Near adult height and BMI changes in growth hormone treated short children with Noonan syndrome: the Belgian experience.

Introduction A variable near adult height (NAH) outcome after growth hormone (GH) therapy in Noonan syndrome (NS) patients with short stature has been reported. The main objective of this study was to evaluate NAH and body mass index (BMI) evolution in a large Belgian cohort of NS patients treated for short stature. The secondary objectives were to investigate whether sex, genotype, the presence of a thoracic deformity and/or a heart anomaly might affect NAH and to validate the recently developed NAH prediction model by Ranke et al. Methods Clinical and auxological data of GH treated short NS patients born before 2001 were extracted from the national Belgrow registry. NAH was available in 54 (35 male) genotyped NS using a gene panel of 9 genes, showing pathogenic variants in PTPN11 in 32 and in SOS1 in 5 patients, while in 17 patients gene panel analysis was inconclusive (no mutation group). Results After a median (P10; P90) duration of 5.4 (2.2-10.3) years of GH therapy with a median dose of 0.05 mg/kg/day NS patients reached a median NAH of -1.7 (-3.4; -0.8) SDS. Median total height gain was 1.1 (0.1; 2.3) SDS. Sex, genotype and the presence of a thoracic or cardiac malformation did not correlate with NAH or total height gain. Linear regression modelling revealed that height SDS at start (beta=0.90, p<0.001), mid-parental height SDS (beta =0.27; p=0.005), birth weight SDS (beta=0.15; p=0.051), age at start (beta=0.07; p=0032) were independently associated with NAH SDS. Median BMI SDS increased significantly (p<0.001) from -1.0 (-2.5; 0.0) at start to -0.2 (-1.5; 0.9) at NAH. The observed NAH in a subgroup of 44 patients with more than 3 years of GH treatment was not statistically different from the predicted NAH by the Noonan NAH prediction model of Ranke. Conclusion Long-term GH therapy at a dose of 0.05 mg/kg/day in short NS patients is effective in improving adult height and BMI, irrespective of the genotype and presence or absence of cardiac and or thoracic anomalies.

A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

Background: Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. Methods: We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. Results: The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. Conclusion: We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

Post-Hypoglycemic hyperglycemia are highly relevant markers for stratification of glycemic variability and partial remission status of pediatric patients with new-onset type 1 diabetes.

AIMS: To evaluate whether parameters of post-hypoglycemic hyperglycemia (PHH) correlated with glucose homeostasis during the first year after type 1 diabetes onset and helped to distinguish pediatric patients undergoing partial remission or not. METHODS: In the GLUREDIA (GLUcagon Response to hypoglycemia in children and adolescents with new-onset type 1 DIAbetes) study, longitudinal values of clinical parameters, continuous glucose monitoring metrics and residual ß-cell secretion from children with new-onset type 1 diabetes were analyzed during the first year after disease onset. PHH parameters were calculated using an in-house algorithm. Correlations between PHH parameters (i.e., PHH frequency, PHH duration, PHH area under the curve [PHHAUC]) and glycemic homeostasis markers were studied using adjusted mixed-effects models. RESULTS: PHH parameters were strong markers to differentiate remitters from non-remitters with PHH/Hyperglycemia duration ratio being the most sensitive (ratio<0.02; sensitivity = 86% and specificity = 68%). PHHAUC moderately correlated with parameters of glucose homeostasis including TIR (R2 = 0.35, p-value < 0.05), coefficient of variation (R2 = 0.22, p-value < 0.05) and Insulin-Dose Adjusted A1c (IDAA1C) (R2 = 0.32, p-value < 0.05) and with residual ß-cell secretion (R2 = 0.17, p-value < 0.05). Classification of patients into four previously described glucotypes independently validated PHH parameters as reliable markers of glucose homeostasis and improved the segregation of patients with intermediate values of IDAA1C and estimated C-peptide (CPEPEST). Finally, a combination of PHH parameters identified groups of patients with specific patterns of hypoglycemia. CONCLUSION: PHH parameters are new minimal-invasive markers to discriminate remitters from non-remitters and evaluate glycemic homeostasis during the first year of type 1 diabetes. PHH parameters may also allow patient-targeted therapeutic management of hypoglycemic episodes.

