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IntroductionTo analyse the perspectives of healthcare professionals (HCPs) regarding the acceptance of digital health solutions for growth hormone (GH) deficiency care. This study identified factors impacting HCPs’ intent to use and recommend digital solutions supporting recombinant-human growth hormone (r-hGH) therapy in Italy and Korea with a use case of connected drug delivery system (Aluetta® with Smartdot™) integrated in a platform for GH treatment support (the Growzen™ digital health ecosystem).MethodsParticipatory workshops were conducted in Rome, Italy, and Seoul, Korea, to collect the perspectives of 22 HCPs on various predefined topics. HCPs were divided into two teams, each moderated by a facilitator. The workshops progressed in five phases: introduction of the project and experts, capturing views on the current context of digitalisation, perceived usefulness and ease of use of Aluetta® with Smartdot™, exploration of the perception of health technology evolution, and combined team recommendations. Data shared by HCPs on technology acceptance were independently analysed using thematic analysis, and relevant findings were shared and validated with experts.ResultsHCPs from both Italy and Korea perceived Aluetta® with Smartdot™ and the Growzen™ based digital health ecosystem as user-friendly, intuitive, and easy-to-use solutions. These solutions can result in increased adherence, a cost-effective healthcare system, and medication self-management. Although technology adoption and readiness may vary across countries, it was agreed that using digital solutions tailored to the needs of users may help in data-driven clinical decisions and strengthen HCP–patient relationships.ConclusionHCPs’ perspectives on the digitalisation in paediatric GH therapies suggested that digital solutions enable automatic, real-time injection data transmission to support adherence monitoring and evidence-based therapy, strengthen HCP–patient relationships, and empower patients throughout the GH treatment process.

IntroductionAmong girls assessed for pubertal precocity, pelvic ultrasound (pUS) may represent a pivotal tool to predict the time expected to elapse between sonographic assessment and the onset of menarche (TUS-M). Accordingly, the present analysis is meant to define the statistical relationship between sonographic parameters and TUS-M, in order to identify the most reliable predictor of the timing of menarche.MethodsRetrospective, multicenter analysis. Girls assessed for sexual precocity and showing sonographic and clinical findings consistent with pubertal onset upon referral were considered eligible. Patients treated with GnRH analogues were excluded and only those who had subsequently achieved complete and spontaneous pubertal attainment and for whom the exact date of menarche was available were included. Overall, we enrolled 184 girls from five tertiary care Italian Centers.ResultsThe time elapsed (months) between baseline endocrine assessment and spontaneous achievement of menarche showed a negative statistically significant correlation (p

IntroductionNon-compliance to recombinant human growth hormone (rhGH) treatment is universally recognized as a key detrimental factor to achieve the expected clinical outcomes in adult GH deficiency (aGHD). The Easypod™ electronic device allows objective measurement of adherence. Adherence to treatment has been reported to be related with IGF-1 levels and consequently with clinical satisfactory results. The aim of this multicentric, observational, retrospective, 24- month study, is to objectively assess aGHD patients’ compliance to rhGH, using the Easypod™ device. Additionally, the study aims to compare the biochemical responses of adherent vs non-adherent patients.MethodsForty-three patients (28 females and 15 males) affected by aGHD and equipped with Easypod™ from 3 Italian centers were included in the study. Adherence to treatment was defined as the proportion of injections correctly administered during the observational period, out of the expected total number of injections. All patients were evaluated for IGF-1, glucose, insulin, HOMA and QUICKI index, total/LDL/HDL cholesterol and triglycerides.ResultsMean adherence rate was consistently under 85% across the 2-year observation period (73% at year 2). A trend toward significant difference in adherence was shown when comparing female and male patients (respectively 76% and 61%) after a 2-year period. Among the anamnestic features, the prescribed frequency of administration of rhGH and the number of administered therapies appeared to be the most relevant adherence-influencing factors. A strong direct correlation between IGF-1 z-score and adherence to rhGH therapy was detected in the whole population.DiscussionCompliance to rhGH therapy is still a major issue in aGHD treatment. Adherence relates to therapy efficacy in aGHD. The use of Easypod™ could be beneficial for physicians to better manage aGHD patients and to achieve improved better biochemical and clinical responses.

