Height benefit of GnRH agonists after age 8 in a Portuguese cohort of central precocious puberty.

OBJECTIVE: Idiopathic central precocious puberty (iCPP) is common in paediatric endocrinology. Gonadotropin-releasing hormone agonists (GnRHa) are safe, but the effect on final height and the ideal timing for treatment remains controversial. This study aims to assess the effectiveness of GnRHa on growth outcomes in girls with iCPP treated before and after the age of 8 years old. DESIGN AND PATIENTS: This retrospective longitudinal study evaluated data from Portuguese girls with iCPP who completed treatment between 2010 and 2021. MEASUREMENTS: Auxological and clinical characteristics were compared according to age at treatment onset. RESULTS: A cohort of 134 girls with iCPP, was divided into early treatment (ET) (<8 years, n = 48) and later treatment (LT) groups (≥8 years, n = 86). In both groups, most children presented with Tanner II and III. Tanner IV was more frequent in LT group (p = .003). At the end of treatment, predicted adult height increased in both groups (ET p = .032; LT p = .04) and bone age significantly slowed down in all participants (p = .008, p = .034). The height gain was greater in the ET group, but without significant differences (p = .065). CONCLUSIONS: Treatment with GnRHa improved final height in all girls with iCPP, even when initiated after 8 years. To achieve better outcomes, treatment should be provided promptly after diagnosis.

Association of diabetic ketoacidosis and HbA1c at onset with year-three HbA1c in children and adolescents with type 1 diabetes: Data from the International SWEET Registry.

OBJECTIVE: To establish whether diabetic ketoacidosis (DKA) or HbA1c at onset is associated with year-three HbA1c in children with type 1 diabetes (T1D). METHODS: Children with T1D from the SWEET registry, diagnosed <18 years, with documented clinical presentation, HbA1c at onset and follow-up were included. Participants were categorized according to T1D onset: (a) DKA (DKA with coma, DKA without coma, no DKA); (b) HbA1c at onset (low [<10%], medium [10 to <12%], high [≥12%]). To adjust for demographics, linear regression was applied with interaction terms for DKA and HbA1c at onset groups (adjusted means with 95% CI). Association between year-three HbA1c and both HbA1c and presentation at onset was analyzed (Vuong test). RESULTS: Among 1420 children (54% males; median age at onset 9.1 years [Q1;Q3: 5.8;12.2]), 6% of children experienced DKA with coma, 37% DKA without coma, and 57% no DKA. Year-three HbA1c was lower in the low compared to high HbA1c at onset group, both in the DKA without coma (7.1% [6.8;7.4] vs 7.6% [7.5;7.8], P = .03) and in the no DKA group (7.4% [7.2;7.5] vs 7.8% [7.6;7.9], P = .01), without differences between low and medium HbA1c at onset groups. Year-three HbA1c did not differ among HbA1c at onset groups in the DKA with coma group. HbA1c at onset as an explanatory variable was more closely associated with year-three HbA1c compared to presentation at onset groups (P = .02). CONCLUSIONS: Year-three HbA1c is more closely related to HbA1c than to DKA at onset; earlier hyperglycemia detection might be crucial to improving year-three HbA1c.

Immune cell and cytokine patterns in children with type 1 diabetes mellitus undergoing a remission phase: A longitudinal study.

OBJECTIVE: Type 1 diabetes (T1D) develops in distinct stages, before and after disease onset. Whether the natural course translates into different immunologic patterns is still uncertain. This study aimed at identifying peripheral immune patterns at key time-points, in T1D children undergoing remission phase. METHODS: Children with new-onset T1D and healthy age and gender-matched controls were recruited at a pediatric hospital. Peripheral blood samples were evaluated by flow cytometry at 3 longitudinal time-points: onset (T1), remission phase (T2) and established disease (T3). Cytokine levels were quantified by multiplex assay. Fasting C-peptide, HbA1c, and 25OHD were also measured. RESULTS: T1D children (n = 28; 10.0 ± 2.6 years) showed significant differences from controls in circulating neutrophils, T helper (Th)17 and natural killer (NK) cells, with relevant variations during disease progression. At onset, neutrophils, NK, Th17 and T cytotoxic (Tc)17 cells were decreased. As disease progressed, neutrophil counts recovered whereas NK counts remained low. Th17 and Tc17 cells behavior followed the neutrophil variation pattern. B-cells were lowest in the remission phase and regulatory T-cells significantly declined after remission. Two cytokine response profiles were identified. Low cytokine-responders showed higher circulating fasting C-peptide levels at onset and longer remission periods. C-peptide inversely correlated with pro-inflammatory and cytotoxic cells. CONCLUSIONS: Our data suggest an association between immune cells, cytokine patterns and metabolic counterparts. The dynamic changes of circulating immune cells during disease progression involve key innate and acquired immune cell types. This longitudinal picture of T1D progression may enable disease staging and patient stratification, essential for individualized treatment.

