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Purpose: Glucocorticoids (GCs) are commonly used for several acute and chronic pediatric diseases. However, chronic treatment may result in hypothalamic-pituitary-adrenal axis (HPA) dysfunction. Glucocorticoid-induced adrenal insufficiency (GI-AI) is indeed the most frequent cause of adrenal insufficiency (AI) in children, possibly resulting in a life-threatening event such as adrenal crisis (AC). It is generally underestimated, especially when using non-systemic glucocorticoid formulations. This review aims at summarizing current evidence on the effects of long-term GC treatment on the HPA axis, management of GC tapering and assessment of the HPA recovery., Methods: We conducted a narrative review of the relevant literature focusing on pathogenic mechanisms, predictive factors, diagnosis and treatment of GI-AI., Results: All types of GCs, whatever the route of administration, may have suppressive effects on the HPA axis, especially when compounds with higher potency and long half-life are used. Moreover, chronic GC administration is the most common cause of Cushing syndrome in children. In order to overcome the risk of GI-AI, slow withdrawal of GCs is necessary. When approaching the replacement dose, it is recommended to switch to shorter half-life formulations such as hydrocortisone. Assessment of HPA axis recovery with basal and stimulated cortisol levels may help detecting children at risk of AC that may require hydrocortisone supplementation., Conclusion: The management of GI-AI in children is challenging and many areas of uncertainty remain. Improving the knowledge on long-term GC effects on HPA in children, the management of steroid discontinuation and emergency dosing may help preventing GI-AI symptoms and acute hospital admission for AC., (© 2024. The Author(s).)

Background and Aim: To assess the performance of Friedewald's and Sampson's formulas in relation to high or borderline-high levels of measured LDL-Cholesterol (LDL-C) in youths with overweight/obesity (OW/OB)., Methods and Results: A cross-sectional study was performed in 1694 youths (age 5-17 years) with OW/OB observed in Italian centers of Messina (group 1) and Naples (group 2). LDL-C levels were both measured and calculated using Friedewald's (LDL-C F ) and Sampson's (LDL-C S ) formulas. The two groups were similar for sex, age, BMI, BMI Z-score, and measured LDL-C. Levels of LDL-C F and LDL-C S were higher in group 1 than group 2. In the overall sample, 9.9 % youths had measured LDL-C ≥130 mg/dL and 27.8 % ≥ 110 mg/dL, without differences between centers. The two formulas showed comparable high sensitivity and specificity in relation to levels of measured LDL-C ≥130 mg/dL or ≥110 mg/dL. However, LDL-C F showed a higher positive predictive value than LDL-C S ., Conclusions: Both formulas estimate with high accuracy measured LDL-C levels in youths with OW/OB. Therefore, calculated LDL-C can be a useful tool for universal screening when direct LDL-C measurement is not available. The Friedewald's formula is more feasible in clinical practice for simplicity of calculation., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Madeo, Zagaroli, Vandelli, Calcaterra, Crinò, De Sanctis, Faienza, Fintini, Guazzarotti, Licenziati, Mozzillo, Pajno, Scarano, Street, Wasniewska, Bocchini, Bucolo, Buganza, Chiarito, Corica, Di Candia, Francavilla, Fratangeli, Improda, Morabito, Mozzato, Rossi, Schiavariello, Farello, Iughetti, Salpietro, Salvatoni, Giordano, Grugni and Delvecchio.)

Introduction: Growth hormone deficiency (GHD) may be associated with subtle cardiovascular abnormalities, reversible upon starting GH treatment. Data on vascular morphology and function in GHD children are scanty and inconclusive. The aim of our study was to evaluate the effects of GHD and GH treatment on endothelial function and intima-media thickness (IMT) in children and adolescents., Methods: We enrolled 24 children with GHD (10.85 ± 2.71 years) and 24 age-, sex-, and BMI-matched controls. We evaluated anthropometry, lipid profile, asymmetric dimethylarginine (ADMA), brachial flow-mediated dilatation (FMD), and IMT of common (cIMT) and internal (iIMT) carotid artery at study entry in all subjects and after 12 months of treatment in GHD children., Results: At baseline GHD, children had higher total cholesterol (163.17 ± 18.66 vs. 149.83 ± 20.68 mg/dL, p = 0.03), LDL cholesterol (91.18 ± 20.41 vs. 77.08 ± 19.73 mg/dL, p = 0.019), atherogenic index (AI) (2.94 ± 0.71 vs. 2.56 ± 0.4, p = 0.028), and ADMA (215.87 ± 109.15 vs. 164.10 ± 49.15 ng/mL, p < 0.001), compared to controls. GHD patients also exhibited increased higher waist-to-height ratio (WHtR) compared to controls (0.48 ± 0.05 vs. 0.45 ± 0.02 cm, p = 0.03). GH therapy resulted in a decrease in WHtR (0.44 ± 0.03 cm, p = 0.001), total (151.60 ± 15.23 mg/dL, p = 0.001) and LDL cholesterol (69.94 ± 14.40 mg/dL, p < 0.0001), AI (2.28 ± 0.35, p = 0.001), and ADMA (148.47 ± 102.43 ng/mL, p < 0.0001). GHD showed lower baseline FMD than controls (8.75 ± 2.44 vs. 11.85 ± 5.98%, p = 0.001), which improved after 1-year GH treatment (10.60 ± 1.69%, p = 0.001). Baseline cIMT and iIMT were comparable between the two groups, but slightly reduced in GHD patients after treatment., Conclusion: GHD children may exhibit endothelial dysfunction in addition to other early atherosclerotic markers like visceral adiposity, and altered lipids, which can be restored by GH treatment., (© 2023 S. Karger AG, Basel.)

