Insulin Clearance at the Pubertal Transition in Youth with Obesity and Steatosis Liver Disease.

No data are available on insulin clearance (ClI) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether ClI in fasting and post-oral glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. ClI was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting ClI (nmol/pmol × 10-2) was significantly lower in pubertal [0.11 (0.08-0.14)] than in prepubertal individuals [0.12 (0.09-0.16)] and higher in class III [0.15 (0.11-0.16)] than in class I obesity [0.11 (0.09-0.14)]. OGTT ClI was higher in boys [0.08 (0.06-0.10)] than in girls [0.07 (0.06-0.09)]; in prepubertal [0.08 (0.06-0.11)] than in pubertal individuals [0.07 (0.05-0.09)]; in class III [0.14 (0.08-0.17)] than in class I obesity [0.07 (0.05-0.10)]; and in severe SLD [0.09 (0.04-0.14)] than in no steatosis [0.06 (0.04-0.17)]. It was lower in participants with prediabetes [0.06 (0.04-0.07)]. OGTT ClI was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in ClI in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities.

Prevalence of prediabetes in children and adolescents by class of obesity.

BACKGROUND: To evaluate prevalence of prediabetes (impaired fasting glucose, IFG; impaired glucose tolerance, IGT; and high glycated haemoglobin, h-HbA1c) in children and adolescents in relation to class of age and obesity; to appraise association with estimates of insulin metabolism, cardiovascular risk factors and alanine aminotransferase (ALT) levels. METHODS: Study of marginal prevalence (i.e., as function of sex, age and obesity class) of isolated and combined IFG, IGT and h-HbA1c in children (age 4-9.9 years) and adolescents (age 10-17.9 years) and association to blood pressure (BP), total, HDL and non-HDL cholesterol, triglycerides, ALT and insulin sensitivity/secretion indexes. RESULTS: Data of 3110 participants (51% males, 33% children; 33% overweight, 39% obesity class I, 20.5% class II, 7.5% class III) were available. Unadjusted prevalence of prediabetes was 13.9% in children (2.1% IFG, 6.7% IGT, 3.9% h-HbA1c, IFG-IGT 0.06%) and 24.6% in adolescents (3.4% IFG, 9.4% IGT, 5.5% h-HbA1c, IFG-IGT 0.09%). Combined h-HBA1c was found in very few adolescents. Prevalence of prediabetes increased significantly by class of obesity up to 20.5% in children and 31.6% in adolescents. Phenotypes of prediabetes were differently but significantly associated with increased systolic and diastolic BP (by 2-7.3 and ~8 mmHg, respectively), triglycerides (by 23-66 mg/dl), and ALT levels (by 10-22 UI/L) depending on the prediabetes phenotype. CONCLUSION AND RELEVANCE: It is worth screening prediabetes in children aged <10 years old with obesity classes II and III and in adolescents. In those with prediabetes, monitoring of blood pressure, triglycerides and ALT levels must be encouraged.

Management of Childhood-onset Craniopharyngioma in Italy: A Multicenter, 7-Year Follow-up Study of 145 Patients.

CONTEXT: Nationwide data on children diagnosed with craniopharyngioma (CP) are not available in Italy. OBJECTIVE: This work aimed to identify patients' characteristics, type of surgical approach, complications and recurrences, number of pituitary deficits, and number of patients starting growth hormone (GH) treatment. METHODS: A retrospective multicenter collection took place of 145 patients aged 0 to 18 years who underwent surgery for CP between 2000 and 2018, and followed up in 17 Italian centers of pediatric endocrinology. RESULTS: Age at diagnosis was 8.4 ± 4.1 years. Duration of symptoms was 10.8 ± 12.5 months and headache was most frequent (54%), followed by impaired growth (48%) and visual disturbances (44%). Most lesions were suprasellar (85%), and histology was adamantinomatous in all cases but two. Surgical approach was transcranial (TC) in 67.5% of cases and transsphenoidal (TS) in 31.%. The TC approach was prevalent in all age groups. Postsurgery complications occurred in 53% of cases, with water-electrolyte disturbances most frequent. Radiotherapy was used in 39% of cases. All patients but one presented with at least one hormone pituitary deficiency, with thyrotropin deficiency most frequent (98.3%), followed by adrenocorticotropin (96.8%), arginine vasopressin (91.1%), and GH (77.4%). Body mass index (BMI) significantly increased over time. A hypothalamic disturbance was present in 55% of cases. GH therapy was started during follow-up in 112 patients at a mean age of 10.6 years, and 54 developed a recurrence or regrowth of the residual lesion. CONCLUSION: CP is often diagnosed late in Italy, with TC more frequent than the TS surgical approach. Postsurgery complications were not rare, and hypopituitarism developed almost in all cases. BMI shows a tendency to increase overtime.