Prevalence of underweight, overweight, and obesity in children and adolescents with type 1 diabetes: Data from the international SWEET registry.

OBJECTIVE: To assess the prevalence of underweight (UW), overweight (OW), and obesity in children and adolescents with type 1 diabetes (T1D). METHODS: An international cross-sectional study including 23 026 T1D children (2-18 years, duration of diabetes ≥1 year) participating in the SWEET prospective, multicenter diabetes registry. Body mass index SD score (BMI-SDS) was calculated using the World Health Organization BMI charts. Children were categorized as UW (BMI-SDS < -2SD), OW (+1SD < BMI-SDS ≤ +2SD), and obese (OB) (BMI-SDS > +2SD). Hierarchic regression models were applied with adjustment for sex, age, and duration of diabetes. RESULTS: The prevalence of UW, OW, and obesity was: 1.4%, 22.3%, and 7.3% in males and 0.6%, 27.2%, and 6.8% in females. Adjusted BMI-SDS was significantly higher in females than in males (mean ± SEM: 0.54 ± 0.05 vs 0.40 ± 0.05, P < 0.0001). In males, BMI-SDS significantly decreased by age (P < 0.0001) in the first three age categories 0.61 ± 0.06 (2 to <10 years), 0.47 ± 0.06 (10 to <13 years), 0.34 ± 0.05 (13 to <16 years). In females, BMI-SDS showed a U-shaped distribution by age (P < 0.0001): 0.54 ± 0.04 (2 to <10 years), 0.39 ± 0.04 (10 to <13 years), 0.55 ± 0.04 (13 to <16 years). BMI-SDS increased by diabetes duration (<2 years: 0.38 ± 0.05, 2 to <5 years: 0.44 ± 0.05, and ≥5 years: 0.50 ± 0.05, P < 0.0001). Treatment modality did not affect BMI-SDS. Adjusted HbA1c was significantly higher in females than in males (8.20% ± 0.10% vs 8.06% ± 0.10%, P < 0.0001). In both genders, the association between HbA1c and BMI-SDS was U-shaped with the highest HbA1c in the UW and obesity groups. CONCLUSIONS: The high rate of OW and obesity (31.8%) emphasize the need for developing further strategies to prevent and treat excess fat accumulation in T1D.

A description of clinician reported diagnosis of type 2 diabetes and other non-type 1 diabetes included in a large international multicentered pediatric diabetes registry (SWEET).

BACKGROUND: Although type 1 diabetes (T1D) remains the most frequent form of diabetes in individuals aged less than 20 years at onset, other forms of diabetes are being increasingly recognized. OBJECTIVES: To describe the population of children with other forms of diabetes (non-type 1) included in the multinational SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) database for children with diabetes. METHODS: Cases entered in the SWEET database are identified by their physician as T1D, type 2 diabetes (T2D) and other types of diabetes according to the ISPAD classification. Etiologic subgroups are provided for other types of diabetes. Descriptive analyses were tabulated for age at onset, gender, daily insulin doses, and hemoglobin A1c (A1C) for each type and subtype of diabetes and when possible, values were compared. RESULTS: Of the 27 104 patients included in this report, 95.5% have T1D, 1.3% T2D, and 3.2% other forms of diabetes. The two most frequent etiologies for other forms of diabetes were maturity onset diabetes of the young (MODY) (n = 351) and cystic fibrosis-related diabetes (CFRD) (n = 193). The cause was unknown or unreported in 10% of other forms of diabetes. Compared with T1D, children with T2D and CFRD were diagnosed at an older age, took less insulin and had lower A1C (all P < .0001). CONCLUSION: In centers included in SWEET, forms of diabetes other than type 1 remain rare and at times difficult to characterize. Sharing clinical information and outcome between SWEET centers on those rare forms of diabetes has the potential to improve management and outcome.