Case Report: Aggressive neural crest tumors in a child with familial von Hippel Lindau syndrome associated with a germline VHL mutation (c.414A>G) and a novel KIF1B gene mutation.

Introduction: Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10. Case presentation: We diagnosed a 9-year-old girl of normal appearance and severe refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation of VHL gene (c.414A>G), also present in three members of her family. At age 13, a pelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life. Discussion: This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine.

Congenital hyperinsulinemic hypoglycemia (HH) requiring treatment as the presenting feature of Kabuki syndrome.

Kabuki syndrome is a congenital condition characterized by a set of facial dysmorphic features that often help the clinician to suspect the diagnosis. However, more insidious symptoms can rarely occur, such as manifestations of hypoglycemia in newborns with congenital hyperinsulinism hypoglycemia, especially when a variant of the KDM6A gene is found. In those cases, a treatment with diazoxide can be started and can be replaced with lanreotide if a satisfying glycemic control is not achieved. We report the case of a female patient born at 37 weeks of gestational age, without any obvious facial dysmorphic features, after a non-complicated pregnancy, that presented with feeding difficulties, drowsiness, and irritability revealing a hyperinsulinemic hypoglycemia. Further testing at 6 months old found a KDM6A mutation. The patient was initially treated by diazoxide alone, but its dosage had to be lowered because of the occurrence of treatment side effects, and lanreotide had been added to maintain acceptable blood sugar levels. A congenital hyperinsulinemia hypoglycemia revealed heterozygous truncating variant in the KDM6A gene, also known as X-linked Kabuki syndrome in a newborn. In cases of neonatal hypoglycemia, the first-line therapy is diazoxide. Our report shows that analogues of somatostatin such as lanreotide should be considered if the diazoxide regimen is not tolerated.

Characterization, evolution and risk factors of diabetes and prediabetes in a pediatric cohort of renal and liver transplant recipients.

Background: Hyperglycemia (HG) and prediabetes are rarely sought in pediatric liver (LT) and renal (RT) transplantation, yet their presence indicates a high risk of diabetes and cardiovascular disease. The objectives of our DIABGRAFT study were to retrospectively (rDIABGRAFT) and longitudinally (pDIABGRAFT) characterize HG and (pre)diabetes in a cohort of children with LT or/and RT. Methods: We retrospectively analyzed risk factors of HG from 195 children with LT from 2012 to 2019 and twenty children with RT from 2005 to 2019 at Cliniques universitaires Saint-Luc. In addition, we prospectively followed four LT and four RT children to evaluate the evolution of their glucose metabolism. Results: Our rDIABGRAFT study showed that 25% and 35% of LT and RT children respectively presented transient HG and 20% of RT developed diabetes. The occurrence of HG was associated with the use of glucocorticoids and with acute events as graft rejection and infection. In our pDIABGRAFT cohort, biological markers of diabetes were in the normal range for HbA1C, fasting glucose and insulin levels. However, oral glucose tolerance test and glucose sensors showed insulin resistance, impaired glucose tolerance and HG in the post-prandial afternoon period. Conclusion: Our study shows that children with LT and RT were more at risk of developing HG when glucocorticoids were required and that HbA1C and fasting glucose lack sensitivity for early detection of glucose intolerance. Also, measurement of glycemia immediately after the transplantation and in postprandial period is key to detect dysglycemia since insulin resistance prevailed in our cohort. ClinicalTrialsgov ID: NCT05464043.

Influence of the occurrence and duration of partial remission on short-term metabolic control in type 1 diabetes: the DIABHONEY pediatric study.