"Impact of COVID-19 pandemic lockdown on early onset of puberty: experience of an Italian tertiary center".

At the end of 2019, an emerging atypical pneumonia called COVID-19 (coronavirus disease 2019), caused by the novel coronavirus defined as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), was first reported. COVID-19 rapidly expanded leading to an epidemic in China, followed by a global pandemic during the year 2020. In few weeks Italy was assaulted by a severe health emergency, constraining the Italian government to put in place extraordinary restrictive measures, such as school closures and a strict lockdown extended to the entire country at the beginning of March 2020. Since the beginning of lockdown, the Endocrinology Unit of Bambino Gesù Children's Hospital has recorded a rapid increase of the outpatient consultations for suspected precocious or early puberty. We have now retrospectively analyzed all the consultations recorded in the database of our outpatient clinic from March to September 2020, and compared them with the consultations recorded in the same database from March to September 2019. Our preliminary data suggest a significant increase of precocious puberty cases in girls during the first period of COVID-19 pandemic. Further investigations in larger cohorts of children are needed in order to correlate the observed increase of precocious puberty with specific pathogenic factors.

Metreleptin for the treatment of progressive encephalopathy with/without lipodystrophy (PELD) in a child with progressive myoclonic epilepsy: a case report.

BACKGROUND: A number of genetic syndromes associated with variants in the BSCL2/seipin gene have been identified. Variants that cause skipping of exon 7 are associated with progressive encephalopathy with/without lipodystrophy (PELD), which is characterized by the development of progressive myoclonic epilepsy at a young age, severe progressive neurological impairment, and early death, often in childhood. Because the genetic basis of PELD is similar to that of congenital lipodystrophy type 2, we hypothesized that a patient with PELD may respond to treatments approved for other congenital lipodystrophic syndromes. CASE PRESENTATION: We describe a 5-year-old boy with an extremely rare phenotype involving severe progressive myoclonic epilepsy who received metreleptin (a recombinant analogue of leptin) to control metabolic abnormalities. At the age of two, he had no subcutaneous adipose tissue, with hypertriglyceridemia, hypertransaminasemia and hepatic steatosis. He also had a moderate psychomotor delay and generalized tonic seizures. At 4 years, he had insulin resistance, hypercholesterolemia, hypertriglyceridemia, mild hepatosplenomegaly and mild hepatic steatosis; he began a hypolipidemic diet. Severe psychomotor delay and myoclonic/myoclonic atonic seizures with absences was evident. At 5 years of age, metreleptin 0.06 mg/kg/day was initiated; after 2 months, the patient's lipid profile improved and insulin resistance resolved. After 1 year of treatment, hepatic steatosis improved and abdominal ultrasound showed only mild hepatomegaly. Seizure frequency decreased but was not eliminated during metreleptin therapy. CONCLUSIONS: Metreleptin may be used to control metabolic disturbances and may lead to better seizure control in children with PELD.

The impact of IGF-I, puberty and obesity on early retinopathy in children: a cross-sectional study.