Introduction: Perinatal asphyxia is one of the three most important causes of neonatal mortality and morbidity. Therapeutic hypothermia represents the standard treatment for infants with moderate-severe perinatal asphyxia, resulting in reduction in the mortality and major neurodevelopmental disability. So far, data in the literature focusing on the endocrine aspects of both asphyxia and hypothermia treatment at birth are scanty, and many aspects are still debated. Aim of this narrative review is to summarize the current knowledge regarding the short- and long-term effects of perinatal asphyxia and of hypothermia treatment on the endocrine system, thus providing suggestions for improving the management of asphyxiated children., Results: Involvement of the endocrine system (especially glucose and electrolyte disturbances, adrenal hemorrhage, non-thyroidal illness syndrome) can occur in a variable percentage of subjects with perinatal asphyxia, potentially affecting mortality as well as neurological outcome. Hypothermia may also affect endocrine homeostasis, leading to a decreased incidence of hypocalcemia and an increased risk of dilutional hyponatremia and hypercalcemia., Conclusions: Metabolic abnormalities in the context of perinatal asphyxia are important modifiable factors that may be associated with a worse outcome. Therefore, clinicians should be aware of the possible occurrence of endocrine complication, in order to establish appropriate screening protocols and allow timely treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Improda, Capalbo, Poloniato, Garbetta, Dituri, Penta, Aversa, Sessa, Vierucci, Cozzolino, Vigone, Tronconi, del Pistoia, Lucaccioni, Tuli, Munarin, Tessaris, de Sanctis and Salerno.)

Metabolic syndrome (MetS) is defined by a cluster of several cardio-metabolic risk factors, specifically visceral obesity, hypertension, dyslipidemia, and impaired glucose metabolism, which together increase risks of developing future cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). This article is a narrative review of the literature and a summary of the main observations, conclusions, and perspectives raised in the literature and the study projects of the Working Group of Childhood Obesity (WGChO) of the Italian Society of Paediatric Endocrinology and Diabetology (ISPED) on MetS in childhood obesity. Although there is an agreement on the distinctive features of MetS, no international diagnostic criteria in a pediatric population exist. Moreover, to date, the prevalence of MetS in childhood is not certain and thus the true value of diagnosis of MetS in youth as well as its clinical implications, is unclear. The aim of this narrative review is to summarize the pathogenesis and current role of MetS in children and adolescents with particular reference to applicability in clinical practice in childhood obesity.

Diencephalic syndrome (DS) is a rare pediatric condition associated with optic pathway gliomas (OPGs). Since they are slow-growing tumors, their diagnosis might be delayed, with consequences on long-term outcomes. We present a multicenter case series of nine children with DS associated with OPG, with the aim of providing relevant details about mortality and long-term sequelae. We retrospectively identified nine children (6 M) with DS (median age 14 months, range 3-26 months). Four patients had NF1-related OPGs. Children with NF1 were significantly older than sporadic cases (median (range) age in months: 21.2 (14-26) versus 10 (3-17); p = 0.015). Seven tumors were histologically confirmed as low-grade astrocytomas. All patients received upfront chemotherapy and nutritional support. Although no patient died, all of them experienced tumor progression within 5.67 years since diagnosis and were treated with several lines of chemotherapy and/or surgery. Long-term sequelae included visual, pituitary and neurological dysfunction. Despite an excellent overall survival, PFS rates are poor in OPGs with DS. These patients invariably present visual, neurological or endocrine sequelae. Therefore, functional outcomes and quality-of-life measures should be considered in prospective trials involving patients with OPGs, aiming to identify "high-risk" patients and to better individualize treatment.