Objective: To evaluate the residual effect of partial remission (PR) on immediate post-PR glycemic control according to its occurrence and duration in a cohort of children with type 1 diabetes mellitus (T1DM). Patients and Methods: Values of glycemic control parameters [i.e. HbA1C, insulin dose-adjusted hemoglobin A1C (IDAA1C), glycemic target-adjusted HbA1C (GTAA1C)] and data from glucose monitoring devices from 189 pediatric patients with new-onset type 1 diabetes were collected retrospectively from 24 months. Patients were characterized according to their remission status (PR+ and PR-). PR+ patients were subdivided into three subgroups regarding PR duration [i.e. short (⩾3-⩽6 months), intermediate (>6-⩽12 months), and long PR (>12-⩽14 months)]. We compared glycemic control data from each PR+ subgroup at +6 and +12 months post-PR with PR- patients at the same postdiagnosis time. Second, PR+ subgroups were compared with each other. Results: PR+ patients showed improved glycemic control (i.e. HbA1C, IDAA1C, and GTAA1C) at + 6 months post-PR when compared with nonremitters (PR-), independently of the PR duration subgroups (p < 0.05). Interestingly, patients in long PR+ subgroup exhibited higher positive residual effect than short PR+ subgroup with lower GTAA1C scores (p = 0.02), better time in range (TIR) (p = 0.003), less time in hypoglycemia (10.45 versus 16.13%, p = 0.03) and less glycemic variability (83.1 mg/dl versus 98.84 mg/dl, p = 0.03). No significant differences were found for glucose control between PR+ and PR- patients at +12 months post-PR. Conclusion: This study supports the positive impact of PR occurrence and duration on short-term metabolic control (better HbA1C levels, IDAA1C and GTAA1C scores, TIR, and less glycemic variability) with the residual effect increasing according to PR duration.

Effect of nationwide reimbursement of real-time continuous glucose monitoring on HbA1c, hypoglycemia and quality of life in a pediatric type 1 diabetes population: The RESCUE-pediatrics study.

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

Glycemic Variability Patterns Strongly Correlate With Partial Remission Status in Children With Newly Diagnosed Type 1 Diabetes.

OBJECTIVE: To evaluate whether indexes of glycemic variability may overcome residual ß-cell secretion estimates in the longitudinal evaluation of partial remission in a cohort of pediatric patients with new-onset type 1 diabetes. RESEARCH DESIGN AND METHODS: Values of residual ß-cell secretion estimates, clinical parameters (e.g., HbA1c or insulin daily dose), and continuous glucose monitoring (CGM) from 78 pediatric patients with new-onset type 1 diabetes were longitudinally collected during 1 year and cross-sectionally compared. Circadian patterns of CGM metrics were characterized and correlated to remission status using an adjusted mixed-effects model. Patients were clustered based on 46 CGM metrics and clinical parameters and compared using nonparametric ANOVA. RESULTS: Study participants had a mean (± SD) age of 10.4 (± 3.6) years at diabetes onset, and 65% underwent partial remission at 3 months. ß-Cell residual secretion estimates demonstrated weak-to-moderate correlations with clinical parameters and CGM metrics (r2 = 0.05-0.25; P < 0.05). However, CGM metrics strongly correlated with clinical parameters (r2 >0.52; P < 0.05) and were sufficient to distinguish remitters from nonremitters. Also, CGM metrics from remitters displayed specific early morning circadian patterns characterized by increased glycemic stability across days (within 63-140 mg/dL range) and decreased rate of grade II hypoglycemia (P < 0.0001) compared with nonremitters. Thorough CGM analysis allowed the identification of four novel glucotypes (P < 0.001) that segregate patients into subgroups and mirror the evolution of remission after diabetes onset. CONCLUSIONS: In our pediatric cohort, combination of CGM metrics and clinical parameters unraveled key clinical milestones of glucose homeostasis and remission status during the first year of type 1 diabetes.

Characterization of Post-Hypoglycemic Hyperglycemia in Children and Adolescents With Type 1 Diabetes: The EPHICA Study.