BACKGROUND: Childhood obesity has been correlated with coronary heart disease, but the correlation with microvascular disease remains unclear. The retinal microcirculation is affected early in the process of atherosclerosis and it offers the opportunity to indirectly study the effects of obesity on small brain vessels. Insulin-like growth factor 1 (IGF-I) is involved in angiogenesis and it has a crucial role in retinal vascularization. METHODS: A single-centre cross-sectional study was performed in 268 children and adolescents (116 males; mean age 13.03 ± 1.9 years,) with overweight/obesity, in order to identify risk factors for early retinopathy. RESULTS: Nine patients (3.3%) showed signs of retinopathy, defined as arteriovenous crossings and/or papilledema. Body mass index and fat mass, analysed by Dual X-ray Absorptiometry, were not different in patients with or without retinopathy. Patients with retinopathy were pubertal and showed higher waist circumference (107.78 ± 15.83 versus 99.46 ± 10.85 cm; p: 0.027), waist circumference/height ratio (0.66 ± 0.07 versus 0.62 ± 0.05; p: 0.04) and IGF-I SDS (0.03 ± 1.3 versus - 0.66 ± 0.9; p: 0.04). Multivariate analysis (after correction for sex, age, family history of type 2 diabetes mellitus, obesity, cardiovascular disease, hypertension and dyslipidaemia) showed that waist circumference/height ratio and IGF-I SDS were the only variables independently correlated with the presence of retinopathy. CONCLUSIONS: Retinal vascular changes may become evident as an early complication of overweight and obesity, even during childhood and adolescence. Relatively high levels of IGF-I during this phase may act as an additional risk factor for microvascular damage. The screening for retinopathy should be proposed to all children and adolescents with overweight/obesity.

Lipoid congenital adrenal hyperplasia by steroidogenic acute regulatory protein (STAR) gene mutation in an Italian infant: an uncommon cause of adrenal insufficiency.

BACKGROUND: Lipoid congenital adrenal hyperplasia (CAH) (OMIM n. 201710) is the most severe form of congenital adrenal hyperplasia. It is characterized by severe adrenal and gonadal steroidogenesis impairment due to a defect in the conversion of cholesterol to pregnenolone. Affected infants experience salt loss, but glucocorticoid and mineralocorticoid replacement therapy enables long-term survival. Classic lipoid congenital adrenal hyperplasia is relatively common in Japan and Korea but extremely rare in Caucasian populations. CASE PRESENTATION: A female infant of Italian origin came to our attention in late infancy with a clinical picture of acute adrenal insufficiency. The study of the STAR gene revealed two genomic variants c.562C > T and c.577C > T in compound heterozygosity. At the protein level, the two mutations determine the p.Arg188Cys variant (rs104894090) and the p.Arg193Ter variant (rs387907235), respectively. Sanger sequencing was used to confirm the identified variants and to perform familial study. The mother carried the p.Arg188Cys variant, while the father carried the p.Arg193Ter variant. CONCLUSION: To our knowledge this is the second case of classic lipoid congenital adrenal hyperplasia reported in the Italian population. STAR mutations resulting in lipoid congenital adrenal hyperplasia should be considered all over the world in the differential diagnosis of newborn babies and infants with primary adrenal insufficiency.

Water Balance and 'Salt Wasting' in the First Year of Life: The Role of Aldosterone-Signaling Defects.

In newborns and infants, dehydration and salt wasting represent a relatively common cause of admission to hospital and may result in life-threatening complications. Kidneys are responsible for electrolyte homoeostasis, but neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron, leading to reduced ability to concentrate urine. High extrarenal fluid losses often contribute to the increased occurrence of electrolyte disorders. Aldosterone is essential for sodium retention in the kidney, salivary glands, sweat glands and colon. A partial and transient aldosterone resistance is present in newborns and infants, thus reducing the capability of maintaining sodium balance in specific pathological conditions. The present review examines the mechanisms making infants more susceptible to salt wasting. Peculiar aspects of renal physiology in the first year of life and management of electrolyte disorders (i.e. sodium and potassium) are considered. Finally, inherited disorders associated with neonatal salt wasting are examined in detail. © 2016 S. Karger AG, Basel.

Congenital primary adrenal insufficiency and selective aldosterone defects presenting as salt-wasting in infancy: a single center 10-year experience.

