartum than at the 24th and 36th gestational weeks. At the 36th gestational week, cortisol was greater (P < 0.05) and TGF-ß1 lower (P < 0.05) than at the 24th gestational and the 1st postpartum weeks. At the 1st postpartum week, cortisol correlated negatively with anti-Tg (r = -0.419) (P < 0.05). ΔTGF-ß1 was the best negative and Δoestradiol the best positive predictor of the 1st postpartum week anti-TPO (P < 0.05, b = -0.509; P < 0.05, b = 0.459 respectively). CONCLUSIONS: At postpartum, increased TGF-ß1 is related to a less pronounced anti-TPO increase as compared to the 3rd trimester, suggesting an immunosuppressive role for TGF-ß1. During pregnancy and postpartum, oestradiol, cortisol, and TGF-ß1 are associated with suppression of thyroid autoantibodies.

Antioxidation improves in puberty in normal weight and obese boys, in positive association with exercise-stimulated growth hormone secretion.

BACKGROUND: Oxidative stress is associated with obesity while the evidence for the role of GH in pro- and antioxidation is inconclusive. This study investigates the relationships between growth hormone (GH), pro- and antioxidation in relation to obesity and puberty before and after an acute bout of exercise. METHODS: In this case-control study, 76 healthy normal-weight and obese, prepubertal and pubertal boys underwent a blood sampling before and immediately after an aerobic exercise bout until exhaustion at 70% maximal oxygen consumption. Markers of prooxidation (thiobarbituric acid reactive substances (TBARS) and protein carbonyls (PCs)) and antioxidation (glutathione (GSH), oxidized glutathione disulfide (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPX), catalase, and total antioxidant capacity (TAC)) and hormones (GH, insulin-like growth factor (IGF)-1, IGF-BP-3, luteinizing hormone, follicle-stimulating hormone, and testosterone) were measured. RESULTS: Baseline and postexercise TBARS and PCs were greater, while baseline GSH, GSH/GSSG ratio, GPX, and TAC were lower in obese than that in normal-weight participants. In all participants, waist was the best negative and positive predictor for postexercise GPX and TBARS, respectively. Baseline TAC was greater in pubertal than that in pre-pubertal participants. In all participants, baseline GH was the best negative predictor for postexercise PCs. Significant positive linear correlation exists between the exercise-associated GH, and GSSG increases in pubertal normal-weight boys. CONCLUSIONS: Higher prooxidation and lower antioxidation were observed in obese boys, while antioxidation improves with puberty and postexercise, paralleling GH accentuated secretion.

Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review.

OBJECTIVE: Synthesis of functional MRI (fMRI) and functional connectivity (FC) analysis data on human stress system (SS) function, as it relates to the dynamic function of the Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks. METHODS: Systematic search of Medline, Scopus, Clinical Trials.gov, and Google Scholar databases of studies published prior to September 2022 resulted in 28 full-text articles included for qualitative synthesis. RESULTS: Acute stress changes the states of intra-/inter- neural network FCs and activities from those of resting, low arousal state in the SN, DMN and CEN, during which intra- and inter-network FCs and activities of all three networks are low. SS activation is positively linked to the activity of the SN and negatively to that of the DMN, while, in parallel, it is associated with an initial decrease and a subsequent increase of the intra- network FC and activity of the CEN. The FC between the DMN and the CEN increases, while those between the SN and the CEN decrease, allowing time for frontal lobe strategy input and "proper" CEN activity and task decision. SN activation is linked to sensory hypersensitivity, "impaired" memory, and a switch from serial to parallel processing, while trait mindfulness is associated with FC changes promoting CEN activity and producing a "task-ready state". CONCLUSION: SS activation is tightly connected to that of the SN, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression- to-activation response of the CEN, all adaptive changes favoring proper decisions and survival.

Childhood Obesity, Hypothalamic Inflammation, and the Onset of Puberty: A Narrative Review.

The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been associated with the earlier onset of puberty. Obesity-induced hypothalamic inflammation may cause premature activation of gonadotropin-releasing hormone (GnRH) neurons, resulting in the development of precocious or early puberty. Mechanisms involving phoenixin action and hypothalamic microglial cells are implicated. Furthermore, obesity induces structural and cellular brain alterations, disrupting metabolic regulation. Imaging studies reveal neuroinflammatory changes in obese individuals, impacting pubertal timing. Magnetic resonance spectroscopy enables the assessment of the brain's neurochemical composition by measuring key metabolites, highlighting potential pathways involved in neurological changes associated with obesity. In this article, we present evidence indicating a potential association among obesity, hypothalamic inflammation, and precocious puberty.

