The real-life management of glucose homeostasis abnormalities in pediatric onco-hematological diseases: data from a national survey.

Glycemic abnormalities are a frequent finding in pediatric oncological patients, both during treatment and after its discontinuation. Moreover, impaired glucose tolerance (IGT), impaired fasting glycemia (IFG) and diabetes mellitus (DM) are not rarely diagnosed in non-oncological hematological diseases. To explore the current pediatric Italian approach to the diagnosis and the management of the glycemic alterations in this clinical setting and, thus, to identify and enforce current clinical needs, we submitted an online 23-items survey to all the Italian Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) centers, and surveys were descriptively analyzed. Thirty-nine AIEOP centers were involved in the study. In 2021, among 75278 children and adolescents affected by an oncological or a hematological disease, 1.2 and 0.65% developed DM, while IGT or IFG were widespread in 2.3 and 2.8%, respectively. The main causes of DM were the use of corticosteroids in patients with cancer and the iron overload in patients with thalassemia. Venous fasting plasma glycemia was the most used tool to detect glycemic abnormalities. The performance of oral glucose tolerance test (OGTT) was extremely limited, except when IFG occurred. Despite the diagnosis of DM, ∼45% of patients with cancer and 30% of patients with one hematological disease did not receive an appropriate treatment. In the other cases, insulin was the drug of first choice. Emerging technologies for diabetes care (glucose sensors and insulin pumps) are not largely used yet. The results of our study support the standardization of the care of the glycemic abnormalities during or after onco-hematologic diseases in the pediatric age. Despite the scarce data in pediatric literature, proper guidelines are needed.

Can GH Therapy Worsen a Clinically Silent Chiari Malformation? A Case Report and Systematic Literature Review.

BACKGROUND: The link between the effects of recombinant human growth hormone (rhGH) therapy in patients with growth hormone deficiency (GHD) and Chiari malformation type I (CM-1) is controversial. SUMMARY: We report the case of a patient with an unusual association of GHD due to ectopic posterior pituitary and CM-1. Our patient developed a headache and worsening of CM-1 after the initiation of rhGH therapy. Following an atlo-occipital decompression surgery, the patient was able to resume therapy with a marked growth improvement. Based on this observation, we provide a systematic review of the current literature about these two pathologies. KEY MESSAGES: A careful follow-up of all patients with CM-1 treated with GH is mandatory, paying particular attention to the appearance of any neurological signs and symptoms.

Expert Opinion on the Management of Growth Hormone Deficiency in Brain Tumor Survivors: Results From an Italian Survey.

Background: Growth hormone deficiency (GHD) is the first and most common endocrine complication in pediatric brain tumor survivors (BTS). GHD can occur due to the presence of the tumor itself, surgery, or cranial radiotherapy (CRT). Aims: This study aimed to evaluate management and adherence to current guidelines of the Italian centers engaged in the diagnosis and follow-up of GHD patients with BTS. Methods: A multidisciplinary scientific board of pediatric endocrinologists, oncologists and radiologists with neuroimaging expertise discussed and reviewed the main issues relating to the management of GHD in pediatric BTS and developed a survey. The survey included questions relating to organizational aspects, risk factors, diagnosis, definition of stable disease, and treatment. The online survey was sent to an expanded panel of specialists dedicated to the care of pediatric BTS, distributed among the three specialty areas and throughout the country (23 Italian cities and 37 Centers). Results: The online questionnaire was completed by 86.5% (32 out of 37) of the Centers involved. Most had experience in treating these patients, reporting that they follow more than 50 BTS patients per year. Responses were analyzed descriptively and aggregated by physician specialty. Overall, the results of the survey showed some important controversies in real life adherence to the current guidelines, with discrepancies between endocrinologists and oncologists in the definition of risk factors, diagnostic work-up, decision-making processes and safety. Furthermore, there was no agreement on the neuroimaging definition of stable oncological disease and how to manage growth hormone therapy in patients with residual tumor and GHD. Conclusions: The results of the first Italian national survey on the management of GHD in BTS highlighted the difference in management on some important issues. The time to start and stop rhGH treatment represent areas of major uncertainty. The definition of stable disease remains critical and represents a gap in knowledge that must be addressed within the international guidelines in order to increase height and to improve metabolic and quality of life outcomes in cancer survivors with GHD.