BACKGROUND: Salt-wasting represents a relatively common cause of emergency admission in infants and may result in life-threatening complications. Neonatal kidneys show low glomerular filtration rate and immaturity of the distal nephron leading to reduced ability to concentrate urine. METHODS: A retrospective chart review was conducted for infants hospitalized in a single Institution from 1(st) January 2006 to 31(st) December 2015. The selection criterion was represented by the referral to the Endocrinology Unit for hyponatremia (serum sodium <130 mEq/L) of suspected endocrine origin at admission. RESULTS: Fifty-one infants were identified. In nine infants (17.6 %) hyponatremia was related to unrecognized chronic gastrointestinal or renal salt losses or reduced sodium intake. In 10 infants (19.6 %) hyponatremia was related to central nervous system diseases. In 19 patients (37.3 %) the final diagnosis was congenital adrenal hyperplasia (CAH). CAH was related to 21-hydroxylase deficiency in 18 patients, and to 3ß-Hydroxysteroid dehydrogenase (3ßHSD) deficiency in one patient. Thirteen patients (25.5 %) were affected by different non-CAH salt-wasting forms of adrenal origin. Four familial cases of X-linked adrenal hypoplasia congenita due to NROB1 gene mutation were identified. Two unrelated girls showed aldosterone synthase deficiency due to mutation of the CYP11B2 gene. Two unrelated infants were affected by familial glucocorticoid deficiency due to MC2R gene mutations. One girl showed pseudohypoaldosteronism related to mutations of the SCNN1G gene encoding for the epithelial sodium channel. Transient pseudohypoaldosteronism was identified in two patients with renal malformations. In two infants the genetic aetiology was not identified. CONCLUSIONS: Emergency management of infants presenting with salt wasting requires correction of water losses and treatment of electrolyte imbalances. Nevertheless, the differential diagnosis may be difficult in emergency settings, and sometimes hospitalized infants presenting with salt-wasting are immediately started on steroid therapy to avoid life-threatening complications, before the correct diagnosis is reached. Physicians involved in the management of infants with salt-wasting of suspected hormonal origin should remember that, whenever practicable, a blood sample for the essential hormonal investigations should be collected before starting steroid therapy, to guide the subsequent diagnostic procedures and in particular to address the analysis of candidate genes.

Brain Magnetic Resonance Imaging as First-Line Investigation for Growth Hormone Deficiency Diagnosis in Early Childhood.

BACKGROUND/AIMS: The diagnosis of growth hormone (GH) deficiency (GHD) in infancy and early childhood is not straightforward. GH stimulation tests are unsafe and unreliable in infants, and normative data are lacking. This study aims to investigate whether brain magnetic resonance imaging (MRI) may replace GH stimulation tests in the diagnosis of GHD in children younger than 4 years. METHODS: We examined a retrospective cohort, with longitudinal follow-up, of 68 children consecutively diagnosed with GHD before the age of 4 years. The prevalence of hypothalamic-pituitary (HP) alterations at MRI and the associations with age and either isolated GHD (IGHD) or multiple pituitary hormone deficiency (MPHD) were assessed. RESULTS: The prevalences of IGHD and MPHD were 54.4 and 45.6%, respectively. In the first group, brain MRI showed abnormalities in 83.8%: isolated pituitary hypoplasia in 48.7% and complex defects in 35.1%. In patients with MPHD, MRI showed complex alterations in 100%. All children younger than 24 months showed HP MRI abnormalities, regardless of the diagnosis. Complex defects were found in 94% of patients younger than 12 months and in 75% of patients between 13 and 24 months. CONCLUSION: Our data suggest that brain MRI may represent the first-line investigation for diagnosing GHD in infancy and early childhood.

Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies.

Alloimmune antenatal membranous nephropathy (MN) during pregnancy results from antibodies produced by a neutral endopeptidase (NEP)-deficient mother. Here we report two recent cases that provide clues to the severity of renal disease. Mothers of the two children had circulating antibodies against NEP showing the characteristic species-dependent pattern by immunofluorescence on kidney slices. A German mother produced predominantly anti-NEP IgG4 accompanied by a low amount of IgG1. Her child recovered renal function within a few weeks. In sharp contrast, an Italian mother mainly produced complement-fixing anti-NEP IgG1, which also inhibits NEP enzymatic activity, whereas anti-NEP IgG4 has a weak inhibitory potency. Her child was dialyzed for several weeks. A kidney biopsy performed at 12 days of age showed MN, ischemic glomeruli, and arteriolar and tubular lesions. A second biopsy performed at 12 weeks of age showed aggravation with an increased number of collapsed capillary tufts. Both mothers were homozygous for the truncating deletion mutation 466delC and were thus NEP deficient. The 466delC mutation, identified in three previously described families, suggests a founder effect. Because of the potential severity of alloimmune antenatal MN, it is essential to identify families at risk by the detection of anti-NEP antibodies and NEP antigen in urine. On the basis of the five families identified to date, we propose an algorithm for the diagnosis of the disease and the prevention of complications.