Background: Severe hypercalcemia is rare in newborns; even though often asymptomatic, it may have important sequelae. Hypophosphatemia can occur in infants experiencing intrauterine malnutrition, sepsis and early high-energy parenteral nutrition (PN) and can cause severe hypercalcemia through an unknown mechanism. Monitoring and supplementation of phosphate (PO4) and calcium (Ca) in the first week of life in preterm infants are still debated., Case Presentation: We report on a female baby born at 29 weeks' gestation with intrauterine growth retardation (IUGR) experiencing sustained severe hypercalcemia (up to 24 mg/dl corrected Ca) due to hypophosphatemia while on phosphorus-free PN. Hypercalcemia did not improve after hyperhydration and furosemide but responded to infusion of PO4. Eventually, the infant experienced symptomatic hypocalcaemia (ionized Ca 3.4 mg/dl), likely exacerbated by contemporary infusion of albumin. Subsequently, a normalization of both parathyroid hormone (PTH) and alkaline phosphatase (ALP) was observed., Conclusions: Although severe hypercalcemia is extremely rare in neonates, clinicians should be aware of the possible occurrence of this life-threatening condition in infants with or at risk to develop hypophosphatemia. Hypophosphatemic hypercalcemia can only be managed with infusion of PO4, with strict monitoring of Ca and PO4 concentrations.

Objectives: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP., Design: Retrospective study among three paediatric University Hospitals in Italy and UK., Methods: 184 children (72 females) aged 12.4 ± 2.08 years underwent primed (/P + ) or unprimed (/P - ) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P - ) or received LDSS (CDGP + ). The cohort included 34 CDG P - /P + , 12 CDGP + /P + , 51 GHD/P + , 29 CDG P - /P - , 2 CDGP + /P - and 56 GHD/P - . FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (-1 ≤ Δ SDS FH-SDS TH ≤ +1) were outcomes of interest., Results: GHD/P + had better FH-SDS (-0.87 vs -1.49; P = .023) and ΔSDS FH-TH (-0.35 vs -0.77; P = .002) than CDGP - /P + . Overall, GHD/P + showed the highest degree of success (90%, P = .006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P = .0009). GHD/P + showed a trend towards a higher proportion of permanent GHD compared to GHD/P - (30.43% vs 15.09%; P = .067)., Conclusion: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP., (© 2020 John Wiley & Sons Ltd.)

Background: COVID-19 pandemic has markedly affected emergency care, due to sudden limitation of health care capacity by general practitioners (GP) and urgent need for infection control strategies. We evaluated the activity of the Emergency Department (ED) during the national lockdown (March 8-April 30), as well as the outcomes of our infection control strategy., Results: Despite a reduction in access by one fifth, a proportion of febrile patients comparable to 2019 was seen (829/2492, 33.3% vs 4580/13.342, 34.3%, p = 0.3). Diagnostic swab for COVID-19 was performed in 25% of patients, especially in subjects with co-morbidities or multiple access. Six infected cases were identified, all presenting with febrile disease. Only two positive patients fulfilled the criteria for diagnostic swab provided by the Italian Health Authorities, because of close contact with suspected or confirmed cases. The rate of admission for febrile or respiratory conditions was higher than the same period of 2019 (33.4% vs 25.9%, p < 0.0001). None of the 105 health-care professionals working during the study time lapse exhibited anti-SARS-CoV-2 seroconversion. Among the 589 patients with information available, 54.9% declared no medical consultation at all prior to coming to ED, while only 40 (of which 27 with fever) had been examined by their GP before coming to ED. Nevertheless, 35.6% of the cases were already taking medications. None of the 9 patients requiring intensive care reported recent pediatric consultation, despite symptoms duration up to 30 days., Conclusion: Our results provide evidence that the reduced capacity of primary care facilities during the national lockdown may have caused a high rate of self-medication as well as a delayed provision of care in some patients. Identification of pediatric patients affected with SARS-CoV-2 infection remains a challenge because of the absence of reliable predictive factors. Finally, the use of specific triage centers, with dedicated pathways to diagnose SARS-CoV-2 infection, trace contacts and allow adequate care after swabs, is effective in preventing spreading of the infection.

Subclinical hypothyroidism (SH) is biochemically defined as serum TSH levels above the upper limit of the reference range in the presence of normal free T4 (FT4) concentrations. While there is a general agreement to treat subjects with serum TSH levels above 10 mU/L, the management of mild form (TSH concentrations between 4.5 and 10 mU/L) is still a matter of debate. In children, mild SH is often a benign and remitting condition and the risk of progression to overt thyroid dysfunction depends on the underlying condition, being higher in the autoimmune forms. The major concern is to establish whether SH in children should always be considered an expression of mild thyroid dysfunction and may deserve treatment. Current data indicate that children with mild SH have normal linear growth, bone health and intellectual outcome. However, slight metabolic abnormalities and subtle deficits in specific cognitive domains have been reported in children with modest elevation of TSH concentration. Although these findings are not sufficient to recommend levothyroxine treatment for all children with mild SH, they indicate the need for regular monitoring to ensure early identification of children who may benefit from treatment. In the meanwhile, the decision to initiate therapy in children with mild SH should be based on individual factors.