The rare DRB1*04:08-DQ8 haplotype is the main HLA class II genetic driver and discriminative factor of Early-onset Type 1 diabetes in the Portuguese population.

Introduction: Early-onset Type 1 diabetes (EOT1D) is considered a disease subtype with distinctive immunological and clinical features. While both Human Leukocyte Antigen (HLA) and non-HLA variants contribute to age at T1D diagnosis, detailed analyses of EOT1D-specific genetic determinants are still lacking. This study scrutinized the involvement of the HLA class II locus in EOT1D genetic control. Methods: We conducted genetic association and regularized logistic regression analyses to evaluate genotypic, haplotypic and allelic variants in DRB1, DQA1 and DQB1 genes in children with EOT1D (diagnosed at ≤5 years of age; n=97), individuals with later-onset disease (LaOT1D; diagnosed 8-30 years of age; n=96) and nondiabetic control subjects (n=169), in the Portuguese population. Results: Allelic association analysis of EOT1D and LaOT1D unrelated patients in comparison with controls, revealed that the rare DRB1*04:08 allele is a distinctive EOT1D susceptibility factor (corrected p-value=7.0x10-7). Conversely, the classical T1D risk allele DRB1*04:05 was absent in EOT1D children while was associated with LaOT1D (corrected p-value=1.4x10-2). In corroboration, HLA class II haplotype analysis showed that the rare DRB1*04:08-DQ8 haplotype is specifically associated with EOT1D (corrected p-value=1.4x10-5) and represents the major HLA class II genetic driver and discriminative factor in the development of early onset disease. Discussion: This study uncovered that EOT1D holds a distinctive spectrum of HLA class II susceptibility loci, which includes risk factors overlapping with LaOT1D and discriminative genetic configurations. These findings warrant replication studies in larger multicentric settings encompassing other ethnicities and may impact target screening strategies and follow-up of young children with high T1D genetic risk as well as personalized therapeutic approaches.

Diabetes-related antibody-testing is a valuable screening tool for identifying monogenic diabetes - A survey from the worldwide SWEET registry.

AIMS: To evaluate access to screening tools for monogenic diabetes in paediatric diabetes centres across the world and its impact on diagnosis and clinical outcomes of children and youth with genetic forms of diabetes. METHODS: 79 centres from the SWEET diabetes registry including 53,207 children with diabetes participated in a survey on accessibility and use of diabetes related antibodies, c-peptide and genetic testing. RESULTS: 73, 63 and 62 participating centres had access to c-peptide, antibody and genetic testing, respectively. Access to antibody testing was associated with higher proportion of patients with rare forms of diabetes identified with monogenic diabetes (54 % versus 17 %, p = 0.01), lower average whole clinic HbA1c (7.7[Q1,Q2: 7.3-8.0]%/61[56-64]mmol/mol versus 9.2[8.6-10.0]%/77[70-86]mmol/mol, p < 0.001) and younger age at onset (8.3 [7.3-8.8] versus 9.7 [8.6-12.7] years p < 0.001). Additional access to c-peptide or genetic testing was not related to differences in age at onset or HbA1c outcome. CONCLUSIONS: Clinical suspicion and antibody testing are related to identification of different types of diabetes. Implementing access to comprehensive antibody screening may provide important information for selecting individuals for further genetic evaluation. In addition, worse overall clinical outcomes in centers with limited diagnostic capabilities indicate they may also need support for individualized diabetes management. TRIAL REGISTRATION: NCT04427189.

Do GnRH Agonists Really Increase Body Weight Gain? Evaluation of a Multicentric Portuguese Cohort of Patients With Central Precocious Puberty.

