Sulfonylurea-insensitive permanent neonatal diabetes caused by a severe gain-of-function Tyr330His substitution in Kir6.2

Background/Aims: Mutations in KCNJ11, the gene encoding the Kir6.2 subunit of pancreatic and neuronal KATP channels, are associated with a spectrum of neonatal diabetes diseases. Methods: Variant screening was used to identify cause of neonatal diabetes, and continuous glucose monitoring used to assess effectiveness of sulfonylurea treatment. Electrophysiological analysis of variant KATP channel function was used to determine molecular basis. Results: We identified a previously uncharacterized KCNJ11 mutation, c.988T>C [pTyr330His], in an Italian child diagnosed with sulfonylurea-resistant permanent neonatal diabetes and developmental delay (iDEND). Functional analysis of recombinant KATP channels reveals that this mutation causes a drastic gain-of-function, due to a reduction in ATP-inhibition. Further, we demonstrate that the Tyr330His substitution causes a significant decrease in sensitivity to the sulfonylurea, glibenclamide. Conclusions: In this subject, the KCNJ11(c.988T>C) mutation provoked neonatal diabetes, with mild developmental delay, which was insensitive to correction by sulfonylurea therapy. This is explained by the molecular loss of sulfonylurea sensitivity conferred by the Tyr330His substitution, and highlights the need for molecular analysis of such mutations.

Monogenic forms of DSD: An update

DSD encompasses a wide range of pathologies that impact gonad formation, development and function in both 46,XX and 46,XY individuals. The majority of these conditions are considered to be monogenic, although the expression of the phenotype may be influenced by genetic modifiers. Although considered monogenic, establishing the genetic etiology in DSD has been difficult compared to other congenital disorders for a number of reasons including the absence of family cases for classical genetic association studies and the lack of evolutionary conservation of key genetic factors involved in gonad formation. In recent years, the widespread use of genomic sequencing technologies has resulted in multiple genes being identified and proposed as novel monogenic causes of 46,XX and/or 46,XY DSD. In this review, we will focus on the main genomic findings of recent years, which consists of new candidate genes or loci for DSD as well as new reproductive phenotypes associated with genes that are well established to cause DSD. For each gene or loci, we summarise the data that is currently available in favor of or against a role for these genes in DSD or the contribution of genomic variants within well-established genes to a new reproductive phenotype. Based on this analysis we propose a series of recommendations that should aid the interpretation of genomic data and ultimately help to improve the accuracy and yield genetic diagnosis of DSD.

THE IMPACT OF TYPE 1 DIABETES MELLITUS ON BONE HEALTH IN CHILDREN

This paper gives an overview of the impact of type 1 diabetes on bone health in children and adolescents. First, we analyse studies using DXA (dual x-ray absorptiometry) to assess BMC (bone mineral content) and BMD (bone mineral density). Then, we discuss modern, non-invasive techniques including pQCT (peripheral quantitative computer tomography) and HRpQCT (high-resolution peripheral quantitative computer tomography) for the detailed assessment of bone health aspects including bone mass, bone geometry, bone microarchitecture and bone strength. Thereafter, we explore some of the mechanisms that are responsible for diabetic bone disease in children, like low bone turnover and high sclerostin levels. Finally, we summarise some of the evidence for the importance of microvascular disease in the pathophysiology of diabetic bone disease.

The diagnosis of growth hormone deficiency remains a judgment call – and that is good

The diagnosis of GHD still does not reflect evidence-based and generally accepted practice, and reliance on growth hormone stimulation testing (GST) leads to a high rate of false positive diagnosis of idiopathic isolated GHD (IIGHD). While searching for more definitive indicators of GHD is attractive, it should not distract from currently available steps to reduce erroneous IIGHD diagnoses. This paper describes opportunities to improve the accuracy of the GST which include: 1) meticulous selection of candidates for GST, since a low prevalence of GHD among short children in general is a major factor undermining the test’s diagnostic accuracy; 2) departure from traditional pass/fail diagnostic GH cutoffs towards, instead, formulation of diagnoses along a continuum that spans actual GHD -> provisional GHD -> not GHD; 3) response to the provisional diagnosis of IIGHD based on GST with additional post-test observation or alternative growth-promoting interventions rather than immediate hGH treatment; 4) re-examination and often correction of a prior IIGHD diagnosis with the onset of puberty. Modern medicine is increasingly offering diagnostic tests that aim to eliminate the need for provisional diagnoses. But a pitfall of such a “definitive” test for GHD would be the temptation to respond to its results definitively. Given the nuances, variations, and fluctuations in GH axis function over time, children evaluated for growth concerns are still best served by clinical judgment that combines thoroughness, patience, flexibility, and healthy skepticism into the diagnosis of GHD.