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.

Transient central precocious puberty: a new entity among the spectrum of precocious puberty?

OBJECTIVE: Recently, we observed some cases of Precocious Puberty (PP) with a partial central activation of hypothalamic-pituitary-gonadal (HPG) axis that tended to normalized in 6-12 months. To evaluate the frequency of this form within the spectrum of forms of PP, we retrospectively assessed the clinical, hormonal and ultrasound characteristics of patients attending to our Center for signs of PP, between 2007 and 2017. To hypothesize some causes of this "pubertal poussée" a questionnaire about environmental data was provided to patients. METHODS: 96 girls were recruited for the study and divided into three Groups. Group 1: 56 subjects with Central PP (CPP) requiring treatment with GnRH analogue; Group 2: 22 subjects with transient activation of pubertal axis, that tended to normalize, "Transient CPP"(T-CPP); Group 3: 18 subjects with Isolated Thelarche (IT). RESULTS: Mean age at diagnosis was 6.8 ± 1.0 years in Group 1, 5.9 ± 1.3 years in Group 2 and 5.6 ± 1.5 years in Group 3. A significant increase of diagnosis of T-CPP was observed over the study period. Significantly higher use of some homeopathic medicines and potential exposure to pesticides was reported in Group 2 vs Group 1. CONCLUSIONS: To our knowledge, we first reported a form defined as T-CPP, characterized by partial activation in the HPG axis normalizing over time. An increased use of homeopathic medicines and exposure to environmental pollutants in these patients was evidenced.

Diabetes and Prediabetes in Children With Cystic Fibrosis: A Systematic Review of the Literature and Recommendations of the Italian Society for Pediatric Endocrinology and Diabetes (ISPED).

Cystic fibrosis related diabetes (CFRD) is a comorbidity of cystic fibrosis (CF) that negatively impacts on its clinical course. Prediabetes is an important predictor of either CFRD development and unfavorable prognosis of CF in both pediatric and adult patients. International guidelines recommend insulin only in case of CFRD diagnosis. Whether early detection and treatment of prediabetes may contribute to improve the clinical course of CF is still debated. A subgroup of pediatric diabetologists of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED) performed a systematic review of the literature based on predefined outcomes: impact of pre-diabetes on clinical outcomes and on the risk of developing CFRD; diagnosis of diabetes and pre-diabetes under 10 years of age; effectiveness of therapy on glycemic control, impact of therapy on pulmonary function and nutritional status. Thirty-one papers were selected for the analysis data presented in these papers were reported in tables sorted by outcomes, including comprehensive evidence grading according to the GRADE approach. Following the grading of the quality of the evidence, the entire ISPED diabetes study group achieved consensus for the Italian recommendations based on both evidence and clinical experience. We concluded that in patients with CF, prediabetes should be carefully considered as it can evolve into CFRD. In patients with CF and prediabetic conditions, after complete evaluation of the OGTT trend, glucometrics, glycemic values measured during pulmonary exacerbations and/or steroid therapy, early initiation of insulin therapy could have beneficial effects on clinical outcomes of patients with CF and prediabetes.

Cardiovascular risk factors in children and adolescents with type 1 diabetes in Italy: a multicentric observational study.