Introduction: There are several concerns associated with gonadotropin-releasing hormone agonist (GnRHa) treatment for central precocious puberty (CPP), such as obesity and changes in body mass index (BMI). We aimed to investigate whether any anthropometric differences exist and if they persist over time. Methods: We conducted an observational study of Portuguese children (both sexes) diagnosed with CPP between January 2000 and December 2017, using a digital platform, in order to analyze the influence of GnRHa treatment on BMI-SD score (BMI-SDS). Results: Of the 241 patients diagnosed with CPP, we assessed 92 patients (8% boys) in this study. At baseline, 39% of the patients were overweight. BMI-SDS increased with treatment for girls but then diminished 1 year after stopping GnRHa therapy (p = 0.018). BMI-SDS variation at the end of treatment was negatively correlated with BMI-SDS at baseline (p < 0.001). Boys grew taller and faster during treatment than did girls (p < 0.001), and therefore, their BMI-SDS trajectory might be different. Conclusions: This study showed an increase of body weight gain during GnRHa treatment only in girls, which reversed just 1 year after stopping treatment. The overall gain in BMI-SDS with treatment is associated with baseline BMI-SDS.

The COVID-19 Pandemic Affects Seasonality, With Increasing Cases of New-Onset Type 1 Diabetes in Children, From the Worldwide SWEET Registry.

OBJECTIVE: To analyze whether the coronavirus disease 2019 (COVID-19) pandemic increased the number of cases or impacted seasonality of new-onset type 1 diabetes (T1D) in large pediatric diabetes centers globally. RESEARCH DESIGN AND METHODS: We analyzed data on 17,280 cases of T1D diagnosed during 2018-2021 from 92 worldwide centers participating in the SWEET registry using hierarchic linear regression models. RESULTS: The average number of new-onset T1D cases per center adjusted for the total number of patients treated at the center per year and stratified by age-groups increased from 11.2 (95% CI 10.1-12.2) in 2018 to 21.7 (20.6-22.8) in 2021 for the youngest age-group, <6 years; from 13.1 (12.2-14.0) in 2018 to 26.7 (25.7-27.7) in 2021 for children ages 6 to <12 years; and from 12.2 (11.5-12.9) to 24.7 (24.0-25.5) for adolescents ages 12-18 years (all P < 0.001). These increases remained within the expected increase with the 95% CI of the regression line. However, in Europe and North America following the lockdown early in 2020, the typical seasonality of more cases during winter season was delayed, with a peak during the summer and autumn months. While the seasonal pattern in Europe returned to prepandemic times in 2021, this was not the case in North America. Compared with 2018-2019 (HbA1c 7.7%), higher average HbA1c levels (2020, 8.1%; 2021, 8.6%; P < 0.001) were present within the first year of T1D during the pandemic. CONCLUSIONS: The slope of the rise in pediatric new-onset T1D in SWEET centers remained unchanged during the COVID-19 pandemic, but a change in the seasonality at onset became apparent.

PDX1- and NGN3-mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages.

BACKGROUND AIMS: Reprogramming of multipotent adult bone marrow (BM)-derived mesenchymal stromal/stem cells (MSC) (BM-MSC) represents one of several strategies for cell-based therapy of diabetes. However, reprogramming primary BM-MSC into pancreatic endocrine lineages has not yet been consistently demonstrated. METHODS: To unravel the role and interaction of key factors governing this process, we used well-characterized telomerase-immortalized human MSC (hMSC-TERT). Pancreatic endocrine differentiation in hMSC-TERT was induced by two major in vitro strategies: (i) endocrine-promoting culture conditions and (ii) ectopic expression of two master regulatory genes of the endocrine lineage, human neurogenin 3 (NGN3) and human pancreatic duodenal homeobox 1 (PDX1). RESULTS: Both approaches triggered pancreatic endocrine gene expression, notably insulin, glucose-transporter 2 and somatostatin. Transgenic overexpression of NGN3 and/or PDX1 proteins not only induced direct target genes, such as NEUROD1 and insulin, and but also triggered parts of the gene expression cascade that is involved in pancreatic endocrine differentiation. Notably, ectopic NGN3 alone was sufficient to initiate the expression of specific beta-cell lineage-associated genes, most importantly PDX1 and insulin. This was demonstrated both transcriptionally by mRNA expression and reporter gene analyzes and at a protein level by Western blotting. Such reprogramming of hMSC-TERT cells induced glucose-insensitive insulin biosynthesis and secretion. CONCLUSIONS: Our results indicate that establishment of glucose-dependent insulin secretion in partially reprogrammed human MSC may depend on additional maturation factors. Moreover, hMSC-TERT provides a suitable cell model for investigating further the molecular mechanisms of reprogramming and maturation of adult MSC towards pancreatic endocrine lineages.