Background: In patients with diabetes, the dynamics in which hypoglycemia recovers impacts cardiovascular disease risk. Our study investigated the extents of "post-hypoglycemic hyperglycemia (PHH)" (i.e. hypoglycemia that recover to hyperglycemia in any circumstance) and factors likely to influence PHH characteristics in a pediatric cohort of patients with type 1 diabetes (T1D). Methods: We collected retrospective continuous glucose monitoring (CGM) data from 142 pediatric patients with T1D to characterize episodes of PHH during a two-month follow-up period. Factors influencing PHH were determined using univariate and multivariate analyses. Results: In our EPHICA cohort, PHH rate was 0.6 ± 0.3 episode/day and correlated (r=0.33; p<0.0001) with hyperglycemia rate (2.6 ± 0.5 episodes/day). The global proportion of hyperglycemia corresponding to PHH was 0.22 ± 0.1, yet 14.8% of patients had more than 1/3 of hyperglycemia related to PHH. Episodes of PHH lasted 239.6 ± 124.8 minutes with a hyperglycemic peak of 258.8 ± 47.1 mg/dL. Only 12.2% of PHH occurred at night. While a younger age (<12 years) and lower body mass index (BMI) (SDS: -2 to 1.6) were associated with higher daily PHH rates, teenagers (≥12 years) and obese patients experienced longer PHH and higher hyperglycemic peaks. Parameters of glycemic variability (i.e. HbA1C, IDAA1C and GTAA1C) moderately correlated with PHH duration and related hyperglycemic peak. Multivariate analysis confirmed these results, as factors likely to influence PHH rate were phenotype (age and BMI) and glycemic variability parameters (time in range, mean glycemia, HbA1C and GTAA1C). Conclusion: Our EPHICA study highlights the importance of PHH as a prominent component of hyperglycemia in some children and adolescents with T1D. Factors associated with PHH features are age, BMI and parameters of glycemic control. Young and lean children are more prone to experience hypoglycemia that recover with hyperglycemia, but adolescents and obese children tend to experience hyperglycemia of longer duration.

Characterization and risk factors of hyperglycaemia during treatment of childhood hematologic malignancies.

BACKGROUND: Secondary forms of diabetes are often understudied and underdiagnosed in children and adolescents with cancer. The objectives of our cohort study were to study the incidence and risk factors for hyperglycaemia in leukaemia and lymphoma patients. METHODS: We retrospectively collected 15 years of data from paediatric patients treated for acute lymphoblastic leukaemia (ALL), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL) immediately at cancer diagnosis. We studied risk factors for hyperglycaemia in univariate and multivariate analyses. RESULTS: Our study cohort included 267 patients corresponding to 179 patients with ALL, 48 with NHL and 40 with HL. Eighteen per cent of ALL patients (32/179) and 17% of NHL patients (8/48) developed hyperglycaemia, with more than 61% developing hyperglycaemia within the first month of treatment. No hyperglycaemia was observed in HL patients. Multivariate analysis showed the following hyperglycaemia risk factors for ALL patients: overweight or obesity (OR 3.793) and pubertal onset (OR 4.269) at cancer diagnosis, steroid-resistant disease (OR 3.445) and hematopoietic stem cell transplant (HSCT) (OR 4.754). CONCLUSION: In our cohort, 18% of patients with ALL or NHL developed early-onset hyperglycaemia after chemotherapy/radiotherapy. Patients with ALL with increased hyperglycaemia risk can be readily identified by measuring BMI and puberty stage at cancer diagnosis. Also, glucose monitoring should be reinforced when patients show steroid-resistant disease and/or require HSCT.

Intra-amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants.

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines.

Amiodarone-induced thyroid dysfunction in children: insights from the THYRAMIO study.

BACKGROUND: Amiodarone treatment is effective against various types of arrhythmias but is associated with adverse effects affecting, among other organs, thyroid function. Amiodarone-induced thyroid dysfunction was not thoroughly evaluated in children as it was in adults, yet this affection may lead to irreversible neurodevelopmental complications. Our study aimed to define the incidence and risk factors of amiodarone-induced thyroid dysfunction in children. METHODS: The study was designed as an observational study with a retrospective clinical series of 152 children treated by amiodarone in the Pediatric Cardiology Unit of our center from 1990 to 2019. All patients were divided into three groups according to their thyroid status: euthyroid, AIH (amiodarone-induced hypothyroidism) or AIT (amiodarone-induced thyrotoxicosis). Patients from these three groups were compared in terms of key clinical and therapeutic features. RESULTS: Amiodarone-induced thyroid dysfunction was present in 23% of patients. AIT (5.3%) was three times less common than AIH (17.7%), and its occurrence increased with older age (p < 0.05), treatment dosage (p < 0.05), treatment duration (p < 0.05) and the number of loading doses administered (p < 0.05). There were no distinctive clinical features between euthyroid and AIH groups. A multivariable prediction model of AIT was built, with a yield of 66.7% as positive predictive value and 96.7% as negative predictive value. CONCLUSION: We observed that one in five children developed amiodarone-induced thyroid dysfunction. Special attention is required for older children with a high dosage and long-term therapy and who received a large number of loading doses, since these children are at risk to develop AIT, which is more delicate to manage than AIH.