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11–490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.

Abstract Background CHARGE syndrome (CS) is an autosomal dominant genetic condition whose recognition in the neonatal period is complicated by considerable phenotypic variability. Pediatric patients with genetic disorders have a known high incidence of hypoglycemia, due to many concurring factors. To date, neonatal hypoglycemia is a feature poorly explored in the literature associated with CS. This paper adds to the existing literature on hypoglycemia in CS and provides a brief review of the mechanisms through which CS, as well as the main genetic syndromes associated with neonatal hypoglycemia, may determine it. Case presentation The patient was a term newborn, first-born daughter to non-consanguineous parents. At birth, axial hypotonia with slight hypertonia of the limbs, and dysplastic auricles were noted. The incidental finding of asymptomatic hypoglycemia led to the initiation of glucose infusion on the II day of life, continued for a total of 8 days (maximum infusion rate: 8 mg/kg/min). In-depth endocrinological examinations showed poor cortisol response to the hypoglycemic stimulus, with normal GH values, thyroid function and ACTH. In view of the suspected hypoadrenalism, oral hydrocortisone therapy was initiated. Inappropriately low values of plasmatic and urinary ketones supported the hypothesis of concomitant transient hyperinsulinism, not requiring therapy. A brain MRI was performed, documenting thinning of the optic nerves, non-displayable olfactory bulbs and dysmorphic corpus callosum. An eye examination revealed bilateral chorioretinal coloboma. Temporal bone CT scan showed absence of the semicircular canals. The unexpected findings of coloboma and absence of semicircular canals led to the suspicion of CS, later confirmed by the molecular analysis of CHD7. Conclusions It seems important to consider CS in the differential diagnosis of persistent hypoglycemia in newborns with specific anomalies. At the same time, it is advisable to consider the risk of hypoglycemia in children with CS, as well as other genetic syndromes. Awareness of the many possible causes of hypoglycemia in newborns with genetic conditions may help steer the investigations, allowing for an appropriate and timely treatment.

Abstract Background Pallister-Hall syndrome (OMIM #146510) is a rare autosomal dominant condition caused by a mutation in the GLI3 gene. The cardinal feature of Pallister-Hall syndrome is the presence of hypothalamic hamartomas, which may manifest with seizures, panhypopituitarism and visual impairment. In Pallister-Hall syndrome, dysplastic histogenetic processes responsible for hypothalamic hamartomas are thought to disrupt early craniofacial development. The clinical presentation of Pallister-Hall syndrome may include: characteristic facies (low-set and posteriorly angulated ears, short nose with flat nasal bridge), cleft palate and uvula, bifid epiglottis and laryngotracheal cleft, limb anomalies (e.g., polysyndactyly, short limbs and nail dysplasia), anal atresia, genitourinary abnormalities and congenital heart defects. Case presentation We report the case of two monochorionic diamniotic twins diagnosed with Pallister-Hall syndrome during the neonatal period, after the identification of a hypothalamic hamartoma on day 1 by cerebral ultrasound scan, later confirmed by brain magnetic resonance imaging. Cerebral ultrasound and magnetic resonance imaging presentations were identical in both twins. Discussion and conclusions We review previously published cases (four reports) of hypothalamic hamartomas identified via cerebral ultrasound and compare reported ultrasonographic features. Main differential diagnoses based on cerebral ultrasound findings are discussed. Full description of typical magnetic resonance imaging appearance is also provided. This is the first case reported in the literature of monochorionic diamniotic twins affected by genetically confirmed Pallister-Hall syndrome with identical hypothalamic hamartomas at cerebral ultrasound and magnetic resonance imaging. Moreover, this paper adds to the existing literature on the sonographic appearance of hypothalamic hamartomas. Considering the consistency in hypothalamic hamartomas’ sonographic appearance, we support the use of cerebral ultrasound as a first-line neuroimaging modality in case of clinical suspicion of Pallister-Hall syndrome. Graphical Abstract