Telemonitoring, Telemedicine and Time in Range During the Pandemic: Paradigm Change for Diabetes Risk Management in the Post-COVID Future.

People with diabetes are at greater risk for negative outcomes from COVID-19. Though this risk is multifactorial, poor glycaemic control before and during admission to hospital for COVID-19 is likely to contribute to the increased risk. The COVID-19 pandemic and restrictions on mobility and interaction can also be expected to impact on daily glucose management of people with diabetes. Telemonitoring of glucose metrics has been widely used during the pandemic in people with diabetes, including adults and children with T1D, allowing an exploration of the impact of COVID-19 inside and outside the hospital setting on glycaemic control. To date, 27 studies including 69,294 individuals with T1D have reported the effect of glycaemic control during the COVID-19 pandemic. Despite restricted access to diabetes clinics, glycaemic control has not deteriorated for 25/27 cohorts and improved in 23/27 study groups. Significantly, time in range (TIR) 70-180 mg/dL (3.9-10 mmol/L) increased across 19/27 cohorts with a median 3.3% (- 6.0% to 11.2%) change. Thirty per cent of the cohorts with TIR data reported an average clinically significant TIR improvement of 5% or more, possibly as a consequence of more accurate glucose monitoring and improved connectivity through telemedicine. Periodic consultations using telemedicine enables care of people with diabetes while limiting the need for in-person attendance at diabetes clinics. Reports that sustained hyperglycaemia and early-stage diabetic ketoacidosis may go untreated because of the lockdown and concerns about potential exposure to the risk of infection argue for wider access to glucose telemonitoring. Therefore, in this paper we have critically reviewed reports concerning use of telemonitoring in the acute hospitalized setting as well as during daily diabetes management. Furthermore, we discuss the indications and implications of adopting telemonitoring and telemedicine in the present challenging time, as well as their potential for the future.

Mutation of the MIF type II receptor in two brothers.

The Müllerian inhibiting factor (MIF) is responsible for regression of Müllerian ducts during male sexual differentiation. Mutations in MIF or its type II receptor lead to persistence of the uterus and Fallopian tubes in male children--i.e., persistent Müllerian duct syndrome (PMDS). Both are rare autosomal recessive disorders. We report a 7-month-old male infant who underwent inguinal herniorrhaphy. Remnants of vas deferens and gonads with macroscopic characteristics of ovaries, along with Fallopian tubes and a rudimentary uterus, were found. Karyotype confirmed male sex. Molecular genetics revealed the most frequent MIF type II receptor gene mutation--27 bp deletion. Investigation of the older brother presenting bilateral cryptorchidism at 7 years of age led to similar clinical findings and the same mutation. We report here an MIF type II receptor mutation in two brothers, with the particularity that the surgical findings in the younger son initiated the diagnostic process in both children.

Hypogonadotropic hypogonadism due to compound heterozygous mutations TACR3 in siblings.

The authors present a new association of two heterozygous TACR3 mutations (p.Arg230His and p.Trp275*) responsible for a clinical trait of normosmic congenital hypogonadotropic hypogonadism in a family.

Children with type 1 diabetes of early age at onset - immune and metabolic phenotypes.