Challenges in the management of patients with HNF1B MODY and multisystem manifestations: the cases of two adolescent boys.

INTRODUCTION: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1B mutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features. METHODS: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY. RESULTS: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment. CONCLUSION: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

A toddler with severe vitamin D-dependent rickets type 1 A (VDDR1A), hungry bone syndrome, and severe RSV infection: presentation and therapeutic challenges.

BACKGROUND: Vitamin D-dependent rickets type 1 A (VDDR1A) is an autosomal recessive disorder due to mutations in the CYP27B1 gene which result in inability to generate 1,25(OH)2D. CASE PRESENTATION: An 18-month-old boy with VDDR1A presented with hypotonia and respiratory distress. He had been diagnosed 2 months earlier, having been evaluated for stunted growth, hypotonia, and delayed developmental milestones. He was stabilized with oxygen and bronchodilators for his bronchiolitis and high doses of alfacalcidol, calcium, and phosphate supplements for his hungry bone syndrome. Of note, the patient sustained upper limb fractures after a fall from his bed during admission. Overall, he had a protracted disease course; however, his bone profile gradually improved and he steadily recovered. CONCLUSION: VDDR1A causes failure to thrive, hypotonia, and increased fracture risk and may complicate the clinical course of lower respiratory tract infections. Furthermore, management of hungry bone syndrome requires supraphysiologic doses of vitamin D metabolites and calcium.

PON1-108 TT and PON1-192 RR genotypes are more frequently encountered in Greek PCOS than non-PCOS women, and are associated with hyperandrogenaemia.

OBJECTIVE: To investigate the frequencies of three paraoxonase (PON)1 polymorphisms in Greek polycystic ovary syndrome (PCOS) and non-PCOS women, and their genotypes association with hyperandrogenaemia and insulin resistance. DESIGN: Case-control genetic association study. SETTING: University Hospital Endocrine Unit. PATIENTS: A total of 142 PCOS cases (NIH criteria) and 112 controls. MAIN OUTCOME MEASURE: Genotyping of the c.-108C>T (PON1-108), the c.163T>A (PON1-55) and the c.575A>G (PON1-192) polymorphisms and measurement of baseline androgen and insulin resistance profile. RESULTS: The PON1-108 TT and PON1-192 RR genotypes were more frequently encountered in the PCOS than in the control group. The PON1-192 R allele frequency was greater in the PCOS than in the control group. Comparing the PCOS and the control groups, statistical significances favoured a recessive and a dominant genetic model, respectively, for the single PON1-108 T and PON1-192 R alleles. Free Androgen Index (FAI) levels were higher in patients with PON1-108 TT, whereas Testosterone, FAI and Dehydroepiandrosterone sulphate (DHEAS) levels were higher in patients with PON1-192 RR than patients with the wild or the heterozygous genotype. CONCLUSIONS: The decreased PON1 activity-associated PON1-108 TT and the PON1-192 RR genotypes are more frequently found in Greek PCOS women and are associated with hyperandrogenaemia. Hyperandrogenaemia must depend also on other genetic factors because the same genotypes were not associated with hyperandrogenaemia in the control group. Through identification of the involved polymorphisms, women with PCOS could potentially have a better therapeutic screening.

Inappropriately normal plasma ACTH and cortisol concentrations in the face of increased circulating interleukin-6 concentration in exercise in patients with sarcoidosis.

Sarcoidosis is an autoimmune disease, and hypothalamic-pituitary-adrenal (HPA) axis activity is blunted in autoimmunity. Exercise stimulates the HPA axis, and we hypothesized that in sarcoidosis patients responses to treadmill exercise would be reduced. Hence, we studied 44 sarcoidosis patients [27 untreated (age, mean ± SD, 42 ± 2 years, 12 males, 15 females) and 17 dexamethasone treated (age, 46 ± 4 years, 7 males, 10 females)] and 20 healthy controls (40 ± 5 years old, 9 males, 11 females). Blood samples were drawn before, at peak (exhaustion), and 15 min after treadmill exercise for adrenocorticotropic hormone (ACTH), cortisol, tumor necrosis factor (TNF), interleukin-1ß (IL-1ß) and IL-6 measurements. At peak, plasma ACTH (pg/ml) was increased in untreated (mean ± SE, ΔACTH = 162.8 ± 29.9) and treated (ΔACTH = 123.3 ± 48.1) patients and controls (ΔACTH = 112.3 ± 41.7). Post-exercise, cortisol (ng/ml) was increased (p < 0.05) in untreated patients (Δcortisol = 48.4 ± 14.7) and controls (Δcortisol = 46.0 ± 15.9), but not significantly in treated patients (Δcortisol = 1.43 ± 2.56). At baseline, serum IL-6 (pg/ml) and TNF (pg/ml) were higher in untreated (3.02 ± 0.54 and 3.89 ± 0.72) and treated (1.75 ± 0.33 and 2.16 ± 1.00) patients, respectively, than in controls (0.80 ± 0.66 and 1.58 ± 0.32). At peak exercise, IL-6 was increased in untreated (ΔIL-6 = 0.96 ± 0.14) and treated (ΔIL-6 = 0.91 ± 0.47) patients and controls (ΔIL-6 = 0.96 ± 0.18); IL-1ß was increased only in controls. Hence, the HPA axis of untreated sarcoidosis patients and controls responded similarly to treadmill exercise. In sarcoidosis patients, increased IL-6 was associated with HPA stimulation. Cortisol concentrations were similar between patients and controls, although IL-6 concentrations were higher in patients. Thus, in the face of chronically elevated IL-6 levels in sarcoidosis, there may be dysfunctional IL-6-induced HPA responses or HPA adaptation to high IL-6 concentrations.