Benefits of physical activity in children and adolescents with type 1 diabetes: A systematic review.

AIMS: We performed a systematic review of clinical trials investigating the health benefits of physical activity in pediatric patients with type 1 diabetes. METHODS: To perform this systematic review, search strategies were created and adapted to four databases. Only randomized controlled trials written in English before 1998 and that answered to the PICOS criteria were included. The PRISMA guidelines were followed to ensure highest scientific rigor within studies. RESULTS: Seven studies out of 2655 were included in this systematic review according to the inclusion criteria. These studies showed positive gains on global health: blood lipid profile, physical fitness, quality of life and body size and body composition but only one demonstrated a positive effect on glycemic control. CONCLUSION: Globally, physical activity exerts a positive impact on metabolic (i.e., decrease in total cholesterol, improvement of physical fitness, etc.) and psychological health in children with type 1 diabetes. Yet variations in study protocols or sample size restrict statistical power to reach the outcome of improving glycemic control in most studies. Here, we address the measured outcomes in individual trials and discuss potential key elements to consider for future clinical trials.

Early Treatment with Empagliflozin and GABA Improves ß-Cell Mass and Glucose Tolerance in Streptozotocin-Treated Mice.

While the autoimmune character of T1D (type 1 diabetes) is being challenged, it is currently recognized that inflammation plays a key role in its development. We hypothesized that glucotoxicity could contribute to ß-cell mass destruction through participation in islet inflammation. We evaluated the potential of empagliflozin (EMPA) and GABA (gamma-aminobutyric acid) to protect ß-cell mass against glucotoxicity and to increase ß-cell mass after diagnosis of T1D. Empagliflozin is a SGLT2 (sodium-dependent glucose cotransporter) inhibitor which thereby blocks glucose recapture by the kidney and promotes glucose excretion in urine. GABA is an inhibitory neurotransmitter, which stimulates α-to-ß cell transdifferentiation. In streptozotocin-treated mice, empagliflozin and/or GABA were delivered for a period of five days or three weeks. As compared to untreated T1D mice, EMPA-treated T1D mice had decreased FFA (free fatty acid) levels and improved glucose homeostasis. EMPA-treated T1D mice had higher islet density, with preserved architecture, compared to T1D mice, and EMPA-treated T1D mice also differed from T1D mice by the total absence of immune cell infiltration within islets. Islets from EMPA-treated mice were also less subjected to ER (endoplasmic reticulum) stress and inflammation, as shown by qPCR analysis. Glucose homeostasis parameters and islet area/pancreas area ratio improved, as compared to diabetic controls, when T1D mice were treated for three weeks with GABA and EMPA. T1D EMPA+GABA mice had higher glucagon levels than T1D mice, without modifications of glucagon area/islet area ratios. In conclusion, empagliflozin and GABA, used in monotherapy in streptozotocin-induced diabetic mice, have positive effects on ß-cell mass preservation or proliferation through an indirect effect on islet cell inflammation and ER stress. Further research is mandatory to evaluate whether empagliflozin and GABA may be a potential therapeutic target for the protection of ß-cell mass after new-onset T1D.

Novel insights into glucocorticoid replacement therapy for pediatric and adult adrenal insufficiency.

Adrenal insufficiency is defined as impaired adrenocortical hormone synthesis. According to its source, the deficit is classified as primary (adrenal steroidogenesis impairment), secondary (pituitary adrenocorticotropic hormone deficit) or tertiary (hypothalamic corticotropin-releasing hormone deficit). The management of adrenal insufficiency resides primarily in physiological replacement of glucocorticoid secretion. Standard glucocorticoid therapy is shrouded in several controversies. Along the difficulties arising from the inability to accurately replicate the pulsatile circadian cortisol rhythm, come the uncertainties of dose adjustment and treatment monitoring (absence of reliable biomarkers). Furthermore, side effects of inadequate replacement significantly hinder the quality of life of patients. Therefore, transition to circadian hydrocortisone therapy gains prominence. Recent therapeutic advancements consist of oral hydrocortisone modified-release compounds (immediate, delayed and sustained absorption formulations) or continuous subcutaneous hydrocortisone infusion. In addition to illustrating the current knowledge on conventional glucocorticoid regimens, this review outlines the latest research outcomes. We also describe the management of pediatric patients and suggest a novel strategy for glucocorticoid replacement therapy in adults.