AIMS: To assess the prevalence of cardiovascular risk factors (CVRFs) and to identify the variables associated with CVRFs in a cohort of children and adolescents with Type 1 Diabetes. METHODS: 2021 subjects, 2-18 year-old, were recruited in 17 Italian Pediatric Diabetes Centers. Anthropometric, blood pressure, biochemical (HbA1c, lipid profile, ACR), insulin therapy, physical activity level, smoking and family socio-economic status data were collected. CVRFs prevalence and their distribution were analyzed according to age and binary logistic regression was performed with positivity for at least one major CVRF (BMI-SDS > +2SD, blood pressure > 90th percentile, LDL cholesterol>100 mg/dL) as dependent variable and age, duration of illness, gender, HbA1c and physical activity, as independent variables. RESULTS: The prevalence of CVFRs not at the recommended target was respectively: 32.5% one CVRF, 6.7% two CVRFs and 0.6% three CVRFs, with no significant differences across the 3 age groups (2-10, 10-15, 15-18 years). In the total sample, HbA1c and inadequate physical activity were associated with a higher probability of having at least one major CVRF. This probability was associated with physical activity in the 2-10-year-old group, with physical activity and HbA1c in the 10-15-year-old group and with HbA1c only in subjects older than 15 years. CONCLUSIONS: More than 30% of subjects had at least a major CVRF. Early detection of CVRFs may be useful to enforce the therapeutic intervention in this subgroup, in order to reduce the risk to develop cardiovascular complications.

Alcohol consumption or cigarette smoking and cardiovascular disease risk in youth with type 1 diabetes.

AIM: To assess the association between alcohol consumption and/or cigarette smoking with other unhealthy behaviors and clinical cardiovascular risk factors in youth with type 1 diabetes. METHODS: Two hundred and twenty-eight youth with type 1 diabetes (age 13-19 years) were consecutively enrolled in three Regional Pediatric Diabetes Centers in Italy. Demographic, anthropometric, lifestyle (adherence to the Mediterranean diet pattern and sports participation) and laboratory parameters were compared among youth reporting isolated or combined alcohol consumption and/or cigarette smoking. RESULTS: Ten percent of the youth reported alcohol consumption, 10% cigarette smoking and 6% both alcohol and cigarette use; 74% did not report alcohol or cigarette use. Compared to non-drinker non-smoker youth, smokers showed significantly higher percentages of each of the behavioral and clinical cardiovascular risk factors. Drinkers showed a significantly higher proportion of abdominal adiposity, dyslipidemia and poor adherence to the Mediterranean diet. Alcohol consumption was independently associated with both dyslipidemia and high glycosylated hemoglobin. CONCLUSIONS: Our findings emphasize the need to increase the awareness of youth with T1D about the negative impact of alcohol drinking on cardiovascular risk, since the effects of alcohol might be underestimated with respect to the well-known detrimental effects of smoking. Clustering of unhealthy lifestyle should be discouraged in type 1 diabetes youth in order to promote cardiovascular protection.

Whole lipid profile and not only HDL cholesterol is impaired in children with coexisting type 1 diabetes and untreated celiac disease.

AIMS: Low HDL cholesterol (HDL-C) levels have been described in patients with coexisting type 1 diabetes mellitus (T1DM) and celiac disease (CD). Data on other possible lipid abnormalities that could further increase cardiovascular risk in these patients are scarce and incomplete. Aim of this retrospective multicenter study was to evaluate whole lipid profiles, besides HDL-C, in children with T1DM associated with biopsy-proven CD, and to investigate the influence of age and degree of adherence to gluten-free diet (GFD) on lipid changes. METHODS: A total of 261 children with both T1DM and CD were enrolled. Serum lipid profiles at CD diagnosis were compared with those after 1 year of GFD and with those of 224 matched children with T1DM alone. The adherence to GFD was judged by means of CD-related antibodies. RESULTS: At CD diagnosis, children with T1DM + CD showed higher LDL cholesterol (LDL-C) compared to children with T1DM alone. Gluten withdrawal failed to normalize LDL-C levels, not even in completely adherent individuals. HbA1c values were not influenced by GFD. The youngest children were characterized at diagnosis by lower levels of total cholesterol and on treatment by a greater decrease in triglycerides levels. CONCLUSIONS: An unfavorable lipid profile, characterized not only by low HDL-C levels but also by high LDL-C values, may increase the risk of cardiovascular disease in children with T1DM and untreated CD. Therefore, a strict gluten-free diet is mandatory in these children, especially the youngest.