Objectives We aimed to evaluate children with type 1 diabetes (T1D) with early age at onset (EAO) for clinical, immune and metabolic features in order to identify age-related disease phenotypes. Methods Comparative study of two groups of T1D children: EAO (≤5 years) and later age at onset (LAO; >5 years), regarding the presence of other autoimmune (AI) diseases, diabetes ketoacidosis and immunologic profile at onset and metabolic data 1 year after diagnosis. Statistical analysis was performed with significance set for p < 0.05. Results The study included 137 children (EAO = 52, mean age 3.6 ± 1.5 [mean ± standard deviation (SD)] and LAO = 85, mean age 10.4 ± 2.9). EAO was more associated with concomitant AI diseases (p = 0.032). Despite no differences in disease onset, EAO presented with lower C-peptide levels (p = 0.01) and higher absolute lymphocyte number (p < 0.0001), with an inverse correlation between these two variables (p = 0.028). Additionally, the EAO group had a higher frequency of serum detection of three antibodies (Abs) (p = 0.0008), specifically insulin Abs (p = 0.0001). One year after diagnosis, EAO had higher total daily insulin (TDI) dose (p = 0.008), despite similar hemoglobin A1c (HbA1c). Conclusions Our data show an association of EAO T1D with more AI diseases, higher number of Abs, lower initial insulin reservoir and higher insulin requirements 1 year after diagnosis. In this group, immune imbalance seems more evident and disease progression faster, probably reflecting distinct "immune environment" with different ages at disease onset. Further studies in the field of immunogenetics and immune tolerance are required, to improve patient stratification and find novel targets for therapeutic intervention.

Prepubertal gynaecomastia in a boy with Peutz-Jeghers syndrome: managing the aromatase overexpression.

Background Gynaecomastia, although rarely related to testicular tumours, in boys with Peutz-Jeghers syndrome (PJS) usually occurs due to large-cell calcifying Sertoli cell tumour (LCCSCT). Case presentation A 4-year-old boy, with a genetic diagnosis of PJS, presented gynaecomastia since the age of 2, associated with increased height velocity (HV). He exhibited bilateral breast enlargement (Tanner-B4) and a testicular volume of 4 mL. Testicular ultrasound revealed multifocal microcalcifications in both testicles. A laboratory evaluation showed undetectable gonadotrophins, testosterone and oestrogen and inhibin A of 4.6 pg/mL (0.9-1.7). The boy was subjected to therapy with anastrozole. In the last follow-up, 2 years after the start of therapy, he experienced a less tense Tanner-B2 and a decrease in HV; serum inhibin A had become negative. Conclusions This is one of the most precocious PJS-related gynaecomastia treated with aromatase inhibitors (AIs) reported in the literature. Oestrogen levels, although under the detection limit, may be sufficient to stimulate breast tissue/growth plates. Inhibin A is a good marker of LCCSCT and an indicator of response to AIs.

Diplopia, Convergent Strabismus, and Eye Abduction Palsy in a 12-Year-Old Boy with Autoimmune Thyroiditis.

Pseudotumor cerebri (PTC) is defined by clinical criteria of increased intracranial pressure, elevated intracranial pressure with normal cerebrospinal fluid (CSF) composition, and exclusion of other causes such tumors, vascular abnormalities, or infections. The association of PTC with levothyroxine (LT4) has been reported. A 12-year-old boy has been followed up for autoimmune thyroiditis under LT4. Family history was irrelevant for endocrine or autoimmune diseases. A TSH level of 4.43 µUI/mL (0.39-3.10) motivated a LT4 adjustment from 75 to 88 µg/day. Five weeks later, he developed horizontal diplopia, convergent strabismus with left eye abduction palsy, and papilledema. Laboratorial evaluation revealed elevated free thyroxine level (1.05 ng/dL [0.65-1.01]) and low TSH, without other alterations. Lumbar puncture was performed and CSF opening pressure was 24 cm H2O with normal composition. Blood and CSF cultures were sterile. Brain MRI was normal. LT4 was temporarily discontinued and progressive improvement was observed, with a normal fundoscopy at day 10 and reversion of diplopia one month later. LT4 was restarted at lower dose and gradually titrated. The boy is currently asymptomatic. This case discloses the potential role of LT4 in inducing PTC. Despite its rarity and unclear association, PTC must be seen as a potential complication of LT4, after excluding all other intracranial hypertension causes.