An 8-year-old boy with cystic fibrosis came to our attention for an empty scrotum. General physical examination showed a normal penis and hypoplastic scrotum with non-palpable testes bilaterally. Routine blood investigations showed low levels of LH, testosterone, inhibin B and antiMullerian hormone and elevated levels of FSH. Karyotype was normal. An abdominal ultrasound confirmed the absence of the testes into the scrotum, in the inguinal region and abdomen. At laparoscopy were noted bilaterally hypotrophic spermatic vessels, absence of the vas deferens and a closed inner ring. Inguinal exploration found out a small residual testis and histological examination showed fibrotic tissue. This is the first case of testicular atrophy associated to CFTR mutation described. The process that led to bilateral testicular and vas deferens atrophy remains unexplained, a possible influence of CFTR dysfunction cannot be ruled out, although it is possible that these conditions are independently associated.

BackgroundDelayed puberty is a possible complication of Epidermolysis Bullosa (EB), though the actual incidence is still unknown. In chronic illnesses delayed puberty should be correctly managed since, if untreated, can have detrimental effects on adult height attainment, peak bone mass achievement and psychological health.Aims and methodsThis is a single-centre study on pubertal development, growth and bone status in EB. Auxological, densitometric (areal Bone Mineral Density-aBMD Z-score, Bone Mineral Apparent Density-BMAD Z-score, Trabecular Bone Score-TBS and Bone Strain Index-BSI at Lumbar spine) and body composition data (Total Body DXA scans) were collected. Disease severity was defined according to Birmingham Epidermolysis Bullosa Severity (BEBS) score.ResultsTwenty-one patients (12 Recessive Dystrophic EB-RDEB, 3 Dominant Dystrophic EB, 3 Junctional EB-JEB, 2 EB Simplex and one Kindler EB) aged 13 years (females) or 14 years (males) and above were enrolled (age 16.2±2.5 years, M/F 11/10). Short stature was highly prevalent (57%, mean height -2.12±2.05 SDS) with 55% patients with height ConclusionsPubertal delay is highly prevalent in EB, especially in patients with RDEB and JEB, high severity score and inflammatory state. Moreover, pubertal delay worsens growth impairment and bone health. A study on pubertal induction is ongoing to enlighten possible beneficial effects on adult height attainment and peak bone mass accrual.

GH deficiency (GHD) in adult patients is a complex condition, mainly due to organic lesion of hypothalamic-pituitary region and often associated with multiple pituitary hormone deficiencies (MPHD). The relationships between the GH/IGF-I system and other hypothalamic-pituitary axes are complicated and not yet fully clarified. Many reports have shown a bidirectional interplay both at a central and at a peripheral level. Signs and symptoms of other pituitary deficiencies often overlap and confuse with those due to GH deficiency. Furthermore, a condition of untreated GHD may mask concomitant pituitary deficiencies, mainly central hypothyroidism and hypoadrenalism. In this setting, the diagnosis could be delayed and possible only after recombinant human Growth Hormone (rhGH) replacement. Since inappropriate replacement of other pituitary hormones may exacerbate many manifestations of GHD, a correct diagnosis is crucial. This paper will focus on the main studies aimed to clarify the effects of GHD and rhGH replacement on other pituitary axes. Elucidating the possible contexts in which GHD may develop and examining the proposed mechanisms at the basis of interactions between the GH/IGF-I system and other axes, we will focus on the importance of a correct diagnosis to avoid possible pitfalls.

The existence of common inflammatory biomarkers linking obesity and asthma in children has been hypothesized. Nevertheless, laboratory and clinical characteristics of children with obesity and asthma are still poorly defined. The primary aim of the present study is to investigate the lung function and the cytokine profile, in children with obesity and asthma. In this prospective, cross-sectional pilot study, pulmonary function tests, biochemical parameters, and serum cytokines levels were compared in three groups of 28 children each, matched for age and sex. Obese children showed normal forced spirometry values except an increased distal airway resistance in subjects with obesity and no asthma. Both groups including obese children showed higher leptin and IL-10 levels and lower adiponectin and TNF-alpha levels compared to children with no obesity and asthma. IL-33 and TGF-beta1 levels were higher in children with obesity and asthma vs. children with normal weight and asthma. Finally, IL-6 was undetectable in approximately 70% of obese children with no asthma, in 57% obese asthmatic children and in 100% of children with normal-weight and asthma. Children with obesity and asthma show the most striking cytokine profile, suggesting a pro-inflammatory role of fat mass in asthma development.