The Genetic Basis of Childhood Obesity: A Systematic Review.

Overweight and obesity in childhood and adolescence represents one of the most challenging public health problems of our century owing to its epidemic proportions and the associated significant morbidity, mortality, and increase in public health costs. The pathogenesis of polygenic obesity is multifactorial and is due to the interaction among genetic, epigenetic, and environmental factors. More than 1100 independent genetic loci associated with obesity traits have been currently identified, and there is great interest in the decoding of their biological functions and the gene-environment interaction. The present study aimed to systematically review the scientific evidence and to explore the relation of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with changes in body mass index (BMI) and other measures of body composition in children and adolescents with obesity, as well as their response to lifestyle interventions. Twenty-seven studies were included in the qualitative synthesis, which consisted of 7928 overweight/obese children and adolescents at different stages of pubertal development who underwent multidisciplinary management. The effect of polymorphisms in 92 different genes was assessed and revealed SNPs in 24 genetic loci significantly associated with BMI and/or body composition change, which contribute to the complex metabolic imbalance of obesity, including the regulation of appetite and energy balance, the homeostasis of glucose, lipid, and adipose tissue, as well as their interactions. The decoding of the genetic and molecular/cellular pathophysiology of obesity and the gene-environment interactions, alongside with the individual genotype, will enable us to design targeted and personalized preventive and management interventions for obesity early in life.

Chronic Stress and Steatosis of Muscles, Bones, Liver, and Pancreas: A Review.

BACKGROUND: Chronic stress is a recognized risk factor for poor health, body composition disequilibrium, impaired mental health, and deterioration of quality of life. Chronic stress-related cortisol oversecretion and circadian dysregulation and associated systemic low grade, injurious inflammation ("para-inflammation") contribute to steatosis in various metabolically active solid organs, affecting both their structure and function. The aim of this review was to summarize current knowledge on the impact of chronic stress and associated para-inflammation on skeletal muscle, bone, liver, and pancreas, leading to their steatosis. Current management of these maladaptive conditions is also included and underscored in this review. SUMMARY: Steatosis of metabolically active solid organs is involved in various metabolic processes and considered a risk factor for chronic noncommunicable diseases, yet its role in chronic stress physiology and pathophysiology has been overlooked. KEY MESSAGES: Chronic stress-associated steatosis of several solid organs is generally disregarded in current clinical practice. Physicians should be alert for these steatoses and should address them adequately so as to provide appropriate medical care. New guidelines generated by learned societies are needed, along with large observational studies, to offer novel solutions to this old problem.

Lifestyle and Pharmacological Interventions and Treatment Indications for the Management of Obesity in Children and Adolescents.

Obesity is a multifactorial chronic impairment that further decreases quality of life and life expectancy. Worldwide, childhood obesity has become a pandemic health issue causing several comorbidities that frequently present already in childhood, including cardiovascular (hypertension, dyslipidemia), metabolic (Type 2 diabetes mellitus, fatty liver disease, metabolic syndrome), respiratory, gastrointestinal and musculoskeletal disorders. In addition, obese children frequently experience stress and psychosocial symptoms, including mood disorders, anxiety, prejudice and low self-esteem. Given that cardiovascular risk factors and pediatric obesity have the tendency to pertain into adulthood, obesity management, including weight control and physical activity, should start before the late teens and certainly before the first signs of atherosclerosis can be detected. This review aims to concisely present options for childhood obesity management, including lifestyle modification strategies and pharmacological treatment, as well as the respective treatment indications for the general practitioner.