Background: Long-term consequences of mild subclinical hypothyroidism (SH) in children are still unclear, and the need for levothyroxine (L-T4) supplementation remains controversial. We designed a 2-year, case-control, prospective study of a cohort of children with SH to evaluate the effects of L-T4 therapy on neurocognitive outcome., Methods: Thirty-four children, age 9.1 ± 2.6 years, with long-lasting, idiopathic, and mild SH, and 34 healthy matched controls, were enrolled. Twenty SH children underwent a 2-year L-T4 treatment (group A), whereas 14 refused treatment and were reevaluated after a 2-year-follow-up (group B). IQ and specific cognitive domains were evaluated in all children at study entry and after 2 years of therapy (group A) or observation (group B) in SH individuals., Results: In SH children baseline IQ scores were normal and comparable to controls (full-scale IQ [FSIQ] 100.4 ± 11.3 vs 101.8 ± 14.2, verbal IQ [VIQ] 99.7 ± 13.7 vs 98.3 ± 14.9 and performance IQ [PIQ] 101.2 ± 10.4 vs 105 ± 10.4).In group A, L-T4 treatment was associated with normalization of thyrotropin (6.3 ± 1.0 mIU/L at baseline vs 2.8 ± 1.4 mIU/L at 2 years, P < .001). However, 2-year L-T4 therapy was not associated with a change in IQ scores (FSIQ 104.4 ± 13.8 vs 102.7 ± 11.0; VIQ 101.8 ± 14.9 vs 102.3 ± 11.9; and PIQ 106.5 ± 13.9 vs 102.7 ± 10.7) or in verbal or performance subtest scores. No significant differences were found in IQ scores after 2 years of treatment in group A compared to group B after a 2-year follow-up., Conclusions: Our data suggest neurocognitive function in children is not impaired by persistent, mild, untreated SH and is not significantly modified by 2-year L-T4 supplementation., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Septo-optic dysplasia (SOD) is a heterogeneous congenital condition. The aim of this study was to investigate the clinical phenotypes of a large cohort of children with SOD, Multiple Pituitary Hormone Deficiency (MPHD) and Optic Nerve Hypoplasia (ONH), with a focus on endocrine testing., Methods: Retrospective single-centre longitudinal study of children with SOD (n:171), MPHD (n:53) and ONH (n:35). SOD+ and SOD- indicate patients with or without hypopituitarism, respectively., Findings: All deficits were more frequent and occurred earlier in MPHD than SOD+ [Hazard Ratios (HR): 0·63(0·45,0·89) for GH, 0·48(0·34,0·69) for TSH, 0·55(0·38,0·80) for ACTH, 0·28(0·11,0·68) for gonadotropins], except Diabetes Insipidus (DI) [HR: 2·27(0·88,5·9)]. Severe hypothalamo-pituitary (H-P) abnormalities were more frequent in MPHD [80·0% vs 41·6%, p<0·0001 for Ectopic Posterior Pituitary (EPP)]. Stalk and PP abnormalities were associated with more severe endocrine phenotypes and placed a subgroup of SOD+ at risk of developing deficits earlier. SOD and ONH shared heterogeneous phenotypes ranging from pubertal delay to precocity and from leanness to extreme obesity, whilst MPHD had GnD and obesity only. Mortality was recorded in 4·2% (6/144) SOD and 3·2% (1/31) ONH, and only in patients with multisystem phenotypes., Interpretation: More than a single disease, SOD represents a spectrum of malformative conditions involving different brain structures and characterised by a dynamic and sequential nature of endocrine. In contrast, MPHD displays a more homogeneous phenotype of (mainly) anterior pituitary early-onset failure. Stalk and PP abnormalities place a subgroup of SOD+ at a higher risk of early-onset deficits. Additionally, there are striking differences between the SOD and MPHD cohorts in terms of pubertal progression. The shared phenotypes between ONH and SOD could be partly explained by common hypothalamic dysfunction. The differences between the cohorts are important as they may aid in planning management and preventing morbidity by dictating earlier interventions., Funding: M.C., M.G., and N.I. were supported by the European Society of Paediatric Endocrinology (ESPE) through ESPE Clinical Fellowships., Competing Interests: The authors have nothing to declare., (© 2019 Published by Elsevier Ltd.)