Assessment of gonadotropin concentrations stimulated by gonadotropin-releasing hormone analog by electrochemiluminescence (ECLIA) in girls with precocious puberty and premature thelarche

Objective: The aim of this study is to determine the cutoff values of gonadotropin response to gonadotropin-releasing hormone analogs (GnRHas) corresponding to the activation of the hypothalamic–pituitary–gonadal axis that could differentiate central precocious puberty (CPP) from premature thelarche (PT) and using the electrochemiluminescence assay method. Methods: A total of 49 girls underwent the stimulation test with the intramuscular injection of 3.75 mg leuprolide acetate. Based on the clinical and laboratory characteristics, they were divided into two groups: CPP (n = 22) and PT (n = 27). Baseline estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were collected before GnRHa administration, and LH and FSH at 60 and 120 min, respectively, after GnRHa administration. Results: The girls with CPP presented an increased height Z-score, advanced bone age, and higher baseline LH, FSH, estradiol, and LH/FSH ratio in relation to PT (p < 0.001). Stimulated LH differed significantly between the two groups, and the LH cutoff values were ≥4.29 IU/L (p < 0.001) and ≥3.95 IU/L at 60 and 120 min, respectively (p < 0.001). LH peak was found at 60 min after stimulation. Conclusions: The GnRHa test is effective in distinguishing CPP from PT, and a single sampling, at 60 min, with LH concentrations above 4.29 may be the parameter of choice with the advantage of greater convenience and practicality.

Early insulin-resistance, T2D and treatment options in childhood

Background T2D (Type 2 Diabetes) represents just the tip of the iceberg of the complex metabolic alterations associated with obesity and other clinical conditions associated to impaired adipose tissue storage. Summary Available data have suggested the presence of a continuous spectrum of metabolic alterations developed in the progression from IR to T2D, most of which are likely preventable through the early characterization of all the multiple risk factors involved. Therefore, the complete characterization of the natural history of the disease and the major modifiable factors represents a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life. This review will focus on the main components defining the risk of IR and T2D in childhood with a specific focus on the main aspects of treatment options available in children and adolescents. Key messages Impaired adipose tissue storage documented in obesity results in a continuous spectrum of metabolic alterations ranging from IR to T2DM. These metabolic alterations are mostly likely preventable through the early characterization of all the multiple risk factors involved. The complete characterization of the disease and of the major modifiable factors represent a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life.

Hypogonadism in male infants and adolescents: new androgen formulations

Background Male hypogonadism may be associated with micropenis and cryptorchidism in newborn, absent or incomplete pubertal development when it occurs during childhood. During puberty, androgen replacement therapy plays a pivotal role in subjects with hypogonadism to induce sexual maturation, growth acceleration, anabolic effects on fat-free mass growth increasing muscle strength, directly and indirectly on the attainment of peak bone mass in young men. Moreover, in newborns with congenital hypogonadism, androgen therapy could be effective to increase genital size. Summary Testosterone replacement therapy (TRT) represents the cornerstone of the management of hypogonadism in boys. During puberty, replacement therapy needs to be modulated with gradual dosing increase to better mimic the physiologic pubertal development. Currently, intramuscular testosterone esters (in particular testosterone enanthate, TE) and subcutaneous testosterone pellets are the only formulations approved by the US Food and Drug Administration (FDA) for delayed puberty, while no preparation is approved for long-term use in the adolescent age. Several new testosterone (T) formulations (as transdermal, nasal, subcutaneous, and oral formulation) are recently developed to improve the pharmacokinetic profile and to ease the administration route increasing patient compliance in adult males with hypogonadism. All these formulations are not approved for pediatric age, although some of them are used as “off-label” regimens. This special issue is aimed to illustrate new T formulations and their potential role as replacement therapy in the pediatric population, as well as to highlight investigational areas to contribute to health care improvement in these patients. Key Messages. Despite the lack of evidence-based guidelines regarding the choice of T formulation in the pediatric population, new formulations appear to have a potential role for TRT in adolescent age. They have been designed for adult age with a little flexibility of dosage, although a few formulations may be attractive for pubertal induction and penile enlargement thanks to their greater flexibility and easing of administration. On the other hand, long-acting and stable formulations could meet post-pubertal needs, increasing TRT compliance in a critical phase as the adolescent age. Further controlled, long-term safety, and efficacy studies for all these new T formulations within the pediatric population are needed.

Elevated Urinary VEGF-A,Transferrin, and Angiotensinogen Levels in Normoalbuminuric Children and Adolescents with Type 1 Diabetes; Can They Be Early Markers of Diabetic Kidney Disease?