The Role of SNPs in the Pathogenesis of Idiopathic Central Precocious Puberty in Girls.

The initiation of puberty is a crucial timepoint of development, with its disruptions being associated with multiple physical and psychological complications. Idiopathic Central Precocious Puberty (iCPP) has been correlated with Single-Nucleotide Polymorphisms (SNPs) of certain genes that are implicated in various steps of the process of pubertal onset. The aim of this review was to gather current knowledge on SNPs of genes associated with iCPP. We searched articles published on the PubMed, EMBASE and Google Scholar platforms and gathered current literature. KISS1, KISS1R, PLCB1, PRKCA, ITPR1, MKRN3, HPG axis genes, NPVF/NPFFR1, DLK1, KCNK9Q, LIN28B, PROK2R, IGF-1, IGF2, IGF-1R, IGF-2R, IGFBP-3, insulin, IRS-1, LEP/LEPR, PPARγ2, TAC3, TACR3, Estrogen receptors, CYP3A4 and CYP19A1 were studied for implication in the development of precocious puberty. SNPs discovered in genes KISS1, KISS1R, PLCB1, MKRN3, NPVF, LIN28B, PROK2R, IRS-1 TAC3, and CYP3A4 were significantly correlated with CPP, triggering or protecting from CPP. Haplotype (TTTA)13 in CYP19A1 was a significant contributor to CPP. Further investigation of the mechanisms implicated in the pathogenesis of CPP is required to broaden the understanding of these genes' roles in CPP and possibly initiate targeted therapies.

Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.

CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids. OBJECTIVE: To investigate LTL in children with CAH. METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 ± 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z. RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05). CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.

The impact of physical activity, quality of life and eating habits on cardiometabolic profile and adipokines in youth with T1D.

PURPOSE: Individuals with Type-1-Diabetes (T1D) are at higher risk of having premature cardiovascular-disease (CVD). Physical activity and healthy lifestyle are major components in the prevention of diabetes' related comorbidities and complications. The aim of this study was to investigate the impact of physical activity, eating habits and quality of life in children and adolescents with T1D on diabetic control, cardiovascular and biochemical profile, infection indices, and adipokine levels. METHODS: This cross-sectional study involved 80 participants (36 boys/44 girls) with T1D, aged (mean ± SD) 14.9 ± 3.4 years, who attended the Diabetes and Metabolism Clinic of a University Children's Hospital, using anthropometric studies, lipid profile, high-sensitivity-C-Reactive-Protein(hs-CRP), Interleukin-6(IL6), leptin and adiponectin levels. Physical activity was assessed with pedometers (total-steps/week) and questionnaire. RESULTS: In 20(25%) children the level of exercise was >75th percentile, in 20(25%) <25th percentile and in 40(50%) children ranged between 25-75th percentile, respectively. Higher levels of physical activity were associated with weight (beta = -0.053, p < 0.001), waist circumference (beta = -0.077, p < 0.001), BMI (beta = -0.167, p = 0.009), muscle mass (beta = -0.0619, p = 0.001) and HDL-C (beta = 0.039, p = 0.033). Quality of life was positively related to weight (beta = 5.49511, p = 0.002), waist circumference (beta = 6.593345, p = 0.012), muscle mass (beta = 7.324088, p < 0.001) and T1D duration (beta = 19.22442, p = 0.005). Lipid profile was positively associated with sweets and chocolate consumption (beta = 0.348, p < 0.05), while vegetable (beta = -0.245, p < 0.05) and white milk consumption (beta = -0.2295, p < 0.05) were negatively associated with waist/height ratio. CONCLUSIONS: In the present study, higher levels of physical activity were associated with improved lipid profile (HDL-C, triglycerides) and body composition [waist circumference, Body-Mass-Index (BMI] of children and adolescents with T1D. Higher scoring in quality-of-life questionnaires were related to older children with longer diabetes duration. Unhealthy eating habits unfavorably affected lipid profile and body composition in T1D youth.

Non-Traditional Cardiovascular Risk Factors in Adolescents with Obesity and Metabolic Syndrome May Predict Future Cardiovascular Disease.