Long-term safety and efficacy of Omnitrope®, a somatropin biosimilar, in children requiring growth hormone treatment: Italian interim analysis of the PATRO Children study.

BACKGROUND: PATRO Children is an ongoing observational, longitudinal, non-interventional, global post-marketing surveillance study, which is investigating the long-term safety and effectiveness of Omnitrope®, a somatropin biosimilar to Genotropin®, in children with growth disturbances. The primary endpoint of PATRO Children is long-term safety and the secondary endpoint is effectiveness, which is assessed by analysing auxological data such as height (HSDS) and height velocity (HVSDS) standard deviation scores. Here, we report the data from the Italian interim analysis of PATRO Children data up to August 2015. METHODS: PATRO Children is enrolling children who are diagnosed with conditions of short stature requiring GH treatment and are receiving Omnitrope®. Adverse events (AEs) are assessed in all Omnitrope®-treated patients. Height is evaluated yearly to near-adult (final) height, and is herein reported as HSDS; height velocity is also assessed and reported as a standard deviation score (HVSDS). RESULTS: Up to August 2015, a total of 186 patients (mean age 10.2 years, 57.5 % males) were enrolled :156 [84 %] had growth hormone deficiency, 12 [6.5 %] were born small for gestational age, seven [3.8 %] had Prader-Willi syndrome, one [0.5 %] had Turner syndrome and one [0.5 %] had chronic renal insufficiency; seven [3.8 %] patients had other indication profiles. The mean treatment duration with Omnitrope® was 28.1 ± 19.1 months. AEs were reported in 35.6 % of patients and included headache, pyrexia, arthralgia, abdominal pain, leg and/or arm pain and increased blood creatine phosphokinase. Two serious AEs in two patients were thought to be drug-related; one patient experienced a minimal increase in a known residual craniopharyngioma, and another a gait disturbance with worsening of walking difficulties. Similar to investigational studies, Omnitrope® treatment was associated with improvements in both HSDS and HVSDS. CONCLUSIONS: Omnitrope® appears to be well tolerated and effective for the treatment of a wide range of paediatric indications, which is consistent with the outcomes from controlled clinical trials. These results need to be interpreted with caution until the data from the global PATRO Children study are available.

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.

Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD.

OBJECTIVE: The diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents. DESIGN: Retrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests. METHODS: Seventy four patients with organic GHD (GH peak <10µg/L after two provocative tests) and 298 control subjects (GH response >10µg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS. RESULTS: The optimal GH cut-off for arginine resulted 6.5µg/L, 5.1µg/L for ITT and 6.8µg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity. CONCLUSIONS: The results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Diagnosis of emergencies/urgencies in gynecology and during the first trimester of pregnancy.

Several surgical and/or medical emergencies/urgencies may occur in gynecologic patients and in pregnant women during the first trimester. Particularly, ectopic pregnancies, ruptured or hemorrhagic ovarian cysts, ovarian or adnexal torsions, threatened or inevitable miscarriages, phlogistic gynecological disorders, complications involving the uterine fibroids, endometriosis, and spontaneous uterine rupture are possible acute complications. The diagnosis is suspected on the basis of symptoms (acute pelvic and/or abdominal pain, with or without vaginal bleeding or discharge, until acute abdomen with peritonitis), by means physical evaluation (abdominal, pelvic, and bimanual gynecological examinations), by means of transabdominal (TAS) and/or transvaginal (TVS) sonography, and laboratory tests. However, the diagnosis is often not that simple, especially when the symptoms and clinical signs are minimal, and ultrasound (US) examination is not diriment. The differential diagnosis of abdominal/pelvic pain is broad and includes primarily gastrointestinal and urogenital disorders. Generally, TAS should usually be used in conjunction with TVS for evaluation of the female pelvis. If the US examination is not conclusive, CT or MRI, especially in pregnant patients, should be considered.