Increasing evidence indicates that adults with Congenital Adrenal Hyperplasia (CAH) may have a cluster of cardiovascular (CV) risk factors. In addition, ongoing research has highlighted that children and adolescents with CAH are also prone to developing unfavorable metabolic changes, such as obesity, hypertension, insulin resistance, and increased intima-media thickness, which places them at a higher risk of developing CV disease in adulthood. Moreover, CAH adolescents may exhibit subclinical left ventricular diastolic dysfunction and impaired exercise performance, with possible negative consequences on their quality of life. The therapeutic management of patients with CAH remains a challenge and current treatment regimens do not always allow optimal biochemical control. Indeed, overexposure to glucocorticoids and mineralocorticoids, as well as to androgen excess, may contribute to the development of unfavorable metabolic and CV abnormalities. Long-term prospective studies on large cohorts of patients will help to clarify the pathophysiology of metabolic alterations associated with CAH. Meanwhile, further efforts should be made to optimize treatment and identify new therapeutic approaches to prevent metabolic derangement and improve long-term health outcomes of CAH patients.

Background: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out)., Purpose: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD., Methods: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD., Results: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls., Conclusions: DNAJC17 mutations are not frequently present in patients with TD.

Purpose: To evaluate glucose homeostasis in children with growth hormone (GH) deficiency (GHD) receiving long-term replacement therapy., Methods: We evaluated glucose, insulin, HOmeostasis Model Assessment (HOMA-IR), and HbA1c in 100 GHD children at diagnosis and during 5 years of therapy. One hundred healthy children comparable to patients were evaluated at baseline and after 1 and 5 years., Results: No difference was detected at baseline between GHD patients and controls in glucose (79.58 ± 9.96 vs. 77.18 ± 8.20 mg/dl), insulin (4.50 ± 3.24 vs. 4.30 ± 2.60 µU/ml), HbA1c (5.20 ± 0.31 vs. 5.25 ± 0.33%) levels, and HOMA-IR (0.93 ± 0.72 vs. 0.86 ± 0.61). One year of GH was associated with a significant increase in insulin (7.21 ± 4.84, p < 0.001) and HOMA-IR (1.32 ± 0.98, p < 0.001) in GHD children, which became different from controls (p < 0.001 and p = 0.004). These parameters did not change further during the following years of treatment in GHD subjects. In contrast, controls did not show significant changes in insulin (4.40 ± 2.60) and HOMA-IR (0.82 ± 0.60) during the first year; however, at the fifth year of the study a significant increase in insulin (6.50 ± 3.50, p = 0.004) and HOMA-IR (1.29 ± 0.54, p < 0.001) was documented, making these parameters comparable between patients and controls., Conclusions: Our results suggest that growth hormone (GH) treatment is not associated with significant impairment of insulin sensitivity in GHD children. The slight impairment observed in GHD adolescents after long-term GH is comparable to that physiologically occurring in healthy pubertal subjects.

Context: Growth hormone deficiency (GHD) in children may be associated with early cardiovascular risk factors and alterations in left ventricular (LV) structure and function; data on cardiopulmonary functional capacity are lacking., Objectives: Aim of the study was to evaluate the effect of GHD and growth hormone (GH) therapy on cardiopulmonary functional capacity, left and right cardiac structure and function, and body composition in children and adolescents., Design: Prospective, case-control study., Patients and Methods: Twenty-one untrained GHD children (11.3 ± 0.8 years) underwent cardiopulmonary exercise testing, echocardiography and dual-energy x-ray absorptiometry, before and after 12 months of GH therapy. Twenty-one controls matched for sex, pubertal status, body mass index, and physical activity (PA) were evaluated at baseline and after 1 year., Results: At baseline, GHD patients showed reduced LV mass (LVM; 63.32 ± 7.80 vs 80.44 ± 26.29 g/m2, P = 0.006), peak oxygen consumption (VO2peak; 22.92 ± 4.80 vs 27.48 ± 6.71 mL/Kg/min, P = 0.02), peak workload (80.62 ± 29.32 vs 103.76 ± 36.20 W, P = 0.02), and O2 pulse (4.93 ± 1.30 vs 7.67 ± 2.93 mL/beat, P = 0.0003), compared with controls. GHD patients also exhibited lower lean body mass (LBM 65.36 ± 7.84% vs 76.13 ± 8.23%, P < 0.001), and higher fat mass (FM 30.84 ± 7.92% vs 22.19 ± 8.18%, P = 0.001) than controls. GH therapy resulted in a significant increase of LVM (72.01 ± 15.88, P = 0.03), VO2peak (26.80 ± 4.97; P = 0.01), peak workload (103.67 ± 32.24, P = 0.001), O2 pulse (6.64 ± 1.68, P = 0.0007), and LBM (75.36 ± 7.59%, P = 0.0001), with a reduction in FM (22.62 ± 7.73%, P = 0.001). No difference was found in either left or right ventricular function., Conclusion: Our results suggest that cardiac structure, body composition and cardiopulmonary functional capacity are impaired in children with untreated GHD and can be restored after short-term GH replacement therapy., (Copyright © 2017 Endocrine Society)