Objective: We hypothesized that diabetic kidney disease (DKD) begins early, before albuminuria occurs. We therefore aimed to assess potential early urinary biomarkers of (DKD) in normoalbuminuric and normotensive children and adolescents with Type 1 Diabetes (T1D) to evaluate the relationship between these markers and clinical and laboratory risk factors for DKD. Methods: This cross-sectional study included 75 children and adolescents with T1D (62% females, mean age 13.9 ± 3.2 years) with normoalbuminuria [an albumin/creatinine ratio (ACR) below 30 mg/g creatinine]. Fifty-five age- and sex-matched healthy children and adolescents served as controls. For the assessment of early DKD, urinary levels of angiotensinogen (AGT), transferrin, nephrin, vascular endothelial growth factor-A (VEGF-A), and kidney injury molecule-1 (KIM-1) were measured in adequately collected 24-h urine samples using enzyme-linked immunoassays. Results: The mean disease duration was 7.3± 3.2 (ranged 2.1 - 15.7) years and the mean HbA1c level was 8.8±1.4%. The median levels of urine VEGF-A/Cr, AGT/Cr, and Transferrin/Cr were significantly higher in normoalbuminuric patients with T1D, compared with those of controls (p<0.001, p=0.02, and p=0.001, respectively), but there was no difference in nephrin/Cr and KIM-1/Cr between the two groups. Although, none of the patients had albuminuria, the median level of urine ACR was significantly higher in the patient group than the control group (p=0.003). The ACR was positively correlated with glomerular filtration rate (GFR). Urinary transferrin/Cr, AGT/Cr, and VEGF-A/Cr were significantly correlated with ACR, but not with either GFR or diabetic risk factors including HbA1c or disease duration. Conclusion: Normoalbuminuric and normotensive children and adolescents with T1D have elevated urinary VEGF, AGT and transferrin levels, which may indicate the development of DKD before albuminuria occurs.

High glycemic variability is associated with worse Continuous Glucose Monitoring metrics in children and adolescents with type 1 diabetes

Objective: The primary aim of this study was to quantify the prevalence of children and adolescents with T1D who achieve the recommended target for CV identifying the determining factors to reach this target. The secondary aim was to examine the relationship between CV, the other metrics derived from CGM data and clinical parameters. Method: CGM data were collected from 805 children/adolescents with T1D. Several CGM metrics and patients' characteristics were evaluated. Participants were stratified by CV≤36% and CV>36%. Binary logistic regression analysis was run to identify the determining factors of high CV. Results CV was positively correlated with %TBR<70mg/dL, %TBR<54 mg/dL, %TAR>250 mg/dL, LBGI, HBGI and negatively with %TIR. CV≤36% was found in 31.4% of the subjects. The CV>36% group spent less time in %TIR, more time in hypoglycemia and hyperglycemia with lower proportion of subjects using rtCGM and CSII. Percentage of TBR<70mg/dL and TAR>250mg/dL were significant predictors of CV>36%, whereas age, gender, BMI, duration of diabetes, type of CGM device, type of insulin therapy administration and %TIR were not significant predictors (p<0.001,R2Nagelkerke=0.48). Conclusions: CV identifies children and adolescents with worse glycemic control at higher risk of both hypoglycemia and hyperglycemia.

Circulating irisin levels in preadolescents and adolescents born preterm

Introduction. Prematurity is associated with increased cardiometabolic risk later in life. The adipomyokine irisin has been acknowledged as a modulator of energy metabolism and insulin sensitivity. The aim of this study was to investigate circulating levels of irisin and their relation to anthropometric measurements and cardiometabolic phenotype in a population of preterm-born children vs. full-term-born peers. Methods. A total of 160 children (87 born preterm aged 8.1-14.8 years and 73 born full-term of similar age and gender distribution) were studied. Arterial blood pressure, anthropometry, body composition assessments with dual energy X-ray absorptiometry (DXA) and skin fold measurements were performed. Blood biochemistry and circulating levels of irisin, insulin, cortisol, leptin, and adiponectin were also determined. Results. The preterm group had higher diastolic blood pressure, triceps skin fold, subscapular skin fold (SSF) and abdominal skin fold measurements and more central adiposity than the full-term group. Irisin was significantly lower (p=0.002), whereas leptin was higher (p=0.03), in the preterm than the full-term group. Irisin correlated positively with gestational age (r=0.19, p=0.01), birthweight (r=0.23, p=0.003) and high-density lipoprotein cholesterol (r=0.20, p=0.01), and negatively with SSSF (r=-0.25 p=0.003) and chronological age (r=-0.21, p=0.008). Conclusion. Lower levels of irisin and a slightly unhealthy adiposity and cardiometabolic pattern were detected in preterm-born children in comparison to their full-term-born peers. Whether low irisin levels in preadolescents and adolescents born prematurely could be of prognostic value for the development of cardiometabolic sequelae later in life remains to be further studied.