Design of, and first data from, PATRO Children, a multicentre, noninterventional study of the long-term efficacy and safety of Omnitrope(®) in children requiring growth hormone treatment.

OBJECTIVE: To describe the rationale, design and first data from PATRO Children, a postmarketing surveillance of the long-term efficacy and safety of somatropin (Omnitrope(®)) for the treatment of children requiring growth hormone treatment. METHODS: PATRO Children is a multicentre, open, longitudinal, noninterventional study being conducted in children's hospitals and specialised endocrinology clinics. The primary objective is to assess the long-term safety of Omnitrope(®) in routine clinical practice. Eligible patients are infants, children and adolescents (male or female) who are receiving treatment with Omnitrope(®) and who have provided informed consent. Patients who have been treated with another recombinant human growth hormone (rhGH) product before starting Omnitrope(®) are eligible for inclusion. All adverse events (AEs) are monitored and recorded, with particular emphasis on: long-term safety; the recording of malignancies; the occurrence and clinical impact of anti-hGH antibodies; the development of diabetes during Omnitrope(®) treatment in children short for gestational age (SGA); safety issues in patients with Prader-Willi syndrome (PWS). Efficacy assessments include auxological parameters, plus insulin-like growth factor-1 and insulin-like growth factor binding protein-3. RESULTS: As of September 2012, 1837 patients were enrolled in the study from 184 sites in 10 European countries. To date, efficacy data are reassuring and consistent with previous studies. In addition, there have been no confirmed cases of diabetes occurring under Omnitrope(®) treatment, no reports of malignancy and no safety issues in PWS patients. CONCLUSIONS: The efficacy and safety profile of Omnitrope(®) in the PATRO Children study so far are as expected. The ongoing study will extend the safety database for Omnitrope(®), and rhGH products more generally, in paediatric indications. Of particular interest, PATRO Children will add important information on the diabetogenic potential of rhGH in children born SGA, the risk of malignancies in children receiving rhGH, and AEs with a possible causal relationship to rhGH treatment in children with PWS.

Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990 s: an 18-year longitudinal study based on anti-endomysial antibodies.

Between 1987 and 2004, 331 consecutive children, all newly diagnosed with type 1 diabetes mellitus in our pediatric clinic, underwent repeated serological screening for celiac disease (CD) by means of anti-endomysial antibodies, measured prospectively between 1994 and 2004, and retrospectively, using frozen banked serum, between 1987 and 1993. There were 22 cases (6.6%) of biopsy-proven CD among the 331 diabetic children. The prevalence of CD was significantly (P = 0.015) higher after 1994 (10.6%) than before 1994 (3.3%). The rapid change in the risk of CD among Italian diabetic children that occurred in the mid-1990 s could be related to changes in environmental factors, namely, eating habits and viral infections.

Active and total ghrelin concentrations in the newborn.

BACKGROUND: Ghrelin is a peptide with a potent capacity to release GH and other metabolic activities. An acyl modification is indispensable for biological activity. Acylated and desacylated forms of ghrelin are both present in the blood. No data exist about the ratio between active ghrelin and total ghrelin in the first period of life. OBJECTIVE: To investigate whether ghrelin may be involved in physiological roles during fetal life. INFANTS AND METHODS: Ghrelin, growth hormone (GH), and leptin concentrations were measured in cord plasma in 98 newborns of healthy mothers. Acyl-ghrelin and the sum of acylated and desacylated forms of ghrelin (total ghrelin) were measured using specific radioimmunoassays. RESULTS: Acylated ghrelin and total ghrelin did not correlate with birth weight, gestational age, body mass index, head circumference, birth length, leptin or GH in plasma cord blood. CONCLUSIONS: The absence of clinically significant correlations between both active and total ghrelin and GH, leptin or anthropometric data does not enable us to ascribe a precise role to ghrelin in prenatal life.