Familial Forms of Cushing Syndrome in Primary Pigmented Nodular Adrenocortical Disease Presenting with Short Stature and Insidious Symptoms: A Clinical Series.

Cushing syndrome (CS) is a rare disease in children, frequently associated with subtle or periodic symptoms that may delay its diagnosis. Weight gain and growth failure, the hallmarks of hypercortisolism in pediatrics, may be inconsistent, especially in ACTH-independent forms of CS. Primary pigmented nodular adrenocortical disease (PPNAD) is the rarest form of ACTH-independent CS, and can be associated with endocrine and nonendocrine tumors, forming the Carney complex (CNC). Recently, phenotype/genotype correlations have been described with particular forms of CNC where PPNAD is isolated or associated only with skin lesions. We present four familial series of CS due to isolated PPNAD, and compare them to available data from the literature. We discuss the clinical and molecular findings, and underline challenges in diagnosing PPNAD in childhood.

Integration of Routine Parameters of Glycemic Variability in a Simple Screening Method for Partial Remission in Children with Type 1 Diabetes.

Although different criteria were used to define partial remission in type 1 diabetes, the IDAA1C formula has prevailed as it correlates with stimulated C-peptide levels. Our retrospective study evaluated clinical variables associated with the occurrence of IDAA1C-defined partial remission in a series of 239 pediatric patients. Diabetic ketoacidosis and age at diagnosis, but no other clinical feature, influenced the occurrence of remission. We then evaluated whether parameters of glycemic variability used in clinical routine may reliably define partial remission, as these would alleviate confounding factors related to insulin treatment. Using multiple linear regression, we observed that HbA1C levels and percentage of normoglycemia were efficient and sufficient to predict partial remission. These parameters were entered into a formula, called glycemic target-adjusted HbA1C (GTAA1C), that corresponded to HbA1C(%) - (3 × % of normoglycemic values(70-180 mg/dL)). With a threshold of 4.5, this alternative formula predicted partial remission with a sensitivity and a specificity of 72.3% and 92%, respectively, and yielded strong correlation with IDAA1C levels and BETA-2 score, which is a correlate of ß-cell function after islet transplantation. We propose GTAA1C, based on routine and objective markers of glycemic variability, as a valid alternative for definition of partial remission in type 1 diabetes.

Blood versus urine ketone monitoring in a pediatric cohort of patients with type 1 diabetes: a crossover study.

BACKGROUND: The aim of our study was to determine the influence of routine ketone monitoring on hyperglycemic events (HE) and ketosis in youngsters with type 1 diabetes (T1D). METHODS: Our single-site, controlled and randomized study was conducted on children and adolescents with T1D outside of remission phase. During two crossover periods of 6 months, patients (n = 22) experiencing HE tested ketones alternatively with a blood ketone meter or urine ketone test strips and gave their opinion on screening methods after completion of clinical trial. Moreover, we evaluated levels of awareness of ketone production in a series of 58 patients and sometimes parents via a multiple-choice questionnaire. RESULTS: Based on self-monitoring data, patients experienced a mean of 4.8 HE/month (range 0-9.3). Patients performed accurate ketone tests more frequently during urine (46%) than during blood-testing (29%) periods (p < 0.05); while globally, 50% of ketone tests were inaccurate (i.e. without HE). Ketosis occurred significantly more often during urine (46.4%) than during blood (14.8%) monitoring (p = 0.01), although no episodes of diabetic ketoacidosis (DKA) were noticed. Duration of hyperglycemia was not different whether patients measured ketones or not, suggesting that ketone monitoring did not affect correction of glycemia. Patients evaluated blood monitoring more frequently as being practical, reliable, and useful compared with urine testing. Scores in the awareness questionnaire were globally low (36.8%) without difference between patients and their parents. CONCLUSIONS: Although our study shows differences in outcomes (e.g. accurate use, detection of ketosis) of urine versus blood ketone monitoring, these did not affect the occurrence of HE. Whereas ketone monitoring is part of standardized diabetes education, its implementation in daily routine remains difficult, partly because patient awareness about mechanisms of ketosis is lacking.