Glucose tolerance affects pubertal growth and final height of children with cystic fibrosis.

There are few data about the impact of cystic fibrosis-related diabetes (CFRD) on growth. We analyzed 17 children with cystic fibrosis (CF) presenting with newly diagnosed CFRD during puberty, in comparison with a matched control group of 52 CF children with normal glucose tolerance (NGT). Anthropometric evaluation showed that body mass index at CFRD diagnosis was significantly reduced in children with CFRD, in comparison with children with NGT (CFRD: -0.48 ± 1.08 vs. NGT: 0.2 ± 0.99; P=0.01), and the same difference remained evident at the end of follow up (CFRD: -0.49 ± 0.95 vs. NGT: 0.13 ± 0.89; P=0.04). Height standard deviation score (SDS) at baseline was slightly but not significantly lower in CFRD children (CFRD: -0.71 ± 0.83 vs. NGT: -0.25 ± 1.08; P=0.08), while final height SDS was significantly reduced (CFRD: -1.61 ± 1.12 vs. NGT: -0.61 ± 1.15; P=0.003). Mean final height SDS of the whole group was lower than mean target height SDS (final height SDS: -0.86 ± 1.2 vs. target height SDS: -0.3 ± 0.85; P<0.001). Target adjusted final height was lower in CFRD children, although the difference between CFRD and NGT children did not reach statistical significance (CFRD: -0.8 ± 1.03 vs. NGT: -0.47 ± 0.9; P=0.09). Pubertal growth and final height are negatively affected by CFRD. Intensive insulin treatment does not appear to be effective in normalizing growth, even when treatment is started early in the course of the disease, before the onset of clinical deterioration.

Routine screening by brain magnetic resonance imaging is not indicated in every girl with onset of puberty between the ages of 6 and 8 years.

CONTEXT: It is still controversial whether all girls with central precocious puberty (CPP) should undergo brain magnetic resonance imaging (MRI) for unveiling intracranial pathology. OBJECTIVES: The objectives of the study were to determine the prevalence and type of intracranial lesions in otherwise normal girls with central precocious puberty (idiopathic CPP) and to identify the clinical and biochemical predictors of brain abnormalities. DESIGN AND SETTING: This was a retrospective study conducted at the Endocrine Unit of "Bambino Gesù" Children's Hospital (Rome, Italy) from 1990 to 2012. PATIENTS: One hundred eighty-two girls were consecutively diagnosed with CPP. All girls underwent a thorough endocrine assessment and brain MRI with a detailed examination of the hypothalamic-pituitary area. None of them had a history of neurological diseases, endocrine disorders, neurofibromatosis or other genetic syndromes, or previous hormonal therapies. MAIN OUTCOME MEASURE: Prevalence of brain abnormalities at MRI scan was measured. RESULTS: Brain MRI showed no alteration in 157 (86%), incidentalomas of the hypothalamic-pituitary area unrelated to CPP in 19 (11%), and hamartomas in six girls (3%). Girls with hamartomas were younger than 6 years and had significantly higher mean baseline and stimulated LH values (P < .001), LH to FSH ratio (P < .001), serum 17ß-estradiol levels (P < .001), and uterine length (P < .05). However, all the parameters overlapped extensively in girls with or without cerebral alterations. CONCLUSIONS: Our data cast doubt on the need of routine screening by brain MRI in girls with idiopathic CPP older than 6 years. Evidence-based criteria to drive clinical decision making about the use of MRI are lacking.

Controversies in the definition and treatment of idiopathic short stature (ISS).

The term idiopathic short stature (ISS) refers to short children with no identifiable disorder of the growth hormone (GH)/insulin like growth factor (IGF) axis and no other endocrine, genetic or organ system disorder. This heterogeneous group of short children without GH deficiency (GHD) includes children with constitutional delay of growth and puberty, familial short stature, or both, as well as those with subtle cartilage and bone dysplasias. In rare cases, ISS is due to IGF molecular abnormalities. In this review we tackle the major challenges in the definition and treatment of ISS.