BackgroundThe impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).Case descriptionA woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On second postpartum day, the mother was in good condition and was switched to oral steroid therapy. On third postpartum day she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.ConclusionsWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.

Background: The management of children and adolescents with chronic kidney disease (CKD) and growth failure candidate for recombinant human growth hormone therapy (rhGH) is based on an appraisal of the literature established on a 2006 consensus statement and 2019 Clinical practice recommendations. The performance of these guidelines has never been tested.Aims: The objective of this study was to establish the level of adherence to international guidelines based on the 2006 consensus and the 2019 criteria that lead to the initiation of growth hormone treatment by both pediatric endocrinologists and pediatric nephrologists.Methods: A multidisciplinary team of pediatric endocrinologists and pediatric nephrologists, members of the Italian Society of Pediatric Endocrinology or of the Italian Society of Pediatric Nephrology, discussed and reviewed the main issues related to the management of pediatric patients with CKD who need treatment with rhGH. Experts developed 11 questions focusing on risk assessment and decision makings in October 2019 and a survey was sent to forty pediatric endocrinologists (n = 20) and nephrologists (n = 20) covering the whole national territory. The results were then analyzed and discussed in light of current clinical practice guidelines and recent recommendations.Results: Responses were received from 32 of the 40 invited specialists, 17 of whom were pediatric endocrinologists (42.5%) and 15 pediatric nephrologists (37.5%). Although all the centers that participated in the survey agreed to follow the clinical and biochemical diagnostic work-up and the criteria for the treatment of patients with CKD, among the Italian centers there was a wide variety of decision-making processes.Conclusions: Despite current guidelines for the management of children with CKD and growth failure, its use varies widely between centers and rhGH is prescribed in a relatively small number of patients and rarely after kidney transplantation. Several raised issues are not taken into account by international guidelines and a multidisciplinary approach with mutual collaboration between specialists will improve patient care based on their unmet needs.

Acromegaly guidelines updated in 2010 revisited criteria of disease control: if applied, it is likely that a percentage of patients previously considered as cured might present postglucose GH nadir levels not adequately suppressed, with potential implications on management. This study explored GH secretion, as well as hormonal, clinical, neuroradiological, metabolic, and comorbid profile in a cohort of 40 acromegalic patients considered cured on the basis of the previous guidelines after a mean follow-up period of 17.2 years from remission, in order to assess the impact of the current criteria. At the last follow-up visit, in the presence of normal IGF-I concentrations, postglucose GH nadir was over 0.4 μg/L in 11 patients (Group A) and below 0.4 μg/L in 29 patients (Group B); moreover, Group A showed higher basal GH levels than Group B, whereas a significant decline of both GH and postglucose GH nadir levels during the follow-up was observed in Group B only. No differences in other evaluated parameters were found. These results seem to suggest that acromegalic patients considered cured on the basis of previous guidelines do not need a more intensive monitoring than patients who met the current criteria of disease control, supporting instead that the cut-off of 0.4 mcg/L might be too low for the currently used GH assay.

OBJECTIVE: A common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy. DESIGN: Prospective study of GHD patients evaluated before and during short- (1 year, n=100) and long-term (5 years, n=50) rhGH therapy. METHODS: Effects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant. RESULTS: The different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A significant increase in high-density lipoprotein cholesterol occurred in the d3GHR group. Normalization of IGF1 levels and decrease in BF% were maintained after 5 years. Insulin sensitivity restored to basal values, though in d3GHR patients fasting glucose remained significantly higher than at baseline. After both 1 and 5 years, percentage of subjects with impaired glucose tolerance, similar in the two groups at baseline, decreased in fl/fl while doubled in d3GHR patients. In this last group, a long-term significant reduction in total and low-density lipoprotein cholesterol was also observed. CONCLUSION: The functional difference of d3GHR may influence some metabolic effects of rhGH on GHD adults. [ABSTRACT FROM AUTHOR]