Objective: Poor linear growth is one of the main concerns in children with congenital adrenal hyperplasia (CAH). We aimed to analyze factors affecting growth trajectory in children with classical CAH., Methods: Clinical records of children followed from infancy up to the end of growth at two Italian tertiary referral hospitals were reviewed. Fifty-seven patients (31 males), treated with hydrocortisone and fludrocortisone only, were included. Clinical observations were divided into three groups: 0 to 2 years, 172 observations; from 2 years to puberty onset, 813 observations; after puberty onset, 527 observations. Height velocity, pubertal growth spurt, and final height were evaluated as outcomes., Results: Final height standard deviation score (SDS) was lower than target height SDS (-0.74 ± 1.1 versus -0.31 ± 1.01; P<.001). Target-adjusted final height SDS was -0.44 ± 1.8 in males and -0.13 ± 1.1 in females (P = .001). Total pubertal growth was 21.9 ± 7.3 cm in males and 19.2 ± 8.2 cm in females (P = .19). Hydrocortisone dose increased and height-velocity SDS decreased during puberty. At multivariable analysis, height-velocity SDS was adversely affected by hydrocortisone dose (P = .038) and directly related to adrenocorticotropic hormone (ACTH) levels (P = .023). Target-adjusted final-height SDS was adversely affected by hydrocortisone dose (P<.001) and positively related to mineralocorticoid therapy (P = .001) and ACTH levels (P = .02). Total pubertal growth (cm) was positively related to ACTH levels (P = .01)., Conclusion: Height outcome of CAH patients is now better than previously reported. During puberty, the lowest effective dose of hydrocortisone should be used to optimize pubertal growth spurt and final height., Abbreviations: 17-OHP = 17-alpha-hydroxyprogesterone ACTH = adrenocorticotropic hormone BMI = body mass index CAH = congenital adrenal hyperplasia GH = growth hormone HPA = hypothalamus-pituitary-adrenal PRA = plasma renin activity SDS = standard deviation score SV = simple virilizing SW = salt-wasting.

Background: Coexistence of congenital adrenal hyperplasia (CAH) and congenital hypothyroidism (CH) due to TG mutation in the same non-consanguineous family is rare., Case Series: We report 4 siblings born to unrelated parents, the father being an asymptomatic carrier of homozygous p.V281L and heterozygous p.I172N CYP21A2 mutations. Sibling 1 had salt-wasting CAH (CYP21A2 genotype Intron 2 splice/p.I172N and p.V281L). She also had CH (TG genotype p.R296/ p.T1416Rfs*30) and learning difficulties. Poor compliance and morbid obesity resulted in short stature, precocious puberty, hirsutism, amenorrhoea, insulin insensitivity and a possible adrenal adenoma. Sibling 3 (CYP21A2 and TG genotype similar to sibling 1) is a boy presenting with salt-wasting CAH, CH, and developmental delay. He was overweight and underwent precocious puberty. Although siblings 2 and 4 (both females) share the same CYP21A2 genotype (Intron 2 splice/p.V281L), the former only had biochemical evidence of CAH, while the latter presented at 9.8 years of age with a history of pubarche at 7 years and advanced bone age., Conclusions: We report the unusual occurrence of 2 rare autosomal recessive diseases, CAH and CH. Our cases highlight the phenotypic variability of CAH and CH due to TG mutations, even within a single family, and illustrate the importance of optimal disease control.
., (© 2017 S. Karger AG, Basel.)

In addition to promoting linear growth, GH plays a key role in the regulation of bone and muscle development and metabolism. Although GH deficiency is frequently listed among the causes of secondary osteoporosis in children, its impact on bone and muscle health and on fracture risk is still not completely established. Current data suggest that childhood-onset GH deficiency can affect bone and muscle mass and strength, with GH replacement therapy exerting beneficial effects. Moreover, GH withdrawal at final height can result in reduced peak bone and muscle mass, potentially leading to increased fracture risk in adulthood. Thus, the muscle-bone unit in GH deficient subjects should be monitored during childhood and adolescence in order to prevent osteoporosis and increased fracture risk and GH replacement should be tailored to ensure an optimal bone and muscle health., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), formerly known as autoimmune polyendocrine syndrome type 1, is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE's function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications.