Obesity in adolescence is associated with significant morbidity and predisposes adolescents to the development of cardiovascular disease (CVD). Although a number of traditional CVD risk factors have been identified in youth, limited data exist regarding non-traditional CVD risk factors. In 89 adolescents with metabolic syndrome (MetS), with 60 age-, gender-, and BMI-matched controls, we determined the non-traditional CVD risk factors (hs-CRP, TG/HDL ratio, ApoB/ApoA1 ratio, NAFLD) in order to investigate whether they may be used as biomarkers for predicting future CVD, and we evaluated their response to the implementation of a multidisciplinary, personalized, lifestyle intervention program for 1 year. We demonstrated that the TG/HDL ratio, IL-2, IL-6, IL-17A, and INF-γ were significantly increased in subjects with MetS than in controls, and may be used as biomarkers to predict future CVD. Subjects with MetS had an increased mean carotid intima-media thickness (cIMT) and prevalence of NAFLD than the controls, while the prevalence of NAFLD correlated strongly with cIMT and IL-6 concentrations. Most of the non-traditional cardiovascular risk factors improved following the implementation of a lifestyle intervention program. These findings indicate that adolescents with MetS may have a greater risk for developing atherosclerosis early in life, while early lifestyle intervention is crucial for preventing the arteriosclerotic process in youth.

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .

A rare case of a giant prolactinoma with atypical histological features: 5 years of follow-up.

BACKGROUND: Giant prolactinomas are rare in childhood and adolescence and represent a challenge in diagnosis and management. CASE PRESENTATION: A 15.7-year-old male adolescent presented with short stature and delayed puberty. On clinical examination, mild right central VII paresis, gait instability, decreased visual acuity, and impaired visual fields were noted. Investigations showed hyperprolactinemia (2209 ng/mL), secondary hypothyroidism, hypogonadotropic hypogonadism, and growth hormone deficiency. Imaging studies showed an enormous invasive skull base mass. Craniotomy was undertaken to debulk the tumor and perform biopsies. Histology revealed a very large atypical, prolactin-secreting pituitary macroadenoma, i.e., a giant prolactinoma. After commencing cabergoline treatment, prolactin concentrations decreased in 5 months and normalized 18 months later, while significant shrinkage of the tumor was observed. The diagnostic work-up for genetic syndromes often associated with sporadic macroadenomas was negative. CONCLUSION: Giant prolactinomas presenting with multiple pituitary hormone deficiencies in childhood or adolescence are rare and require prompt diagnosis and multidisciplinary management.

Association between Telomere Length and Pediatric Obesity: A Systematic Review.

OBJECTIVE: Telomere length (TL) is a robust marker of biological aging, and increased telomere attrition is noted in adults with obesity. The primary objective of this systematic review was to summarize current knowledge on the effects of childhood obesity in TL. The secondary objective was to assess the effect of weight management interventions in TL. METHODS: The following databases were searched: PubMed, Scopus, Web of Science and Heal-link.gr from inception to September 2021. The search was performed using the following combinations of terms: "telomer*" [All Fields] AND ("length" [All Fields] OR "lengths" [All Fields]) AND "obes*" [All Fields] AND ("child*" [All Fields] OR "adolescen*" [All Fields]). RESULTS: A total of 16 original articles were included in this systematic review. Eleven of them were cross-sectional and five were lifestyle interventions. CONCLUSIONS: There was a tendency towards a negative association between childhood obesity and TL. Life-style interventions in children have been associated with increased TL peripherally, indicating a possible association of the redistribution of younger cells in the periphery with the favorable effect of these interventions. Further prospective studies with larger sample sizes that employ other markers of cell aging would potentially elucidate this important mechanistic relation.

Could COVID-19's Aftermath on Children's Health Be Felt into the 22nd Century?

The COVID-19 pandemic has massively affected people's health, societies, and the global economy. Our lives are no longer as they were before COVID-19, and, most likely, will never be the same again. We hypothesize that the effect of the COVID-19 pandemic on population health and the economy will last for a very long time and will still be felt in the 22nd century. Our hypothesis is based on evidence from the 1918-1919 influenza pandemic, the Dutch famine during the Second World War, and the 2007-2008 economic crisis, as well as from the rationally predicted impact of COVID-19 on human development. We expect that the COVID-19 pandemic, including the mitigation measures taken against it, will affect children's development in multiple ways, including obesity, both while in utero and during critical and sensitive windows of development, including the early childhood years and those of puberty and adolescence. The psychosocial and biological impact of this effect will be considerable and unequally distributed. The implications will last at least a lifetime, and, through inter-generational transmission, will likely take us to future generations, into the 22nd century. We argue for the urgent need of designing and initiating comprehensive longitudinal cohort studies to closely monitor the long-term effects of COVID-19 on children conceived, born, and raised during the pandemic. Such an approach requires a close and effective collaboration between scientists, healthcare providers, policymakers, and the younger generations, and it will hopefully uncover evidence necessary to understand and mitigate the impact of the pandemic on people's lives in the 21st and 22nd centuries.