Background: The p.R63W mutation in the hepatocyte nuclear factor-4 alpha (HNF4A) results in macrosomia and atypical Fanconi syndrome, in addition to hyperinsulinaemic hypoglycaemia (HI). We describe 2 infants carrying this mutation, presenting with additional features. Cases Series: Patient 1, a male born with a birth weight of 1.7 SDS, was diagnosed with HI on day 2 of life. He responded to 3-10 mg/kg/day of diazoxide. Raised serum creatinine led to the investigation of renal tubular function, showing leaking of electrolytes and protein. The patient also had conjugated hyperbilirubinaemia with liver steatosis. Patient 2 was a male born with a weight of 0.36 SDS. His mother had renal Fanconi syndrome. He received parenteral nutrition and presented with HI at 1 month of age, while establishing enteral feeds. Biochemistry workup showed renal tubular leaking of calcium, sodium, and phosphate. A hypoglycaemia screen documented HI, and the patient was commenced on 2 mg/kg/day of diazoxide. Continuous glucose monitoring was performed in his mother, revealing overnight hypoglycaemia., Conclusion: Renal Fanconi syndrome represents the only HNF4A feature showing complete penetrance. Our cases suggest that the p.R63W HNF4A mutation must be considered in subjects with a normal birth weight and postulate the possibility of liver involvement as a part of this condition., (© 2016 S. Karger AG, Basel.)

Context: PATIENTS with classic congenital adrenal hyperplasia (CAH) are treated with lifelong glucocorticoids (GCs). Cardiovascular and metabolic effects of such therapy in adolescents have never been quantified., Objective: Our objective was to investigate left ventricular (LV) morphology, function, and exercise performance in adolescents with CAH., Design and Setting: We conducted a cross-sectional and controlled study conducted at a tertiary referral center., Patients: Twenty patients with classic CAH (10 females) aged 13.6 ± 2.5 years and 20 healthy controls comparable for sex and pubertal status were enrolled in the study and compared with a group of 18 patients without CAH receiving a similar dose of GCs for juvenile idiopathic arthritis., Main Outcomes Measures: Echocardiographic assessment and symptom-limited exercise testing were performed. Anthropometric, hormonal and biochemical parameters were also measured., Results: Compared with healthy controls, patients with CAH exhibited an increased body mass index (P < .001), waist-to-height ratio (P < .001), and percent body fat (P < .001) as well as higher insulin concentrations and homeostasis model assessment of insulin resistance index even after adjustment for body mass index (P = .03 and P = .05, respectively). Moreover, CAH patients exhibited an impaired exercise capacity as shown by reduced peak workload (99 ± 27 vs 126 ± 27 W, P < .01) and higher systolic blood pressure response at peak (156 ± 18 vs 132 ± 11 mm Hg, P < .01; Δ = 45 ± 24 vs 22 ± 10 mm Hg, P = .05) with respect to healthy controls. CAH males displayed mild LV diastolic dysfunction as documented by significant prolongation of both isovolumic relaxation time (118 ± 18 vs 98 ± 11 milliseconds, P < .05) and mitral deceleration time (138 ± 25 vs 111 ± 15 milliseconds, P < .01). No significant differences in cardiovascular function were found between CAH and juvenile idiopathic arthritis patients., Conclusion: Adolescents with CAH exhibit impaired exercise performance and enhanced systolic blood pressure response during exercise. In our population, such abnormalities appear related to GC therapy rather than CAH per se. CAH males, but not females, present mild LV diastolic dysfunction that correlates with testosterone concentrations suggesting a sex hormone-related difference.

Background: Autoimmune polyendocrine syndrome type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy, is a rare autosomal recessive disease due to pathogenic variants in the AIRE gene. Classic features of the syndrome are mucocutaneous candidiasis, chronic idiopathic hypoparathyroidism and Addison disease. However, other endocrine and non-endocrine components, may occur with a different prevalence. In addition to ectodermal features, which are quite common features of the disease, APS 1 patients may experience other types of skin alterations, such as vasculitic skin rash. An early diagnosis of APS 1 can be very challenging, due to the high clinical heterogeneity, and a considerable delay may occur between the appearance of symptoms and the diagnosis., Case Presentation: We report on a girl affected by APS 1 who presented with cutaneous vasculitis when she was seven-months old, some years before the onset of the common components of the disease., Conclusion: Clinical picture of APS 1 may be characterized by isolated rare or atypical autoimmune or immune-mediated manifestations, even years before the onset of the classic components of the disease. Among these uncommon features, skin rashes of variable form and duration may occur, most of them being associated with histopathological features of vasculitis. Our case suggests that cutaneous vasculitis may represent a first sign of APS 1. The clinical significance of cutaneous vasculitis in the context of APS 1 is still debated. It may represent a rare, unusual, early component of the disease or a clinical manifestation secondarily related to the typical APS 1 components (i.e. autoimmune thyroid disease), which are frequently associated with rheumatologic-like signs and symptoms. Alternatively, it may be the expression of an independent disease co-occuring with APS 1. In conclusion, our case suggests that children presenting with unexplained vasculitic skin rash should be followed-up in order to early identify APS 1.

CHARGE association is characterized by ocular Coloboma, Heart malformations, choanal Atresia, Retardation of growth and development, Genital abnormalities and inner and external Ear abnormalities. Growth failure is a frequent find mainly associated with feeding difficulties or systemic diseases. To date, GH deficiency has been reported in only few patients with CHARGE association however long-term effects of GH treatment, up to final height, have never been reported. We describe a patient with CHARGE association and GH deficiency treated with GH from the age of 3 years and 10 months up to adult height.

Healthcare domain is characterized by a huge amount of data, contained in medical records, reports, test results and so on. In order to give support to healthcare workers and manage relevant data in effective and efficient way, it is important to correctly classify the unstructured parts of text, embedded in the medical documents. In this paper, we propose a classification system for medical records categorization, focused on the combination of different methodologies, based on lexical, syntactical and semantic analysis of the documents. We will show that a Classification System based on a combination of different text analysis methodologies overcomes the performances of each methodology taken alone. The obtained results will be presented in terms of Accuracy-Rejection Curves. Eventually, pro and cons of the architecture proposed and some future work will be pointed out.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease, caused by mutations of a single gene named Autoimmune regulator gene (AIRE) which results in a failure of T-cell tolerance. Central tolerance takes place within the thymus and represents the mechanism by which potentially auto-reactive T-cells are eliminated through the negative selection process. The expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (mTECs) in the thymus is a key process in the central tolerance and is driven by the protein encoded by AIRE gene, the transcription factor autoimmune regulator (AIRE). A failure in this process caused by AIRE mutations is thought to be responsible of the systemic autoimmune reactions of APECED. APECED is characterized by several autoimmune endocrine and non-endocrine manifestations and the phenotype is often complex. Although APECED is the paradigm of a monogenic autoimmune disorder, it is characterized by a wide variability of the clinical expression even between siblings with the same genotype, thus implying that additional mechanisms, other than the failure of Aire function, are involved in the pathogenesis of the disease. Unraveling open issues of the molecular basis of APECED, will help improve diagnosis, management, and therapeutical strategies of this complex disease.

Subclinical hypothyroidism (SH) is a condition characterized by a mild persistent thyroid failure. The main cause is represented by autoimmune thyroiditis, but mutations in genes encoding proteins involved in TSH pathway are thought to be responsible for SH, particularly in cases arising in familial settings. Patients with the syndrome of TSH unresponsiveness may have compensated or overt hypothyroidism with a wide spectrum of clinical and morphological alterations depending on the degree of impairment of TSH-receptor (TSH-R) function. We describe the case of two brothers with non autoimmune SH carrying the same heterozygous mutation in the extracellular domain of TSH-R and presenting with different clinical, biochemical and morphological features. The first one had only a slight persistent elevation of TSH, a normal thyroid ultrasound and did never require l- thyroxine (L-T4) replacement treatment. The second one had a neonatal persistent moderate TSH levels increase associated with a thyroid gland hypoplasia and was treated with L-T4 since the first months of life.These two cases support the recent association of TSH-R mutations inheritance as an autosomal dominant pattern with variable expressivity and suggest that the decision to start replacement therapy in patients with persistent SH due to TSH resistance should be individualized.

Background: Subclinical hypothyroidism (SH) is a relatively common condition characterized by a mild persistent thyroid failure. The management of children with SH is still a controversial issue and the decision to treat with L-thyroxine represents a clinical dilemma. Thyroid hormone and TSH play an important role in skeletal growth and bone mineral homeostasis., Aim: To evaluate whether untreated idiopathic SH may affect bone health in childhood and to compare two different diagnostic tools such as dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS)., Patients and Methods: Twenty-five children and adolescents (11 males) aged 9.8 ± 3.5 years (range 4.2-18.7) with untreated idiopathic SH were enrolled in the study. SH was diagnosed on the basis of normal FT4 levels with TSH concentrations between 4.2 and 10 mU/l. Children have been followed for 3.3 ± 0.3 years from the time of SH diagnosis. Twenty-five healthy children, age- and sex-matched, were enrolled as controls. Patients and controls underwent DXA to evaluate lumbar spine bone mineral density (BMD) and QUS at proximal phalanges of the non-dominant hand to assess bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) and bone transmission time (BTT)., Results: Mean BMD Z-score was -0.4 ± 1.36 in patients and -0.2 ± 1.2 in controls. Mean Ad-SoS Z-score was 0.01 ± 1.0 in patients and 0.1 ± 1.2 in controls and mean BTT Z-score was -0.03 ± 0.8 and 0.04 ± 1.1 respectively. All values were within the normal range, both in patients and in controls. There were no statistically significant differences between the two groups., Conclusion: Bone health, evaluated by lumbar spine DXA and phalangeal QUS, is not impaired in our children, despite long-term duration of idiopathic SH. Data about bone status provided by QUS are comparable to those provided by DXA. Therefore, QUS may represent a good, cheaper and safe screening test for bone evaluation in children with SH.